Pharmaceutical compositions comprising hydromorphone and naloxone

WO 2011/141488 PCT/EP2011/057566

PHARMACEUTICAL COMPOSITIONS COMPRISINGHYDROMORPHONE AND NALOXONE

FIELD OF THE INVENTION

The present invention relates to prolonged release pharmaceutical dosage formscomprising hydromorphone or a pharmaceutically acceptable salt thereof andnaloxone or a pharmaceutically acceptable salt thereof, the manufacture thereof aswell as their use for administration to human beings.

BACKGROUND OF THE INVENTION

Prolonged release pharmaceutical dosage forms represent an important tool in amedical practioner’s armoury for treating diseases. One of the general benefitsgenerally attributed to prolonged release pharmaceutical dosage forms versusimmediate release pharmaceutical dosage forms includes increased patientcompliance as a consequence of reduced administration frequency.

There are various technologies available for obtaining prolonged release dosageforms. Prolonged release properties may be conveyed by so-called prolonged releasematrix systems, prolonged release coatings, osmotic dosage forms, multi-layereddosage forms etc.

When developing a prolonged release formulation, it is generally necessary to choosethe respective formulation technology with respect to the physico-chemical andphysiological properties of the pharmaceutically active agent(s) in question. Thismeans a substantial amount of work for the formulation specialist. This will be evenmore so where the dosage form comprises pharmaceutically active agents suchopioid agonists which theoretically can be abused, i.e. are not used for medicinalpurposes. WO 2011/141488 PCT/EP2011/057566 -2-

There is thus a continuing interest in pharmaceutical dosage forms which compriseopioid analgesic as pharmaceutically active agents, which provide prolonged releaseproperties and account for opioids’ potential of being abused.

SUMMARY OF THE INVENTION

It is an objective of the present invention to provide prolonged releasepharmaceutical dosage forms and methods of manufacture thereof.

These and other objectives as they will become apparent from the ensuingdescription are attained by the subject matter of the independent claims. Some of thepreferred embodiments are referred to by the dependent claims.

To some extent, the present invention is based on the finding that one can produceprolonged release pharmaceutical dosage forms comprising hydromorphone or apharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof combining various beneficialaspects. These include stability, alcohol tolerance, tamper resistance and the like.

In a first aspect, the present invention relates to an oral prolonged releasepharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition provides alcohol resistance. WO 2011/141488 PCT/EP2011/057566 -3-

In a second aspect, the present invention relates to an oral prolonged releasepharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are present in the pharmaceutical composition in aweight ratio in a range of about 2:1 to about 1:3, preferably of about2:1, about 1:1, about 1:2 or about 1:3.

In an embodiment of this second aspect, the composition may comprise a prolongedrelease matrix and/or a prolonged release coating.

In a third aspect, the present invention relates to an oral prolonged releasepharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions releases the pharmaceutically active agents withsubstantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In a fourth aspect, the present invention relates to an oral prolonged releasepharmaceutical composition comprising at least: WO 2011/141488 PCT/EP2011/057566 -4- a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions has less than 2.0% of total substances related tohydromorphone or a pharmaceutically acceptable salt or derivativethereof and/or related to naloxone or a pharmaceutically acceptablesalt or derivative thereof.

In a fifth aspect the present invention relates to an oral prolonged releasepharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the prolonged release pharmaceutical composition is heat treated.

In a first variation to this fifth aspect the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, c) wherein the at least one prolonged release material andhydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 -5- derivative thereof are combined such that a prolonged release matrixis formed; and d) wherein the prolonged release pharmaceutical composition is heattreated.

In a second variation to this fifth aspect the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; c) wherein the at least one prolonged release material andhydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined such that a prolonged release matrixis formed; and d) wherein the prolonged release pharmaceutical composition is heattreated; e) wherein at least one prolonged release material is applied in the formof a prolonged release coating which is disposed on the prolongedrelease matrix; and f) wherein the composition is optionally cured.

The prolonged release coating may either be disposed on each prolonged releasematrix if the prolonged release matrix is manufactured in the form of multi-particulates such as granules or it may be disposed on the formulation comprising theprolonged release matrix if e.g. prolonged release matrix multi-particulates such as WO 2011/141488 PCT/EP2011/057566 -6- granules are compressed into a tablet. The coating will then be disposed on themonolithic formulation.

In a first embodiment of this fifth aspect of the invention and its first and secondvariation, hydromorphone or a pharmaceutically acceptable salt or derivative thereofand naloxone or a pharmaceutically acceptable salt or derivative thereof are presentin the pharmaceutical composition in a weight ratio of about 2:1, about 1:1, about 1:2or about 1:3.

In addition or alternatively to this first embodiment, in a second embodiment of thisfifth aspect of the invention and its first and second variation, the pharmaceuticalcomposition may be alcohol resistant.

In addition or alternatively to this first or second embodiment, in a third embodimentof this fifth aspect of the invention and its first and second variation, thepharmaceutical composition may after storage under stressed conditions release thepharmaceutically active agents with substantially the same release rate as beforesubjecting the pharmaceutical composition to stressed conditions.

In addition or alternatively to this first, second or third embodiment, in a fourthembodiment of this fifth aspect of the invention and its first and second variation, thepharmaceutical composition may after storage under stressed conditions have lessthan 3.0 % of total substances related to hydromorphone or a pharmaceuticallyacceptable salt or derivative thereof and/or related to naloxone or a pharmaceuticallyacceptable salt or derivative thereof.

The invention also relates to a method of manufacturing an oral prolonged releasepharmaceutical composition comprising at least the steps of: WO 2011/141488 PCT/EP2011/057566 -7- a) producing granules comprising at least one prolonged release material,at least hydromorphone or a pharmaceutically acceptable or derivativesalt thereof and at least naloxone or a pharmaceutically acceptable saltor derivative thereof, b) optionally selecting granules of step a) of substantially uniform size; c) optionally compressing said granules of step a) or step b) to obtain anoral prolonged release pharmaceutical composition in the form of atablet, d) optionally heat treating said compressed granules of step c); e) optionally disposing a prolonged release coating either on the granulesof step b) which may have been heat treated or on the compressedgranules of step c) which may have been heat treated; f) optionally curing the composition.

In one embodiment, granules of step a) are manufactured by wet or dry granulation.In another embodiment, the granules are obtained by wet or melt extrusion.

In one embodiment, the granules are optionally screened in order to select granulesof substantially uniform size. For example, granules may be selected to have a meansize in the range of about 100 pm to about 2 mm, more preferably in the range ofabout 100 pm to about 1 mm.

Another aspect of the present invention relates to prolonged release pharmaceuticalcompositions as they are obtainable by methods in accordance with the invention.

Such pharmaceutical compositions may be alcohol resistant as described hereinafter.They may also provide physical and chemical stability. WO 2011/141488 PCT/EP2011/057566 -8-

The pharmaceutical compositions may be used for treating moderate to severe pain,in particular cancer pain, neuropathic pain, visceral pain or bone pain. When used fortreating these types of pain, the pharmaceutical compositions may beneficiallyinfluence side effects such as constipation, urinary retention, breath depression andbowel function as they may occur when using only hydromorphone or apharmaceutically acceptable salt or derivative thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention as illustratively described in the following may suitably bepracticed in the absence of any element or elements, limitation or limitations, notspecifically disclosed herein.

The present invention will be described with respect to particular embodiments andwith reference to certain figures but the invention is not limited thereto but only bythe claims. Terms as set forth hereinafter are generally to be understood in theircommon sense unless indicated otherwise.

Where the term “comprising” is used in the present description and claims, it doesnot exclude other elements. For the purposes of the present invention, the term“consisting of’ is considered to be a preferred embodiment of the term “comprisingof’. If hereinafter a group is defined to comprise at least a certain number ofembodiments, this is also to be understood to disclose a group which preferablyconsists only of these embodiments.

Where an indefinite or definite article is used when referring to a singular noun, e.g.“a”, “an” or “the”, this includes a plural of that noun unless something else isspecifically stated. WO 2011/141488 PCT/EP2011/057566 -9-

In the context of the present invention the terms “about” or “approximately” denotean interval of accuracy that the person skilled in the art will understand to still ensurethe technical effect of the feature in question. The term typically indicates deviationfrom the indicated numerical value of ±10%, and preferably of ±5%.

The term “zn vitro release” and its grammatical variations as well as similarexpression refers to the release rate by which a pharmaceutically active agent, e.g.hydromorphone HC1 is released from the pharmaceutical composition when the invitro release rate is tested by the paddle method according to the EuropeanPharmacopeia as described in as described in the Ph. Eur. 2.9.3 6th edition. Thepaddle speed is typically set at 75 or 100 rpm in 500 ml or 900 ml simulated gastricfluid (SGF) dissolution medium with pH 1.2. Aliquots of the dissolution media arewithdrawn at the respective time points and analyzed by HPLC with a C18 column,eluted with 30mM phosphate buffer in acetonitrile (70:70; pH 2.9) with a flow rate of1.0 ml/min and detected at 220 nm. It is specifically indicated if in the context of thepresent invention in vitro release rates are determined using a different test method(such as SGF with 40% (v/v) of ethanol).

The amount of dissolution liquid and the rotational speed of the paddle apparatusmay depend on the amount of active agent tested. For example, pharmaceuticalcompositions comprising up to 16 mg hydromorphone HC1 may be tested at 75 rpmin 500 ml dissolution liquid while higher dosage strengths may be tested at 100 rpmin 900 ml dissolution liquid.

The term “Simulated Gastric Fluid, pH 1.2” refers to 0.1 N HC1, pH 1.2. WO 2011/141488 PCT/EP2011/057566 - 10-

In the context of the present invention, the terms “immediate release” or“conventional release” refer to pharmaceutical compositions showing a release of theactive substance(s) which is not deliberately modified by a special formulationdesign and/or manufacturing methods. For oral dosage forms this means that thedissolution profile of the active substance(s) depends essentially on its (theirs)intrinsic properties. Typically, the terms “immediate release” or “conventionalrelease” refer to pharmaceutical compositions which release in vitro >75% (byweight) of the pharmaceutically active agent(s) at 45 min.

In the context of the present, the terms “prolonged release” and “controlled release”are used interchangeably and refer to pharmaceutical compositions showing a slowerrelease of the active agent(s) than that of a conventional release pharmaceuticalcomposition administered by the same route. Prolonged or controlled release isachieved by a special formulation design and/or manufacturing method. Typically,the terms “prolonged release” and “controlled release refer to pharmaceuticalcompositions which release in vitro <75% (by weight) of the pharmaceutically activeagent at 45 min.

Prolonged release properties may be obtained by different means such as by acoating which is then designated as a prolonged release coating, a matrix which isthen designated by as a prolonged release matrix or e.g. by an osmotic structure ofthe pharmaceutical composition.

In order to obtain “prolonged or controlled release” properties, one typically usesmaterials which are known to prolong the release from a dosage form comprising e.g.a prolonged release matrix and/or prolonged release coating. Typical examples ofsuch “prolonged or controlled release materials” are hydrophobic polymers such asethyl cellulose, hydrophilic polymers such as hydroxypropyl cellulose and the like. WO 2011/141488 PCT/EP2011/057566 - 11 -

The nature of the “prolonged or controlled release material” may depend on whetherthe release properties are attained by a “prolonged release matrix” or a “prolongedrelease coating”. The term “prolonged release materials” thus describes both types ofmaterials. The term “prolonged release matrix material” indicates that a material isused for obtaining a prolonged release matrix. Likewise, the term “prolonged releasecoating material” indicate that a material is used for obtaining a prolonged releasecoating.

The terms “prolonged release matrix formulation” or “controlled release matrixformulation” refer to a pharmaceutical composition including at least one prolongedrelease material or controlled release material, and at least one hydromorphone andnaloxone or the pharmaceutically acceptable salts or derivatives thereof The terms“prolonged release material” and “controlled release material” can be usedinterchangeably. In a “prolonged release matrix formulation” or “controlled releasematrix formulation”, the “prolonged release material” or “controlled releasematerial” are combined with the pharmaceutically active agents to form a mixturefrom which the pharmaceutically active agent is released over prolonged periods oftime, such as e.g. 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.

It is to be understood that a material will be considered to act as prolonged orcontrolled release material if the dissolution profile of the pharmaceutically activeagent(s) is slowed down compared to an immediate or conventional releaseformulation. If a prolonged or controlled release material can be used formanufacturing a prolonged or controlled release matrix, it will be considered as aprolonged or controlled release matrix material. WO 2011/141488 PCT/EP2011/057566 - 12-

Pharmaceutically acceptable excipients which are used to adjust an alreadyprolonged or controlled release to a specific profile are not necessarily considered tobe prolonged or controlled release materials.

It is to be understood that a prolonged release matrix or a controlled release matrixdoes not necessarily consist only of the pharmaceutically active agent(s) and theprolonged or controlled release material. The prolonged or controlled release matrixmay comprise in addition pharmaceutically acceptable excipients such as fillers,lubricants, glidants, etc.

The terms “prolonged release coating formulation” or “controlled release coatingformulation” refer to a pharmaceutical composition including at least one prolongedrelease material or controlled release material, and at least one hydromorphone andnaloxone or the pharmaceutically acceptable salts or derivatives thereof The terms“prolonged release material” and “controlled release material” can be usedinterchangeably. In a “prolonged release coating formulation” or “controlled releasecoating formulation”, the “prolonged release material” or “controlled releasematerial” are disposed on the pharmaceutically active agents to form a diffusionbarrier. Other than in prolonged release matrix formulation, the actives are notintimately mixed with the prolonged release material and the prolonged releasecoating does not form a three dimensional structure within which the actives aredistributed. As the term implies, the prolonged release material forms a layer abovethe actives. The pharmaceutically active agent is released from a prolonged releasecoating formulation over prolonged periods of time, such as e.g. 8, 10, 12, 14, 16, 18,20, 22 or 24 hours.

It is to be understood that a material will be considered to act as prolonged orcontrolled release material if the dissolution profile of the pharmaceutically active WO 2011/141488 PCT/EP2011/057566 - 13 - agent(s) is slowed down compared to an immediate or conventional releaseformulation. If a prolonged or controlled release material can be used formanufacturing a prolonged or controlled release coating, it will be considered as aprolonged or controlled release coating material.

Pharmaceutically acceptable excipients which are used to adjust an alreadyprolonged or controlled release to a specific profile are not necessarily considered tobe prolonged or controlled release materials.

When it is mentioned that a prolonged release coating is disposed onpharmaceutically active agents, this is not to be construed as meaning that such acoating will necessarily be directly layered on such active pharmaceutically agents.Of course, if pharmaceutically active agents are layered on a carriers such as nu-pareil beads, the coating may be disposed directly thereon. However, thepharmaceutically active agents may also be first embedded in a polymer layer or e.g.a prolonged release matrix. Subsequently the prolonged release coating may bedisposed on e.g. granules which comprise a prolonged release matrix or on tabletswhich are made from such granules by compression for example. A pharmaceutical composition with a controlled or prolonged release coating may beobtained by combining the pharmaceutically active agents with a carriers such asnon-pareil beads and disposing a prolonged release coating on said combinations.Such coating may be made from polymers such cellulose ethers with ethyl cellulosebeing preferred, acrylic resins, other polymers and mixtures thereof. Such controlledor prolonged release coatings may comprise additional excipients such as pore-formers, binders and the like. WO 2011/141488 PCT/EP2011/057566 - 14-

It is further to be understood, that the term “prolonged release matrix formulation”or “controlled release matrix formulation” does not exclude pharmaceuticalcompositions with a prolonged or controlled release matrix and an additionalprolonged or controlled release coating being disposed on the matrix. Likewise theterm “prolonged release coating formulation” or “controlled release coatingformulation” does not exclude pharmaceutical compositions with a prolonged orcontrolled release coating which is disposed on prolonged release matrix or acontrolled release matrix.

In fact, the invention in various embodiments considers prolonged release matrixformulations which also comprise a prolonged release coating.

The terms “prolonged release dosage form” and “controlled release dosage form” canbe used interchangeably and refer to the administration form of a pharmaceuticalcomposition of the present invention comprising the at least one pharmaceuticallyactive agent in prolonged release form as e.g. in form of a “prolonged release matrixformulation”, in the form of a “prolonged release coating formulation, combinationsthereof or in other prolonged release formulations such as osmotic formulations. Theterms “prolonged release matrix formulation” and “prolonged release dosage form”can be used interchangeably if the prolonged release dosage form consists essentiallyof the prolonged release matrix formulation. This means that a prolonged releasedosage form can comprise in addition to the prolonged release matrix e.g. cosmeticcoatings and pharmaceutically acceptable excipients such fillers, lubricants, etc.

For some embodiments, the term “prolonged release matrix dosage form” mayindicate that the dosage form comprises a prolonged release matrix as the solestructure being responsible for prolonging the release. This, however, does not WO 2011/141488 PCT/EP2011/057566 - 15 - exclude that the dosage form may comprise an immediate release portion asdescribed hereinafter.

For some embodiments, the term “prolonged release coating dosage form” mayindicate that the dosage form comprises a prolonged release coating as the solestructure being responsible for prolonging the release. This, however, does notexclude that the dosage form may comprise an immediate release portion asdescribed hereinafter.

The release rates indicated always refer to the formulation such as a monolithic tabletor multi-particulates. The release rates will be chosen such that a pharmaceuticalcomposition can be administered e.g. on a twice a day or once a day basis, i.e. every12 hours or every 24 hours. Typically, the release will occur by diffusion through theprolonged or controlled release matrix and/or coating, erosion of the prolonged orcontrolled matrix and/or coating or combinations thereof

Oral solid dosage forms may take the form of tablets, granules, multiparticulates,mini-tablets and the like. Mini-tablets are dosage forms wich comprisepharmaceutically active agents in a prolonged release matrix with optionally aprolonged release coating disposed thereon. They take a round form with a thicknessof about 1 to about 5 mm and a diameter of about 1 to 5 mm. A thickenss anddiameter of about 1 to about 4 mm, of about 1 to about 3 mm and of anout 2 mm isalso considered. Multiparticulate and/or mini-tablets may be filled into e.g. capsulesare embedded in other excipients to form e.g. a tablet or to be filled into capsules.

In a preferred embodiment, the dosage forms in accordance with the inventioncomprise a prolonged release matrix with a controlled release coating. WO 2011/141488 PCT/EP2011/057566 - 16-

The term “heat treatment” is used in the context of heat treating a prolonged releasematrix formulation. The term “curing” is used in the context of heat treating aprolonged release coating formulation and relates to the effects of heat on thecoalescence of the coating. If a composition comprises a prolonged release matrixand a prolonged release coating, the term “heat treatment” or “heat treated” denotesthat the prolonged release matrix has been heat treated before the prolonged releasecoating was applied.

Pharmaceutical compositions in accordance with the invention, and in particularthose which are oral dosage forms, may be alcohol resistant.

The term “alcohol resistance” and its grammatical variations refer to the property ofpharmaceutical compositions of the invention to release about the same or lessamount of the pharmaceutically active agents in vitro, the in vitro release rate beingtested in 500 or 900 ml of Simulated Gastric Fluid, pH 1.2 with up to 40% (v/v)ethanol using the Ph. Eur. Paddle method at 100 rpm at 37° C compared to the invitro release rate being tested in 500 or 900 ml of Simulated Gastric Fluid, pH 1.2with up to 0% (v/v) ethanol using the Ph. Eur. Paddle method at 75 or 100 rpm at 37°C. The amount of dissolution liquid and the rotational speed of the paddle apparatusmay depend on the amount of active agent tested. For example, pharmaceuticalcompositions comprising up to 16 mg hydro morphone HCI may be tested at 75 rpmin 500 ml dissolution liquid while higher dosage strengths may be tested at 100 rpmin 900 ml dissolution liquid.

Resistance to alcohol extraction can e.g. be tested by subjecting the formulation toSimulated Gastric Fluid (SGF), pH 1.2 with 40% ethanol. A typical manner in orderto obtain “500 ml of Simulated Gastric Fluid (SGF), pH 1.2 with 40% ethanol” is bymixing 600 ml of SGF with 420 ml of 95% ethanol/water (which provides 400 ml of WO 2011/141488 PCT/EP2011/057566 - 17- 100% ethanol) and taking 500 ml of the mixture. The effect of the additional 20 mlof water from the 95% ethanol will be minimal in the percentages of SGF andethanol in the 500 ml mixture. A typical manner in order to obtain 900 ml of Simulated Gastric Fluid (SGF), pH 1.2with 40% ethanol” is by mixing 600 ml of SGF with 420 ml of 95% ethanol/water(which provides 400 ml of 100% ethanol) and taking 900 ml of the mixture. Theeffect of the additional 20 ml of water from the 95% ethanol will be minimal in thepercentages of SGF and ethanol in the 100 ml mixture.

In certain embodiments, the present invention is directed to a prolonged releasepharmaceutical composition comprising at least two pharmaceutically active agents,namely hydromorphone and naloxone or their pharmaceutically acceptable salts orderivatives and at least one prolonged release material being combined to form aprolonged release matrix; wherein the ratio of the amount of hydromorphone or apharmaceutically acceptable salt or derivative thereof released after 0.5, 1 or 2 hoursof in vitro dissolution of the dosage form in 500 or 900 ml of Simulated GastricFluid, pH 1.2 with up to 40% ethanol using the Ph. Eur. paddle method at 75 or 100rpm at 37 C compared to the amount of hydromorphone or a pharmaceuticallyacceptable salt or derivative thereof released after 0.5, 1 or 2 hours in vitrodissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid, pH 1.2with 0% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37° C is about2:1 or less, about 1.5:1 or less, about 1:1 or less, about 1:1.2 or less, about 1:1.4 orless, about 1:1.6 or less, about 1:1.8 or less, about 1:2 or less, about 1:2.5 or lessabout 1:3 or less or about 1:5 or less, and wherein the ratio of the amount ofnaloxone or a pharmaceutically acceptable salt or derivative thereof released after0.5, 1 or 2 hours of in vitro dissolution of the dosage form in 500 or 900 ml ofSimulated Gastric Fluid, pH 1.2 with up to 40% ethanol using the Ph. Eur. paddle WO 2011/141488 PCT/EP2011/057566 - 18- method at 75 or 100 rpm at 37° C compared to the amount of naloxone or apharmaceutically acceptable salt or derivative thereof after 0.5, 1 or 2 hours in vitrodissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid, pH 1.2with 0% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37° C is about2:1 or less, about 1.5:1 or less, about 1:1 or less, about 1:1.2 or less, about 1:1.4 orless, about 1:1.6 or less, about 1:1.8 or less, about 1:2 or less, about 1:2.5 or lessabout 1:3 or less or about 1:5 or less. Preferably, the ratio is about 1:1 or less such as1:1.5 or 1:2 for hydromorphone and/or naloxone.

The present invention as disclosed herein with respect to all aspects andembodiments is meant to encompass the use of any pharmaceutically acceptable saltor derivative of hydromorphone and naloxone. Any embodiment of the inventionreferring to hydromorphone and naloxone is also meant to refer to salts andpreferably the hydrochloride salts thereof unless indicated otherwise.

Pharmaceutically acceptable salts include, but are not limited to, inorganic acid saltssuch as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acidsalts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like;sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and thelike; amino acid salts such as arginate, asparginate, glutamate and the like, and metalsalts such as sodium salt, potassium salt, cesium salt and the like; alkaline earthmetals such as calcium salt, magnesium salt and the like; organic amine salts such astriethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt,dicyclo hexylamine salt, Ν,Ν'-dibenzylethylenediamine salt and the like.

Pharmaceutically acceptable derivatives of hydromorphone and naloxone includeesters thereof as well as modified forms such as glycosylated, pegylated or hesylatedforms of hydromorphone and naloxone. WO 2011/141488 PCT/EP2011/057566 - 19-

If in the following reference is made to a pharmaceutically active agent such ashydromorphone, this always also includes the reference to a pharmaceuticallyacceptable salt or derivative of the free base of this pharmaceutically active agentunless it is specifically indicated that the reference to the pharmaceutically activeagent, such as use of the term “hydromorphone” should only refer to the free base.

The use of the hydrochloride salts of both hydromorphone and naloxone can bepreferred.

In a preferred embodiment, the pharmaceutical dosage forms comprisehydro morphone or a pharmaceutically acceptable salt or derivative thereof ornaloxone or a pharmaceutically acceptable salt or derivative thereof as the solepharmaceutically active agents.

The pharmaceutical compositions may comprise about 1 to about 64 mg such asabout 1 mg, about 2 mg, about 4 mg, about 8 mg, about 12 mg, about 16 mg, about24 mg, about 32 mg, about 40 mg, about 48 mg or about 64 mg hydromorphonehydrochloride or equimolar amounts of any other pharmaceutically acceptable salt orderivative including but not limited to hydrates and solvates or of the free base.Where reference is made to amounts of hydromorphone hydrochloride this relates toanhydrous hydromorphone hydrochloride. If a hydrated version of hydromorphonehydrochloride is used, this will be used in an amount equivalent to the afore-mentioned amounts of anhydrous hydromorphone hydrochloride.

The pharmaceutical compositions may comprise about 1 to about 256 mg, such asabout 1 mg, about 2 mg, about 4 mg, about 8 mg, about 12 mg, about 16 mg, about24 mg, about 32 mg, about 48 mg, about 64 mg, about 96 mg, about 128 or about WO 2011/141488 PCT/EP2011/057566 -20- 256 mg of naloxone hydrochloride or equimolar amounts of any otherpharmaceutically acceptable salt, derivative or form including but not limited tohydrates and solvates or of the free base. Where reference is made to amounts ofnaloxone hydrochloride this relates to anhydrous naloxone hydrochloride. If ahydrated version of naloxone hydrochloride is used, this will be used in an amountequivalent to the afore-mentioned amounts of anhydrous naloxone hydrochloride.

In some embodiments, the present invention is directed to a prolonged releasepharmaceutical composition comprising at least hydromorphone or apharmaceutically acceptable salt or derivative thereof or naloxone or apharmaceutically acceptable salt or derivative thereof and at least one prolongedrelease material which is preferably combined with these pharmaceutically activeagents to form a prolonged release matrix; wherein the amount of hydromorphone ora pharmaceutically acceptable salt or derivative thereof and/or naloxone or apharmaceutically acceptable salt or derivative thereof released in vitro in 500 or 900ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddle method at 100 rpmat 37° C is: at 1 h: 25 to 55% by weight of the pharmaceutically active agents, at 2 h: 45 to 75% by weight of the pharmaceutically active agents, at 3 h: 55 to 85% by weight of the pharmaceutically active agents, at 4 h: 60 to 90% by weight of the pharmaceutically active agents, at 6 h: 70 to 100% by weight of the pharmaceutically active agents, at 8 h: more than 85% by weight of the pharmaceutically active agents, at 10 h: more than 90% by weight of the pharmaceutically active agents. WO 2011/141488 PCT/EP2011/057566 -21 -

The pharmaceutically active agents may preferably be hydromorphone HC1 andnaloxone HC1 being preferred. The prolonged release pharmaceutical compositionmay comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter.

In some embodiments, the present invention is directed to a prolonged releasepharmaceutical composition comprising at least hydromorphone or apharmaceutically acceptable salt or derivative thereof or naloxone or apharmaceutically acceptable salt or derivative thereof and at least one prolongedrelease material which is preferably combined with these pharmaceutically activeagents to form a prolonged release matrix; wherein the amount of hydromorphoneand/or a pharmaceutically acceptable salt or derivative thereof or naloxone or apharmaceutically acceptable salt or derivative thereof released in vitro in 500 or 900ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddle method at 100 rpmat 37° C is: at 1 h: 30 to 50% by weight of the pharmaceutically active agents, at 2 h: 50 to 70% by weight of the pharmaceutically active agents, at 3 h: 60 to 80% by weight of the pharmaceutically active agents, at 4 h: 65 to 85% by weight of the pharmaceutically active agents, at 6 h: 75 to 95% by weight of the pharmaceutically active agents, at 8 h: more than 90% by weight of the pharmaceutically active agents, at 10 h: more than 95% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HC1 andnaloxone HC1 being preferred. The prolonged release pharmaceutical composition WO 2011/141488 PCT/EP2011/057566 -22- may comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter.

In some embodiments, the present invention is directed to a prolonged releasepharmaceutical composition comprising at least hydromorphone or apharmaceutically acceptable salt or derivative thereof or naloxone or apharmaceutically acceptable salt or derivative thereof and at least one prolongedrelease material which is preferably combined with these pharmaceutically activeagents to form a prolonged release matrix; wherein the amount of hydromorphone ora pharmaceutically acceptable salt or derivative thereof and/or naloxone or apharmaceutically acceptable salt or derivative thereof released in vitro in 500 or 900ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddle method at 100 rpmat 37° C is: at 1 h: 10 to 30% by weight of the pharmaceutically active agents, at 2 h: 34 to 54% by weight of the pharmaceutically active agents, at 3 h: 53 to 73% by weight of the pharmaceutically active agents, at 4 h: 65 to 85% by weight of the pharmaceutically active agents, at 6 h: 75 to 95% by weight of the pharmaceutically active agents, at 8 h: 80 to 100% by weight of the pharmaceutically active agents, at 10 h: more than 90% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HC1 andnaloxone HC1 being preferred. The prolonged release pharmaceutical compositionmay comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter. WO 2011/141488 PCT/EP2011/057566 -23 -

In some embodiments, the present invention is directed to a prolonged releasepharmaceutical composition comprising at least hydromorphone or apharmaceutically acceptable salt or derivative thereof or naloxone or apharmaceutically acceptable salt or derivative thereof and at least one prolongedrelease material which is preferably combined with these pharmaceutically activeagents to form a prolonged release matrix; wherein the amount of hydromorphone ora pharmaceutically acceptable salt or derivative thereof and/or naloxone or apharmaceutically acceptable salt or derivative thereof released in vitro in 500 or 900ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddle method at 100 rpmat 37° C is: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agents, at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HC1 andnaloxone HC1 being preferred. The prolonged release pharmaceutical compositionmay comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter. WO 2011/141488 PCT/EP2011/057566 -24-

Preferably, the amount of the pharmaceutically active agents released in vitro in 500or 900 ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddle method at100 rpm at 37° C is: at 1 h: 8 to 42% by weight of the pharmaceutically active agents, at 2 h: 18 to 52% by weight of the pharmaceutically active agents, at 3 h: 33 to 67% by weight of the pharmaceutically active agents, at 4 h: 38 to 72% by weight of the pharmaceutically active agents, at 6 h: 43 to 77% by weight of the pharmaceutically active agents, at 8 h: 53 to 87% by weight of the pharmaceutically active agents, at 10 h: 63 to 97% by weight of the pharmaceutically active agents, at 12 h: 73 to 100% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HCl andnaloxone HCl being preferred. The prolonged release pharmaceutical compositionmay comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter.

More preferably, the amount of the pharmaceutically active agents released in vitroin 500 or 900 ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddlemethod at 100 rpm at 37° C is: at 1 h: 15 to 37% by weight of the pharmaceutically active agents, at 2 h: 25 to 47% by weight of the pharmaceutically active agents, at 3 h: 38 to 62% by weight of the pharmaceutically active agents, at 4 h: 42 to 66% by weight of the pharmaceutically active agents, at 6 h: 50 to 74% by weight of the pharmaceutically active agents, at 8 h: 60 to 84% by weight of the pharmaceutically active agents, at 10 h: 68 to 92% by weight of the pharmaceutically active agents, WO 2011/141488 PCT/EP2011/057566 -25 - at 12 h: 78 to 100% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HC1 andnaloxone HC1 being preferred. The prolonged release pharmaceutical compositionmay comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter.

Even more preferably, the amount of the pharmaceutically active agents released invitro in 500 or 900 ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddlemethod at 100 rpm at 37° C is: at 1 h: 19 to 33% by weight of the pharmaceutically active agents, at 2 h: 29 to 43% by weight of the pharmaceutically active agents, at 3 h: 43 to 47% by weight of the pharmaceutically active agents, at 4 h: 47 to 61 % by weight of the pharmaceutically active agents, at 6 h: 55 to 69% by weight of the pharmaceutically active agents, at 8 h: 65 to 79% by weight of the pharmaceutically active agents, at 10 h: 73 to 87% by weight of the pharmaceutically active agents, at 12 h: 83 to 100% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HC1 andnaloxone HC1 being preferred. The prolonged release pharmaceutical compositionmay comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter.

As mentioned above, in a first aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: WO 2011/141488 PCT/EP2011/057566 -26- a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition provides alcohol resistance.

It will be described below how prolonged release pharmaceutical compositions ofhydromorphone and naloxone providing alcohol resistance and the above mentionedrelease properties can be manufactured.

In a second aspect, the present invention relates to an oral prolonged releasepharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are present in the pharmaceutical composition in aweight ratio in a range of about 2:1 to about 1:3, preferably of about2:1, about 1:1, about 1:2 or about 1:3.

As mentioned above, in a third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein WO 2011/141488 PCT/EP2011/057566 -27- c) the pharmaceutical composition after storage under stressedconditions releases the pharmaceutically active agents withsubstantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

Storage under stressed conditions in the context of the present invention means that apharmaceutical composition is subjected to increased temperature and/or relativehumidity (RH) for prolonged periods of time. For example, typical stressedconditions refer to storage over at least one, two, three, four, five, six, twelth oreigtheen months at 25°C and 60% RH. Other stressed conditions refer to storage overat least one, two, three, four, five, six or twelth months at 30°C and 65% RH Otherstressed conditions refer to storage over at least one, two, three, four, five or sixmonths at 40°C and 75% RH.

Such stressed storage conditions are used to determine whether a pharmaceuticalcomposition has a shelf life sufficient for long time storage under conditions as theyare common in patients’ households without negative effects on its safety andefficacy. Such negative effects may include that the in-vitro release rates change overtime so that the efficacy of the composition is affected as different amounts ofactives are released after administration. Similarly, negative effects may also resultfrom degradation of the pharmaceutically active agents which may either decreasethe overall amount of functional pharmaceutically active agent or lead to formationof toxic by-products.

If changes in the in vitro release profile or with respect to the amount of the activeagent(s) of a pharmaceutical composition are observed after storage under stressedconditions, this may be indicative of stability problems. If such changes are not WO 2011/141488 PCT/EP2011/057566 -28- observed, this means vice versa that the pharmaceutical composition is storagestable.

The above mentioned stressed storage conditions can be used to estimate whether apharmaceutical dosage will have a shelflife of at least about 12 months, at leastabout 18 months, at least about 24 months or at least about 36 months. Usually ashelf life of 18 months or more may be desirable as this is usually better compatiblewith e.g. supply of excipients, actives etc. for manufacturing purposes. If apharmaceutical composition is storage stable, i.e. has essentially the same releaserate after storage over at least one, two, three, four, five or more months at 25°C and60% RH, this will be usually indicative of shelflife of at least about 12 months. If apharmaceutical composition is storage stable, i.e. has essentially the same releaserate after storage over at least one, two, three, four, five or more months at 30°C and65% RH, this will be usually indicative of shelflife of at least about 18 months. If apharmaceutical composition is storage stable, i.e. has essentially the same releaserate after storage over at least one, two, three, four, five or more months at 40°C and75% RH, this will be usually indicative of a shelflife of at least about 24 monthssuch as 36 months.

The term “substantially the same release rate” refers to the situation where the invitro release rate for a pharmaceutical composition which has been subjected tostressed conditions is compared to a reference composition. The referencecomposition is an identical pharmaceutical composition which, however, has notbeen subjected to stressed conditions. If the in vitro release profile of thecomposition subjected to stressed conditions does not deviate by more than about20%, preferably by no more than about 15%, more preferably by no more than 10%and even more preferably by no more than about 5% from the in vitro release profile WO 2011/141488 PCT/EP2011/057566 -29- of the reference composition, the in-vitro release rate is considered to be substantiallythe same.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 25°C at 60% relativehumidity for at least one month releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 25°C at 60% relativehumidity for at least two months releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release matrix material; WO 2011/141488 PCT/EP2011/057566 -30- b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 25°C at 60% relativehumidity for at least five months releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 30°C at 65% relativehumidity for at least one month releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 30°C at 65% relativehumidity for at least two months releases the pharmaceutically active WO 2011/141488 PCT/EP2011/057566 -31 - agents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release matrix material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 30°C at 65% relativehumidity for at least five months releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 40°C at 75% relativehumidity for at least one month releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; WO 2011/141488 PCT/EP2011/057566 -32- b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 40°C at 75% relativehumidity for at least two months releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 40°C at 75% relativehumidity for at least five months releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In a fourth aspect, the present invention relates to an oral prolonged releasepharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions, preferably at 25°C at 60% relative humidity for at leastfive months, has less than about 4.0% such as less than about 3.0%, WO 2011/141488 PCT/EP2011/057566 -33- preferably less than about 2.0% and more preferably less than about1% , less than about 0.5% or even less than about 0.2% of totalsubstances related to hydromorphone or a pharmaceuticallyacceptable salt or derivative thereof and/or related to naloxone or apharmaceutically acceptable salt or derivative thereof.

Stressed conditions are the same as mentioned above.

The term “hydromorphone and/or naloxone related substances” or the like refers tosubstances that arise from chemical reactions of hydromorphone or naloxone,pharmaceutically acceptable salts and derivatives thereof such as e.g. degradation.These substances can be distinguished as known hydromorphone related substanceswhere the identity of the substance and its origin is known, as known naloxonerelated substances where the identity of the substance and its origin is known, and asunknown substances. For unknown substances, their identity is not known. However,it is assumed that they arise from hydromorphone and/or naloxone, pharmaceuticallyacceptable salts and derivatives thereof. It is to be understood that the term“hydromorphone and naloxone related substances” includes the sum of knownhydromorphone related substances, known naloxone related substances and unknownsubstances and is thus equivalent to the term “total hydromorphone and naloxonerelated substances”.

Terms like “less than about 4 % of substances related to hydromorphone andnaloxone, or to pharmaceutically acceptable salts or derivatives thereof” or “lessthan about 3 % of substances related to hydromorphone and naloxone or topharmaceutically acceptable salts or derivatives thereof’ etc. indicate that the amountof total substances as described in the preceding paragraph is less than e.g. 4% or 3%by weight based on the total amount of the active ingredient which is present in WO 2011/141488 PCT/EP2011/057566 -34- lower amounts (i.e. hydromorphone or naloxone), or a pharmaceutically acceptablesalt or derivative thereof which is present in the pharmaceutical composition in thelower amount. Thus, if a pharmaceutical composition comprises hydromorphone HC1and naloxone HC1 in 1:2 ratio by weight, the amount of total substances is calculatedfrom the sum of known hydromorphone HC1 related substances, known naloxoneHC1 related substances and unknown substances which is then referenced to theamount of hydromorphone HC1. If a pharmaceutical composition compriseshydromorphone HC1 and naloxone HC1 in 2:1 ratio by weight, the amount of totalsubstances is calculated from the sum of known hydromorphone HC1 relatedsubstances, known naloxone HC1 related substances and unknown substances whichis then referenced to the amount of naloxone HC1. “Known hydromorphone related substances” include hydromorphone n-oxide,noroxymorphone, pseudohydromorphone. “Known naloxone related substances” include noroxymorphon, 10a-hydroxynaloxon, 7,8-didehydronaloxon, pseudonaloxon, 3-o-allylnaloxon.

Terms like “less than 4 % of known substances related to hydromorphone, or topharmaceutically acceptable salts or derivatives thereof” or “less than 3 % of knownsubstances related to hydromorphone, or to pharmaceutically acceptable salts orderivatives thereof’ etc. indicate that the amount of known hydromorphone relatedsubstances is less than e.g. 4% or 3% of known hydromorphone related substance byweight based on the total amount of hydromorphone, or a pharmaceuticallyacceptable salt or derivative thereof in the composition.

Terms like “less than 4 % of known substances related to naloxone, or topharmaceutically acceptable salts or derivatives thereof’ or “less than 3 % of known WO 2011/141488 PCT/EP2011/057566 -35- substances related to naloxone, or to pharmaceutically acceptable salts or derivativesthereof’ etc. indicate that the amount of known naloxone related substances is lessthan e.g. 4% or 3.0% of known naloxone related substance by weight based on thetotal amount of naloxone, or a pharmaceutically acceptable salt or derivative thereofin the composition.

In order to assess stability one may subject a pharmaceutical composition to stressedconditions as mentioned above and determine the amount of total hydromorphoneand/or naloxone related substances. One then determines the amount of totalhydromorphone and/or naloxone related substances for an identical pharmaceuticalcomposition which has not been subjected to stressed conditions. This composition isconsidered to be a reference composition. The detection of “ total hydromorphonerelated and/or naloxone substances” is typically performed by HPLC analysis usinge.g. CAT columns. The amount of the substances including the amount of unknownsubstances is then determined by calculating the area under the respective peaks inthe chromatogram. The identity of substances can be determined by doing the sameanalysis with pure known reference substances. In a further aspect the presentinvention aims at providing pharmaceutical compositions which after storage understressed conditions have less than 4 %, less than 3%, less than 2%, less than 1%, lessthan 0.5%, less than 0.2% or even less than 0.1% of total substances related tohydromorphone or a pharmaceutically acceptable salt or derivative thereof and/orrelated to naloxone or a pharmaceutically acceptable salt or derivative thereof.

In a further aspect the present invention aims at providing pharmaceuticalcompositions which after storage under stressed conditions have less than 1 % suchas less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1% oreven less than 0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less than 1% such as less WO 2011/141488 PCT/EP2011/057566 -36- than 0.5% of known substances related to naloxone or a pharmaceutically acceptablesalt or derivative thereof.

Stressed storage conditions may be the same as mentioned above. Thus typicalstressed conditions may refer to storage over at least one, two, three, four, five or sixmonths at 25°C and 60% RH, at 30°C and 65% RH or at 40°C and 75% RH. A pharmaceutical composition will thus be considered to be stable if after subjectingit to stressed conditions, it has no more than about 4% such as no more than about3%, preferably no more than about 2%, more preferably no more than about 1% andeven more preferably no more than about 0.5% of hydromorphone and/or naloxonerelated substances.

In one embodiment of this fourth aspect, the invention relates to an oral prolongedrelease pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 25°C and 60% relativehumidity for at least one month has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1%, less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof. WO 2011/141488 PCT/EP2011/057566 -37- In another embodiment of this fourth aspect, the invention relates to an oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 25°C and 60% relativehumidity for at least two months has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1%, less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof.

In yet another embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 25°C and 60% relativehumidity for at least five months has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1%, less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof. WO 2011/141488 PCT/EP2011/057566 -38- In one embodiment of this fourth aspect, the invention relates to an oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 30°C and 65% relativehumidity for at least one month has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1% , less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof.

In another embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 30°C and 65% relativehumidity for at least two months has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1% , less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof. WO 2011/141488 PCT/EP2011/057566 -39- In yet another embodiment of this fourth aspect, the invention relates to an oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 30°C and 65% relativehumidity for at least five months has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1% of total substances, less than about0.5% or even less than about 0.2% related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof

In a further embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 40°C and 70% relativehumidity for at least one month has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1% , less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof WO 2011/141488 PCT/EP2011/057566 -40- In one embodiment of this fourth aspect, the invention relates to an oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 40°C and 70% relativehumidity for at least two months has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1%, less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof.

In one embodiment of this fourth aspect, the invention relates to an oral prolongedrelease pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 40°C and 70% relativehumidity for at least five months has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1% , less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof. WO 2011/141488 PCT/EP2011/057566 -41 - In one embodiment of this fourth aspect, the invention relates to an oral prolonged release pharmaceutical composition comprising at least: a. at least one prolonged release material; b. at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c. the pharmaceutical composition after storage at 25°C and 60% relativehumidity for at least one month has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof

In another embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 25°C and 60% relativehumidity for at least two months has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or WO 2011/141488 PCT/EP2011/057566 -42- even less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof

In yet another embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 25°C and 60% relativehumidity for at least five months has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof

In one embodiment of this fourth aspect, the invention relates to an oral prolongedrelease pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 30°C and 65% relativehumidity for at least one month has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or a WO 2011/141488 PCT/EP2011/057566 -43 - pharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof.

In another embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 30°C and 65% relativehumidity for at least two months has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof.

In yet another embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 30°C and 65% relativehumidity for at least five months has less than about 1 % such as less WO 2011/141488 PCT/EP2011/057566 -44- than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof

In a further embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 40°C and 70% relativehumidity for at least one month has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof

In one embodiment of this fourth aspect, the invention relates to an oral prolongedrelease pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein WO 2011/141488 PCT/EP2011/057566 -45 - c) the pharmaceutical composition after storage at 40°C and 70% relativehumidity for at least two months has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof

In one embodiment of this fourth aspect, the invention relates to an oral prolongedrelease pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 40°C and 70% relativehumidity for at least five months has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof

It will be described below how prolonged release pharmaceutical compositions ofhydromorphone and naloxone being stable can be manufactured. It will be apparentfrom this description that selection of anhydrous diluents and the choice of lubricant WO 2011/141488 PCT/EP2011/057566 -46- may be a means to positively influence stability. Heat treatment may improvephysical stability such as robustness and hardness..

As mentioned above, in a fifth aspect the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the prolonged release pharmaceutical composition is heat treated.

In a first variation to this fifth aspect the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, c) wherein the at least one prolonged release material andhydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined such that a prolonged release matrixis formed; and d) wherein the prolonged release pharmaceutical composition is heattreated.

In a second variation to this fifth aspect the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; WO 2011/141488 PCT/EP2011/057566 -47- b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; c) wherein the at least one prolonged release material, hydromorphone ora pharmaceutically acceptable salt or derivative thereof and naloxoneor a pharmaceutically acceptable salt or derivative thereof arecombined such that a prolonged release matrix is formed; d) wherein the prolonged release matrix is heat treated; e) wherein at least one prolonged release material is applied in the formof a prolonged release coating which is disposed on the prolongedrelease matrix; and f) wherein the composition is optionally cured.

The prolonged release coating may either be disposed on each prolonged releasematrix if the prolonged release matrix is manufactured in the form of multi-particulates such as granules or it may be disposed on the formulation comprising theprolonged release matrix if e.g. prolonged release matrix multi-particulates such asgranules are compressed into a tablet. The coating will then be disposed on themonolithic formulation.

The above heat treated pharmaceutical compositions may be preferably provided inthe form of multiparticulates or mini-tablets that are filled into capsules.

Heat treatment may be performed such that the hardness/breaking strength of thepharmaceutical composition is increased for the heat treated versus the non heattreated composition. By heat treating pharmaceutical compositions in accordancewith the invention, one may thus obtain compositions with improvedhardness/breaking strength proportional to the tablet weight, size and shape. Heat WO 2011/141488 PCT/EP2011/057566 -48- treatment may improve physical stability such as robustness and hardness and insome although not all cases also positively influence chemical stability As will beshown below, heat treatment may have an effect on in vitro release properties. Thus,heat treatment may further decrease the in vitro release compared to a non-heattreated composition. However, after heat treatment for relatively short periods oftime (e.g. 30 min at 55°C) the in vitro release rate will not change any further uponfurther heat treatment, i.e. remains substantially the same. It is further observed thatsuch heat treated compositions when being subjected to stressed conditions will havesubstantially the same in vitro release rate as the same heat treated compositionwhich has not been subjected to stressed conditions. Similarly such heat treatedcompositions will have less than about 4% of total hydromorphone and/or naloxonerelated substances and less than about 1% of known hydromorphone or knownnaloxone-related substance upon storage under stressed conditions.

Heat treatment will positively effect physical stability as can be deduced from areduced occurrence of e.g. cracks and improved intactness of the formulation. Thisshould help to ensure a reproducible release behavior also in vivo settings as changesdue to e.g. an altered surface which occure as a consequence of cracks will beminimized. Further, heat treatment in general improves the hardness of theformulation in case of a prolonged release matrix formulation by usually about 3 toabout 7 kP such as about 6 kP to an overall value of about 10 to 15 about kP such asabout 11 kP. Hardness is usually tested using a mechanical strength tester such as aHolland C50 tablet hardness tester. 10 tablets are tested to provide a mean valueevery 15-20 mins during the compression run.

The term “heat treatment” refers to a thermal treatment under either or both increasedtemperature for a prolonged period of time. Typically, heat treatment takes place at atemperature in the range of about 30°C to about 95°C and for a time in the range of WO 2011/141488 PCT/EP2011/057566 -49- about 10 min to about 3 hours. Typically heat treatment conditions may thus betreatment for at least about 15 min, at least about 30 min, at least about 45 min, atleast about 60 min, at least about 75 min, at least about 90 min, at least about 120min, at least about 150 min, at least about 180 min or at least about 240 min at aboutat least 30°C, at about at least 40°C, at about at least 50°C, at about at least 60°C orat about at least 80°C at ambient humidity. Heat treatment conditions may beselected according to the specific prolonged release matrix materials being used. Ingeneral the temperature will be around the melting and/or softening temperature ofthe prolonged release matrix materials being used. Such conditions may thus ensurethat the prolonged release matrix materials are sufficiently soft to mobilise and to fillpores in the prolonged release matrix and/or e.g. compressed granules. In case offormulations using e.g. hydrophobic polymers such as ethyl cellulose and fattyalcohols such as stearyl or cetostearyl alcohol, a temperature of about 55°C may beappropriate. In general, heat treatment for at least 30 min at 55°C may be sufficientto ensure physical stability.

Heat treatment can be performed in a convection oven, in an open oven, undervacuum, in the coating drum using conventional heat, microwave and any othersources of heat. Heat treatment in a coating drum can be preferred. If thepharmaceutical compositions comprise a prolonged release coating either alone or inaddition to a controlled release matrix, heat treatment of such prolonged releasecoatings is also designated as curing which helps coalescence of e.g. polymercoatings.

Prolonged release pharmaceutical compositions in accordance with some aspects ofthe invention may comprise a prolonged release matrix and/or coating which ensuresprolonged release of the active ingredients and/or they may alternatively rely on acoating for imparting controlled release properties. In case of a prolonged release WO 2011/141488 PCT/EP2011/057566 -50- coating, the actives may be disposed on bead-like structures such as non pareil beadsor granules or they may be incorporated into extruded granules or spheroids which assuch do not provide prolonged release. The prolonged release coating is then layeredthereon.

If a prolonged release coating is used it may be layered on individual prolongedrelease matrices such as granules or mini-tablets or it may layered on a monolithicformulation such as tablets or mini-tablets which are obtained by compressingprolonged release matrix granules.

If prolonged release coating is used the prolonged release composition may beoptionally cured in order to enhance coalescence of the coating and thus to improvestability and intactness of the coating. The curing conditions may be the same asdescribed above for coatings. Curing can further slow down the release properties. Acuring step of about 20 minutes to 30 minutes at about 50° to 100° may be sufficientto slow down the release such that it won't substantially changes after storage understressed conditions as the coating’s properties will not substantially change anymore.

Pharmaceutical compositions in accordance with the invention may also comprise aprolonged release matrix with one or more prolonged release coatings thereon.

In addition prolonged release compositions comprising a prolonged release matrix orprolonged release coating may comprise e.g. a fraction of at least one or both of thepharmaceutically active agents in immediate release form. Such an immediate releasephase which may account for up to 30% of the overall amount of thepharmaceutically active agent(s) being present in the composition can ensure an earlyonset of therapeutic efficacy. WO 2011/141488 PCT/EP2011/057566 -51 -

The prolonged release compositions in accordance with the invention may beformulated into different dosage forms. For example, prolonged release compositionsmay take the form of tablets or mini-tablets. Tablets may be a monolithic tabletcomprising e.g. a continuous prolonged release matrix. However, tablets or mini-tablets may be also be made from multiparticulates which are compressed intotablets. Such multiparticulates may e.g. comprise a prolonged release matrixoptionally with an immediate release phase or active loaded beads with a prolongedrelease coating and optionally an immediate release phase thereon. The dosage formmay also take the form of such multiparticulates, e.g. granules or mini-tablets whichmay be filled into a capsule.

The in vitro release rates of the prolonged release pharmaceutical compositions willbe chosen such that a therapeutic efficacy in vivo is achieved over preferably at leasttwelve hours and in some instance even up to twenty four hours. Such compositionsmay be described as “twice a day” or “once a day” formulations as they may beadministered on such a regimen. A preferred embodiment of all embodiments and aspects as described above (inparticular of the embodiments of the first, second, third, fourth and fifth aspect of theinvention), the pharmaceutical compositions may comprise a prolonged releasematrix and a prolonged release coating. These pharmaceutical compositionsaccording to the first to fifth aspect may comprise hydromorphone and naloxone orthe pharmaceutically acceptable salt or derivatives thereof in the above mentionedratios and amounts. In the embodiments of the above mentioned aspects of theinvention, hydromorphone or a pharmaceutically acceptable salt or derivative thereofand naloxone or a pharmaceutically acceptable salt or derivative thereof may thus becombined with a prolonged release material such that a prolonged release matrix isformed on which a prolonged release coating is then disposed. The prolonged release WO 2011/141488 PCT/EP2011/057566 -52- coating may be disposed on individual prolonged release matrix formulations so thata multiparticulate formulation is obtained. These multi-particulates may be directlyfilled into capsules or blended with other excipients to obtain a dosage form. In otherembodiments, the prolonged release matrix formulation may take the form of e.g.granules which are compressed into mini-tablets or a monolithic dosage from such astablets on which the prolonged release coating is then disposed. The manufacture ofthe prolonged release matrix may preferably be undertaken using an anhydrousmethod as described below. Manufacturing a prolonged release matrix in ananhydrous manner will have a beneficial effect on chemical stability as expressede.g. by a substantially same in vitro release profile after storage under stressedconditions. Heat treatment will beneficially influence physical stability. Amultiparticulate nature may have positive effects of food effects upon administration.

The prolonged release material may be any material that is known to be capable ofimparting controlled release properties on the active agent when being formulatedinto a prolonged release matrix.

Such materials may be hydrophilic and/or hydrophobic materials such as gums,cellulose ethers, acrylic polymers, protein-derived materials etc.

Prolonged materials may also include fatty acids, fatty alcohols, glyceryl esters offatty acids, polyethylene glycols, mineral and oils and waxes. Fatty acids and fattyalcohols preferable are those with a Cio to C30 chain, preferably with a C12 to C24chain and more preferably with a C14 to C20 chain or a Ci6 to C20 chain. Materialssuch as stearyl alcohol, cetostearyl alcohol, cetyl alcohol, myristyl alcohol andpolyalkylene glycols may be preferred. Waxes may be selected from natural andsynthetic waxes such as beeswax, carnauba wax. Oils may be vegetable oils andinclude for example castor oil. WO 2011/141488 PCT/EP2011/057566 -53-

The prolonged release matrix materials which may be considered in the context ofthe present invention may also be selected from cellulose ethers.

The term “cellulose ethers” comprises cellulose-derived polymers derivatized with atleast alkyl and/or hydroxyalkyl groups which may be hydrophilic or hydrophobic.

For example, the prolonged release matrix material may be a hydrophilic hydroxyalkyl cellulose such as a hydroxy (Cl - C6) alkyl celluloses such as hydroxypropylcellulose, hydroxypropylmethyl cellulose and particularly preferably hydroxy ethylcellulose.

Examples of hydrophobic cellulose ethers include e.g. ethyl cellulose. The use ofethyl cellulose may be preferred. Hydrophobic cellulose ethers such as ethylcellulose may be particularly suitable for imparting alcohol resistance topharmaceutical compositions. A particularly suitable material for prolonged release matrix formulations inaccordance with the present invention may be selected from the group of acrylicresins. Such acrylic resins may be made from (meth)acrylic acid (co) polymers.

There are various types of (meth)acrylic acid (co)polymers available which may becharacterised according to the nature of their residues such as neutral (meth)acrylicacid (co)polymers, (meth)acrylic acid (co)polymers with anionic residues or(meth)acrylic acid ester copolymers with cationic residues.

Neutral (meth)acrylic acid (co)polymers include polymers having 95 to 100% byweight of polymerised monomers having neutral residues. Monomers with neutral WO 2011/141488 PCT/EP2011/057566 -54- residues can be C1-C4 alkyl esters of acrylic or methacrylic acid such asmethylmethacrylate, ethylmethacrylate, butylmethacrylate, methylacrylate,ethylacrylate and butylacrylate. For example, neutral (meth)acrylic acid(co)polymers may comprise 20 to 40 % by weight ethylacrylate and 60 to 80 % byweight methylmethacrylate. Such polymers are e.g. available under the trade nameEudragit® NE which is a copolymer of 30 % by weight ethylacrylate and 70 % byweight methylmethacrylate. This polymer is usually provided in the form of a 30 %or 40% aqueous dispersion (Eudragit® NE 30 D, Eudragit® NE 40 D or Eudragit®NM 30 D). (Meth)acrylic acid (co)polymers with functional anionic residues may be(meth)acrylic acid (co)polymers having 25 to 95 % by weight of radicallypolymerised Ci to C4 alkyl esters of acrylic or methacrylic acid and 5 to 75 % byweight of methacrylate monomers with an anionic group in the alkyl residue. Ci toC4 alkyl esters of acrylic or methacrylic acid are again methylmethacrylate, ethylmethacrylate, butylmethacrylate, methylacrylate, ethylacrylate and butylacrylate. A(meth)acrylate monomer with an anionic group in the alkyl residue may be forexample acrylic acid and preferably methacrylic acid. Such methacrylic acidcopolymers with an anionic functional group may comprise e.g. 40 to 60 % byweight methacrylic acid and 60 to 40 % by weight methylmethacrylate or 60 to 40 %by weight ethyl acrylate. These types of polymers are available as Eudragit® LI 00 /Eudragit® L 12.5 or Eudragit® L 100-55 / Eudragit® L 30 D-55, respectively.

For example, Eudragit® L 100 is a copolymer of 50 % by weight methylmethacrylateand 50 % by weight methacrylic acid. It is also provided as a 12.5% solution(Eudragit® L 12.5). Eudragit® L 100-55 is a copolymer of 50 % by weightethylacrylate and 50 % by weight methacrylic acid. It is also provided as 30 %dispersion (Eudragit® L 30 D-55). WO 2011/141488 PCT/EP2011/057566 -55- (Meth)acrylic acid (co)polymers with an anionic functional group may also comprise20 to 40 % by weight methacrylic acid and 80 to 60 % by weightmethylmethacrylate. These types of polymers are usually available under the tradename Eudragit® S. It is also provided as a 12. 5 % solution (Eudragit® S 12.5).Another type of methacrylic acid copolymers with an anionic functional group isavailable under the trade name Eudragit® FS which typically comprises 10 to 30 %by weight methylmethacrylate, 50 to 70 % by weight methylacrylate and 5 to 15 %by weight methacrylic acid. Thus, Eudragit®FS may be a polymer of 25 % by weightmethylmethacrylate, 65 % by weight methylacrylate and 10 % by weight methacrylicacid. It is usually provided as 30 % dispersion (Eudragit® FS 30 D). (Meth)acrylic acid (co)polymers with functional cationic groups may be methacrylicacid copolymers with tertiary amino groups. Such polymers may comprise 30 % to 80 % by weight of radically polymerised C1-C4 alkyl esters of acrylic acid ormethacrylic acid and 70 to 20 % by weight methacrylate monomers with a tertiaryamino group in the alkyl rest.

Suitable monomers with a functional tertiary amino group are disclosed e.g. in US4,705,695, column 3, line 64 to column 4, line 13. They include for exampledimethylaminoethyl acrylate, 2-dimethylaminopropyl acrylate, dimethylaminopropylmethacrylate, dimethylaminobenzyl acrylate, dimethylaminobenzyl methacrylate, (3-dimethylamino-2,2-dimethyl)propyl acrylate, dimethylamino-2,2-dimethylpropylmethacrylate, (3-diethylamino-2,2-dimethyl)propyl acrylate anddiethylamino-2,2-dimethylpropylmethacrylate. Particularly suitable isdimethylaminoethyl methacrylate. The amount of monomers with a tertiary aminogroup in the copolymer may vary between 20 to 70 %, between 40 to 60 %. Theamount of Ci to C4 alkyl esters of acrylic or methacrylic acid may be within 70 to 30 WO 2011/141488 PCT/EP2011/057566 -56- % by weight. Ci to C4 alcohol esters of acrylic or methacrylic acid includemethylmethacrylate, ethylmethacrylate, butylmethacrylate, methylacrylate,ethylacrylate and butylacrylate. A common (meth)acrylic acid (co)polymer with atertiary amino group may comprise 20 to 30 % by weight methylmethacrylate, 20 to30 % by weight butylmethacrylate and 60 to 40 % by weight dimethylaminoethylmethacrylate. For example the commercially available Eudragit® E 100 comprises25 % by weight methylmethacrylate, 25 % by weight butylmethacrylate and 50 % byweight dimethylaminoethyl methacrylate. Another common commercially availablepolymer, Eudragit®E PO comprises copolymers of methylmethacrylate,butylmethacrylate and dimethylaminoethyl methacrylate in a ratio of 25:25:50.

Another type of (meth)acrylic acid (co)polymers with functional cationic groups is(meth)acrylic acid (co)polymers with a quaternary amino group. This type of(meth)acrylic acid (co)polymers typically comprises 50 to 70 % of radicallypolymerised methylmethacrylate, 20 to 40 % by weight of ethylacrylate and 12 to 2% by weight of 2-trimethylammoniumethyl methacrylate chloride. Such polymersare e.g. available under the trade names Eudragit®RS or Eudragit®RE.

For example, Eudragit®RS comprises radically polymerised units of 65 % by weightmethylmethacrylate, 30 % by weight ethylacrylate and 5 % by weight 2-trimethylamoniumethyl methacrylate chloride. Eudragit®RE comprises radicallypolymerised units of 60 % by weight methylmethacrylate, 30 % by weightethylacrylate and 10 % by weight 2-trimethylamoniumethyl methacrylate chloride.

Prolonged release matrix materials which are particularly suitable for the presentinvention are e.g. the neutral (meth)acrylic acid (co)polymers or the (meth)acrylicacid (co)polymers with anionic functional groups. One may for example usemixtures of these types of polymers. WO 2011/141488 PCT/EP2011/057566 -57-

For example, one may use Eudragit®NE as a neutral (meth)acrylic acid (co)polymerand Eudragit®RSPO as a (meth)acrylic acid (co)polymer with an anionic functionalgroup. One may also use a mixture of these types of polymers.

However, one may also use a mixture of (meth)acrylic acid (co)polymers and otherprolonged release matrix materials such as cellulose ethers. For example, one mayuse a mixture of a neutral (meth)acrylic acid (co)polymer and a hydrophobiccellulose ether. A particularly suitable example is the combination of a Eudragit®NEtogether with ethyl cellulose. Another prolonged release material which may be usedfor the present invention may be polymers such as polyethylene oxide.

As regards polyethylene oxides, particularly those polyethylene oxides with amolecular weight in the range of 1 x 105 - 5 x 105 may be used.

Prolonged release materials which are particularly suitable for the present inventionare e.g. the neutral (meth)acrylic acid (co)polymers or the (meth)acrylic acid(co)polymers with anionic functional groups. One may for example use mixtures ofthese types of polymers.

For example, one may use Eudragit®NE as a neutral (meth)acrylic acid (co)polymerand Eudragit®RSPO as a (meth)acrylic acid (co)polymer with an anionic functionalgroup. One may also use a mixture of these types of polymers.

The use of (meth)acrylic acid (co)polymers can be particularly suitable for increasinghardness/breaking strength upon heat treatment. WO 2011/141488 PCT/EP2011/057566 -58-

However, one may also use a mixture of (meth)acrylic acid (co)polymers and otherprolonged release matrix materials such as cellulose ethers. For example, one mayuse a mixture of a neutral (meth)acrylic acid (co)polymer and a hydrophobiccellulose ether. A particularly suitable example is the combination of aEudragit®NE together with ethyl cellulose. Another example is a mixture ofcellulose ether such as hydrophobic cellulose ethers (e.g. ethyl cellulose) with a fattyalcohol (e.g. stearyl alcohol). A mixture of (meth)acrylic acid (co)polymers such asneutral (meth)acrylic acid (co)polymer (e.g. Eudragit®NE) and cellulose ethers suchas hydrophobic cellulose ethers (e.g. ethyl cellulose) may also comprise a fattyalcohol (such as stearyl or cetostearyl alcohol) as a further prolonged release matrixmaterial. Such mixtures may allow combining beneficial characteristics such asalcohol resistance and increased hardness and improved stability upon heattreatment.

The amount of prolonged release material(s) in the prolonged release formulationmay be of about 5 to 90 % by weight, of about 10 to 70% by weight, of about 20 to60 % by weight, of about 20% to about 55% by weight, of about 25% to about 50%by weight, of about 25% to about 45% by weight and preferably of about 30 to about40% by weight based on the weight of the pharmaceutical composition. The amountof prolonged release material that is incorporated into the composition can be oneway of adjusting the prolonged release properties. For example, if the amount ofprolonged release material is increased, the release can be further prolonged. Theaforementioned amounts refer to the overall content of prolonged release materials ina pharmaceutical composition. These amounts may thus refer to a mixture of variousprolonged release materials such as a neutral (meth)acrylic acid (co)polymer, ahydrophobic cellulose ether and/or a fatty alcohol. WO 2011/141488 PCT/EP2011/057566 -59-

If cellulose ether is among the prolonged release materials, it will typically bepresent in an amount of about 5% to about 50% by weight, of about 5% to about45% by weight, of about 5% to about 40% by weight, of about 5% to about 35% byweight, of about 5% to about 30% by weight, of about 5% to about 25% by weight,of about 5% to about 20% by weight such as of about 5% by weight, of about 7% byweight, of about 10% by weight, of about 15% by weight, of about 18% by weight orof about 20% by weight based on the weight of the pharmaceutical composition.

If fatty alcohol is among the prolonged release materials, it will typically be presentin an amount of about 5% to about 50% by weight, of about 5% to about 45% byweight, of about 5% to about 40% by weight, of about 5% to about 35% by weight,of about 10% to about 30% by weight, of about 10% to about 25% by weight such asof about 10% by weight, of about 15% by weight, of about 20% by weight or about25% by weight based on the weight of the pharmaceutical composition.

If (meth)acrylic acid (co)polymer is among the prolonged release materials, it willtypically be present in an amount of about 5% to about 50% by weight, of about 5%to about 45% by weight, of about 5% to about 40% by weight, of about 5% to about35% by weight, of about 10% to about 30% by weight, of about 10% to about 25%by weight such as of about 10% by weight, of about 15% by weight, of about 20% byweight or about 25% by weight based on the weight of the pharmaceuticalcomposition.

The pharmaceutical compositions in accordance with the invention may also includepharmaceutically acceptable excipients such fillers, lubricants, binders, release ratemodifiers,, anti-tacking agents etc. WO 2011/141488 PCT/EP2011/057566 -60-

Fillers which may also be designated as diluents may include e.g. lactose, preferablyanhydrous lactose, glucose or saccharose, starches, their hydrolysates,microcrystalline cellulose, cellatose, sugar alcohols such as sorbitol or mannitol,polysoluble calcium salts like calcium hydrogen phosphate, dicalcium- or tricalciumphosphate and combinations of two or more of the above fillers..

It has been observed that the combination of hydromorphone and naloxone can bemoisture sensitive in particular if cellulose ethers are used as prolonged releasematerial. In view of this situation it can be preferred to use fillers which do notimport moisture e.g. in the form of water. In preferred embodiments one may thususe anhydrous fillers such as anhydrous lactose.

Lubricants can include highly dispersed silica, talcum, com starch, magnesium oxideand magnesium- or calcium stearate, fats like hydrated castor oil, sodium stearylfumarate and combinations of two or more of the above lubricants.

It can be preferred to use a combination of magnesium stearate and talcum aslubricants. It has been found that if appropriate amounts of these lubricants arechosen, one can e.g. improve flow properties of granules used for compressing.

It thus can be preferred to use a lubricant amount of about 0.5% to about 4% byweight, of about 0.7% to about 3% by weight, of about 1% to about 2% by weightsuch as of about 1.0% by weight, of about 1.1 % by weight, of about 1.2 % byweight, of about 1.3 % by weight, of about 1.4 % by weight, of about 1.5 % byweight, of about 1.6% by weight, of about 1.7 % by weight, of about 1.8% byweight, of about 1.9 % by weight or of about 2.0 % by weight based on the weight ofthe pharmaceutical composition. An amount of about 0.75% to about 1.25% byweight based on the weight of the pharmaceutical composition can be preferred, WO 2011/141488 PCT/EP2011/057566 -61 - particularly if magnesium stearate and talc are used. The aforementioned amountsrefer to the amount of all lubricants (i.e. including mixtures) in the composition.

Binders can include hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose, polyvinyl pyrollidone, carbopol, and combinations thereof

It can be preferred to use HPC as a binder as this may positively influence thehardness of the tablets.

It thus can be preferred to use a binder amount of about 1% to about 10% by weight,of about 2% to about 9% by weight, of about 3% to about 7% by weight, of about3% to about 6% by weight, of about 4% to about 5% by weight such as of about 4.0% by weight, of about 4.1 % by weight, of about 4.2 % by weight, of about 4.3 % byweight, of about 4.4 % by weight, of about 4.5 % by weight, of about 4.6% byweight, of about 4.7 % by weight, of about 4.8 % by weight, of about 4.9 % byweight or of about 5.0 % by weight based on the weight of the pharmaceuticalcomposition. An amount of about 4.4% to about 5.0% by weight based on the weightof the pharmaceutical composition can be preferred, particularly of HPC is used asbinder. The aforementioned amounts refer to the amount of all binders (i.e. includingmixtures) in the composition.

It can be preferred to not use povidone as a binder.

Release rate modifiers are pharmaceutically acceptable excipients which may beused to tune the release which otherwise would be obtained using the prolongedrelease materials, e.g. to accelerate the release or to further slow it down. Suchrelease modifiers may be hydrophilic substances such as polyethylenglycols,hydroxypropylmethlycellulose, hydroxyethylcellulose, and the like or hydrophobic WO 2011/141488 PCT/EP2011/057566 -62- substances such as oils, waxes and the like. Other release modifiers may includesome the aforementioned (meth)aycrylic acid(co)polymers such as polymers of theEudragit® RLPO type or gums such as xanthan gum.

Release rate modifiers such as polymers of the Eudragit/®RLPO type, low molecularweight hydroxypropylmethlycellulose such Hypromellose KI OOM or xanthan gummay be preferred.

Such release rate modifiers may be present in an amount of about 1% to about 20%by weight, of about 2% to about 19% by weight, of about 3% to about 18% byweight, of about 4% to about 17% by weight, of about 5% to about 15% by weightsuch as of about 5 % by weight, of about 6% by weight, of about 7% by weight, ofabout 8% by weight, of about 9% by weight, of about 10% by weight, of about 11%by weight, of about 12% by weight, of about 13% by weight, of about 14% byweight or of about 15% by weight based on the weight of the pharmaceuticalcomposition. The aforementioned amounts refer to the amount of all release ratemodifiers (i.e. including mixtures) in the composition.

It is to be understood that the functions of pharmaceutically acceptable excipientsmay be overlapping. For example, a spheronising agent such as microcrystallinecellulose can also be used as filler if appropriate amounts are chosen. Further, HPMCmay not only act as release rate modifying agent but also as binder if e.g. used inprolonged release formulation with a coating.

Prolonged release coatings may be made from materials which are common in theart. WO 2011/141488 PCT/EP2011/057566 -63-

They may thus be selected from e.g. prolonged release materials selected e.g. from (i) an alkylcellulose; (ii) an acrylic polymer; (iii) polyvinylalcohol or (iv) mixturesthereof. Hydrophobic representatives of the afore-mentioned groups can be preferred.The coating may be applied in the form of an organic or aqueous solution ordispersion.

In some embodiments, the controlled release coating is derived from an aqueousdispersion of the hydrophobic controlled release material. The coated compositioncan then be cured.

In preferred embodiments, the controlled release coatings include a plasticizer suchas those described herein below.

In certain embodiments, one may coat with an amount of coating material which issufficient to obtain a weight gain level from about 2 to about 20%, e.g., about 2 toabout 15% and preferably about 5 to about 10% such as 6%, 7%, 8% or 9% in orderto obtain sufficiently prolong the release from the formulation..

Cellulosic materials and polymers, including alkyl celluloses are prolonged releasematerials well suited for coating substrates, e.g., beads, granules, tablets, etc.according to the invention. Simply by way of example, one preferred alkyl cellulosicpolymer is ethyl cellulose

One commercially available aqueous dispersion of ethyl cellulose is Aquacoat® suchas Aquacoat® ECD30 (FMC Corp., Philadelphia, Pennsylvania, U.S.A.). Aquacoatis prepared by dissolving the ethyl cellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactant and a WO 2011/141488 PCT/EP2011/057566 -64- stabilizer. After homogenization to generate submicron droplets, the organic solventis evaporated under vacuum to form a pseudo latex.

Another aqueous dispersion of ethyl cellulose is commercially available asSurelease® (Colorcon, Inc., West Point, Pennsylvania, U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during the manufacturingprocess. A hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleicacid) is prepared as a homogeneous mixture, which is then diluted with an alkalinesolution to obtain an aqueous dispersion which can be applied directly ontosubstrates.

In other of the present invention, the prolonged release coating material is apharmaceutically acceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethylmethacrylates, cynaoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamide copolymer, poly(methyl methacrylate),polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride) and glycidylmethacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised of one or moreammonium methacrylate copolymers. Ammonium methacrylate copolymers are wellknown in the art, and are described as fully polymerized copolymers of acrylic andmethacrylic acid esters with a low content of quaternary ammonium groups. Typicalexamples include Eudragit® RS30D which is a low permeability ammoniummethacrylate polymer and Eudragit®RL30D which is a high permeabilityammonium methacrylate polymer. Eudragit RL and Eudragit RS are water swellable, WO 2011/141488 PCT/EP2011/057566 -65- and the amount of water absorbed by these polymers is pH-dependent, however,dosage forms coated with Eudragit RL and RS are pH-independent.

The acrylic coatings may comprise a mixture of two acrylic resin lacquerscommercially available from Rohm Pharma under the Trade namesEudragit®RL30D and Eudragit®RS30D, respectively. The Eudragit®RL/RSdispersions of the present invention may be mixed together in any desired ration inorder to ultimately obtain a prolonged-release formulation having a desirabledissolution profile.

Other polymers which can be used as a prolonged release coating materials if theyare applied at sufficient amounts are e.g. hydrophilic polymers such ashyrdoxypropylmethylcellulose.

The above mentioned coatings may also be applied in combination. Further it ispossible to influence the release properties of a dosage form by increasing theamount of the coating material and thus the thickness of the coating.

In embodiments of the present invention where the coating comprises an aqueousdispersion of a hydrophobic controlled release material, the inclusion of an effectiveamount of a plasticizer in the aqueous dispersion of hydrophobic material mayfurther improve the physical properties of the prolonged release coating. Forexample, because ethyl cellulose has a relatively high glass transition temperatureand may not form flexible films under normal coating conditions, it can be preferredto incorporate a plasticizer into an ethyl cellulose coating containing prolongedrelease coating before using the same as a coating material. Generally, the amount ofplasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 % by weight of the film-former. WO 2011/141488 PCT/EP2011/057566 -66-

Examples of suitable plasticizers for ethyl cellulose include water insolubleplasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate,and triacetin, although it is possible that other water-insoluble plasticizers (such asacetylated monoglycerides, phthalate esters, castor oil, etc.) may be used. Triethylcitrate is an especially preferred plasticizer for the aqueous dispersions of ethylcellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of the present inventioninclude, but are not limited to citric acid esters such as triethyl citrate NF XVI,tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. Otherplasticizers which have proved to be suitable for enhancing the elasticity of the filmsformed from acrylic films such as Eudragit®RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin.

In the following it is described how a prolonged release matrices which may be usedfor all aspects and variations of the invention may be composed.

The invention for all its aspects and variations thus considers as a first option an oralprolonged release pharmaceutical composition comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE asprolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) the hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 -67- derivative thereof is combined with said prolonged release material toform a prolonged release matrix.

The invention for all its aspects and variations thus considers as a second option anoral prolonged release pharmaceutical composition comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) the hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof is combined with said prolonged release material toform a prolonged release matrix.

The invention for all its aspects and variations thus considers as a third option an oralprolonged release pharmaceutical composition comprising at least: a) at least one fatty alcohol as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) the hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix.

The invention for all its aspects and variations thus considers as a fourth option anoral prolonged release pharmaceutical composition comprising at least: WO 2011/141488 PCT/EP2011/057566 -68- a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one cellulose ether, preferably at least one hydrophobic celluloseether such as ethyl cellulose as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) the hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix.

The invention for all its aspects and variations thus considers as a fifth option an oralprolonged release pharmaceutical composition comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one fatty alcohol as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) the hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix.

The invention for all its aspects and variations thus considers as a sixth option whichmay be particularly preferred, an oral prolonged release pharmaceutical compositioncomprising at least: WO 2011/141488 PCT/EP2011/057566 -69- a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose and at least one fatty alcohol asprolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) the hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix.

The invention for all its aspects and variations thus considers as a seventh option anoral prolonged release pharmaceutical composition comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE, at leastone cellulose ether, preferably at least one hydrophobic cellulose ethersuch as ethyl cellulose and at least one fatty alcohol as prolongedrelease materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) the hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix.

The prolonged release materials may be used in the amounts mentioned above. WO 2011/141488 PCT/EP2011/057566 -70-

In a first embodiment of the first to seventh option, the pharmaceutical compositionis heat treated as described above.

In addition or alternatively to this first embodiment of the first to seventh option, thepharmaceutical composition may comprise an anhydrous filler such as anhydrouslactose.

In addition or alternatively to this first and second embodiment of the first to seventhoption, the pharmaceutical composition may comprise magnesium stearate and/ortalc in the above mentioned amounts.

In addition or alternatively to this first, second and third embodiment of the first toseventh option, the pharmaceutical composition may comprise HPC in the abovementioned amounts.

In addition or alternatively to this first, second, third and fourth embodiment of thefirst to seventh option, the pharmaceutical composition may comprise HPC in theabove mentioned amounts.

In addition or alternatively to this first, second, third, fourth and fifth embodiment ofthe first to seventh option, the pharmaceutical composition may comprise anadditional prolonged release coating. Such a coating may comprise preferably ethylcellulose as prolonged release coating material.

These pharmaceutical compositions according to the first to seventh option maycomprise hydromorphone and naloxone or a pharmaceutically acceptable salt orderivatives thereof in the above mentioned ratios and amounts. They may furtherprovide the above mentioned in vitro release data and alcohol resistance as described WO 2011/141488 PCT/EP2011/057566 -71 - above. Further, these compositions may provide storage stability. They may also beof a multiparticulate nature. They may further provide the pharmacokineticparameters as mentioned herein.

Of one attempts to realize specific in vitro release rates, one can use combinations ofthe above mentioned measures. For example, if the release from a prolonged releasematrix is deemed too fast one may apply a prolonged release coating in addition. Inaddition or alternatively, one may add additional prolonged release matrix materialssuch as hydrophobic polymers, with ethyl cellulose being preferred and/or fattyalcohols to granules which already comprise a prolonged release matrix and to thencompress these granules together with the additional prolonged release matrixmaterials into e.g. tablets. In a preferred embodiment, such prolonged release matrixformulations which are coated with such prolonged release matrix formulations andthen are used as a multiparticulate formulation.

The pharmaceutical compositions in accordance with the invention as describedherein may be formulated to provide a mean AUCt of about 1162 h*pg/ml to about2241 h*pg/ml and preferably of about 1328 to about 2075 h*pg/ml per mgadministered amount of hydro morphone and a mean Cmax of about 122 pg/ml toabout 234 pg/ml and preferably of about 139 to about 218 pg/ml per mg administeredamount of hydromorphone and mean tmax of about lh to about 4.5h, preferably ofabout 1,5h to about 4h and more preferably of about 1,5h to about 3h. These valuesrefer preferably to single dose administration to healthy subjects. Preferably,administration is in the fasted state. The mean values of Cmax, AUCt and tmax referto the geometric mean.

The “Cmax value” indicates the maximum blood plasma concentration of the activeagent hydromorphone. WO 2011/141488 PCT/EP2011/057566 -72-

The “tmax value” indicates the time point at which the Cmax value is reached. Inother words, tmax is the time point of the maximum observed plasma concentration.

The “AUC (Area Under the Curve)” value corresponds to the area of theconcentration curve. The AUC value is proportional to the amount of the activeagent absorbed into the blood circulation in total and is hence a measure for thebioavailability.

The “AUCt value” is the value for the area under the plasma concentration-timecurve from the time of administration to the last measurable concentration. AUCtvalues are usually calculated using the linear trapezoidal method.

If pharmacokinetic parameters such as mean tmax, cmax and AUCt are measured forhealthy subjects which may be healthy human, they are typically obtained bymeasuring the development of blood plasma values over time in a test population ofapproximately 16 to 24 healthy human subjects. Regulatory bodies such as theEuropean Agency for the Evaluation of Medicinal Products (EMEA) or the Food andDrug Administration (FDA) will usually accept data obtained from e.g. 16 or 24 testpersons. However, initial trials involving fewer participants such as 8 to 16participants may also be acceptable.

The term “healthy” subjects in this context refers to a typical male or female ofusually Caucasian origin with average values as regards height, weight andphysiological parameters such as blood pressure etc. Healthy human subjects for thepurposes of the present invention are selected according to inclusion and exclusioncriteria which are based on and in accordance with recommendations of theInternational Conference for Harmonization of Clinical Trials (ICH). For the WO 2011/141488 PCT/EP2011/057566 -73- purposes of the present invention, healthy subjects may be identified according to theinclusion and exclusion criteria as outlaid in Example 7.

Thus, inclusion criteria comprise e.g. an age between >18 and <45 years; a BMIwithin the range 19-29 kg/m2, and within the weight range 60 - 100 kg for malesand 55 - 90 kg for females; that females must be non-nursing, non-pregnant, andprovide a negative urine β-hCG pregnancy test within 24 hours before receiving thestudy medication; generally good health, evidenced by a lack of significantlyabnormal findings on medical history, physical examination, clinical laboratory tests,vital signs, and ECG etc.

Exclusion criteria comprise e.g. exposure to any investigational drug or placebowithin 3 months of the first dose of study medication, any significant illness withinthe 30 days before the first dose of study medication, any clinically significantabnormalities identified at prestudy screening for medical history, physicalexamination or laboratory analyses, use of any prescription medication (except HRTfor postmenopausal females and contraceptive medication) in the 21 days, or over thecounter medication including acid controllers, vitamins, herbal products and/ormineral supplements in the 7 days, before first dose of study medication, concurrentmedical condition known to interfere with gastrointestinal drug absorption (e.g.delayed gastric emptying, mal absorption syndromes), distribution (e.g. obesity),metabolism or excretion (e.g. hepatitis, glomerulonephritis), history of or concurrentmedical condition, which in the opinion of the investigator would compromise theability of the subject to safely complete the study, history of seizure disorders forwhich subjects required pharmacologic treatment, current history of smoking morethan 5 cigarettes a day, subjects with evidence of active or past history of substanceor alcohol abuse according to DSM-IV criteria, subjects who reported regularconsumption of 2 or more alcoholic drinks per day or have blood alcohol levels of WO 2011/141488 PCT/EP2011/057566 -74- >0.5% at screening, donation of more than 500 mL of blood or blood products orother major blood loss in the 3 months before first dose of study medication, anypositive results in the prestudy screen for ethanol, opiates, barbiturates,amphetamines, cocaine metabolites, methadone, propoxyphene, phencyclidine,benzodiazepines, and cannabinoids in the specimen of urine collected at screening,known sensitivity to hydromorphone, naloxone, or related compounds etc.

The afore-mentioned pharmacokinetic data may preferably be obtainable with aprolonged release pharmaceutical composition comprising at least hydromorphone ora pharmaceutically acceptable salt or derivative thereof or naloxone or apharmaceutically acceptable salt or derivative thereof and at least one prolongedrelease material which is preferably combined with these pharmaceutically activeagents to form a prolonged release matrix; wherein the amount of hydromorphone ora pharmaceutically acceptable salt or derivative thereof or naloxone or apharmaceutically acceptable salt or derivative thereof released in vitro in 500 or 900ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddle method at 100 rpmat 37° C is: at 1 h: 25 to 55% by weight of the pharmaceutically active agents, at 2 h: 45 to 75% by weight of the pharmaceutically active agents, at 3 h: 55 to 85% by weight of the pharmaceutically active agents, at 4 h: 60 to 90% by weight of the pharmaceutically active agents, at 6 h: 70 to 100% by weight of the pharmaceutically active agents, at 8 h: more than 85% by weight of the pharmaceutically active agents, at 10 h: more than 90% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HC1 andnaloxone HC1 being preferred. The prolonged release pharmaceutical composition WO 2011/141488 PCT/EP2011/057566 -75- may comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter.

The afore-mentioned pharmacokinetic data may even more preferably be obtainablewith a prolonged release pharmaceutical composition comprising at leasthydromorphone or a pharmaceutically acceptable salt or derivative thereof ornaloxone or a pharmaceutically acceptable salt or derivative thereof and at least oneprolonged release material which is preferably combined with these pharmaceuticallyactive agents to form a prolonged release matrix; wherein the amount ofhydro morphone or a pharmaceutically acceptable salt or derivative thereof ornaloxone or a pharmaceutically acceptable salt or derivative thereof released in vitroin 500 or 900 ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddlemethod at 100 rpm at 37° C is: at 1 h: 30 to 50% by weight of the pharmaceutically active agents, at 2 h: 50 to 70% by weight of the pharmaceutically active agents, at 3 h: 60 to 80% by weight of the pharmaceutically active agents, at 4 h: 65 to 85% by weight of the pharmaceutically active agents, at 6 h: 75 to 95% by weight of the pharmaceutically active agents, at 8 h: more than 90% by weight of the pharmaceutically active agents, at 10 h: more than 100% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HC1 andnaloxone HC1 being preferred. The prolonged release pharmaceutical compositionmay comprise these actives in the above indicated amounts and weight ratio of about WO 2011/141488 PCT/EP2011/057566 -76- 2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter.

Prolonged release pharmaceutical compositions as mentioned hereinafter can beobtained using a method of manufacturing comprising at least the steps of: a) producing granules comprising at least one prolonged release material,at least hydromorphone or a pharmaceutically acceptable or derivativesalt thereof and at least naloxone or a pharmaceutically acceptable saltor derivative thereof, b) optionally selecting granules of step a) of substantially uniform size; c) optionally adding additional prolonged release materials; d) compressing said granules of step a), step b) or step c) to obtain anoral prolonged release pharmaceutical composition in the form of atablet, e) optionally heat treating said compressed granules of step d); f) optionally disposing a prolonged release coatings either on thegranules of step a), b) or c) or on the monolithic composition obtainedin step d) or e); g) optionally curing the obtained composition.

It is to be understood that at least the compression step c) produces an oral prolongedrelease pharmaceutical composition in the form of a tablet which comprises aprolonged release matrix. However, the granules obtained in step a) may alsoalready comprise a prolonged release matrix.

Prolonged release pharmaceutical compositions as mentioned hereinafter can also beobtained using a method of manufacturing comprising at least the steps of: a) producing granules comprising at least one prolonged release material,at least hydromorphone or a pharmaceutically acceptable or WO 2011/141488 PCT/EP2011/057566 -77- derivative salt thereof and at least naloxone or a pharmaceuticallyacceptable salt or derivative thereof, b) optionally selecting granules of step a) of substantially uniform size; c) optionally heat treating said granules of step a) or step); d) optionally disposing a prolonged release coatings either on thegranules of step a), b) or or c); e) optionally curing the obtained composition.

The person skilled in the art is aware of different means and methods for producinggranules according to step a).

In one embodiment, such granules may be produced by wet or dry granulation.Thus, for producing granules, step a) may comprise the following steps: aa) blending a prolonged release material with at least hydromorphoneor a pharmaceutically acceptable or derivative salt thereof and atleast naloxone or a pharmaceutically acceptable salt or derivativethereof and optionally with a pharmaceutically acceptableexcipient, ab) wet or dry granulating said blend of step aa) to obtain granules, andoptionally spheronising them, ac) drying said granules of step ab).

The pharmaceutically acceptable excipients may include the fillers, binders,lubricants, release rate modifiers, spheronising agents, anti-tacking agents, etc. asmentioned above. However, some of these excipients such as e.g. lubricants may beadded at a later stage (see below). WO 2011/141488 PCT/EP2011/057566 -78-

Different technology is available to obtain such granules. One may use e.g. drumgranulation or fluidized bed granulation.

Alternatively and/or additionally granules according to step a) may be producedcomprising the steps of: aa) blending a prolonged release matrix material with at leasthydromorphone or a pharmaceutically acceptable or derivative saltthereof and at least naloxone or a pharmaceutically acceptable saltor derivative thereof and optionally with a pharmaceuticallyacceptable excipient, ab) extruding said blend of step aa) to obtain granules, ac) drying said granules of step ab).

The pharmaceutically acceptable excipients may include the fillers, binders,lubricants, release rate modifiers, spheronising agents, anti-tacking agents, etc. asmentioned above. However, some of these excipients such as e.g. lubricants may beadded at a later stage (see below).

Different extruder technology is available to obtain extruded granules. For example,one may use a single screw or twin screw extruder. For twin screw extruders, onemay use counter-rotating or co-rotating screws having optionally paddle means.

As mentioned above, the granules which may be produced by wet granulationextrusion may be dried before being mixed with the at least one pharmaceuticallyactive agent.

Typically, drying takes place at humidity in the range of about 0.5 % to about 5.0 %at a temperature in the range of about 20°C to about 90°C and for a time in the range WO 2011/141488 PCT/EP2011/057566 -79- of about 10 min to about 3 hours. Drying at ambient humidity at a temperature in therange of about 40°C to about 90°C and for a time in the range of about 15 min toabout 2 hours can be preferred.

The granules may then be optionally screened in order to select granules ofsubstantially uniform size. Selecting granules of substantially uniform size beforecompressing them may improve the prolonged release properties of the finalprolonged release pharmaceutical composition as the active and the granules are thenassumed to be more uniformly distributed which may prevent irregularities in therelease profile. Granules for which at least about 70%, preferably at least about 80%,more preferably at least about 90% are of about the same mean size will typically beconsidered as being of substantially uniform size.

Preferably, granules are selected of a mean size in the range of about 100 pm toabout 2 mm, more preferably in the range of about 100 pm to about 1 mm, and evenmore preferably in the range of about 100 pm to about 600 pm. Selection may beperformed using a sieve with an appropriate mesh size.

In some embodiments the granules may be milled before selecting them for theirsize. Milling may both increase the yield of the selection step and improve thegranules’ suitability for the subsequent compression step. For milling one may usefor example a rotary hammer mill or top/bottom driven conical mill.

Even though granules may be produced by wet granulation, anyhdrousmanufacturing steps and methods such as anhydrous extrusion may be preferred, atleast where hydromorphone and naloxone or its pharmaceutically acceptable salts orderivatives thereof are to be included in a prolonged release matrix. The preferencefor anhydrous manufacturing steps and methods when making a prolonged release WO 2011/141488 PCT/EP2011/057566 - 80- matrix is that this has a beneficial impact on the chemical stability of hydro morphoneor naloxone or its pharmaceutically acceptable salts or derivatives. Once the activeagents have been included in such a prolonged release matrux, the optional additionalapplication of e.g. a prolonged release coating does not have be in an anhydrousmanner. It is to be understood that the term “anhydrous manufacturing” indicates thatthe process that leads to a prolonged release matrix may be performed in the absenceof substantial amounts of water. This does not mean that the components which areused do not comprise molecular bound water. Thus, even where the process isperformed in an anhydrous manner such as extrusion, naloxone hydrochloride maye.g. be provided as a dihydrate and fillers such as lactose may be provided as lactosemonohydrate even though anhydrous lactose can be preferred.

For compressing the pharmaceutically active agent(s) with the granules, one may usetypical tabletting equipment such as Example Fette or Kilian press.

When compressing granules and active(s), one may also include pharmaceuticallyacceptable excipients as they are commonly used in the art. For example, one mayadd lubricants, anti-tacking agents, binders and the like. For lubricants, the use ofmagnesium stearate and/or talc in the aforementioned amounts can be of advantage.

As mentioned above, prolonged release pharmaceutical dosage forms in accordancewith the invention may be additionally subjected to a heat treatment step as has beendescribed above.

The prolonged release coating may be produced by methods common in the art sucha fluidized bed spraying.

As described above, the invention relates in some embodiments to oral prolongedrelease pharmaceutical compositions comprising hydromorphone or a WO 2011/141488 PCT/EP2011/057566 - 81 - pharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt of derivative thereof comprising hydromorphone ora pharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt of derivative thereof in weight rations in a range of5 about 2:1 to about 1:3, preferably of about 2:1, 1:1, 1:2 or 1:3. It is to be understoodthat particularly for these embodiments, hydromorphone or a pharmaceuticallyacceptable salt or derivative thereof and naloxone of a pharmaceutically acceptablesalt or derivative thereof can be comprised within distinct pharmaceuticalcompositions which can then be administered simultaneously or sequentially to 10 provide the benefits of such a fixed ratio.

The invention is now illustrated with respect to specific examples. These examplesare, however, not to be construed as limiting. WO 2011/141488 PCT/EP2011/057566 - 82-

EXAMPLES

Example 1:

Tablets of the composition as shown in Table 1 were manufactured.

Tablets F880/99 F880/105 F893/31 Ingredient Amount(mg) Amount(mg) Amount(mg) Hydromorphone HC1 2.0 2.0 2.0 Naloxone HC1 4.0 4.0 4.0 Stearyl alcohol 25.0 25.0 25.0 Ethyl cellulose N45 20.0 20.0 ___ Lactose anhydrous 76.4 76.4 76.4 Eudragit RSPO* — — 20.0 Sodium stearylfumarate 2.6 2.6 2.6 Hypromellose KI OOM 20.0 — 20.0 Xanthan Gum ‘extra’ — 12.0 — Total 150.0 142.0 150 *The amount indicated refers to the amount of solids used. 10 Hydromorphone HC1 and naloxone HC1 were mixed with lactose anhydrous, stearylalcohol and either ethyl cellulose N45 or Eudragit RSPO as a prolonged releasepolymer in a double cone mixer for 10 min.

Subsequently the blend was melt extruded using a heated twin screw extruder.. 15 WO 2011/141488 PCT/EP2011/057566 - 83 -

The temperature profile for the extruder was as follows:

Extruder type twin screw Heating zone 1 (feedingzone) 25°C Heating zone 2 50-55°C Heating zone 3 73-83°C Heating zones 5-10 70-80°C Die head 50-55

The feeder rate was 10-15kg/h. The screw speed was set at 150-250rpm. The dieplate design allowed for multiple strand extrusion. Compressed air was used to coolthe extruded strands on conveyor belt.

Subsequently, the strands were milled to obtain granules. For milling, a Retsch millwith a 1.25 mm screen was used. This gave a substantially unimodal size distributionof the granules mainly in the range 100 to 600 pm.

The granules were then blended with sodium stearyl fumarate which was included asa lubricant. In addition, Hypromellose KI 00M was included as a release modifier.These components were blended for an additional 5 min. The granules were thencompressed into tablets using a Kilian press.

Tablets F880/99, F880/105 and F893/31 were then analyzed as regards in vitrorelease behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HC1 with pH 1.2). Aliquotsof the dissolution media are withdrawn at the respective time points and analyzed byHPLC at 220 nm. WO 2011/141488 PCT/EP2011/057566 - 84-

The in vitro release are indicated as percentage (based on the label content of activetested) in table 2.

Table 2

Tablets iiiiiiiiill:|iiiiiii Dissolutionmedium 0.1 N HCl pH 1.2 0.1 N HCl pH 1.2 0.1 N HCl pH 1.2 Active tested Hm Nal Hm iliiiiiiii Hm iliiiiii 0.5h 25 24 29 28 25 23 lh 37 35 41 40 36 33 2h 55 53 59 56 53 49 3h 68 66 71 68 65 62 4h 78 77 79 77 75 71 5h 88 86 86 83 83 79 6h 94 92 91 88 89 85 7h 97 96 93 91 92 89 8h 99 97 96 94 95 92 9h 99 98 97 96 97 95 lOh 99 98 98 97 97 96 llh 99 98 99 98 97 96 12h 99 98 99 98 97 96

Hm = hydromorphone HC1, Nal = naloxone HC1, 0.1 N HC1 w/o 40% EtOH = 0.1 N HC1 pH 1.2 without 40% ethanol; Values are averages of 6 measurements.

The tablets were further evaluated with respect to their alcohol resistance. To this 10 end in vitro release rates were determined using the Ph. European paddle method at75 rpm in 500 simulated gastric fluid (SGF) dissolution medium (0.1 N HC1 with pH1.2) with 40% EtOH. Aliquots of the dissolution media are withdrawn at therespective time points and analyzed by HPEC at 220 nm. 15 The in vitro release rates are indicated as percentage (based on the label content ofactive tested) in table 3. WO 2011/141488 PCT/EP2011/057566 - 85 -

Table 3

Tablet F880/99 Dissolutionmedium 0.1 N HCl w 40% EtOH 0.1 N HCl w 40% EtOH 0.1 N HCl w 40% EtOH Active tested Hm Nal Hm iiiiiili Hm Nal 15min 0 0 0 0 0 0 30 min 12 11 9 9 12 11 45 min 16 16 23 21 17 16 60 min 21 20 39 36 21 20 90 min 25 24 63 59 25 23 120min 31 30 83 77 31 29

Hm = hydromorphone HCl, Nal = naloxone HCl, 0.1 N HCl w 40% EtOH = 0.1 N HCl pH 1.2 with40% ethanol, Values are averages of 6 measurements.

Example 2

Tablets of the composition as shown in Table 4 were manufactured. 10 Table 4

Tablets F880/77 F880/83 F893/89 Ingredient Amount(mg) Amount(mg) Amount(mg) Hydromorphone HCl 2.0 2.0 2.0 Naloxone HCl 4.0 4.0 4.0 Stearyl alcohol 25.0 25.0 15.0 Ethyl cellulose N45 20.0 20.0 20 Lactose anhydrous 76.4 76.4 76.4 Sodium stearylfumarate 2.6 2.6 2.6 Hypromellose K100M”Extra” 20.0 7.5 12.5 Total 150 142.5 137.5 WO 2011/141488 PCT/EP2011/057566 - 86-

Hydromorphone HCI and naloxone HCI were mixed with lactose anhydrous, stearylalcohol and ethyl cellulose as a prolonged release polymer in a double cone mixer for10 min.

Subsequently the blend was melt extruded using a heated twin screw extruder.

The temperature profile for the extruder was as follows:

Extruder type twin screw Heating zone 1 (feedingzone) 25°C Heating zone 2 50-55°C Heating zone 3 73-83°C Heating zones 5-10 70-80°C Die head 50-55

The feeder rate was 10-15kg/hr. The screw speed was set at 150-250rpm. The dieplate design allowed for multiple strand extrusion. Compressed air was used to coolthe extruded strands on a conveyor belt.

Subsequently, the strands were milled to obtain granules. For milling, a Retsch millwith a 1.25 mm screen was used. This gave a substantially unimodal size distributionof the granules mainly in the range 100 to 600 pm.

The granules were then blended with sodium stearyl fumarate which was included asa lubricant. In addition, Hypromellose KI 00M was included as a release modifier.These components were blended for an additional 5 min. The granules were thencompressed into tablets using a Kilian press. WO 2011/141488 PCT/EP2011/057566 - 87-

Tablets F880/77, F880/83 and F880/89 were then analyzed as regards in vitro releasebehavior using the Ph. European paddle method at 75 rpm in 500 ml simulatedgastric fluid (SGF) dissolution medium (0.1 N HC1 with pH 1.2). Aliquots of the 5 dissolution media are withdrawn at the respective time points and analyzed by HPLCat 220 nm.

Tablets F880/77, F880/83 and F880/89 were further evaluated with respect to theiralcohol resistance. To this end in vitro release rates were determined using the Ph. 10 European paddle method at 75 rpm in 500 ml simulated gastric fluid (SGF)dissolution medium (0.1 N HC1 with pH 1.2) with 40% EtOH. Aliquots of thedissolution media are withdrawn at the respective time points and analyzed by HPLCat 220 nm. 15 The in vitro release data is indicated as percentage (based on the label content ofactive tested) in tables 5 to 6. WO 2011/141488 PCT/EP2011/057566 -88-

Table 5

Tablets liliiiOiiMliiiiiiii iiiiiiiiiililiiiiiii Dissolutionmedium 0.1 N HCI pH 1.2 0.1 N HCI pH 1.2 0.1 N HCI pH 1.2 Active tested Hm Nal Hm iiiiiiii Hm Nal 0.5h 16 14 25 24 23 20 lh 24 22 40 39 35 33 2h 38 35 68 67 51 49 3h 50 45 87 86 65 63 4h 59 54 96 96 78 76 5h 68 62 99 99 87 86 6h 76 70 100 100 95 93 7h 82 77 100 100 96 95 8h 87 82 101 100 96 95 9h 92 86 101 101 97 96 lOh 95 90 101 100 96 96 llh 97 93 101 101 97 96 12h 99 94 102 101 97 96

Hm = hydromorphone HCI, Nal = naloxone HCI; Values are averages of 6 measurements. 5 Table 6

Tablets F880/77 F880/83 F880/89 Dissolutionmedium 0.1 N HCI w40% EtOH 0.1 N HCI w40% EtOH 0.1 N HCI w 40% EtOH Active tested Hm iiiiiiii Hm Nal Hm Nal 15 min 15 14 12 10 10 8 30 min 25 22 19 17 16 14 45 min 37 34 24 23 21 20 60 min n.d. n.d. 29 28 25 23 90 min n.d. n.d. 37 35 32 30 120 min n.d. n.d. 43 42 38 36

Hm = hydromorphone HCI, Nal = naloxone HCI, 0.1 N HCI w 40% EtOH = 0.1 N HCI pH 1.2 with 40% ethanol, n.d. = not determined; Values are averages of 6 measurements. 10 WO 2011/141488 PCT/EP2011/057566 - 89-

Example 3:

Granules of the composition as shown in table 7 were manufactured. 5 Table 7

Tablets PN3450 iiiiiiii iiiiiiii Ingredient Amount (mg) Amount(mg) Amount(mg) Hydromorphone HC1 4.0 4.0 4.0 Naloxone HC1 8.0 8.0 8.0 Hydroxypropylcellulose 5.0 5.0 5.0 Stearyl alcohol 17.5 25.0 25.0 Ethyl cellulose N45 7.5 10.0 15.0 Lactose anhydrous 46.0 46.0 46.0 Magnesium stearate 1.25 1.25 1.25 Talc 0.75 0.75 0.75 Total 90 100 105

Hydromorphone HC1 and naloxone HC1 were mixed with lactose anhydrous, stearyl 10 alcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.

Subsequently the blend was melt extruded using a heated twin screw extruder. 15 The temperature profile was as follows: WO 2011/141488 PCT/EP2011/057566 -90-

Extruder type twin screw Heating zone 1 (feedingzone) 25°C Heating zone 2 50-55°C Heating zone 3 73-83°C Heating zones 5-10 70-80°C Die head 50-55

The feeder rate was 10-15kg/hr. The screw speed was set at 150-250rpm. The dieplate design allowed for multiple strand extrusion. Compressed air was used to coolthe extruded strands on a conveyor belt.

The granules were milled and the milled granules were blended with magnesiumstearate and talc in a tumbler mixer. Subsequently, the blended granules werecompressed into tablets and heat treated for 30 minutes at 55°C.

Figure 1 shows for e.g. for the case of PN3450 that heat treatment of the prolongedmatrix improves the physical stability of the formulation, e.g. in that the appearanceof cracks is reduced and the intactness of the tablet is improved. Similar observationswere made for the other heat treated tablets mentioned herein. This may positvelyinfluence the in vitro release properties of the formulation, particularly in an in vivosetting as cracks may e.g. affect the release properties in an unpredictable mannerdue to e.g. a sudden change in the surface of the tablet. Furthermore, the hardness ofthe tablets is increase by usually 6 kP to 10 to 11 kP.

Tablets PN3450, PN3451 and PN3452 were then analyzed as regards in vitro releasebehavior using the Ph. European paddle method at 75 rpm in 500 ml simulatedgastric fluid (SGF) dissolution medium (0.1 N HCI with pH 1.2). Aliquots of the WO 2011/141488 PCT/EP2011/057566 -91 - dissolution media are withdrawn at the respective time points and analyzed by HPLCat 220 nm.

The in vitro release data is indicated as percentage (based on the label content of5 active tested) in table 9.

Table 9

Tablets PN3450 iiiiieiiiiiiiii Dissolutionmedium 0.1 N HCIpH1.2 0.1 N HCIpH1.2 0.1 N HC1 pH 1.2 Active tested Hm Nal Hm iiiiii Hm Nal lh 51,50 50,80 40.54 39.69 33.22 32,31 2h 68,10 67,60 54,82 53,92 45,89 45,04 3h 78,50 78,30 64,22 63,54 54,80 54,05 4h 85,50 85,60 71,72 71,11 61,85 61,21 5h 90,50 90,70 77,74 77,28 67,57 67,06 6h 93,90 94,30 82,11 81,72 72,22 71,97 7h 95,90 96,60 85,82 85,65 76,29 75,94 8h 96,90 97,90 89,19 89,24 79,75 79,63 9h 97,50 98,50 91,82 91,93 82,81 82,73 lOh 97,50 98,60 93,71 94,04 85,24 85,59 llh 97,00 98,30 95,19 95,72 87,60 87,83 12h 97,20 98,40 96,54 97,26 89,43 89,91

Hm = hydromorphone HC1, Nal = naloxone HC1; Values are averages of 6 measurements. 10 Subsequently, tablets PN350, PN3451 and PN3452 were placed in PVC blisters andstored for 3 months at 25°C and 60% RH or for 1, 2 and 3 months at 40°C and 75%RH.

All tablets were tested either initially or after storage for total related substances. 15 WO 2011/141488 PCT/EP2011/057566 -92-

The results are shown in table 10.

Table 10

Tablets PN3450 PN3450 iiiiiiiii iiiiiiiii iiliiiiiii iiiiiiiiiii Container iiiiiiiii iiiiiiiii iiiiiiiiiii iiiiiiiiiii iiiiiiiiiii: iiiiiiiiiiiii Storage iiiiiiiii % RH iiiiiiiii: % RH iiiiiiiii % RH iiiiiiiii % RH iiiiiiiii:% RH iiiiiiilii RH Initial 0,15% 0.15% 0.15% 0.15% 0.16% 0.16% 1 month ___ 0.26% ___ 0.31% ___ 0.33% 2 months — 0.28% — 0.39% — 0.29% 3 months 0.33% 0.24% 0.34% 0.24% 0.36% 0.32%

Example 4:

Granules of the composition as shown in Table 11 were manufactured. 10

Table 11

Tablets F923/16 Ingredient Amount(mg) Hydromorphone HC1 4.0 Naloxone HC1 8.0 Hydroxypropylcellulose 5.0 Stearyl alcohol 25.0 Ethyl cellulose N45 10.0 Lactose anhydrous 46.0 Total 98 WO 2011/141488 PCT/EP2011/057566 -93-

Hydromorphone HCI and naloxone HCI were mixed with lactose anhydrous, stearylalcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.

Subsequently the blend was melt extruded using a heated twin screw extruder. Thegranules were milled and the milled granules were blended with magnesium stearateand talc in a tumbler mixer. Subsequently, the blended granules were compressedinto tablets.

Tablets F923/16 were heat treated for 15 min at 55°C. The heat treated tablets werelabeled F922/58A.

Tablets F923/16 were heat treated for 30 min at 55°C. The heat treated tablets werelabeled F922/58B.

Tablets F923/16 were heat treated for 45 min at 55°C. The heat treated tablets werelabeled F922/58C.

Tablets F923/16 as well as their heat treated counterparts were then analyzed asregards in vitro release behavior using the Ph. European paddle method at 75 rpm in500 ml simulated gastric fluid (SGF) dissolution medium (0.1 N HCI with pH 1.2).Aliquots of the dissolution media are withdrawn at the respective time points andanalyzed by HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 12. WO 2011/141488 PCT/EP2011/057566 -94-

Table 12

Tablets F923/16 iiiiiiiiiiliii iiiiiiiiiiiiiii iiiiiiiiiiiiiii Dissolutionmedium 0.1 N HCIpH 1.2 0.1 N HCIpH 1.2 0.1 N HCIpH 1.2 0.1 N HCIpH 1.2 Active tested Hm ill Hm Nal Hm Nal Hm illii lh 48 47 40,06 39,10 39,12 38,17 38,31 37,54 2h 64 64 53,93 52,15 53,47 52,68 52,43 51,04 3h 75 74 63,75 62,68 63,79 62,34 62,19 61,07 4h 82 82 71,05 70,47 70,74 69,86 69,53 68,41 5h 86 87 78,03 77,01 76,58 75,71 75,37 76,35 6h 91 92 81,42 81,27 81,27 80,61 79,94 79,05 7h 94 94 84,75 84,56 85,59 82,89 83,97 83,26 8h 95 96 87,70 87,62 88,74 88,42 87,17 86,71 9h 96 97 91,27 90,97 90,86 90,71 89,67 88,92 lOh 96 97 92,80 92,86 92,88 92,73 92,80 92,34 llh 96 97 94,14 94,45 94,32 94,42 93,73 91,82 12h 98 97 95,16 95,46 96,33 95,58 94,60 94,55

Hm = hydromorphone HCI, Nal = naloxone HCI; Values are averages of 6 measurements. 5 Example 5:

Tablets with a prolonged release matrix and of comparable composition as inexample 3 but comprising 20 mg ethyl cellulose were prepared. These tablets werethen subjected to different heat treatments. 10

F922/70C: heat treated for 45 min at 55°C F922/70D: heat treated for 60 min at 55°C F922/70E: heat treated for 75 min at 55°C 15 Tablets F922/70C, F922/70D and F922/70E were then analyzed as regards in vitrorelease behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HCI with pH 1.2). Aliquots WO 2011/141488 PCT/EP2011/057566 -95- of the dissolution media are withdrawn at the respective time points and analyzed byHPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content of 5 active tested) in table 13.

Table 13

Tablets F922 /70C iiiiiiiiiiiiii iiiiillliiiiiii Dissolutionmedium 0.1 N HOpH 1.2 iiiiiilliiiliiiipH 1.2 iiiiiiiiiiiiiipH1.2 Active tested Hm Nal Hm iiiii Hm Nal lh 23,09 21,44 22,56 20,95 21,89 20,37 2h 33,32 31,48 31,65 29,87 31,24 29,27 3h 41,16 38,85 38,90 36,71 38,24 36,14 4h 47,38 45,14 44,50 42,18 44,05 41,80 5h 52,37 49,95 49,65 47,36 49,11 46,87 6h 57,11 54,79 53,72 51,77 53,39 51,11 7h 60,75 59,23 57,67 55,57 57,25 55,11 8h 65,12 62,84 61,13 59,31 60,78 58,65 9h 68,15 66,50 64,27 62,44 63,93 61,81 lOh 71,75 69,40 67,47 65,21 66,76 64,95 llh 74,02 72,26 70,10 68,42 69,53 67,72 12h 76,49 75,01 72,82 70,86 71,83 70,16

Hm = hydromorphone HC1, Nal = naloxone HC1; Values are averages of 6 measurements.

Example 6

Tablets F906/46 with a prolonged release matrix and of comparable composition asin example 3 but comprising 20 mg ethyl cellulose were prepared. These tablets were15 then subjected to different heat treatments.

F906/95B: F906/46 heat treated for 15 min at 55°C F906/95C: F906/46 heat treated for 45 min at 55°C WO 2011/141488 PCT/EP2011/057566 -96-

Tablets F906/46, F906/95B and F906/95C were then analyzed as regards in vitrorelease behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HC1 with pH 1.2). Aliquots5 of the dissolution media are withdrawn at the respective time points and analyzed by HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 14. 10

Table 14

Tablets F906/46 F9906/95B F906/95C Dissolutionmedium 0.1 N HCIpH 1.2 0.1 N HCI 0.1 N HCI Active tested Hm iiiii Hm iiiii Hm iliiiii lh 42,23 41,72 35,2 34,1 35,9 34,8 2h 57,26 57,35 48,8 47,8 49,8 48,9 3h 68,41 69,12 58,1 57,4 59,4 58,7 4h 89,71 89,87 64,5 64,0 65,4 65,0 5h 95,66 96,01 71,6 71,4 71,4 71,3 6h 96,21 96,69 77,2 77,3 77,8 77,8 7h 96,24 96,80 80,6 80,7 82,6 82,5 8h 96,29 96,70 85,6 85,7 85,6 85,5 9h 96,24 96,75 88,1 88,2 89,7 89,6 lOh 96,27 96,88 91,6 91,7 90,6 90,4 llh 96,38 96,87 93,4 93,7 93,1 93,4 12h 96,26 96,85 94,7 95,2 93,9 94,3

Hm = hydromorphone HC1, Nal = naloxone HC1; Values are averages of 6 measurements. 15 Example 7

Tablets of the composition as shown in table 15 were manufactured. WO 2011/141488 PCT/EP2011/057566 -97-

Table 15

Tablets iiiiiiiii F933/69 iiiiiiiii iieiii Ingredient Amount (mg) Amount(mg) Amount(mg) Amount (mg) Hydromorphone HC1 2.0 4.0 4.0 4.0 Naloxone HC1 4.0 2.0 4.0 12.0 Hydroxypropylcellulose 5.0 5.0 5.0 5.0 Stearyl alcohol 25.0 25.0 25.0 25.0 Ethyl cellulose N45 10.0 10.0 10.0 10.0 Lactose anhydrous 52.0 52.0 50.0 42.0 Talc 1.25 1.25 1.25 1.25 Magnesium Stearate 0.75 0.75 0.75 0.75 Total 100 100 100 100

Hydromorphone HC1 and naloxone HC1 were mixed with lactose anhydrous, stearyl5 alcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.Subsequently the blend was melt extruded using a heated twin screw extruder asdescribed above. 10 The granules were milled and the milled granules were blended with magnesiumstearate and talc in a tumbler mixer. Subsequently, the blended granules werecompressed into tablets. The tablets were then heat treated for 30 min at 55°C.

Tablets F933/67, F933/69, F933/71 and F933/73 were then analyzed as regards in 15 vitro release behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HC1 with pH 1.2). Aliquots WO 2011/141488 PCT/EP2011/057566 -98- of the dissolution media are withdrawn at the respective time points and analyzed by HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content of 5 active tested) in table 16.

Table 16

Tablets iiiiiiliiiiiiiii iiiiiiliiiiiiiii iiiiiiiiliilliiiiiii liiiiiiiiiiiiiiiiiii: Dissolutionmedium 0.1 N HCIpH 1.2 iiiiiiiiiiiiiiiiii:pH 1.2 iiiiiiiiiiiiiiiiii:pH 1.2 0.1 N HCIpH 1.2 Activetested Hm Nal Hm iiiii Hm iiiii Hm Nal lh 38,16 37,43 38,24 37,75 39,15 38,22 42,14 40,53 2h 52,62 51,72 53,18 52,23 53,69 52,54 57,09 55,52 3h 62,53 61,83 63,45 62,35 63,42 62,60 67,91 66,23 4h 70,09 69,43 71,23 70,26 70,94 70,02 75,35 73,88 5h 76,18 75,56 77,48 76,50 76,89 75,93 81,10 79,68 6h 81,03 80,48 82,50 81,63 81,66 80,68 85,90 84,79 7h 84,93 84,74 86,70 85,77 85,49 84,77 89,59 88,81 8h 88,38 88,30 89,90 88,98 88,63 87,76 92,33 91,74 9h 91,30 91,17 92,81 91,81 91,11 90,31 94,21 93,78 lOh 93,48 93,63 94,97 94,13 93,16 92,53 96,13 95,87 llh 95,36 95,66 96,71 96,03 94,67 93,84 97,31 97,29 12h 96,88 97,32 98,06 97,47 95,98 95,37 98,78 99,08

Hm = hydromorphone HC1, Nal = naloxone HC1; Values are averages of 6 measurements.

Example 8

Tablets F918/109 with a similar composition as in examples 1 to 7 weremanufactured and cured for 60 minutes at 55°C. They were stored for 1 month at 15 25°C and 60° relative humidity (RH) or for 1 month at 40°C and 75% RH. WO 2011/141488 PCT/EP2011/057566 -99-

Tablets F919/77 with a similar composition as in examples 1 to 7 were manufacturedcured for 30 minutes at 55°C. They were stored for 1 or 2 months at 40°C and 75%RH. 5 Tablets F918/109 and F919/77 were then analyzed either initially or after storage asregards in vitro release behavior using the Ph. European paddle method at 75 rpm in500 simulated gastric fluid (SGF) dissolution medium (0.1 N HC1 with pH 1.2).Aliquots of the dissolution media are withdrawn at the respective time points andanalyzed by HPLC at 220 nm. 10

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in tables 17 and 18.

Table 17

Tablets F918/109 F918/109 F918/109 Storage 1 month,25°C, 60% RH 1 month,40°C\ 75%RH Dissolutionmedium 0.1 N PH HCl 0.1 N HClpH 1.2 0.1 N HClpH 1.2 Active tested Hm iiiiii Hm iiiiii Hm Nal lh 32,11 31,09 32,85 31,47 35,03 33,83 2h 44,68 43,47 45,64 44,07 47,77 46,49 3h 53,86 52,54 54,62 52,89 56,80 55,47 4h 60,84 59,48 61,71 59,87 63,65 62,30 5h 66,90 65,53 67,71 65,84 69,30 67,88 6h 71,81 70,44 72,41 70,53 74,05 72,68 7h 75,90 74,65 76,58 74,83 78,18 76,77 8h 79,41 78,30 80,24 78,49 81,63 80,26 9h 82,63 81,70 83,33 81,67 84,72 83,36 lOh 85,28 84,41 85,86 84,19 87,31 86,03 llh 87,67 86,88 88,37 86,72 89,39 88,21 12h 89,71 89,22 90,14 88,69 91,13 90,18

Hm = hydromorphone HC1, Nal = naloxone HC1; Values are averages of 6 measurements. WO 2011/141488 PCT/EP2011/057566 - 100 -

Table 18

Tablets F919/77 F919/77 F919/77 Storage 1 month,40°C, 75%RH 1 month,40°C, 75%RH Dissolutionmedium 0.1 N PH HCl 0.1 N HClpH 1.2 0.1 N HClpH 1.2 Active tested Hm ililll Hm iiii Hm Nal lh 30,29 29,36 30,49 29,50 31,07 30,12 2h 42,41 41,49 41,88 40,81 42,69 41,64 3h 51,14 50,30 50,08 48,95 50,93 49,78 4h 58,01 57,25 56,59 55,39 57,40 56,41 5h 63,64 63,05 61,98 60,72 62,60 61,78 6h 68,66 68,05 66,43 65,29 67,16 66,22 7h 72,77 72,37 70,28 69,16 71,10 70,16 8h 76,30 76,10 73,60 72,66 74,52 73,49 9h 79,47 79,32 76,55 75,72 77,38 76,63 lOh 82,27 82,18 79,24 78,34 79,95 79,19 llh 84,62 84,57 81,50 80,82 82,36 81,72 12h 86,68 86,83 83,43 82,82 84,36 84,07

Hm = hydromorphone HC1, Nal = naloxone HC1; Values are averages of 6 measurements.

Example 9

Tablets F899/29, F899/39 and F908/93 were produced similarly to examples 1 to 8. 10 Subsequently, tablets F899/29 and F899/39 were placed in Duma fos containers andstored for 1, 2 or 5 months at 25°C and 60% RH or at 40°C and 75% RH. TabletsF908/93 were placed either in PVC containers or in PVC coated PVdC blisters andstored for 1, 2 or 5 months at 25°C and 60% RH or at 40°C and 75% RH. 15 All tablets were tested either initially or after storage for total related substances. WO 2011/141488 PCT/EP2011/057566 - 101 -

The results are shown in tables 19 and 20.

Table 19

Tablets F899/29 F899/29 iiiiiiiiiiiiiiiii F899/29 Container Duma fos Duma fos Duma fos Duma fos Storage 25°C/60% RH 40°C/75% RH ilitiiiieii 40°C/75% RH Initial 0,05% 0.05% 0.16% 0.16% 1 month — 0.09% — 0.17% 2 months ___ 0.26% ___ 0.24% 5 months 0.17% 0.30% 0.10% 0.24%

Table 20

Tablet F908/93 F908/93 F908/93 F908/93 Container PVC PVC PVS/PVdC PVCVPVdC Storage 25°C/60% RH 40°C/75% RH 25°C/60% RH 40°C/75% RH Initial 0,10% 0.10% 0.10% 0.10% 1 month 0.21% 0.24% 0.40% 0.31% 2 months 0.25% 0.30% 0.65% 0.46% 5 months — 0.49% — 0.64%

Example 10

Tablets of the composition as shown in Table 21 were manufactured. WO 2011/141488 PCT/EP2011/057566 - 102 -

Table 21

Tablets 933/107B iiiiiiiiii F929/85B F929/79B Ingredient Amount(mg) Amount(mg) Amount (mg) Amount(mg) Hydromorphone HC1 4.00 4.00 4.00 4.00 Naloxone HC1 8.00 8.00 8.00 8.00 Hydroxypropylcellulose 5.00 5.00 5.00 5.00 Ethyl cellulose N45 15.0 15.0 15.0 15.0 Stearyl alcohol 25.0 25.0 25.0 25.0 Lactose anhydrous 46.0 46.0 46.0 46.0 Magnesium Stearate 1.25 1.25 1.25 1.25 Talcum 0.75 0.75 0.75 0.75 Total 105 105 105 105 Surelease E7-7050* 7.00 5.00 3.75 Opadry II brown* 2.30 2.50 3.75 Purified water** 28.0 20.0 15.0 Total 105 114.3 112.5 112.5 *The amount indicated refers to the amount of solids used. ** Evaporated during coating 5

Hydromorphone HC1 and naloxone HC1 were mixed with lactose anhydrous, stearylalcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.Subsequently the blend was melt extruded using a heated twin screw extruder as 10 described above. The milled granules were blended with magnesium stearate and talcin a tumbler mixer. Subsequently, the blended granules were compressed into tablets.The tablets were then heat treated for 45 min at 55°C. Subsequently the coatingswere applied. WO 2011/141488 PCT/EP2011/057566 - 103 -

Tablets F933/107B, F929/73B, F929/85B and F929/79B were then analyzed asregards in vitro release behavior using the Ph. European paddle method at 75 rpm in500 ml simulated gastric fluid (SGF) dissolution medium (0.1 N HCI with pH 1.2).Aliquots of the dissolution media are withdrawn at the respective time points and 5 analyzed by HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 22. 10 Table 22

Tablets F933/107B F929/73B F929/85B F929/79B Dissolutionmedium iiiiliiHiiiiipH 1.2 0.1 N HCIpH 1.2 0.1 N HCIpH 1.2 0.1 N PH HCI bbbriihhhhhhhhhhhh Active tested Hm iiiii Hm Nal Hm Nal Hm Nal lh 41,11 40,19 0,13 0,19 8,61 7,26 29,21 27,74 2h 56,10 55,15 0,81 0,65 17,89 15,80 43,70 41,98 3h 66,02 64,99 1,58 1,27 25,06 22,59 54,21 52,41 4h 73,90 73,07 2,55 1,97 31,14 28,42 62,18 60,40 5h 79,71 79,18 3,45 2,65 36,34 33,38 68,94 67,27 6h 84,28 83,60 5,08 3,95 41,15 38,09 74,37 72,63 7h 88,19 87,84 6,76 5,45 45,75 42,60 78,62 77,05 8h 91,29 91,03 8,56 7,05 50,55 47,25 82,91 81,37 9h 93,91 93,62 10,18 8,51 54,51 51,28 86,11 84,57 lOh 95,95 95,91 11,92 10,05 58,50 55,34 88,67 87,31 llh 97,67 98,06 13,56 11,62 61,91 58,80 91,23 90,11 12h 98,57 98,74 15,37 13,27 65,24 62,11 92,91 91,70

Hm = hydromorphone HCI, Nal = naloxone HCI; Values are averages of 6 measurements.

Example 11 15

Tablets of the composition as shown in Table 23 were manufactured. WO 2011/141488 PCT/EP2011/057566 - 104 -

Table 23

Tablets F94I/07B F929/91C F929/97C Ingredient Amount(mg) Amount(mg) Amount(mg) Hydromorphone HCI 4.00 4.00 4.00 Naloxone HCI 4.00 4.00 4.00 Hydroxypropylcellulose 5.00 5.00 5.00 Ethyl cellulose N45* 7.50 7.50 7.50 Stearyl alcohol 17.5 17.5 17.5 Lactose anhydrous 50.0 50.0 50.0 Magnesium Stearate 1.25 1.25 1.25 Talcum 0.75 0.75 0.75 Total 90 90 90 Surelease E7-7050* 7.50 10.0 Opadry II brown* 5.00 5.00 Purified water** 30.0 40.0 Total 90 102.5 105 *The amount indicated refers to the amount of solids used. ** Evaporated during coating 5

Hydromorphone HCI and naloxone HCI were mixed with lactose anhydrous, stearylalcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.Subsequently the blend was melt extruded using a heated twin screw extruder as10 described above. The milled granules were blended with magnesium stearate and talcin a tumbler mixer. Subsequently, the blended granules were compressed into tablets.The tablets were then heat treated for 45 min at 55°C. Subsequently the coatingswere applied. WO 2011/141488 PCT/EP2011/057566 - 105 -

Tablets F941/07B, F929/91C and F929/97C were then analyzed as regards in vitrorelease behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HC1 with pH 1.2). Aliquots5 of the dissolution media are withdrawn at the respective time points and analyzed by HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 24. 10

Table 24

Tablets F941/07B, F929/91C iiiiiiiiiiiiiii Dissolutionmedium 0.1 N HC1pH 1.2 0.1 N HC1 0.1 N HC1 Active tested Hm iiiii Hm iiiii Hm iliiiiiii lh 48,75 47,97 12,07 11,02 1,30 0,97 2h 65,20 64,34 25,71 24,46 4,46 3,51 3h 75,96 75,05 35,83 34,48 7,82 6,46 4h 83,03 82,25 44,13 42,68 11,81 10,09 5h 88,29 87,64 51,32 49,85 18,08 16,14 6h 92,21 91,60 57,86 56,41 28,52 26,46 7h 94,81 94,48 63,60 62,18 35,81 33,71 8h 96,53 96,01 68,42 66,99 41,92 39,79 9h 97,31 97,11 72,85 71,44 47,04 44,85 lOh 97,54 97,46 76,94 75,72 51,46 49,24 llh 97,75 97,82 79,73 78,48 55,40 53,22 12h 97,70 97,71 82,77 81,59 58,87 56,65

Hm = hydromorphone HC1, Nal = naloxone HC1; Values are averages of 6 measurements. 15 Tablets F929/91C and F929/97C were further evaluated with respect to their alcoholresistance. To this end in vitro release rates were determined using the Ph. Europeanpaddle method at 75 rpm in 500 ml simulated gastric fluid (SGF) dissolution medium WO 2011/141488 PCT/EP2011/057566 - 106 - (0.1 N HCI with pH 1.2) with 40% EtOH. Aliquots of the dissolution media arewithdrawn at the respective time points and analyzed by HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content of 5 active tested) in table 25.

Table 25

Tablets F929/91C F929/97C Dissolutionmedium iiilM; li HCI wEtOH 0.1 N 40% ICI w EtOH Active tested IHiilll Nal Hm Nal 15 min 1,16 0,78 0,00 0,00 30 min n.d. n.d. n.d. n.d. 45 min n.d. n.d. n.d. n.d. 60 min 12,07 11,02 1,30 0,97 90 min n.d. n.d. n.d. n.d. 120 min 25,71 24,46 4,46 3,51

Hm = hydromorphone HCI, Nal = naloxone HCI, 0.1 N HCI w 40% EtOH = 0.1 N HCI pH 1.2 with10 40% ethanol, n.d. = not determined

Example 12

Tablets of the composition as shown in Table 26 were manufactured. 15 WO 2011/141488 PCT/EP2011/057566 - 107 -

Table 26

Tablets F94I/60B F945/06 F944/86 F945/30 Ingredient Amount (mg) Amount(mg) Amount (mg) Amount(mg) Hydromorphone HC1 4.00 4.00 4.00 4.00 Naloxone HC1 2.00 2.00 8.00 8.00 Hydroxypropylcellulose 5.00 5.00 5.00 5.00 Ethyl cellulose N45 15.0 15.0 10.00 10.00 Stearyl alcohol 25.0 25.0 25.0 25.0 Lactose anhydrous 52.0 52.0 46.0 46.0 Magnesium Stearate 1.25 1.25 1.25 1.25 Talcum 0.75 0.75 0.75 0.75 Total 105 105 100 100 Surelease E7-7050* 12.0 7.50 Opadry II brown* 0.0 5.00 Purified water** 48.0 30.0 Total 105 117 100 112.5 *The amount indicated refers to the amount of solids used. ** Evaporated during coating 5

Hydromorphone HC1 and naloxone HC1 were mixed with lactose anhydrous, stearylalcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.Subsequently the blend was melt extruded using a heated twin screw extruder as 10 described above. The milled granules were blended with magnesium stearate and talcin a tumbler mixer. Subsequently, the blended granules were compressed into tablets.Tablets F941/60B were heat treated for 45 min at 55°C. Tablets F944/86 were heattreated for 30 min at 55°C. Subsequently the coatings were applied. WO 2011/141488 PCT/EP2011/057566 - 108 -

Tablets F941/60B, F945/06, F944/86 and F945/30 were then analyzed as regards invitro release behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HC1 with pH 1.2). Aliquotsof the dissolution media are withdrawn at the respective time points and analyzed by5 HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 27. 10 Table 27

Tablets F941/60B F945/06 F944/86 F945/30 Dissolutionmedium pH 1.2 0.1 N HCIpH 1.2 0.1 N HCIpH1.2 iliii HCI 2 Active tested Hm Nal Hm Nal Hm Nal liilii Nal lh 31,91 31,30 0,07 0,24 42,34 41,05 10,12 8,50 2h 44,71 44,11 0,00 0,00 57,27 55,66 22,45 20,08 3h 53,54 52,76 0,00 0,15 67,40 65,71 31,05 28,40 4h 60,84 59,92 0,00 0,00 75,13 73,49 37,72 34,87 5h 66,54 65,73 0,00 0,00 80,39 79,05 43,69 40,70 6h 71,65 70,74 0,00 0,45 85,16 83,78 49,07 45,90 7h 75,81 74,88 0,00 0,86 88,91 87,48 53,65 50,47 8h 79,32 78,62 0,00 1,15 91,74 90,58 58,14 54,82 9h 82,63 81,74 0,00 1,31 94,30 93,04 61,81 58,69 lOh 85,47 84,67 0,00 1,50 96,59 95,76 65,50 62,36 llh 87,92 87,17 0,00 1,68 97,14 96,57 69,01 65,70 12h 89,64 88,92 0,00 1,87 97,82 97,39 72,00 68,89

Hm = hydromorphone HC1, Nal = naloxone HC1; Values are averages of 6 measurements.

Example 13 15 WO 2011/141488 PCT/EP2011/057566 - 109 -

Tablets of the composition as shown in Table 28 were manufactured.

Table 28

Tablets F941/07B F944/49 F929/103 Ingredient Amount(mg) Amount(mg) Amount(mg) Hydromorphone HCI 4.00 4.00 4.00 Naloxone HCI 4.00 4.00 4.00 Hydroxypropylcellulose 5.00 5.00 5.00 Ethyl cellulose N45 7.50 7.50 7.50 Stearyl alcohol 17.5 17.5 17.5 Lactose anhydrous 50.0 50.0 50.0 Magnesium Stearate 1.25 1.25 1.25 Talcum 0.75 0.75 0.75 Total 90 90 90 Eudragit RL30D* 5.00 14.0 Eudragit RS30D* 5.00 0.00 Talc 5.00 7.00 Triethyl citrate 2.00 2.80 Purified water** 44.8 62.6 Total 90 107 113.8 *The amount indicated refers to the amount of solids used.** Evaporated dining coating

Hydromorphone HCI and naloxone HCI were mixed with lactose anhydrous, stearyl10 alcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.Subsequently the blend was melt extruded using a heated twin screw extruder asdescribed above. The milled granules were blended with magnesium stearate and talc WO 2011/141488 PCT/EP2011/057566 - 110- in a tumbler mixer. Subsequently, the blended granules were compressed into tablets.Tablets were then heat treated for 45 min at 55°C. Subsequently the coatings wereapplied. 5 Tablets F941/07B, F944/49 and F929/103 were then analyzed as regards in vitrorelease behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HC1 with pH 1.2). Aliquotsof the dissolution media are withdrawn at the respective time points and analyzed byHPLC at 220 nm. 10

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 29.

Table 29

Tablets F941/07B iiiiiillglliiiii iiiiililiiiiiii Dissolutionmedium llliiiliHiliiipH 1.2 iiiilMBiiiiipH 1.2 iiiiii:l»ifiiipH 1.2 Active tested Hm Hm iiiii Hm iiiii lh 48,75 47,97 6,04 4,60 14,54 12,42 2h 65,20 64,34 24,83 21,75 39,00 35,75 3h 75,96 75,05 49,18 46,69 57,55 54,52 4h 83,03 82,25 61,94 59,94 70,09 67,76 5h 88,29 87,64 71,03 69,11 78,89 77,01 6h 92,21 91,60 78,22 76,31 85,20 83,57 7h 94,81 94,48 83,60 81,83 89,78 88,43 8h 96,53 96,01 87,96 86,66 93,23 92,16 9h 97,31 97,11 91,56 90,05 95,60 94,58 lOh 97,54 97,46 93,89 92,84 97,08 96,33 llh 97,75 97,82 95,84 95,06 98,16 97,36 12h 97,70 97,71 97,07 96,61 98,46 98,01

Hm = hydromorphone HC1, Nal = naloxone HC1; Values are averages of 6 measurements.

Example 14 WO 2011/141488 PCT/EP2011/057566 - Ill -

Tablets of the composition as shown in Table 30 were manufactured.

Table 30 5

Tablets F944/90 F944/101D Ingredient Amount(mg) Amount(mg) Hydromorphone HC1 4.00 4.00 Naloxone HC1 8.00 8.00 Hydroxypropylcellulose 5.00 5.00 Ethyl cellulose N45 7.50 7.50 Stearyl alcohol 17.5 17.5 Lactose anhydrous 46.0 46.0 Magnesium Stearate 1.25 1.25 Talcum 0.75 0.75 Total 90 90 Sure lease E7-7050* 7.50 Advantia Preferred*(Aquarius HPMC) 5.00 Purified water** 30.0 Total 90 102.5 *The amount indicated refers to the amount of solids used. ** Evaporated during coating

Hydromorphone HC1 and naloxone HC1 were mixed with lactose anhydrous, stearyl 10 alcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.Subsequently the blend was melt extruded using a heated twin screw extruder asdescribed above. The milled granules were blended with magnesium stearate and talcin a tumbler mixer. Subsequently, the blended granules were compressed into tablets. WO 2011/141488 PCT/EP2011/057566

Tablets were then heat treated for 30 min at 55°C. Subsequently the coatings wereapplied.

Tablets F944/90 and F944/101D were then analyzed as regards in vitro release 5 behavior using the Ph. European paddle method at 75 rpm in 500 ml simulatedgastric fluid (SGF) dissolution medium (0.1 N HCI with pH 1.2). Aliquots of thedissolution media are withdrawn at the respective time points and analyzed by HPLCat 220 nm. 10 The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 31.

Table 31

Tablets F944/90 F944/I01D Dissolutionmedium 0.1 N HCIpH 1.2 0.1 N HCI pH 1.2 Active tested Hm Nal Hm Nal lh 51,08 49,95 21,88 20,12 2h 68,55 67,18 38,23 36,15 3h 79,32 77,97 50,93 48,65 4h 86,47 85,26 60,36 58,15 5h 91,63 90,53 67,82 65,77 6h 94,86 94,04 74,74 72,72 7h 96,95 96,34 79,32 77,41 8h 97,90 97,48 83,90 82,14 9h 98,56 98,27 87,03 85,47 lOh 98,97 98,72 90,14 88,73 llh 98,86 98,71 92,32 91,10 12h 98,87 98,76 94,09 93,11 15 Hm = hydromorphone HCI, Nal = naloxone HCI; Values are averages of 6 measurements.

Tablets similar to F994/101D were manufactured. In tablets F994/101B, the weightgain by coating was about 5 mg. Tablets F994/101E were the same as tablets WO 2011/141488 PCT/EP2011/057566 - 113 - F994/101D except that they had been cured 30 minutes at 55°C after the coating hadbeen applied. These tablets were also tested for their in vitro release.

The in vitro release data is indicated as percentage (based on the label content of 5 active tested) in table 32.

Table 32

Tablets F944/I01B F944/101D F944/101E Dissolutionmedium iiiiiliililiiipH 1.2 iiiiiiliBiliiiipH 1.2 iiiiiiliBiliilpH 1.2 Active tested Hm iiili Hm iiili Hm iiili lh 33,91 32,23 21,88 20,12 15,55 13,05 2h 50,66 48,53 38,23 36,15 31,17 28,20 3h 62,06 59,71 50,93 48,65 42,66 39,67 4h 70,64 68,21 60,36 58,15 52,68 49,67 5h 77,57 75,20 67,82 65,77 60,06 56,91 6h 82,52 80,46 74,74 72,72 67,14 64,15 7h 86,96 84,87 79,32 77,41 72,70 69,83 8h 90,51 88,57 83,90 82,14 77,78 75,03 9h 92,75 90,85 87,03 85,47 82,36 79,77 lOh 94,99 93,44 90,14 88,73 85,18 82,76 llh 95,81 94,56 92,32 91,10 87,84 85,55 12h 97,02 95,83 94,09 93,11 90,58 88,36

Hm = hydromorphone HCl, Nal = naloxone HCl; Values are averages of 6 measurements.

Example 15

Tablets of the composition as shown in Table 33 were manufactured. 15 WO 2011/141488 PCT/EP2011/057566

Table 33

Tablets PN3450 iitiiiii F944/82 F945/69 Ingredient Amount(mg) Amount(mg) Amount (mg) Amount(mg) Amount (mg) Hydromorphone HC1 4.0 4.00 4.0 4.00 4.00 Naloxone HC1 8.0 8.00 8.0 8.00 8.00 Hydroxypropylcellulose 5.0 5.00 5.0 5.00 5.00 Stearyl alcohol 17.5 17.5 25.0 25.0 25.0 Ethyl cellulose N45 7.5 7.5 10.0 10.0 10.0 Lactose anhydrous 46.0 46.0 46.0 46.0 46.0 Talc 1.25 1.25 1.25 1.25 1.25 Magnesium Stearate 0.75 0.75 0.75 0.75 0.75 Total 90 90 100 100 100 Stearyl alcohol(extragranular) 15.00 15.00 0.00 Ethylcellulose N45(extragranular) 0.00 0.00 15.00 Total 90 105 100 115 115

Hydromorphone HC1 and naloxone HC1 were mixed with lactose anhydrous, stearyl5 alcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.Subsequently the blend was melt extruded using a heated twin screw extruder asdescribed above. 10 The milled granules were blended with magnesium stearate and talc and theadditional amount of extragranular stearyl alcohol or ethyl cellulose in a tumblermixer. Subsequently, the blended granules were compressed into tablets. The tabletswere then heat treated for 30 min at 55°C. WO 2011/141488 PCT/EP2011/057566 - 115 -

Tablets PN3450, PN3451, F944/78, F944/82 and F945/69 were then analyzed asregards in vitro release behavior using the Ph. European paddle method at 75 rpm in500 ml simulated gastric fluid (SGF) dissolution medium (0.1 N HCI with pH 1.2). 5 Aliquots of the dissolution media are withdrawn at the respective time points andanalyzed by HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 34. 10

Table 34 iTibiOi llieisilll BIIMililll BllllBiSlBBlB F945/69 Disso- liiiOii 0.1 N HCIpH 1.2 llloiflBCliB: BIBlO^liBBBB 0.1 N HCIpH 1.2 0.1 N HCIpH 1.2 ActiveridOdlt; |ii||| Hm llllllll Hm BliiBi Hm Ifillll Hm Ilillll lh 51,50 50,80 43,94 42.52 40,54 39,69 30,89 29,56 38,94 37,56 2h 68,10 67,60 59,69 57,94 54,82 53,92 42,72 41,12 53,24 55,65 3h 78,50 78,30 70,31 68,46 64,22 63,54 51,12 49,36 62,95 61,61 4h 85,50 85,60 77,61 75,77 71,72 71,11 57,95 56,13 70,34 68,94 5h 90,50 90,70 83,81 82,16 77,74 77,28 63,21 61,38 76,28 75,05 6h 93,90 94,30 88,25 86,65 82,11 81,72 67,88 65,91 81,31 80,03 7h 95,90 96,60 91,83 90,29 85,82 85,65 71,76 69,85 85,10 84,05 8h 96,90 97,90 94,57 93,06 89,19 89,24 75,34 73,46 88,53 87,47 9h 97,50 98,50 96,50 95,28 91,82 91,93 78,37 76,52 91,35 90,32 lOh 97,50 98,60 98,34 97,37 93,71 94,04 81,07 79,29 93,67 92,44 llh 97,00 98,30 99,36 98,52 95,19 95,72 83,52 81,76 95,31 94,47 12h 97,20 98,40 99,58 98,93 96,54 97,26 85,64 83,97 96,61 95,71

Hm = hydromorphone HCI, Nal = naloxone HCI; Values are averages of 6 measurements. 15

Example 16

Tablets of the composition as shown in Table 35 were manufactured. WO 2011/141488 PCT/EP2011/057566

Table 35

Tablets PN3642 PN3643 iilliiiii PN3645 Ingredient Amount(mg) Amount(mg) Amount(mg) Amount (mg) Hydromorphone HC1 4.00 4.00 4.00 4.00 Naloxone HC1 8.00 8.00 8.00 8.00 Hydroxypropylcellulose 5.00 5.00 5.00 5.00 Ethyl cellulose N45 7.50 7.50 15.0 15.0 Stearyl alcohol 17.5 17.5 25.0 25.0 Lactose anhydrous 52.0 52.0 46.0 46.0 Magnesium Stearate 0.75 0.75 0.75 0.75 Talcum 1.25 1.25 1.25 1.25 Total 90 90 105 105 Sure lease E7-19030* 5.00 6.00 5.00 9.00 Opadry II brown* 5.00 4.00 5.00 6.00 Purified water** 20.0 24.0 20.0 36.0 Total 100 100 115 120 *The amount indicated refers to the amount of solids used. 5 ** Evaporated during coating

Hydromorphone HC1 and naloxone HC1 were mixed with lactose anhydrous, stearylalcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min. 10 Subsequently the blend was melt extruded using a heated twin screw extruder asdescribed above. The milled granules were blended with magnesium stearate and talcin a tumbler mixer. Subsequently, the blended granules were compressed into tablets.The tablets were then heat treated for 60 min at 55°C. Subsequently the coatingswere applied with Manesty air atomised spray fitted with a 1.2 mm nozzle adjusted 15 to give an even spray pattern and located approximately 15 cm from tablet bed. WO 2011/141488 PCT/EP2011/057566 - 117 -

Atomising air pressure 1.8 bar

Fan width air pressure 2.0 bar

Inlet air temperature 52° C

Outlet air temperature 40-45°C

Air flow 350 m3/hr

Drum speed 20 rpm

Spray rate ca. 6-10 g/min

Cabinet depression -50

Wall thickness of silicon tubing 1.6mm

Bore of silicon tubing 4.8mm

Tablets PN3642, PN3643, PN 3644 and PN3645 were then analyzed as regards invitro release behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HCl with pH 1.2). Aliquotsof the dissolution media are withdrawn at the respective time points and analyzed byHPEC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 36. WO 2011/141488 PCT/EP2011/057566

Table 36

Tablets PN3642 PN3643 PN3644 PN3645 Dissolutionmedium 0.1 N HClpH 1.2 0.1 N HClpH 1.2 0.1 N HClpH 1.2 0.1 N HClpH 1.2 Active tested Hm Nal Hm Nal Hm Nal Hm Nal lh 30,14 28,16 16,15 13,62 23,29 21,81 12,70 10,75 2h 49,65 47,91 35,51 32,66 38,00 36,72 26,59 24,45 3h 63,09 61,54 48,58 45,95 48,11 46,87 36,40 34,25 4h 72,95 71,53 58,85 56,36 55,98 54,76 44,48 42,37 5h 80,56 79,42 67,19 64,83 62,40 61,34 51,12 49,13 6h 86,32 85,32 74,14 71,99 68,00 67,04 56,94 54,86 7h 90,74 89,90 79,91 77,93 72,67 71,84 62,26 60,16 8h 93,79 93,27 84,68 82,84 76,69 76,04 66,72 64,85 9h 95,94 95,81 88,57 87,10 80,26 79,73 70,73 68,92 lOh 97,59 97,63 91,68 90,47 83,28 82,73 74,08 72,62 llh 98,31 98,63 94,10 93,30 86,00 85,59 77,48 75,82 12h 98,77 99,28 96,05 95,31 88,08 87,94 80,30 78,70

Hm = hydromorphone HCl, Nal = naloxone HCl. Values are averages of 6 measurements.

Tablets PN3642, PN3643, PN3644, PN3645 were further evaluated with respect totheir alcohol resistance. To this end in vitro release rates were determined using thePh. European paddle method at 75 rpm in 500 ml simulated gastric fluid (SGF)dissolution medium (0.1 N HCl with pH 1.2) with 40% EtOH. Aliquots of the 10 dissolution media are withdrawn at the respective time points and analyzed by HPLCat 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 37. 15 WO 2011/141488 PCT/EP2011/057566

Table 37

Tablets PN3642 PN3643 PN3644 PN3645 Dissolutionmedium 0.1 N HClpH 1.2 0.1 N HClpH 1.2 0.1 N HClpH 1.2 0.1 N HClpH 1.2 Active tested Hm Nal Hm Nal Hm Nal Hm Nal 15 min 3.8 2.7 1.8 1.4 4.0 2.7 1.4 0.7 30 min 10.2 8.6 5.6 4.5 9.5 8.2 2.1 1.9 45 min 16.7 14.6 9.9 8.3 15.3 13.8 4.6 3.8 60 mi 22.4 20.1 14.1 10.7 20.3 18.5 7.3 6.1 90 min 31.8 29.3 21.9 17.6 27.9 26.1 12.8 11.0 120 min 39.5 36.8 29.4 25.6 34.1 32.4 18.0 15.8

Hm = hydromorphone HCl, Nal = naloxone HCl, 0.1 N HCl w 40% EtOH = 0.1 N HCl pH 1.2 with5 40% ethanol, n.d. = not determined; Values are averages of 6 measurements.

Subsequently, tablets PN3642, PN3643, PN3644 and PN3645 were placed in PVC blisters and stored for 1, 2 and 3 months at 40°C and 75% RH. 10 All tablets were tested either initially or after storage for total related substances.

The results are shown in table 38.

Table 38

Tablets Ι·!· iiiiiiiii iiiiiiiii ιιβϋϋϋ Container PVC iiiiiiiiiiiii; iiiiiiiiiiiii iiiiiiiiiiiii; Storage iiitiiiii % RH Mitiiiii % RH iiiiiiiii % RH iiitiiiii % RH Initial 0.00% 0.00% 0.00% 0.08% 1 month 0.00% 0.05% 0.05% 0.00% 2 months 0.05% 0.00% 0.00% 0.00% 3 months 0.05% 0.05% 0.00% 0.05% WO 2011/141488 PCT/EP2011/057566 - 120 -

All tablets were tested either initially or after storage also for known relatedsubstances. These were noroxymorphone, hydromorphone N-oxide,pseudohydromorphone, naloxone N-oxide, pseudonaloxone. All known substanceswere either less than limit of detection or less than limit of quantification. 5

Example 17

Tablets corresponding to tablets of PN3462 were tested in an open label, single-dosestudy in 15 healthy subjects in the fasted state. The mean AUCt /h*pg/ml was 10 7675.9, the mean Cmax (pg/ml) was 664.6, the mean tmax was 1,9h.

Example 18

Formulations with a prolonged release coating were produced having the 15 composition of Table 39.

Table 39

Formulation A B Ingredient amount per capsule (mg) amount per capsule (mg) Microcrystallinecellulose (MCC) spheres 44.89 44.83 Hydromorphonehydrochloride 3.00 3.00 Naloxone hydrochloridedihydrate 1.65 1.65 Hydroxypropylmethylcellulose,polyethylene glycol filmcoating concentrate(Opadry YS-1 -7006,Clear) HS 1.63 1.68 WO 2011/141488 PCT/EP2011/057566 - 121 -

Aqueous ethylcellulosedispersion (Surelease) 4.66 6.04 Polyvinyl alcohol-polyethylene glycol graftcopolymer (Kollicoat IR)HS 0.34 0.45 Silicon dioxide NF(Syloid 244FP) NF 0.00 0.29 Purified Water USP q.s. q.s. Total -56 -58

For Formulation A, a solution is produced from hydromorphone and naloxonedissolved in water, Opadry Clear ® YS-1-7006. This solution is then sprayed on to amicrocrystalline cellulose (MXX) beads in a fluid bed dryer with a Wurster column.This produces an immediate-release (IR) bead. The IR bead is then sprayed withSure lease dispersion and Kollicoat IR in a fluid bed dryer with a Wurster column, aprolonged release bead is thus formed. The prolonged release beads are then sprayedwith Opadry Clear ® YS-1-7006 aqueous solution. Opadry protects the beads fromagglomeration. The beads are then encapsulated.

For Formulation B, a solution is produced from hydromorphone and naloxonedissolved in water, Opadry Clear ® YS-1-7006. This solution is then sprayed on to amicrocrystalline cellulose (MXX) beads in a fluid bed dryer with a Wurster column.This produces an immediate-release (IR) bead. The IR bead is then sprayed withSure lease dispersion and Kollicoat IR in a fluid bed dryer with a Wurster column, aprolonged release bead is thus formed. The prolonged release beads are then sprayedwith Opadry Clear ® YS-1-7006 aqueous solution. Opadry protects the beads fromagglomeration. The beads are then cured in a fluid bed dryer at 60°C outlettemperature with water spraying for 2 hours. The cured beads are then coated withOpadry Clear coating and mixed with silicon dioxide before encapsulation. WO 2011/141488 PCT/EP2011/057566 - 122-

Formulations A and B were then analyzed as regards in vitro release behavior usingthe USP basket method at 100 rpm in 000 ml simulated gastric fluid (SGF)dissolution medium (0.1 N HCI with pH 1.2) without enzyme. Aliquots of thedissolution media are withdrawn at the respective time points and analyzed byHPLC/UV.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 40. The values in the brackets indicate the range observedwhen measuring six tablets.

Table 40

Formulation A B Dissolutionmedium 0.1 N HCI pH 1.2 0.1 N HCI pH 1.2 Activetested Hm Nal Hm Nal lh 3 (2-3) 4 (3-5) 14(13-15) 15 (14-17) 2h 6 (5-7) 7 (7-8) 40 (39-42) 42 (41-43) 4h 20 (19-22) 12 (12-14) 68 (68-69) 69 (68-69) 8h 67 (65-68) 65 (63-66) 90 (89-90) 89 (88-90) 12h 87 (87-88) 85 (84-86) 97 (97-98) 97 (96-97) 16h 96 (95-96) 94 (93-95) 100 (99-101) 100 (99-101) 24h 102 (101-102) 101 (100-101) 103 (101-104) 103 (101-104)

Hm = hydromorphone HCI, Nal = naloxone HCI; values are the average of 6 measurements, values inthe brackest indicate the observed ranges.

The controlled release bead dosage forms form Formulation A and Formulation Bwere tested against Hydromorph Contin™ in single-dose pK study conducted underfasted conditions. A summary of the results is shown in Figure 2.

The results showed that all three formulations are bioequivalent. Formulation A ispreferred since it resulted in a tmax closest to that of the reference formulation. WO 2011/141488 PCT/EP2011/057566 - 123 -

Thus, when the dosage form according to the invention is in the form of a controlledrelease bead dosage form, it can be preferred that: (i) it is not subjected to a curingstep during manufacture, and (ii) it contains a weight ratio of hydromorphone tonaloxone of 2:1 (this was confirmed in a randomized, double-blind, placebo- 5 controlled, dose-ranging crossover study evaluating the effect of naloxone onintravenous hydromorphone abuse potential in healthy, non-dependent, opioid-experienced recreational drug users).

Example 19 10

This example shows an aqueous method of manufacturing. Granules of thecomposition as shown in Table 41 were manufactured.

Table 41 15

Granules F888/49 iilBliiiiiii Ingredient Amount(mg) Amount (mg) Hydromorphone HCI 2.0 Naloxone HCI 4.0 Ethyl cellulose 32.0 32.0 Eudragit NE 40 D* 23.0 23.0 Lactose Anhydrous 29.7 29.7 Purified Water** 11.5 11.5 Glycerol Monostearate 40-55% 2.3 2.3 Hypromellose 5.2mPas*** 0.23 0.23 Talc 5.8 5.8 Total*** 95.0 97.0 *The amount indicated refers to the amount of solids used**Water was removed from the granules by drying ***The amount refers to the weight of the granules without waterThe amounts refer to Hydromorphone HCI and Naloxone HCI. WO 2011/141488 PCT/EP2011/057566 - 124-

To obtain granules, Hypromellose 5.2 mPas was mixed with purified water untilfully dissolved using a Silverson high shear mixer. Then, whilst heating to 60°C andmaintaining mixing, glycerol monostearate 40-55% was added. When the mixturereached 60°C, heating was discontinued the mixture was cooled to <54°C withmixing being continued. Talc was added to the Eudragit NE 40 D dispersion whilestirring with a Heidolph paddle stirrer until fully dispersed. Then thehypromellose/glycerol monostearate dispersion was added to the Eudragit NE 40 D /talc dispersion with paddle stirring until a homogenous mixture was obtained.Stirring was maintained.

Ethyl cellulose, lactose, and hydromorphone hydrochloride or naloxonehydrochloride were placed into an Aeromatic Fielder S2 fluid bed granulator.

The conditions for fluidised bed granulation were as follows:

Apparatus: Aeromatic-Fielder S2 fluid bed granulator

Nozzle diameter:1.8mm

Spraying pressure: filter chamber

Air velocity (m/s):4-6

Inlet Air temperature (°C):30-40

Spray rate (g/minxkg): 30-50

Spray time (min):120

Product temperature (°C):24-26

The granules were then dried in the fluidized bed granulator at <28°C for 20-30minutes until the moisture content was below 2% w/w. The granules were then WO 2011/141488 PCT/EP2011/057566 - 125 - sieved using a Demi Finex sieve shakerwith a mesh size of 1mm. Subsequently thegranules were milled using a Quadro Comil 197S.

Granules were then pressed into tablets (see Table 42). 5

Table 42

Tablets iiiiiiii iiiiiiii; Ingredient Amount(mg) Amount(mg) Hydromorphone HCI Granules F888/49 95.0 Naloxone HCI Granules F888/55 97.0 Hydromorphone HCI 2.0 Naloxone HCI 4.0 Magnesiumstearate 1.0 1.0 Total 100 100

The amounts refer to Hydromorphone HCI and Naloxone HCI. 10 For obtaining the tablets, granules were blended with hydromorphone HCI, ornaloxone HCI and magnesium stearate using an Apex cone blender. Tablets wereobtained by compressing the blend using a Kilian rotary tablet press at a tablet speedof up to 50,000 tablets /hr. 15 Tablet F888/72 was cured in a convection oven at 60°C for 1 h. The cured tablet waslabeled F892/15.

Tablet F888/83 was cured at 60°C for 1 h. The cured tablet was labeled F892/16. WO 2011/141488 PCT/EP2011/057566 - 126 -

Tablets F892/15 and F892/16 were further subjected to prolonged storage under ICHstressed conditions, namely storage at 25°C/60%RH for 7 months.

For F892/15 the amount of total related substances was 0.28%. The amount ofhydromorphone N-oxide was 0.18%.

For F892/16 the amount of total related substances was 0.56%. The amount ofhydromorphone N-oxide was 0.14%. The amount of noroxymorphone was 0.10%.The amount of naloxone N-oxide was 0.06%.

Some embodiments of the invention relate to: 1. An oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and c) wherein the prolonged release pharmaceutical composition is heattreated. 2. A pharmaceutical composition according to 1, wherein the at least oneprolonged release material and hydromorphone or a pharmaceutically acceptable saltor derivative thereof and naloxone or a pharmaceutically acceptable salt or derivativethereof are combined such that a prolonged release matrix is formed. 3. A pharmaceutical composition according to 1 or 2, wherein a prolongedrelease coating is disposed on the active ingredients hydromorphone or a WO 2011/141488 PCT/EP2011/057566 - 127 - pharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof. 4. A pharmaceutical composition according to 1, 2 or 3, wherein hydro morphone or a pharmaceutically acceptable salt or derivative thereof andnaloxone or a pharmaceutically acceptable salt or derivative thereof are present in thepharmaceutical composition in a weight ratio of about 2:1, about 1:1, about 1:2 orabout 1:3. 5. Pharmaceutical composition according to 1, 2, 3 or 4, wherein the prolongedrelease material is selected from the group comprising hydrophobic or hydrophilicpolymers, protein-derived material, gums, substituted or unsubstituted hydrocarbons,digestible carbohydrates, fatty acids, fatty alcohols, glyceryl esters of fatty acids,natural and synthetic oils and waxes. 6. Pharmaceutical composition according to 5, wherein the prolonged releasematerial is a cellulose ether, a (meth)acrylic based (co)polymer and/or a fattyalcohol. 7. Pharmaceutical composition according to 6, wherein prolonged releasematerial is a neutral (meth)acrylic based (co)polymer, a hydrophobic cellulose etherand/or a fatty alcohol. 8. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6 or 7comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE asprolonged release material; WO 2011/141488 PCT/EP2011/057566 - 128 - b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix 9. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6 or 7,comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 10. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6 or 7,comprising at least: a) at least one fatty alcohol as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 - 129 - derivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 11. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6 or 7,comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one cellulose ether, preferably at least one hydrophobic celluloseether such as ethyl cellulose as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 12. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6 or 7,comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one fatty alcohol as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 - 130- derivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 13. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6 or 7,comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose and at least one fatty alcohol asprolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 14. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6 or 7,comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE, at leastone cellulose ether, preferably at least one hydrophobic cellulose ethersuch as ethyl cellulose and at least one fatty alcohol as prolongedrelease materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 - 131 - derivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 15. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein the pharmaceutical composition comprises additionally atleast one filler, at least one lubricant, at least one binder, at least one release ratemodifiers, at least one spheronising agent and/or at least one anti-tacking agent 16. Pharmaceutical composition according to 15, wherein said filler is anhydrouslactose. 17. Pharmaceutical composition according to 15 or 16, wherein magnesiumstearate and/or talc are used as lubricants. 18. Pharmaceutical composition according to 15, 16 or 17, whereinhydroxypropyl cellulose is used as binder. 19. Pharmaceutical composition according to 15, 16, 17 or 18, whereinhydroxypropylmethyl cellulose, an anionic (meth)acrylic acid (co)polymer such asEudragit RSPO and/or Xanthan gum are used release rate modifiers. 20. Pharmaceutical composition according to 15, 16, 17, 18 or 19, whereinmicrocrystalline cellulose is used as spheronising agent. 21. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 , wherein heat treatment takes place at atemperature in the range of about 30°C to about 95°C and for a time in the range ofabout 10 min to about 3 hours.. WO 2011/141488 PCT/EP2011/057566 - 132- 22. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21, wherein the composition releases thepharmaceutically active agents with the following in vitro release rate whenmeasured using the Ph. Eur. paddle method in 500 or 900 ml of Simulated GastricFluid at 75 or 100 rpm at 37 degrees C°: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agents, at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents. 23. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22, wherein the ratio of the amount of thepharmaceutically active agents released after 0.5, 1 or 2 hours of in vitro dissolutionof the dosage form in 500 ot 900 ml of Simulated Gastric Fluid with up to 40%ethanol using the Ph. Eur. paddle method at 100 rpm at 37 degrees C° compared tothe amount of the active agents released after 0.5, 1 or 2 hours of in vitro dissolutionof the dosage form in 500 or 900 ml of Simulated Gastric Fluid with 0% ethanolusing the Ph. Eur. paddle method at 75 or 100 rpm at 37 degrees C° is about 2:1 orless, is about 1.5:1 or less, is about 1:1 or less, about 1:1.2 or less, about 1:1.4 or less,about 1:1.6 or less, about 1:1.8 or less, about 1:2 or less, about 1:2.5 or less about 1:3or less or about 1:5 or less. WO 2011/141488 PCT/EP2011/057566 - 133 - 24. Pharmaceutical composition according to to any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21,22 or 23, comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions releases the pharmaceutically active agents withsubstantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions. 25. Pharmaceutical composition according to to any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 composition comprising atleast: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions has less than 3% of total substances related tohydromorphone or a pharmaceutically acceptable salt or derivativethereof and/or related to naloxone or a pharmaceutically acceptablesalt or derivative thereof. 26. An oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable salt WO 2011/141488 PCT/EP2011/057566 - 134- or derivative thereof with hydromorphone or a pharmaceuticallyacceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof being present inthe pharmaceutical composition in a weight ratio in a range of about2:1 to about 1:3, preferably of about 2:1, about 1:1, about 1:2 or about1:3. 27. Pharmaceutical composition according to 26, wherein the prolonged releasepharmaceutical composition is heat treated. 28. Pharmaceutical composition according to 26 or 27, wherein the at least oneprolonged release material and hydromorphone or a pharmaceutically acceptable saltor derivative thereof and naloxone or a pharmaceutically acceptable salt or derivativethereof are combined such that a prolonged release matrix is formed. 29. Pharmaceutical composition according to 26, 27 or 28, wherein a prolongedrelease coating is disposed on the active ingredients hydromorphone or apharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof. 30. Pharmaceutical composition according to 26, 27, 28 or 29, wherein theprolonged release material is selected from the group comprising hydrophobic orhydrophilic polymers, protein-derived material, gums, substituted or unsubstitutedhydrocarbons, digestible carbohydrates, fatty acids, fatty alcohols, glyceryl esters offatty acids, natural and synthetic oil and waxes. WO 2011/141488 PCT/EP2011/057566 - 135 - 31. Pharmaceutical composition according to 30, wherein the prolonged releasematerial is a cellulose ether, a (meth)acrylic based (co)polymer and/or a fattyalcohol. 32. Pharmaceutical composition according to 31, wherein prolonged releasematerial is a neutral (meth)acrylic based (co)polymer, a hydrophobic cellulose etherand/or a fatty alcohol. 33. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31 or 32,comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE asprolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix 34. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31 or 32,comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein WO 2011/141488 PCT/EP2011/057566 - 136- c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 35. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31 or 32,comprising at least: a) at least one fatty alcohol as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 36. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31 or 32,comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one cellulose ether, preferably at least one hydrophobic celluloseether such as ethyl cellulose as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 - 137- derivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 37. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31 or 32,comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one fatty alcohol as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 38. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31 or 32,comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose and at least one fatty alcohol asprolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. WO 2011/141488 PCT/EP2011/057566 - 138- 39. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31 or 32,comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE, at leastone cellulose ether, preferably at least one hydrophobic cellulose ethersuch as ethyl cellulose and at least one fatty alcohol as prolongedrelease materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 40. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 or 39, wherein the pharmaceutical composition comprisesadditionally at least one filler, at least one lubricant, at least one binder, at least onerelease rate modifiers, at least one spheronising agent and/or at least one anti-tackingagent 41. Pharmaceutical composition according to 40, wherein said filler is anhydrouslactose. 42. Pharmaceutical composition according to 40 or 41, wherein magnesiumstearate and/or talc are used as lubricants. WO 2011/141488 PCT/EP2011/057566 - 139- 43. Pharmaceutical composition according to 40, 41 or 42, whereinhydroxypropyl cellulose is used as binder. 44. Pharmaceutical composition according to 40, 41, 42 or 43, whereinhydroxypropylmethyl cellulose, an anionic (meth)acrylic acid (co)polymer such asEudragit RSPO and/or Xanthan gum are used release rate modifiers. 45. Pharmaceutical composition according to 40, 41, 42, 43 or 44, whereinmicrocrystalline cellulose is used as spheronising agent. 46. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 39, 40, 41, 42, 43, 44 or 45, wherein heat treatment takesplace at a temperature in the range of about 30°C to about 95°C and for a time in therange of about 10 min to about 3 hours. 47. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 39, 40, 41, 42, 43, 44, 45 or 46, wherein the compositionreleases the pharmaceutically active agents with the following in vitro release ratewhen measured using the Ph. Eur. paddle method in 500 or 900 ml of SimulatedGastric Fluid at 75 or 100 rpm at 37 degrees C°: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agents, at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents. WO 2011/141488 PCT/EP2011/057566 - 140 - 48. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 39, 40, 41, 42, 43, 44, 45, 46 or 47, wherein the ratio of theamount of the pharmaceutically active agents released after 0.5, 1 or 2 hours of invitro dissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid withup to 40% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37 degreesC° compared to the amount of the active agents released after 0.5, 1 or 2 hours of invitro dissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid with0% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37 degrees C° isabout 2:1 or less, is about 1.5:1 or less, is about 1:1 or less, about 1:1.2 or less, about1:1.4 or less, about 1:1.6 or less, about 1:1.8 or less, about 1:2 or less, about 1:2.5 orless about 1:3 or less or about 1:5 or less. 49. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 39, 40, 41, 42, 43, 44 ,45, 46, 47 or 48, comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions releases the pharmaceutically active agents withsubstantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions. 50. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 39, 40, 41, 42, 43, 44 ,45, 46, 47, 48 or 49, comprising atleast: a) at least one prolonged release material; WO 2011/141488 PCT/EP2011/057566 - 141 - b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions has less than 3% of total substances related tohydromorphone or a pharmaceutically acceptable salt or derivativethereof and/or related to naloxone or a pharmaceutically acceptablesalt or derivative thereof 51. An oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the at least one prolonged release material and hydromorphone or apharmaceutically acceptable salt or derivative thereof and naloxone ora pharmaceutically acceptable salt or derivative thereof are combinedsuch that a prolonged release matrix is formed. 52. A pharmaceutical composition according to 51, wherein the prolonged releasepharmaceutical composition is heat treated. 53. A pharmaceutical composition according to 51 or 52, wherein a prolonged release coating is disposed on the active ingredientshydro morphone or a pharmaceutically acceptable salt or derivative thereof andnaloxone or a pharmaceutically acceptable salt or derivative thereof. WO 2011/141488 PCT/EP2011/057566 - 142- 54. A pharmaceutical composition according to 51, 52 or 53, whereinhydro morphone or a pharmaceutically acceptable salt or derivative thereof andnaloxone or a pharmaceutically acceptable salt or derivative thereof are present in thepharmaceutical composition in a weight ratio of about 2:1, about 1:1, about 1:2 orabout 1:3. 55. Pharmaceutical composition according to 51, 52, 53 or 54 wherein theprolonged release material is selected from the group comprising hydrophobic orhydrophilic polymers, protein-derived material, gums, substituted or unsubstitutedhydrocarbons, digestible carbohydrates, fatty acids, fatty alcohols, glyceryl esters offatty acids, natural and synthetic oil and waxes. 56. Pharmaceutical composition according to 55, wherein the prolonged releasematerial is a cellulose ether, a (meth)acrylic based (co)polymer and/or a fattyalcohol. 57. Pharmaceutical composition according to 56, wherein prolonged releasematerial is a neutral (meth)acrylic based (co)polymer, a hydrophobic cellulose etherand/or a fatty alcohol. 58. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56 or 57comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE asprolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein WO 2011/141488 PCT/EP2011/057566 - 143 - c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix 59. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57 or58 comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 60. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57 or58 comprising at least: a) at least one fatty alcohol as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. WO 2011/141488 PCT/EP2011/057566 - 144- 61. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57 or58 comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one cellulose ether, preferably at least one hydrophobic celluloseether such as ethyl cellulose as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 62. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57 or58 comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one fatty alcohol as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. WO 2011/141488 PCT/EP2011/057566 - 145 - 63. Pharmaceutical composition according to any of 49, 50, 51, 52, 53, 54 or 55,comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose and at least one fatty alcohol asprolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 64. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57 or58 comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE, at leastone cellulose ether, preferably at least one hydrophobic cellulose ethersuch as ethyl cellulose and at least one fatty alcohol as prolongedrelease materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. WO 2011/141488 PCT/EP2011/057566 - 146- 65. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63 or 64 wherein the pharmaceutical composition comprisesadditionally at least one filler, at least one lubricant, at least one binder, at least onerelease rate modifiers, at least one spheronising agent and/or at least one anti-tackingagent 66. Pharmaceutical composition according to 65, wherein said filler is anhydrouslactose. 67. Pharmaceutical composition according to 65 or 66, wherein magnesiumstearate and/or talc are used as lubricants. 68. Pharmaceutical composition according to 65, 66 or 67, whereinhydroxypropyl cellulose is used as binder. 69. Pharmaceutical composition according to 65, 66, 67 or 68, whereinhydroxypropylmethyl cellulose, an anionic (meth)acrylic acid (co)polymer such asEudragit RSPO and/or Xanthan gum are used release rate modifiers. 70. Pharmaceutical composition according to 65, 66, 67, 68, 6 8or 69, whereinmicrocrystalline cellulose is used as spheronising agent. 71. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 or 70, wherein heat treatment takesplace at a temperature in the range of about 30°C to about 95°C and for a time in therange of about 10 min to about 3 hours. WO 2011/141488 PCT/EP2011/057566 - 147- 72. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 or 71, wherein the compositionreleases the pharmaceutically active agents with the following in vitro release ratewhen measured using the Ph. Eur. paddle method in 500 or 900 ml of SimulatedGastric Fluid at 75 or 100 rpm at 37 degrees C°: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agents, at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents. 73. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 or 72 wherein the ratio of theamount of the pharmaceutically active agents released after 0.5, 1 or 2 hours of invitro dissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid withup to 40% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37 degreesC° compared to the amount of the active agents released after 0.5, 1 or 2 hours of invitro dissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid with0% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37 degrees C° isabout 2:1 or less, is about 1.5:1 or less, is about 1:1 or less, about 1:1.2 or less, about1:1.4 or less, about 1:1.6 or less, about 1:1.8 or less, about 1:2 or less, about 1:2.5 orless about 1:3 or less or about 1:5 or less. 74. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72 or 73, comprising at least: WO 2011/141488 PCT/EP2011/057566 - 148 - a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions releases the pharmaceutically active agents withsubstantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions. 75. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73 or 74, compositioncomprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions has less than 3% of total substances related tohydromorphone or a pharmaceutically acceptable salt or derivativethereof and/or related to naloxone or a pharmaceutically acceptablesalt or derivative thereof 76. An oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition provides alcohol resistance. WO 2011/141488 PCT/EP2011/057566 - 149 - 77. A pharmaceutical composition according to 76, wherein the prolonged releasepharmaceutical composition is heat treated. 78. A pharmaceutical composition according to 76 or 77, wherein the at least oneprolonged release material and hydromorphone or a pharmaceutically acceptable saltor derivative thereof and naloxone or a pharmaceutically acceptable salt or derivativethereof are combined such that a prolonged release matrix is formed. 79. A pharmaceutical composition according to 76, 77 or 78, wherein a prolongedrelease coating is disposed on the active ingredients hydromorphone or apharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof 80. A pharmaceutical composition according to 76, 77, 78 or 79, whereinhydro morphone or a pharmaceutically acceptable salt or derivative thereof andnaloxone or a pharmaceutically acceptable salt or derivative thereof are present in thepharmaceutical composition in a weight ratio of about 2:1, about 1:1, about 1:2 orabout 1:3. 81. Pharmaceutical composition according to 76, 77, 78, 79 or 80 wherein theprolonged release material is selected from the group comprising hydrophobic orhydrophilic polymers, protein-derived material, gums, substituted or unsubstitutedhydrocarbons, digestible carbohydrates, fatty acids, fatty alcohols, glyceryl esters offatty acids, natural and synthetic oil and waxes. WO 2011/141488 PCT/EP2011/057566 - 150 - 82. Pharmaceutical composition according to 81, wherein the prolonged releasematerial is a cellulose ether, a (meth)acrylic based (co)polymer and/or a fattyalcohol. 83. Pharmaceutical composition according to 82, wherein prolonged releasematerial is a neutral (meth)acrylic based (co)polymer, a hydrophobic cellulose etherand/or a fatty alcohol. 84. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82 or83, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE asprolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix 85. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82 or83, comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein WO 2011/141488 PCT/EP2011/057566 - 151 - c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 86. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82 or83, comprising at least: a) at least one fatty alcohol as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 87. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82 or83, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one cellulose ether, preferably at least one hydrophobic celluloseether such as ethyl cellulose as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 - 152 - derivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 88. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82 or83, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one fatty alcohol as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 89. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82 or83, comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose and at least one fatty alcohol asprolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. WO 2011/141488 PCT/EP2011/057566 - 153 - 90. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82 or83, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE, at leastone cellulose ether, preferably at least one hydrophobic cellulose ethersuch as ethyl cellulose and at least one fatty alcohol as prolongedrelease materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 91. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90 wherein the pharmaceutical composition comprisesadditionally at least one filler, at least one lubricant, at least one binder, at least onerelease rate modifiers, at least one spheronising agent and/or at least one anti-tackingagent 92. Pharmaceutical composition according to 91, wherein said filler is anhydrouslactose. 93. Pharmaceutical composition according to 91 or 92, wherein magnesiumstearate and/or talc are used as lubricants. WO 2011/141488 PCT/EP2011/057566 - 154- 94. Pharmaceutical composition according to 91, 92 or 93, whereinhydroxypropyl cellulose is used as binder. 95. Pharmaceutical composition according to 91, 92, 93 or 94, whereinhydroxypropylmethyl cellulose, an anionic (meth)acrylic acid (co)polymer such asEudragit RSPO and/or Xanthan gum are used release rate modifiers. 96. Pharmaceutical composition according to 91, 92, 93, 94 or 95, whereinmicrocrystalline cellulose is used as spheronising agent. 97. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 or 96 wherein heat treatment takesplace at a temperature in the range of about 30°C to about 95°C and for a time in therange of about 10 min to about 3 hours. 98. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96 or 97, wherein the compositionreleases the pharmaceutically active agents with the following in vitro release ratewhen measured using the Ph. Eur. paddle method in 500 or 900 ml of SimulatedGastric Fluid at 75 or 100 rpm at 37 degrees C°: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agent at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents. WO 2011/141488 PCT/EP2011/057566 - 155 - 99. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97 or 98, wherein the ratio of theamount of the pharmaceutically active agents released after 0.5, 1 or 2 hours of invitro dissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid withup to 40% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37 degreesC° compared to the amount of the active agents released after 0.5, 1 or 2 hours of invitro dissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid with0% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37 degrees C° isabout 2:1 or less, is about 1.5:1 or less, is about 1:1 or less, about 1:1.2 or less, about1:1.4 or less, about 1:1.6 or less, about 1:1.8 or less, about 1:2 or less, about 1:2.5 orless about 1:3 or less or about 1:5 or less. 100. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99, comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions releases the pharmaceutically active agents withsubstantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions. 101. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100, comprising atleast: a) at least one prolonged release material; WO 2011/141488 PCT/EP2011/057566 - 156 - b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions has less than 3% of total substances related tohydromorphone or a pharmaceutically acceptable salt or derivativethereof and/or related to naloxone or a pharmaceutically acceptablesalt or derivative thereof 102. An oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein the c) pharmaceutical composition after storage under stressed conditionsreleases the pharmaceutically active agents with substantially thesame release rate as before subjecting the pharmaceutical compositionto stressed conditions. 103. A pharmaceutical composition according to 102, wherein the prolongedrelease pharmaceutical composition is heat treated. 104. A pharmaceutical composition according to 102 or 103, wherein the at leastone prolonged release material and hydromorphone or a pharmaceutically acceptablesalt or derivative thereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined such that a prolonged release matrix is formed. WO 2011/141488 PCT/EP2011/057566 - 157 - 105. A pharmaceutical composition according to 102, 103 or 104, wherein aprolonged release coating is disposed on the active ingredients hydromorphone or apharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof. 106. A pharmaceutical composition according to 102, 103, 104 or 105, whereinhydro morphone or a pharmaceutically acceptable salt or derivative thereof andnaloxone or a pharmaceutically acceptable salt or derivative thereof are present in thepharmaceutical composition in a weight ratio of about 2:1, about 1:1, about 1:2 orabout 1:3. 107. Pharmaceutical composition according to 102, 103, 104, 105 or 106, whereinthe prolonged release material is selected from the group comprising hydrophobic orhydrophilic polymers, protein-derived material, gums, substituted or unsubstitutedhydrocarbons, digestible carbohydrates, fatty acids, fatty alcohols, glyceryl esters offatty acids, natural and synthetic oil and waxes. 108. Pharmaceutical composition according to 107, wherein the prolonged releasematerial is a cellulose ether, a (meth)acrylic based (co)polymer and/or a fattyalcohol. 109. Pharmaceutical composition according to 108, wherein prolonged releasematerial is a neutral (meth)acrylic based (co)polymer, a hydrophobic cellulose etherand/or a fatty alcohol. 110. Pharmaceutical composition according to any of 102, 103, 104, 105, 106, 107, 108 or 109, comprising at least: WO 2011/141488 PCT/EP2011/057566 - 158 - a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE asprolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix 111. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108 or 109, comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 112. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108 or 109, comprising at least: a) at least one fatty alcohol as prolonged release material; WO 2011/141488 PCT/EP2011/057566 - 159 - b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 113. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108 or 109, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one cellulose ether, preferably at least one hydrophobic celluloseether such as ethyl cellulose as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 114. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108 or 109, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one fatty alcohol as prolonged release materials; WO 2011/141488 PCT/EP2011/057566 - 160 - b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 115. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108 or 109, comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose and at least one fatty alcohol asprolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 116. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108 or 109, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE, at leastone cellulose ether, preferably at least one hydrophobic cellulose ethersuch as ethyl cellulose and at least one fatty alcohol as prolongedrelease matrix materials; WO 2011/141488 PCT/EP2011/057566 - 161 - b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 117. Pharmaceutical composition according to any of 102, 103, 104, 105, 106, 107, 108, 109, 111, 112, 113, 114, 115 or 116 wherein the pharmaceuticalcomposition comprises additionally at least one filler, at least one lubricant, at leastone binder, at least one release rate modifier, at least one spheronising agent and/orat least one anti-tacking agent 118. Pharmaceutical composition according to 117, wherein said filler isanhydrous lactose. 119. Pharmaceutical composition according to 117 or 118, wherein magnesiumstearate and/or talc are used as lubricants. 120. Pharmaceutical composition according to 117, 118 or 119, whereinhydroxypropyl cellulose is used as binder. 121. Pharmaceutical composition according to 117, 118, 119 or 120, whereinhydroxypropylmethyl cellulose, an anionic (meth)acrylic acid (co)polymer such asEudragit RSPO and/or Xanthan gum are used release rate modifiers. WO 2011/141488 PCT/EP2011/057566 - 162 - 122. Pharmaceutical composition according to 117, 118, 119, 120 or 121, whereinmicrocrystalline cellulose is used as spheronising agent. 123. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 or 122,wherein heat treatment takes place at a temperature in the range of about 30°C toabout 95°C and for a time in the range of about 10 min to about 3 hours. 124. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122 or123, wherein the composition releases the pharmaceutically active agents with thefollowing in vitro release rate when measured using the Ph. Eur. paddle method in500 or 900 ml of Simulated Gastric Fluid at 75 or 100 rpm at 37 degrees C°: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agents, at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents. 125. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123or 124, wherein the ratio of the amount of the pharmaceutically active agentsreleased after 0.5, 1 or 2 hours of in vitro dissolution of the dosage form in 500 or900 ml of Simulated Gastric Fluid with up to 40% ethanol using the Ph. Eur. paddlemethod at 75 100 rpm at 37 degrees C° compared to the amount of the active agents WO 2011/141488 PCT/EP2011/057566 - 163 - released after 0.5, 1 or 2 hours of in vitro dissolution of the dosage form in 500 or900 ml of Simulated Gastric Fluid with 0% ethanol using the Ph. Eur. paddle methodat 75 or 100 rpm at 37 degrees C° is about 2:1 or less, is about 1.5:1 or less, is about1:1 or less, about 1:1.2 or less, about 1:1.4 or less, about 1:1.6 or less, about 1:1.8 orless, about 1:2 or less, about 1:2.5 or less about 1:3 or less or about 1:5 or less. 126. Pharmaceutical composition according to any of 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123,124 or 125, comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein the c) pharmaceutical composition after storage under stressed conditionshas less than 3% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or related tonaloxone or a pharmaceutically acceptable salt or derivative thereof 127. An oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein the c) pharmaceutical composition after storage under stressed conditionshas less than 3% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or related tonaloxone or a pharmaceutically acceptable salt or derivative thereof WO 2011/141488 PCT/EP2011/057566 - 164- 128. Pharmaceutical composition according to 127, wherein the prolonged releasepharmaceutical composition is heat treated. 129. A pharmaceutical composition according to 127 or 128, wherein the at leastone prolonged release matrix material and hydromorphone or a the at least oneprolonged release material and hydromorphone or a pharmaceutically acceptable saltor derivative thereof and naloxone or a pharmaceutically acceptable salt or derivativethereof are combined such that a prolonged release matrix is formed. 130. A pharmaceutical composition according to 127, 128 or 129, wherein aprolonged release coating is disposed on the active ingredients hydromorphone or apharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof. 131. A pharmaceutical composition according to 127, 128, 129 or 130, whereinhydro morphone or a pharmaceutically acceptable salt or derivative thereof andnaloxone or a pharmaceutically acceptable salt or derivative thereof are present in thepharmaceutical composition in a weight ratio of about 2:1, about 1:1, about 1:2 orabout 1:3. 132. Pharmaceutical composition according to 127, 128, 129, 130 or 131, whereinthe prolonged release material is selected from the group comprising hydrophobic orhydrophilic polymers, protein-derived material, gums, substituted or unsubstitutedhydrocarbons, digestible carbohydrates, fatty acids, fatty alcohols, glyceryl esters offatty acids, natural and synthetic oil and waxes. WO 2011/141488 PCT/EP2011/057566 - 165 - 133. Pharmaceutical composition according to 132, wherein the prolonged releasematerial is a cellulose ether, a (meth)acrylic based (co)polymer and/or a fattyalcohol. 134. Pharmaceutical composition according to 133, wherein prolonged releasematerial is a neutral (meth)acrylic based (co)polymer, a hydrophobic cellulose etherand/or a fatty alcohol. 135. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133 or 134, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE asprolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix 136. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133 or 134, comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein WO 2011/141488 PCT/EP2011/057566 - 166 - c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 137. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133 or 134, comprising at least: a) at least one fatty alcohol as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 138. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133 or 134, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one cellulose ether, preferably at least one hydrophobic celluloseether such as ethyl cellulose as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 - 167 - derivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 139. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133 or 134, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one fatty alcohol as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 140. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133 or 134, comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose and at least one fatty alcohol asprolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. WO 2011/141488 PCT/EP2011/057566 - 168 - 141. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133 or 134, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE, at leastone cellulose ether, preferably at least one hydrophobic cellulose ethersuch as ethyl cellulose and at least one fatty alcohol as prolongedrelease materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 142. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133, 134, 135, 136, 137, 138, 139, 140, or 141 wherein the pharmaceuticalcomposition comprises additionally at least one filler, at least one lubricant, at leastone binder, at least one release rate modifier, at least one spheronising agent and/orat least one anti-tacking agent 143. Pharmaceutical composition according to 142, wherein said filler isanhydrous lactose. 144. Pharmaceutical composition according to 142 or 143, wherein magnesiumstearate and/or talc are used as lubricants. WO 2011/141488 PCT/EP2011/057566 - 169 - 145. Pharmaceutical composition according to 142, 143 or 144, whereinhydroxypropyl cellulose is used as binder. 146. Pharmaceutical composition according to 142, 143, 144 or 145, whereinhydroxypropylmethyl cellulose, an anionic (meth)acrylic acid (co)polymer such asEudragit RSPO and/or Xanthan gum are used release rate modifiers. 147. Pharmaceutical composition according to 142, 143, 144, 145 or 146, whereinmicrocrystalline cellulose is used as spheronising agent. 148. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, or 147wherein heat treatment takes place at a temperature in the range of about 30°C toabout 95°C and for a time in the range of about 10 min to about 3 hours 149. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147 or148, wherein the composition releases the pharmaceutically active agents with thefollowing in vitro release rate when measured using the Ph. Eur. paddle method in500 or 900 ml of Simulated Gastric Fluid at 75 or 100 rpm at 37 degrees C°: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agents, at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents. WO 2011/141488 PCT/EP2011/057566 - 170 - 150. Pharmaceutical composition according to any of 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148or 149 wherein the ratio of the amount of the pharmaceutically active agents releasedafter 0.5, 1 or 2 hours of in vitro dissolution of the dosage form in 500 or 900 ml ofSimulated Gastric Fluid with up to 40% ethanol using the Ph. Eur. paddle method at75 or 100 rpm at 37 degrees C° compared to the amount of the active agents releasedafter 0.5, 1 or 2 hours of in vitro dissolution of the dosage form in 500 or 900 ml ofSimulated Gastric Fluid with 0% ethanol using the Ph. Eur. paddle method at 75 or100 rpm at 37 degrees C° is about 2:1 or less, is about 1.5:1 or less, is about 1:1 orless, about 1:1.2 or less, about 1:1.4 or less, about 1:1.6 or less, about 1:1.8 or less,about 1:2 or less, about 1:2.5 or less about 1:3 or less or about 1:5 or less. 151. Pharmaceutical composition according to any of 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148,149 or 150, comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein the c) pharmaceutical composition after storage under stressed conditionsreleases the pharmaceutically active agents with substantially thesame release rate as before subjecting the pharmaceutical compositionto stressed conditions. 152. Pharmaceutical dosage form according to any of 1 to 151, whereinhydromorphone hydrochloride and naloxone hydrochloride are used. WO 2011/141488 PCT/EP2011/057566 - 171 - 153. Pharmaceutical dosage form according to any of 1 to 152, wherein about 1mg, about 2 mg, about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 24 mg,about 32 mg, about 40 mg, about 48 mg or about 64 mg hydromorphonehydrochloride are used. 154. Pharmaceutical dosage form according to any of 1 to 153 wherein about 1mg, about 2 mg, about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 24 mg,about 32 mg, about 48 mg, about 64 mg, about 96 mg, about 128 or about 256 mg ofnaloxone hydrochloride are used. 155. Method of manufacturing an oral prolonged release pharmaceuticalcomposition according to any of 1 to 154 comprising at least the steps of: a) producing granules comprising at least one prolonged release material,at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and at least naloxone or a pharmaceuticallyacceptable salt or derivative thereof, b) optionally selecting granules of step a) of substantially uniform size; c) optionally adding additional prolonged release material, d) compressing said granules of step a), b) or c) to obtain an oralprolonged release pharmaceutical composition in the form of a tablet; e) optionally heat treating said compressed granules; f) optionally disposing a prolonged release coatings either on thegranules of step a), b) or c) or on the monolithic composition obtainedin step d) or e); g) optionally curing the obtained composition. 156. Method according to 155, wherein step a) comprises the following steps: WO 2011/141488 PCT/EP2011/057566 - 172 - aa) blending a prolonged release material with at least hydromorphoneor a pharmaceutically acceptable salt or derivative thereof and atleast naloxone or a pharmaceutically acceptable salt or derivativethereof and optionally with a filler, a lubricant, a binder, a releaserate modifier, a spheronising agent and/or an anti-tacking agent; ab) wet or dry granulating said blend of step aa) to obtain granules; ac) drying said granules of step ab). 157. Method according to 156, wherein at least step ab) is performed by rotary pangranulation or fluidized bed granulation. 158. Method according to 155, wherein step a) comprises the following steps: aa) blending a prolonged release material with at least hydromorphoneor a pharmaceutically acceptable salt or derivative thereof and atleast naloxone or a pharmaceutically acceptable salt or derivativethereof and optionally with a spheronising agent, a filler, alubricant, a binder, a release rate modifier, and/or an anti-tackingagent; ab) extruding said blend of step aa) to obtain granules; and optionallyspheronising said granules of step ab); ac) drying said granules of step ab). 159. Method according to any of 155 to 158, wherein drying in step ac) takes placeat humidity in the range of about 0.5 % to about 5.0 % at a temperature in the rangeof about 20°C to about 90°C and for a time in the range of about 10 min to about 3hours. WO 2011/141488 PCT/EP2011/057566 - 173 - 160. Method according to any of 155 to 159, wherein granules of a mean size inthe range of about 100 gm to about 2 mm are selected in step b). 161. Method according to any of 155 to 160, wherein heat treatment takes place ata temperature in the range of about 30°C to about 95°C and for a time in the range ofabout 10 min to about 3 hours. 162. Method according to any of 155 to 160, wherein the prolonged releasematerial is selected from the group comprising hydrophobic or hydrophilic polymers,protein-derived material, gums, substituted or unsubstituted hydrocarbons, digestiblecarbohydrates, fatty acids, fatty alcohols, glyceryl esters of fatty acids, natural andsynthetic oil and waxes. 163. Method according to 162, wherein the prolonged release material is acellulose ether, a (meth)acrylic based (co)polymer and/or a fatty alcohol. 164. Method according to 163, wherein prolonged release material is a neutral(meth)acrylic based (co)polymer, a hydrophobic cellulose ether and/or a fattyalcohol. 165. Method according to any of claims 155 to 164, wherein the pharmaceuticalcomposition comprises additionally at least one filler, at least one lubricant, at leastone binder, at least one release relate modifier, at least one spheronising and at leastone anti-tacking agent. 166. Method according to any of 155 to 165, wherein said filler is anhydrouslactose. WO 2011/141488 PCT/EP2011/057566 - 174- 167. Method according to any of 155 to 166, wherein magnesium stearate and/ortalc are used as lubricants. 168. Method according to any of 155 to 167, wherein hydroxypropyl cellulose isused as binder. 169. Method according to any of 155 to 168, wherein hydroxypropylmethylcellulose, an anionic (meth)acrylic acid (co)polymer such as Eudragit RSPO and/orXanthan gum are used release rate modifiers. 170. Method according to any of 155 to 169, wherein microcrystalline cellulose isused as spheronising agent. 171. Method according to any of 155 to 170, wherein the composition releases thepharmaceutically active agents with the following in vitro release rate whenmeasured using the Ph. Eur. paddle method in 500 or 900 ml of Simulated GastricFluid at 75 or 100 rpm at 37 degrees C°: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agents, at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents. 172. Method according to any of 155 to 171, wherein the ratio of the amount of thepharmaceutically active agents released after 0.5, 1 or 2 hours of in vitro dissolution WO 2011/141488 PCT/EP2011/057566 - 175 - of the dosage form in 500 or 900 ml of Simulated Gastric Fluid with up to 40%ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37 degrees C°compared to the amount of the active agents released after 0.5, 1 or 2 hours of invitro dissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid with0% ethanol using the Ph. Eur. paddle method at 100 rpm at 37 degrees C° is about2:1 or less, is about 1.5:1 or less, is about 1:1 or less, about 1:1.2 or less, about 1:1.4or less, about 1:1.6 or less, about 1:1.8 or less, about 1:2 or less, about 1:2.5 or lessabout 1:3 or less or about 1:5 or less. 173. Method according to any of 155 to 172, wherein hydromorphonehydrochloride and naloxone hydrochloride are used. 174. Method according to any of 155 to 172, wherein about 1 mg, about 2 mg,about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 24 mg, about 32 mg, about40 mg, about 48 mg or about 64 mg hydromorphone hydrochloride are used. 175. Method according to any of 155 to 172, wherein about 1 mg, about 2 mg,about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 24 mg, about 32 mg, about48 mg, about 64 mg, about 96 mg, about 128 or about 256 mg of naloxonehydrochloride are used. 176. Pharmaceutical composition obtainable by a method according to any ofclaims 155 to 175. WO 2011/141488 PCT/EP2011/057566 - 176 -

CLAIMS 1. An oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof with hydromorphone or a pharmaceuticallyacceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof being present inthe pharmaceutical composition in a weight ratio of about 2:1, about 1:1, about 1:2 or about 1:3. 2. Pharmaceutical composition according to claim 1, wherein the at least oneprolonged release material and hydromorphone or a pharmaceutically acceptable saltor derivative thereof and naloxone or a pharmaceutically acceptable salt or derivativethereof are combined such that a prolonged release matrix is formed. 3. Pharmaceutical composition according to claim 2, wherein the prolongedrelease material is selected from the group comprising hydrophobic or hydrophilicpolymers, protein-derived material, gums, substituted or unsubstituted hydrocarbons,digestible carbohydrates, fatty acids, fatty alcohols, glyceryl esters of fatty acids,natural and synthetic oils and natural and synthetic waxes. 4. Pharmaceutical composition according to claim 3, wherein the prolongedrelease material is a cellulose ether, a (meth)acrylic based (co)polymer and/or a fattyalcohol. WO 2011/141488 PCT/EP2011/057566 - 177 - 5. Pharmaceutical composition according to claim 4, wherein prolonged releasematerial is a neutral (meth)acrylic based (co)polymer, a hydrophobic cellulose etherand/or a fatty alcohol. 6. Pharmaceutical composition according to any of claims 2, 3, 4, or 5, whereinthe pharmaceutical composition comprises additionally at least one filler, at least onelubricant, at least one binder, at least one release rate modifiers, at least onespheronising agent and/or at least one anti-tacking agent 7. Pharmaceutical composition according to claim 6, wherein said filler isanhydrous lactose. 8. Pharmaceutical composition according to claim 6 or 7, wherein magnesiumstearate and/or talc are used as lubricants. 9. Pharmaceutical composition according to claim 6, 7, or 8, whereinhydroxypropyl cellulose is used as binder. 10. Pharmaceutical composition according to any of claims 2, 3, 4, 5, 6, 7, 8 or 9,wherein the prolonged release matrix is heat treated. 11. Pharmaceutical composition according to any of claims 2, 3, 4, 5, 6, 7, 8, 9 or10, wherein heat treatment takes place at a temperature in the range of about 30°C toabout 95°C and for a time in the range of about 10 min to about 3 hours. 12. Pharmaceutical composition according to any of claims 2, 3, 4, 5, 6, 7, 8, 9,10 or 11, wherein a prolonged release coating is disposed on the prolonged releasematrix. WO 2011/141488 PCT/EP2011/057566 - 178- 13. Pharmaceutical composition according to any of to any of claims 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11 or 12, wherein the composition releases the pharmaceutically activeagents with the following in vitro release rate when measured using the Ph. Eur.paddle method in 500 or 900 ml of Simulated Gastric Fluid at 75 or 100 rpm at 37degrees C° is: at 1 h: 25 to 55% by weight of the pharmaceutically active agents, at 2 h: 45 to 75% by weight of the pharmaceutically active agents, at 3 h: 55 to 85% by weight of the pharmaceutically active agents, at 4 h: 60 to 90% by weight of the pharmaceutically active agents, at 6 h: 70 to 100% by weight of the pharmaceutically active agents, at 8 h: more than 85% by weight of the pharmaceutically active agents, at 10 h: more than 90% by weight of the pharmaceutically active agents. 14. Pharmaceutical composition according to any of claims 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12 or 13, wherein the ratio of the amount of the pharmaceutically activeagents released after 0.5, 1 or 2 hours of in vitro dissolution of the dosage form in500 or 900 ml of Simulated Gastric Fluid with up to 40% ethanol using the Ph. Eur.paddle method at 75 or 100 rpm at 37 degrees C° compared to the amount of theactive agents released after 0.5, 1 or 2 hours of in vitro dissolution of the dosageform in 500 or 900 ml of Simulated Gastric Fluid with 0% ethanol using the Ph. Eur.paddle method at 75 or 100 rpm at 37 degrees C° is about 2:1 or less, is about 1.5:1or less, is about 1:1 or less, about 1:1.2 or less, about 1:1.4 or less, about 1:1.6 orless, about 1:1.8 or less, about 1:2 or less, about 1:2.5 or less about 1:3 or less orabout 1:5 or less. WO 2011/141488 PCT/EP2011/057566 - 179 - 15. Pharmaceutical composition according to any of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, wherein the pharmaceutical composition after storage understressed conditions releases the pharmaceutically active agents with substantially thesame release rate as before subjecting the pharmaceutical composition to stressedconditions. 16. Pharmaceutical composition according to any of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the pharmaceutical composition after storage understressed conditions has less than 4% of total substances related to hydromorphone ora pharmaceutically acceptable salt or derivative thereof and/or related to naloxone ora pharmaceutically acceptable salt or derivative thereof 17. Pharmaceutical composition according to any of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, wherein the pharmaceutical composition is amultiparticulate formulation. 18. Pharmaceutical composition according to any of claims 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16 or 17, wherein hydromorphone hydrochloride and naloxonehydrochloride are used. 19. Pharmaceutical composition according to any of claims 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17 or 18, wherein hydromorphone hydrochloride is used atamounts equivalent to about 1 mg, about 2 mg, about 4 mg, about 8 mg, about 12mg, about 16 mg, about 24 mg, about 32 mg, about 40 mg, about 48 mg or about 64mg of anhydrous hydromorphone hydrochloride. WO 2011/141488 PCT/EP2011/057566 - 180- 20. Pharmaceutical composition according to any of claim 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein naloxone hydrochloride is used atamounts equivalent to about 1 mg, about 2 mg, about 4 mg, about 8 mg, about 12mg, about 16 mg, about 24 mg, about 32 mg, about 48 mg, about 64 mg, about 96mg, about 128 or about 256 mg of anhydrous naloxone hydrochloride. 21. Method of manufacturing an oral prolonged release pharmaceuticalcomposition according to any of claim 1 to 20 comprising at least the steps of: a) producing granules comprising at least one prolonged release material,at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and at least naloxone or a pharmaceuticallyacceptable salt or derivative thereof, b) optionally selecting granules of step a) of substantially uniform size; c) optionally adding additional prolonged release material; d) optionally compressing said granules of step a), b) or c) to obtain anoral prolonged release pharmaceutical composition in the form of atablet; e) optionally heat treating said compressed granules of steps a), b), c) ord); f) optionally coating with a prolonged releasing coating; g) optionally curing the composition. 22. Method according to claim 20, wherein step a) comprises the following steps: aa) blending a prolonged release material with at least hydromorphoneor a pharmaceutically acceptable salt or derivative thereof and atleast naloxone or a pharmaceutically acceptable salt or derivativethereof and optionally with at least one filler, at least one lubricant, WO 2011/141488 PCT/EP2011/057566 - 181 - at least one binder, at least one release rate modifier, at least onespheronising agent and/or at least one anti-tacking agent; ab) dry granulating or extruding said blend of step aa) to obtaingranules; 5 ac) optionally drying said granules of step ab). 23. Method according to any of claims 21 or 22, wherein heat treatment takesplace at a ambient humidity at a temperature in the range of about 40° C to about 90°C and for a time in the range of about 15 min to about 90 min. 10 24. Oral prolonged release pharmaceutical composition obtainable by a methodaccording to any of claims 21 to 23. 15 WO 2011/141488 PCT/EP2011/057566

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PHARMACEUTICAL COMPOSITIONS COMPRISINGHYDROMORPHONE AND NALOXONE

FIELD OF THE INVENTION

The present invention relates to prolonged release pharmaceutical dosage formscomprising hydromorphone or a pharmaceutically acceptable salt thereof andnaloxone or a pharmaceutically acceptable salt thereof, the manufacture thereof aswell as their use for administration to human beings.

BACKGROUND OF THE INVENTION

Prolonged release pharmaceutical dosage forms represent an important tool in amedical practioner’s armoury for treating diseases. One of the general benefitsgenerally attributed to prolonged release pharmaceutical dosage forms versusimmediate release pharmaceutical dosage forms includes increased patientcompliance as a consequence of reduced administration frequency.

There are various technologies available for obtaining prolonged release dosageforms. Prolonged release properties may be conveyed by so-called prolonged releasematrix systems, prolonged release coatings, osmotic dosage forms, multi-layereddosage forms etc.

When developing a prolonged release formulation, it is generally necessary to choosethe respective formulation technology with respect to the physico-chemical andphysiological properties of the pharmaceutically active agent(s) in question. Thismeans a substantial amount of work for the formulation specialist. This will be evenmore so where the dosage form comprises pharmaceutically active agents suchopioid agonists which theoretically can be abused, i.e. are not used for medicinalpurposes. WO 2011/141488 PCT/EP2011/057566 -2-

There is thus a continuing interest in pharmaceutical dosage forms which compriseopioid analgesic as pharmaceutically active agents, which provide prolonged releaseproperties and account for opioids’ potential of being abused.

SUMMARY OF THE INVENTION

It is an objective of the present invention to provide prolonged releasepharmaceutical dosage forms and methods of manufacture thereof.

These and other objectives as they will become apparent from the ensuingdescription are attained by the subject matter of the independent claims. Some of thepreferred embodiments are referred to by the dependent claims.

To some extent, the present invention is based on the finding that one can produceprolonged release pharmaceutical dosage forms comprising hydromorphone or apharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof combining various beneficialaspects. These include stability, alcohol tolerance, tamper resistance and the like.

In a first aspect, the present invention relates to an oral prolonged releasepharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition provides alcohol resistance. WO 2011/141488 PCT/EP2011/057566 -3-

In a second aspect, the present invention relates to an oral prolonged releasepharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are present in the pharmaceutical composition in aweight ratio in a range of about 2:1 to about 1:3, preferably of about2:1, about 1:1, about 1:2 or about 1:3.

In an embodiment of this second aspect, the composition may comprise a prolongedrelease matrix and/or a prolonged release coating.

In a third aspect, the present invention relates to an oral prolonged releasepharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions releases the pharmaceutically active agents withsubstantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In a fourth aspect, the present invention relates to an oral prolonged releasepharmaceutical composition comprising at least: WO 2011/141488 PCT/EP2011/057566 -4- a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions has less than 2.0% of total substances related tohydromorphone or a pharmaceutically acceptable salt or derivativethereof and/or related to naloxone or a pharmaceutically acceptablesalt or derivative thereof.

In a fifth aspect the present invention relates to an oral prolonged releasepharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the prolonged release pharmaceutical composition is heat treated.

In a first variation to this fifth aspect the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, c) wherein the at least one prolonged release material andhydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 -5- derivative thereof are combined such that a prolonged release matrixis formed; and d) wherein the prolonged release pharmaceutical composition is heattreated.

In a second variation to this fifth aspect the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; c) wherein the at least one prolonged release material andhydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined such that a prolonged release matrixis formed; and d) wherein the prolonged release pharmaceutical composition is heattreated; e) wherein at least one prolonged release material is applied in the formof a prolonged release coating which is disposed on the prolongedrelease matrix; and f) wherein the composition is optionally cured.

The prolonged release coating may either be disposed on each prolonged releasematrix if the prolonged release matrix is manufactured in the form of multi-particulates such as granules or it may be disposed on the formulation comprising theprolonged release matrix if e.g. prolonged release matrix multi-particulates such as WO 2011/141488 PCT/EP2011/057566 -6- granules are compressed into a tablet. The coating will then be disposed on themonolithic formulation.

In a first embodiment of this fifth aspect of the invention and its first and secondvariation, hydromorphone or a pharmaceutically acceptable salt or derivative thereofand naloxone or a pharmaceutically acceptable salt or derivative thereof are presentin the pharmaceutical composition in a weight ratio of about 2:1, about 1:1, about 1:2or about 1:3.

In addition or alternatively to this first embodiment, in a second embodiment of thisfifth aspect of the invention and its first and second variation, the pharmaceuticalcomposition may be alcohol resistant.

In addition or alternatively to this first or second embodiment, in a third embodimentof this fifth aspect of the invention and its first and second variation, thepharmaceutical composition may after storage under stressed conditions release thepharmaceutically active agents with substantially the same release rate as beforesubjecting the pharmaceutical composition to stressed conditions.

In addition or alternatively to this first, second or third embodiment, in a fourthembodiment of this fifth aspect of the invention and its first and second variation, thepharmaceutical composition may after storage under stressed conditions have lessthan 3.0 % of total substances related to hydromorphone or a pharmaceuticallyacceptable salt or derivative thereof and/or related to naloxone or a pharmaceuticallyacceptable salt or derivative thereof.

The invention also relates to a method of manufacturing an oral prolonged releasepharmaceutical composition comprising at least the steps of: WO 2011/141488 PCT/EP2011/057566 -7- a) producing granules comprising at least one prolonged release material,at least hydromorphone or a pharmaceutically acceptable or derivativesalt thereof and at least naloxone or a pharmaceutically acceptable saltor derivative thereof, b) optionally selecting granules of step a) of substantially uniform size; c) optionally compressing said granules of step a) or step b) to obtain anoral prolonged release pharmaceutical composition in the form of atablet, d) optionally heat treating said compressed granules of step c); e) optionally disposing a prolonged release coating either on the granulesof step b) which may have been heat treated or on the compressedgranules of step c) which may have been heat treated; f) optionally curing the composition.

In one embodiment, granules of step a) are manufactured by wet or dry granulation.In another embodiment, the granules are obtained by wet or melt extrusion.

In one embodiment, the granules are optionally screened in order to select granulesof substantially uniform size. For example, granules may be selected to have a meansize in the range of about 100 pm to about 2 mm, more preferably in the range ofabout 100 pm to about 1 mm.

Another aspect of the present invention relates to prolonged release pharmaceuticalcompositions as they are obtainable by methods in accordance with the invention.

Such pharmaceutical compositions may be alcohol resistant as described hereinafter.They may also provide physical and chemical stability. WO 2011/141488 PCT/EP2011/057566 -8-

The pharmaceutical compositions may be used for treating moderate to severe pain,in particular cancer pain, neuropathic pain, visceral pain or bone pain. When used fortreating these types of pain, the pharmaceutical compositions may beneficiallyinfluence side effects such as constipation, urinary retention, breath depression andbowel function as they may occur when using only hydromorphone or apharmaceutically acceptable salt or derivative thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention as illustratively described in the following may suitably bepracticed in the absence of any element or elements, limitation or limitations, notspecifically disclosed herein.

The present invention will be described with respect to particular embodiments andwith reference to certain figures but the invention is not limited thereto but only bythe claims. Terms as set forth hereinafter are generally to be understood in theircommon sense unless indicated otherwise.

Where the term “comprising” is used in the present description and claims, it doesnot exclude other elements. For the purposes of the present invention, the term“consisting of’ is considered to be a preferred embodiment of the term “comprisingof’. If hereinafter a group is defined to comprise at least a certain number ofembodiments, this is also to be understood to disclose a group which preferablyconsists only of these embodiments.

Where an indefinite or definite article is used when referring to a singular noun, e.g.“a”, “an” or “the”, this includes a plural of that noun unless something else isspecifically stated. WO 2011/141488 PCT/EP2011/057566 -9-

In the context of the present invention the terms “about” or “approximately” denotean interval of accuracy that the person skilled in the art will understand to still ensurethe technical effect of the feature in question. The term typically indicates deviationfrom the indicated numerical value of ±10%, and preferably of ±5%.

The term ‘77? vitro release” and its grammatical variations as well as similarexpression refers to the release rate by which a pharmaceutically active agent, e.g.hydromorphone HC1 is released from the pharmaceutical composition when the invitro release rate is tested by the paddle method according to the EuropeanPharmacopeia as described in as described in the Ph. Eur. 2.9.3 6th edition. Thepaddle speed is typically set at 75 or 100 rpm in 500 ml or 900 ml simulated gastricfluid (SGF) dissolution medium with pH 1.2. Aliquots of the dissolution media arewithdrawn at the respective time points and analyzed by HPLC with a C18 column,eluted with 30mM phosphate buffer in acetonitrile (70:70; pH 2.9) with a flow rate of1.0 ml/min and detected at 220 nm. It is specifically indicated if in the context of thepresent invention in vitro release rates are determined using a different test method(such as SGF with 40% (v/v) of ethanol).

The amount of dissolution liquid and the rotational speed of the paddle apparatusmay depend on the amount of active agent tested. For example, pharmaceuticalcompositions comprising up to 16 mg hydromorphone HC1 may be tested at 75 rpmin 500 ml dissolution liquid while higher dosage strengths may be tested at 100 rpmin 900 ml dissolution liquid.

The term “Simulated Gastric Fluid, pH 1.2” refers to 0.1 N HC1, pH 1.2. WO 2011/141488 PCT/EP2011/057566 - 10-

In the context of the present invention, the terms “immediate release” or“conventional release” refer to pharmaceutical compositions showing a release of theactive substance(s) which is not deliberately modified by a special formulationdesign and/or manufacturing methods. For oral dosage forms this means that thedissolution profile of the active substance(s) depends essentially on its (theirs)intrinsic properties. Typically, the terms “immediate release” or “conventionalrelease” refer to pharmaceutical compositions which release in vitro &gt;75% (byweight) of the pharmaceutically active agent(s) at 45 min.

In the context of the present, the terms “prolonged release” and “controlled release”are used interchangeably and refer to pharmaceutical compositions showing a slowerrelease of the active agent(s) than that of a conventional release pharmaceuticalcomposition administered by the same route. Prolonged or controlled release isachieved by a special formulation design and/or manufacturing method. Typically,the terms “prolonged release” and “controlled release refer to pharmaceuticalcompositions which release in vitro &lt;75% (by weight) of the pharmaceutically activeagent at 45 min.

Prolonged release properties may be obtained by different means such as by acoating which is then designated as a prolonged release coating, a matrix which isthen designated by as a prolonged release matrix or e.g. by an osmotic structure ofthe pharmaceutical composition.

In order to obtain “prolonged or controlled release” properties, one typically usesmaterials which are known to prolong the release from a dosage form comprising e.g.a prolonged release matrix and/or prolonged release coating. Typical examples ofsuch “prolonged or controlled release materials” are hydrophobic polymers such asethyl cellulose, hydrophilic polymers such as hydroxypropyl cellulose and the like. WO 2011/141488 PCT/EP2011/057566 - 11 -

The nature of the “prolonged or controlled release material” may depend on whetherthe release properties are attained by a “prolonged release matrix” or a “prolongedrelease coating”. The term “prolonged release materials” thus describes both types ofmaterials. The term “prolonged release matrix material” indicates that a material isused for obtaining a prolonged release matrix. Likewise, the term “prolonged releasecoating material” indicate that a material is used for obtaining a prolonged releasecoating.

The terms “prolonged release matrix formulation” or “controlled release matrixformulation” refer to a pharmaceutical composition including at least one prolongedrelease material or controlled release material, and at least one hydromorphone andnaloxone or the pharmaceutically acceptable salts or derivatives thereof. The terms“prolonged release material” and “controlled release material” can be usedinterchangeably. In a “prolonged release matrix formulation” or “controlled releasematrix formulation”, the “prolonged release material” or “controlled releasematerial” are combined with the pharmaceutically active agents to form a mixturefrom which the pharmaceutically active agent is released over prolonged periods oftime, such as e.g. 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.

It is to be understood that a material will be considered to act as prolonged orcontrolled release material if the dissolution profile of the pharmaceutically activeagent(s) is slowed down compared to an immediate or conventional releaseformulation. If a prolonged or controlled release material can be used formanufacturing a prolonged or controlled release matrix, it will be considered as aprolonged or controlled release matrix material. WO 2011/141488 PCT/EP2011/057566 - 12-

Pharmaceutically acceptable excipients which are used to adjust an alreadyprolonged or controlled release to a specific profile are not necessarily considered tobe prolonged or controlled release materials.

It is to be understood that a prolonged release matrix or a controlled release matrixdoes not necessarily consist only of the pharmaceutically active agent(s) and theprolonged or controlled release material. The prolonged or controlled release matrixmay comprise in addition pharmaceutically acceptable excipients such as fillers,lubricants, glidants, etc.

The terms “prolonged release coating formulation” or “controlled release coatingformulation” refer to a pharmaceutical composition including at least one prolongedrelease material or controlled release material, and at least one hydromorphone andnaloxone or the pharmaceutically acceptable salts or derivatives thereof The terms“prolonged release material” and “controlled release material” can be usedinterchangeably. In a “prolonged release coating formulation” or “controlled releasecoating formulation”, the “prolonged release material” or “controlled releasematerial” are disposed on the pharmaceutically active agents to form a diffusionbarrier. Other than in prolonged release matrix formulation, the actives are notintimately mixed with the prolonged release material and the prolonged releasecoating does not form a three dimensional structure within which the actives aredistributed. As the term implies, the prolonged release material forms a layer abovethe actives. The pharmaceutically active agent is released from a prolonged releasecoating formulation over prolonged periods of time, such as e.g. 8, 10, 12, 14, 16, 18,20, 22 or 24 hours.

It is to be understood that a material will be considered to act as prolonged orcontrolled release material if the dissolution profile of the pharmaceutically active WO 2011/141488 PCT/EP2011/057566 - 13 - agent(s) is slowed down compared to an immediate or conventional releaseformulation. If a prolonged or controlled release material can be used formanufacturing a prolonged or controlled release coating, it will be considered as aprolonged or controlled release coating material.

Pharmaceutically acceptable excipients which are used to adjust an alreadyprolonged or controlled release to a specific profile are not necessarily considered tobe prolonged or controlled release materials.

When it is mentioned that a prolonged release coating is disposed onpharmaceutically active agents, this is not to be construed as meaning that such acoating will necessarily be directly layered on such active pharmaceutically agents.Of course, if pharmaceutically active agents are layered on a carriers such as nu-pareil beads, the coating may be disposed directly thereon. However, thepharmaceutically active agents may also be first embedded in a polymer layer or e.g.a prolonged release matrix. Subsequently the prolonged release coating may bedisposed on e.g. granules which comprise a prolonged release matrix or on tabletswhich are made from such granules by compression for example. A pharmaceutical composition with a controlled or prolonged release coating may beobtained by combining the pharmaceutically active agents with a carriers such asnon-pareil beads and disposing a prolonged release coating on said combinations.Such coating may be made from polymers such cellulose ethers with ethyl cellulosebeing preferred, acrylic resins, other polymers and mixtures thereof. Such controlledor prolonged release coatings may comprise additional excipients such as pore-formers, binders and the like. WO 2011/141488 PCT/EP2011/057566 - 14-

It is further to be understood, that the term “prolonged release matrix formulation”or “controlled release matrix formulation” does not exclude pharmaceuticalcompositions with a prolonged or controlled release matrix and an additionalprolonged or controlled release coating being disposed on the matrix. Likewise theterm “prolonged release coating formulation” or “controlled release coatingformulation” does not exclude pharmaceutical compositions with a prolonged orcontrolled release coating which is disposed on prolonged release matrix or acontrolled release matrix.

In fact, the invention in various embodiments considers prolonged release matrixformulations which also comprise a prolonged release coating.

The terms “prolonged release dosage form” and “controlled release dosage form” canbe used interchangeably and refer to the administration form of a pharmaceuticalcomposition of the present invention comprising the at least one pharmaceuticallyactive agent in prolonged release form as e.g. in form of a “prolonged release matrixformulation”, in the form of a “prolonged release coating formulation, combinationsthereof or in other prolonged release formulations such as osmotic formulations. Theterms “prolonged release matrix formulation” and “prolonged release dosage form”can be used interchangeably if the prolonged release dosage form consists essentiallyof the prolonged release matrix formulation. This means that a prolonged releasedosage form can comprise in addition to the prolonged release matrix e.g. cosmeticcoatings and pharmaceutically acceptable excipients such fillers, lubricants, etc.

For some embodiments, the term “prolonged release matrix dosage form” mayindicate that the dosage form comprises a prolonged release matrix as the solestructure being responsible for prolonging the release. This, however, does not WO 2011/141488 PCT/EP2011/057566 - 15 - exclude that the dosage form may comprise an immediate release portion asdescribed hereinafter.

For some embodiments, the term “prolonged release coating dosage form” mayindicate that the dosage form comprises a prolonged release coating as the solestructure being responsible for prolonging the release. This, however, does notexclude that the dosage form may comprise an immediate release portion asdescribed hereinafter.

The release rates indicated always refer to the formulation such as a monolithic tabletor multi-particulates. The release rates will be chosen such that a pharmaceuticalcomposition can be administered e.g. on a twice a day or once a day basis, i.e. every12 hours or every 24 hours. Typically, the release will occur by diffusion through theprolonged or controlled release matrix and/or coating, erosion of the prolonged orcontrolled matrix and/or coating or combinations thereof

Oral solid dosage forms may take the form of tablets, granules, multiparticulates,mini-tablets and the like. Mini-tablets are dosage forms wich comprisepharmaceutically active agents in a prolonged release matrix with optionally aprolonged release coating disposed thereon. They take a round form with a thicknessof about 1 to about 5 mm and a diameter of about 1 to 5 mm. A thickenss anddiameter of about 1 to about 4 mm, of about 1 to about 3 mm and of anout 2 mm isalso considered. Multiparticulate and/or mini-tablets may be filled into e.g. capsulesare embedded in other excipients to form e.g. a tablet or to be filled into capsules.

In a preferred embodiment, the dosage forms in accordance with the inventioncomprise a prolonged release matrix with a controlled release coating. WO 2011/141488 PCT/EP2011/057566 - 16-

The term “heat treatment” is used in the context of heat treating a prolonged releasematrix formulation. The term “curing” is used in the context of heat treating aprolonged release coating formulation and relates to the effects of heat on thecoalescence of the coating. If a composition comprises a prolonged release matrixand a prolonged release coating, the term “heat treatment” or “heat treated” denotesthat the prolonged release matrix has been heat treated before the prolonged releasecoating was applied.

Pharmaceutical compositions in accordance with the invention, and in particularthose which are oral dosage forms, may be alcohol resistant.

The term “alcohol resistance” and its grammatical variations refer to the property ofpharmaceutical compositions of the invention to release about the same or lessamount of the pharmaceutically active agents in vitro, the in vitro release rate beingtested in 500 or 900 ml of Simulated Gastric Fluid, pH 1.2 with up to 40% (v/v)ethanol using the Ph. Eur. Paddle method at 100 rpm at 37° C compared to the invitro release rate being tested in 500 or 900 ml of Simulated Gastric Fluid, pH 1.2with up to 0% (v/v) ethanol using the Ph. Eur. Paddle method at 75 or 100 rpm at 37°C. The amount of dissolution liquid and the rotational speed of the paddle apparatusmay depend on the amount of active agent tested. For example, pharmaceuticalcompositions comprising up to 16 mg hydro morphone HC1 may be tested at 75 rpmin 500 ml dissolution liquid while higher dosage strengths may be tested at 100 rpmin 900 ml dissolution liquid.

Resistance to alcohol extraction can e.g. be tested by subjecting the formulation toSimulated Gastric Fluid (SGF), pH 1.2 with 40% ethanol. A typical manner in orderto obtain “500 ml of Simulated Gastric Fluid (SGF), pH 1.2 with 40% ethanol” is bymixing 600 ml of SGF with 420 ml of 95% ethanol/water (which provides 400 ml of WO 2011/141488 PCT/EP2011/057566 - 17- 100% ethanol) and taking 500 ml of the mixture. The effect of the additional 20 mlof water from the 95% ethanol will be minimal in the percentages of SGF andethanol in the 500 ml mixture. A typical manner in order to obtain 900 ml of Simulated Gastric Fluid (SGF), pH 1.2with 40% ethanol” is by mixing 600 ml of SGF with 420 ml of 95% ethanol/water(which provides 400 ml of 100% ethanol) and taking 900 ml of the mixture. Theeffect of the additional 20 ml of water from the 95% ethanol will be minimal in thepercentages of SGF and ethanol in the 100 ml mixture.

In certain embodiments, the present invention is directed to a prolonged releasepharmaceutical composition comprising at least two pharmaceutically active agents,namely hydromorphone and naloxone or their pharmaceutically acceptable salts orderivatives and at least one prolonged release material being combined to form aprolonged release matrix; wherein the ratio of the amount of hydromorphone or apharmaceutically acceptable salt or derivative thereof released after 0.5, 1 or 2 hoursof in vitro dissolution of the dosage form in 500 or 900 ml of Simulated GastricFluid, pH 1.2 with up to 40% ethanol using the Ph. Eur. paddle method at 75 or 100rpm at 37 C compared to the amount of hydromorphone or a pharmaceuticallyacceptable salt or derivative thereof released after 0.5, 1 or 2 hours in vitrodissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid, pH 1.2with 0% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37° C is about2:1 or less, about 1.5:1 or less, about 1:1 or less, about 1:1.2 or less, about 1:1.4 orless, about 1:1.6 or less, about 1:1.8 or less, about 1:2 or less, about 1:2.5 or lessabout 1:3 or less or about 1:5 or less, and wherein the ratio of the amount ofnaloxone or a pharmaceutically acceptable salt or derivative thereof released after0.5, 1 or 2 hours of in vitro dissolution of the dosage form in 500 or 900 ml ofSimulated Gastric Fluid, pH 1.2 with up to 40% ethanol using the Ph. Eur. paddle WO 2011/141488 PCT/EP2011/057566 - 18- method at 75 or 100 rpm at 37° C compared to the amount of naloxone or apharmaceutically acceptable salt or derivative thereof after 0.5, 1 or 2 hours in vitrodissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid, pH 1.2with 0% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37° C is about2:1 or less, about 1.5:1 or less, about 1:1 or less, about 1:1.2 or less, about 1:1.4 orless, about 1:1.6 or less, about 1:1.8 or less, about 1:2 or less, about 1:2.5 or lessabout 1:3 or less or about 1:5 or less. Preferably, the ratio is about 1:1 or less such as1:1.5 or 1:2 for hydromorphone and/or naloxone.

The present invention as disclosed herein with respect to all aspects andembodiments is meant to encompass the use of any pharmaceutically acceptable saltor derivative of hydromorphone and naloxone. Any embodiment of the inventionreferring to hydromorphone and naloxone is also meant to refer to salts andpreferably the hydrochloride salts thereof unless indicated otherwise.

Pharmaceutically acceptable salts include, but are not limited to, inorganic acid saltssuch as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acidsalts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like;sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and thelike; amino acid salts such as arginate, asparginate, glutamate and the like, and metalsalts such as sodium salt, potassium salt, cesium salt and the like; alkaline earthmetals such as calcium salt, magnesium salt and the like; organic amine salts such astriethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt,dicyclo hexylamine salt, Ν,Ν'-dibenzylethylenediamine salt and the like.

Pharmaceutically acceptable derivatives of hydromorphone and naloxone includeesters thereof as well as modified forms such as glycosylated, pegylated or hesylatedforms of hydromorphone and naloxone. WO 2011/141488 PCT/EP2011/057566 - 19-

If in the following reference is made to a pharmaceutically active agent such ashydromorphone, this always also includes the reference to a pharmaceuticallyacceptable salt or derivative of the free base of this pharmaceutically active agentunless it is specifically indicated that the reference to the pharmaceutically activeagent, such as use of the term “hydromorphone” should only refer to the free base.

The use of the hydrochloride salts of both hydromorphone and naloxone can bepreferred.

In a preferred embodiment, the pharmaceutical dosage forms comprisehydro morphone or a pharmaceutically acceptable salt or derivative thereof ornaloxone or a pharmaceutically acceptable salt or derivative thereof as the solepharmaceutically active agents.

The pharmaceutical compositions may comprise about 1 to about 64 mg such asabout 1 mg, about 2 mg, about 4 mg, about 8 mg, about 12 mg, about 16 mg, about24 mg, about 32 mg, about 40 mg, about 48 mg or about 64 mg hydromorphonehydrochloride or equimolar amounts of any other pharmaceutically acceptable salt orderivative including but not limited to hydrates and solvates or of the free base.Where reference is made to amounts of hydromorphone hydrochloride this relates toanhydrous hydromorphone hydrochloride. If a hydrated version of hydromorphonehydrochloride is used, this will be used in an amount equivalent to the afore-mentioned amounts of anhydrous hydromorphone hydrochloride.

The pharmaceutical compositions may comprise about 1 to about 256 mg, such asabout 1 mg, about 2 mg, about 4 mg, about 8 mg, about 12 mg, about 16 mg, about24 mg, about 32 mg, about 48 mg, about 64 mg, about 96 mg, about 128 or about WO 2011/141488 PCT/EP2011/057566 -20- 256 mg of naloxone hydrochloride or equimolar amounts of any otherpharmaceutically acceptable salt, derivative or form including but not limited tohydrates and solvates or of the free base. Where reference is made to amounts ofnaloxone hydrochloride this relates to anhydrous naloxone hydrochloride. If ahydrated version of naloxone hydrochloride is used, this will be used in an amountequivalent to the afore-mentioned amounts of anhydrous naloxone hydrochloride.

In some embodiments, the present invention is directed to a prolonged releasepharmaceutical composition comprising at least hydromorphone or apharmaceutically acceptable salt or derivative thereof or naloxone or apharmaceutically acceptable salt or derivative thereof and at least one prolongedrelease material which is preferably combined with these pharmaceutically activeagents to form a prolonged release matrix; wherein the amount of hydromorphone ora pharmaceutically acceptable salt or derivative thereof and/or naloxone or apharmaceutically acceptable salt or derivative thereof released in vitro in 500 or 900ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddle method at 100 rpmat 37° C is: at 1 h: 25 to 55% by weight of the pharmaceutically active agents, at 2 h: 45 to 75% by weight of the pharmaceutically active agents, at 3 h: 55 to 85% by weight of the pharmaceutically active agents, at 4 h: 60 to 90% by weight of the pharmaceutically active agents, at 6 h: 70 to 100% by weight of the pharmaceutically active agents, at 8 h: more than 85% by weight of the pharmaceutically active agents, at 10 h: more than 90% by weight of the pharmaceutically active agents. WO 2011/141488 PCT/EP2011/057566 -21 -

The pharmaceutically active agents may preferably be hydromorphone HCl andnaloxone HCl being preferred. The prolonged release pharmaceutical compositionmay comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter.

In some embodiments, the present invention is directed to a prolonged releasepharmaceutical composition comprising at least hydromorphone or apharmaceutically acceptable salt or derivative thereof or naloxone or apharmaceutically acceptable salt or derivative thereof and at least one prolongedrelease material which is preferably combined with these pharmaceutically activeagents to form a prolonged release matrix; wherein the amount of hydromorphoneand/or a pharmaceutically acceptable salt or derivative thereof or naloxone or apharmaceutically acceptable salt or derivative thereof released in vitro in 500 or 900ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddle method at 100 rpmat 37° C is: at 1 h: 30 to 50% by weight of the pharmaceutically active agents, at 2 h: 50 to 70% by weight of the pharmaceutically active agents, at 3 h: 60 to 80% by weight of the pharmaceutically active agents, at 4 h: 65 to 85% by weight of the pharmaceutically active agents, at 6 h: 75 to 95% by weight of the pharmaceutically active agents, at 8 h: more than 90% by weight of the pharmaceutically active agents, at 10 h: more than 95% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HCl andnaloxone HCl being preferred. The prolonged release pharmaceutical composition WO 2011/141488 PCT/EP2011/057566 -22- may comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter.

In some embodiments, the present invention is directed to a prolonged releasepharmaceutical composition comprising at least hydromorphone or apharmaceutically acceptable salt or derivative thereof or naloxone or apharmaceutically acceptable salt or derivative thereof and at least one prolongedrelease material which is preferably combined with these pharmaceutically activeagents to form a prolonged release matrix; wherein the amount of hydromorphone ora pharmaceutically acceptable salt or derivative thereof and/or naloxone or apharmaceutically acceptable salt or derivative thereof released in vitro in 500 or 900ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddle method at 100 rpmat 37° C is: at 1 h: 10 to 30% by weight of the pharmaceutically active agents, at 2 h: 34 to 54% by weight of the pharmaceutically active agents, at 3 h: 53 to 73% by weight of the pharmaceutically active agents, at 4 h: 65 to 85% by weight of the pharmaceutically active agents, at 6 h: 75 to 95% by weight of the pharmaceutically active agents, at 8 h: 80 to 100% by weight of the pharmaceutically active agents, at 10 h: more than 90% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HC1 andnaloxone HC1 being preferred. The prolonged release pharmaceutical compositionmay comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter. WO 2011/141488 PCT/EP2011/057566 -23 -

In some embodiments, the present invention is directed to a prolonged releasepharmaceutical composition comprising at least hydromorphone or apharmaceutically acceptable salt or derivative thereof or naloxone or apharmaceutically acceptable salt or derivative thereof and at least one prolongedrelease material which is preferably combined with these pharmaceutically activeagents to form a prolonged release matrix; wherein the amount of hydromorphone ora pharmaceutically acceptable salt or derivative thereof and/or naloxone or apharmaceutically acceptable salt or derivative thereof released in vitro in 500 or 900ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddle method at 100 rpmat 37° C is: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agents, at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HCI andnaloxone HCI being preferred. The prolonged release pharmaceutical compositionmay comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter. WO 2011/141488 PCT/EP2011/057566 -24-

Preferably, the amount of the pharmaceutically active agents released in vitro in 500or 900 ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddle method at100 rpm at 37° C is: at 1 h: 8 to 42% by weight of the pharmaceutically active agents, at 2 h: 18 to 52% by weight of the pharmaceutically active agents, at 3 h: 33 to 67% by weight of the pharmaceutically active agents, at 4 h: 38 to 72% by weight of the pharmaceutically active agents, at 6 h: 43 to 77% by weight of the pharmaceutically active agents, at 8 h: 53 to 87% by weight of the pharmaceutically active agents, at 10 h: 63 to 97% by weight of the pharmaceutically active agents, at 12 h: 73 to 100% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HCI andnaloxone HCI being preferred. The prolonged release pharmaceutical compositionmay comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter.

More preferably, the amount of the pharmaceutically active agents released in vitroin 500 or 900 ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddlemethod at 100 rpm at 37° C is: at 1 h: 15 to 37% by weight of the pharmaceutically active agents, at 2 h: 25 to 47% by weight of the pharmaceutically active agents, at 3 h: 38 to 62% by weight of the pharmaceutically active agents, at 4 h: 42 to 66% by weight of the pharmaceutically active agents, at 6 h: 50 to 74% by weight of the pharmaceutically active agents, at 8 h: 60 to 84% by weight of the pharmaceutically active agents, at 10 h: 68 to 92% by weight of the pharmaceutically active agents, WO 2011/141488 PCT/EP2011/057566 -25 - at 12 h: 78 to 100% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HCl andnaloxone HCl being preferred. The prolonged release pharmaceutical compositionmay comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter.

Even more preferably, the amount of the pharmaceutically active agents released invitro in 500 or 900 ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddlemethod at 100 rpm at 37° C is: at 1 h: 19 to 33% by weight of the pharmaceutically active agents, at 2 h: 29 to 43% by weight of the pharmaceutically active agents, at 3 h: 43 to 47% by weight of the pharmaceutically active agents, at 4 h: 47 to 61 % by weight of the pharmaceutically active agents, at 6 h: 55 to 69% by weight of the pharmaceutically active agents, at 8 h: 65 to 79% by weight of the pharmaceutically active agents, at 10 h: 73 to 87% by weight of the pharmaceutically active agents, at 12 h: 83 to 100% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HCl andnaloxone HCl being preferred. The prolonged release pharmaceutical compositionmay comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter.

As mentioned above, in a first aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: WO 2011/141488 PCT/EP2011/057566 -26- a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition provides alcohol resistance.

It will be described below how prolonged release pharmaceutical compositions ofhydromorphone and naloxone providing alcohol resistance and the above mentionedrelease properties can be manufactured.

In a second aspect, the present invention relates to an oral prolonged releasepharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are present in the pharmaceutical composition in aweight ratio in a range of about 2:1 to about 1:3, preferably of about2:1, about 1:1, about 1:2 or about 1:3.

As mentioned above, in a third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein WO 2011/141488 PCT/EP2011/057566 -27- c) the pharmaceutical composition after storage under stressedconditions releases the pharmaceutically active agents withsubstantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

Storage under stressed conditions in the context of the present invention means that apharmaceutical composition is subjected to increased temperature and/or relativehumidity (RH) for prolonged periods of time. For example, typical stressedconditions refer to storage over at least one, two, three, four, five, six, twelth oreigtheen months at 25°C and 60% RH. Other stressed conditions refer to storage overat least one, two, three, four, five, six or twelth months at 30°C and 65% RH Otherstressed conditions refer to storage over at least one, two, three, four, five or sixmonths at 40°C and 75% RH.

Such stressed storage conditions are used to determine whether a pharmaceuticalcomposition has a shelf life sufficient for long time storage under conditions as theyare common in patients’ households without negative effects on its safety andefficacy. Such negative effects may include that the in-vitro release rates change overtime so that the efficacy of the composition is affected as different amounts ofactives are released after administration. Similarly, negative effects may also resultfrom degradation of the pharmaceutically active agents which may either decreasethe overall amount of functional pharmaceutically active agent or lead to formationof toxic by-products.

If changes in the in vitro release profile or with respect to the amount of the activeagent(s) of a pharmaceutical composition are observed after storage under stressedconditions, this may be indicative of stability problems. If such changes are not WO 2011/141488 PCT/EP2011/057566 -28- observed, this means vice versa that the pharmaceutical composition is storagestable.

The above mentioned stressed storage conditions can be used to estimate whether apharmaceutical dosage will have a shelflife of at least about 12 months, at leastabout 18 months, at least about 24 months or at least about 36 months. Usually ashelf life of 18 months or more may be desirable as this is usually better compatiblewith e.g. supply of excipients, actives etc. for manufacturing purposes. If apharmaceutical composition is storage stable, i.e. has essentially the same releaserate after storage over at least one, two, three, four, five or more months at 25°C and60% RH, this will be usually indicative of shelflife of at least about 12 months. If apharmaceutical composition is storage stable, i.e. has essentially the same releaserate after storage over at least one, two, three, four, five or more months at 30°C and65% RH, this will be usually indicative of shelflife of at least about 18 months. If apharmaceutical composition is storage stable, i.e. has essentially the same releaserate after storage over at least one, two, three, four, five or more months at 40°C and75% RH, this will be usually indicative of a shelflife of at least about 24 monthssuch as 36 months.

The term “substantially the same release rate” refers to the situation where the invitro release rate for a pharmaceutical composition which has been subjected tostressed conditions is compared to a reference composition. The referencecomposition is an identical pharmaceutical composition which, however, has notbeen subjected to stressed conditions. If the in vitro release profile of thecomposition subjected to stressed conditions does not deviate by more than about20%, preferably by no more than about 15%, more preferably by no more than 10%and even more preferably by no more than about 5% from the in vitro release profile WO 2011/141488 PCT/EP2011/057566 -29- of the reference composition, the in-vitro release rate is considered to be substantiallythe same.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 25°C at 60% relativehumidity for at least one month releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 25°C at 60% relativehumidity for at least two months releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release matrix material; WO 2011/141488 PCT/EP2011/057566 -30- b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 25°C at 60% relativehumidity for at least five months releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 30°C at 65% relativehumidity for at least one month releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 30°C at 65% relativehumidity for at least two months releases the pharmaceutically active WO 2011/141488 PCT/EP2011/057566 -31 - agents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release matrix material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 30°C at 65% relativehumidity for at least five months releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 40°C at 75% relativehumidity for at least one month releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; WO 2011/141488 PCT/EP2011/057566 -32- b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 40°C at 75% relativehumidity for at least two months releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In one embodiment of this third aspect, the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage at 40°C at 75% relativehumidity for at least five months releases the pharmaceutically activeagents with substantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions.

In a fourth aspect, the present invention relates to an oral prolonged releasepharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions, preferably at 25°C at 60% relative humidity for at leastfive months, has less than about 4.0% such as less than about 3.0%, WO 2011/141488 PCT/EP2011/057566 -33- preferably less than about 2.0% and more preferably less than about1% , less than about 0.5% or even less than about 0.2% of totalsubstances related to hydromorphone or a pharmaceuticallyacceptable salt or derivative thereof and/or related to naloxone or apharmaceutically acceptable salt or derivative thereof

Stressed conditions are the same as mentioned above.

The term “hydromorphone and/or naloxone related substances” or the like refers tosubstances that arise from chemical reactions of hydromorphone or naloxone,pharmaceutically acceptable salts and derivatives thereof such as e.g. degradation.These substances can be distinguished as known hydromorphone related substanceswhere the identity of the substance and its origin is known, as known naloxonerelated substances where the identity of the substance and its origin is known, and asunknown substances. For unknown substances, their identity is not known. However,it is assumed that they arise from hydromorphone and/or naloxone, pharmaceuticallyacceptable salts and derivatives thereof It is to be understood that the term“hydromorphone and naloxone related substances” includes the sum of knownhydromorphone related substances, known naloxone related substances and unknownsubstances and is thus equivalent to the term “total hydromorphone and naloxonerelated substances”.

Terms like “less than about 4 % of substances related to hydromorphone andnaloxone, or to pharmaceutically acceptable salts or derivatives thereof” or “lessthan about 3 % of substances related to hydromorphone and naloxone or topharmaceutically acceptable salts or derivatives thereof’ etc. indicate that the amountof total substances as described in the preceding paragraph is less than e.g. 4% or 3%by weight based on the total amount of the active ingredient which is present in WO 2011/141488 PCT/EP2011/057566 -34- lower amounts (i.e. hydromorphone or naloxone), or a pharmaceutically acceptablesalt or derivative thereof which is present in the pharmaceutical composition in thelower amount. Thus, if a pharmaceutical composition comprises hydromorphone HCIand naloxone HCI in 1:2 ratio by weight, the amount of total substances is calculatedfrom the sum of known hydromorphone HCI related substances, known naloxoneHCI related substances and unknown substances which is then referenced to theamount of hydromorphone HCI. If a pharmaceutical composition compriseshydromorphone HCI and naloxone HCI in 2:1 ratio by weight, the amount of totalsubstances is calculated from the sum of known hydromorphone HCI relatedsubstances, known naloxone HCI related substances and unknown substances whichis then referenced to the amount of naloxone HCI. “Known hydromorphone related substances” include hydromorphone n-oxide,noroxymorphone, pseudohydromorphone. “Known naloxone related substances” include noroxymorphon, 10a-hydroxynaloxon, 7,8-didehydronaloxon, pseudonaloxon, 3-o-allylnaloxon.

Terms like “less than 4 % of known substances related to hydromorphone, or topharmaceutically acceptable salts or derivatives thereof” or “less than 3 % of knownsubstances related to hydromorphone, or to pharmaceutically acceptable salts orderivatives thereof’ etc. indicate that the amount of known hydromorphone relatedsubstances is less than e.g. 4% or 3% of known hydromorphone related substance byweight based on the total amount of hydromorphone, or a pharmaceuticallyacceptable salt or derivative thereof in the composition.

Terms like “less than 4 % of known substances related to naloxone, or topharmaceutically acceptable salts or derivatives thereof’ or “less than 3 % of known WO 2011/141488 PCT/EP2011/057566 -35- substances related to naloxone, or to pharmaceutically acceptable salts or derivativesthereof’ etc. indicate that the amount of known naloxone related substances is lessthan e.g. 4% or 3.0% of known naloxone related substance by weight based on thetotal amount of naloxone, or a pharmaceutically acceptable salt or derivative thereofin the composition.

In order to assess stability one may subject a pharmaceutical composition to stressedconditions as mentioned above and determine the amount of total hydromorphoneand/or naloxone related substances. One then determines the amount of totalhydromorphone and/or naloxone related substances for an identical pharmaceuticalcomposition which has not been subjected to stressed conditions. This composition isconsidered to be a reference composition. The detection of “ total hydromorphonerelated and/or naloxone substances” is typically performed by HPLC analysis usinge.g. CAT columns. The amount of the substances including the amount of unknownsubstances is then determined by calculating the area under the respective peaks inthe chromatogram. The identity of substances can be determined by doing the sameanalysis with pure known reference substances. In a further aspect the presentinvention aims at providing pharmaceutical compositions which after storage understressed conditions have less than 4 %, less than 3%, less than 2%, less than 1%, lessthan 0.5%, less than 0.2% or even less than 0.1% of total substances related tohydromorphone or a pharmaceutically acceptable salt or derivative thereof and/orrelated to naloxone or a pharmaceutically acceptable salt or derivative thereof.

In a further aspect the present invention aims at providing pharmaceuticalcompositions which after storage under stressed conditions have less than 1 % suchas less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1% oreven less than 0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less than 1% such as less WO 2011/141488 PCT/EP2011/057566 -36- than 0.5% of known substances related to naloxone or a pharmaceutically acceptablesalt or derivative thereof.

Stressed storage conditions may be the same as mentioned above. Thus typicalstressed conditions may refer to storage over at least one, two, three, four, five or sixmonths at 25°C and 60% RH, at 30°C and 65% RH or at 40°C and 75% RH. A pharmaceutical composition will thus be considered to be stable if after subjectingit to stressed conditions, it has no more than about 4% such as no more than about3%, preferably no more than about 2%, more preferably no more than about 1% andeven more preferably no more than about 0.5% of hydromorphone and/or naloxonerelated substances.

In one embodiment of this fourth aspect, the invention relates to an oral prolongedrelease pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 25°C and 60% relativehumidity for at least one month has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1%, less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof. WO 2011/141488 PCT/EP2011/057566 -37- In another embodiment of this fourth aspect, the invention relates to an oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 25°C and 60% relativehumidity for at least two months has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1%, less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof.

In yet another embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 25°C and 60% relativehumidity for at least five months has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1%, less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof. WO 2011/141488 PCT/EP2011/057566 -38- In one embodiment of this fourth aspect, the invention relates to an oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 30°C and 65% relativehumidity for at least one month has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1% , less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof.

In another embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 30°C and 65% relativehumidity for at least two months has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1% , less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof. WO 2011/141488 PCT/EP2011/057566 -39- In yet another embodiment of this fourth aspect, the invention relates to an oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 30°C and 65% relativehumidity for at least five months has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1% of total substances, less than about0.5% or even less than about 0.2% related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof

In a further embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 40°C and 70% relativehumidity for at least one month has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1% , less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof WO 2011/141488 PCT/EP2011/057566 -40- In one embodiment of this fourth aspect, the invention relates to an oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 40°C and 70% relativehumidity for at least two months has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1%, less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof

In one embodiment of this fourth aspect, the invention relates to an oral prolongedrelease pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 40°C and 70% relativehumidity for at least five months has less than about 4.0% such as lessthan about 3.0% , preferably less than about 2.0% and morepreferably less than about 1% , less than about 0.5% or even less thanabout 0.2% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or tonaloxone or a pharmaceutically acceptable salt or derivative thereof WO 2011/141488 PCT/EP2011/057566 -41 - In one embodiment of this fourth aspect, the invention relates to an oral prolonged release pharmaceutical composition comprising at least: a. at least one prolonged release material; b. at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c. the pharmaceutical composition after storage at 25°C and 60% relativehumidity for at least one month has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof.

In another embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 25°C and 60% relativehumidity for at least two months has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or WO 2011/141488 PCT/EP2011/057566 -42- even less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof.

In yet another embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 25°C and 60% relativehumidity for at least five months has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof.

In one embodiment of this fourth aspect, the invention relates to an oral prolongedrelease pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 30°C and 65% relativehumidity for at least one month has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or a WO 2011/141488 PCT/EP2011/057566 -43 - pharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof.

In another embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 30°C and 65% relativehumidity for at least two months has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof.

In yet another embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 30°C and 65% relativehumidity for at least five months has less than about 1 % such as less WO 2011/141488 PCT/EP2011/057566 -44- than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof

In a further embodiment of this fourth aspect, the invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 40°C and 70% relativehumidity for at least one month has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof

In one embodiment of this fourth aspect, the invention relates to an oral prolongedrelease pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein WO 2011/141488 PCT/EP2011/057566 -45 - c) the pharmaceutical composition after storage at 40°C and 70% relativehumidity for at least two months has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof

In one embodiment of this fourth aspect, the invention relates to an oral prolongedrelease pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition after storage at 40°C and 70% relativehumidity for at least five months has less than about 1 % such as lessthan about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or even less than about0.05% of known substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and less thanabout 1% such as less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1% oreven less than about 0.05% of known substances related to naloxoneor a pharmaceutically acceptable salt or derivative thereof

It will be described below how prolonged release pharmaceutical compositions ofhydromorphone and naloxone being stable can be manufactured. It will be apparentfrom this description that selection of anhydrous diluents and the choice of lubricant WO 2011/141488 PCT/EP2011/057566 -46- may be a means to positively influence stability. Heat treatment may improvephysical stability such as robustness and hardness..

As mentioned above, in a fifth aspect the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the prolonged release pharmaceutical composition is heat treated.

In a first variation to this fifth aspect the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, c) wherein the at least one prolonged release material andhydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined such that a prolonged release matrixis formed; and d) wherein the prolonged release pharmaceutical composition is heattreated.

In a second variation to this fifth aspect the present invention relates to an oralprolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; WO 2011/141488 PCT/EP2011/057566 -47- b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; c) wherein the at least one prolonged release material, hydromorphone ora pharmaceutically acceptable salt or derivative thereof and naloxoneor a pharmaceutically acceptable salt or derivative thereof arecombined such that a prolonged release matrix is formed; d) wherein the prolonged release matrix is heat treated; e) wherein at least one prolonged release material is applied in the formof a prolonged release coating which is disposed on the prolongedrelease matrix; and f) wherein the composition is optionally cured.

The prolonged release coating may either be disposed on each prolonged releasematrix if the prolonged release matrix is manufactured in the form of multi-particulates such as granules or it may be disposed on the formulation comprising theprolonged release matrix if e.g. prolonged release matrix multi-particulates such asgranules are compressed into a tablet. The coating will then be disposed on themonolithic formulation.

The above heat treated pharmaceutical compositions may be preferably provided inthe form of multiparticulates or mini-tablets that are filled into capsules.

Heat treatment may be performed such that the hardness/breaking strength of thepharmaceutical composition is increased for the heat treated versus the non heattreated composition. By heat treating pharmaceutical compositions in accordancewith the invention, one may thus obtain compositions with improvedhardness/breaking strength proportional to the tablet weight, size and shape. Heat WO 2011/141488 PCT/EP2011/057566 -48- treatment may improve physical stability such as robustness and hardness and insome although not all cases also positively influence chemical stability As will beshown below, heat treatment may have an effect on in vitro release properties. Thus,heat treatment may further decrease the in vitro release compared to a non-heattreated composition. However, after heat treatment for relatively short periods oftime (e.g. 30 min at 55°C) the in vitro release rate will not change any further uponfurther heat treatment, i.e. remains substantially the same. It is further observed thatsuch heat treated compositions when being subjected to stressed conditions will havesubstantially the same in vitro release rate as the same heat treated compositionwhich has not been subjected to stressed conditions. Similarly such heat treatedcompositions will have less than about 4% of total hydromorphone and/or naloxonerelated substances and less than about 1% of known hydromorphone or knownnaloxone-related substance upon storage under stressed conditions.

Heat treatment will positively effect physical stability as can be deduced from areduced occurrence of e.g. cracks and improved intactness of the formulation. Thisshould help to ensure a reproducible release behavior also in vivo settings as changesdue to e.g. an altered surface which occure as a consequence of cracks will beminimized. Further, heat treatment in general improves the hardness of theformulation in case of a prolonged release matrix formulation by usually about 3 toabout 7 kP such as about 6 kP to an overall value of about 10 to 15 about kP such asabout 11 kP. Hardness is usually tested using a mechanical strength tester such as aHolland C50 tablet hardness tester. 10 tablets are tested to provide a mean valueevery 15-20 mins during the compression run.

The term “heat treatment” refers to a thermal treatment under either or both increasedtemperature for a prolonged period of time. Typically, heat treatment takes place at atemperature in the range of about 30°C to about 95°C and for a time in the range of WO 2011/141488 PCT/EP2011/057566 -49- about 10 min to about 3 hours. Typically heat treatment conditions may thus betreatment for at least about 15 min, at least about 30 min, at least about 45 min, atleast about 60 min, at least about 75 min, at least about 90 min, at least about 120min, at least about 150 min, at least about 180 min or at least about 240 min at aboutat least 30°C, at about at least 40°C, at about at least 50°C, at about at least 60°C orat about at least 80°C at ambient humidity. Heat treatment conditions may beselected according to the specific prolonged release matrix materials being used. Ingeneral the temperature will be around the melting and/or softening temperature ofthe prolonged release matrix materials being used. Such conditions may thus ensurethat the prolonged release matrix materials are sufficiently soft to mobilise and to fillpores in the prolonged release matrix and/or e.g. compressed granules. In case offormulations using e.g. hydrophobic polymers such as ethyl cellulose and fattyalcohols such as stearyl or cetostearyl alcohol, a temperature of about 55°C may beappropriate. In general, heat treatment for at least 30 min at 55°C may be sufficientto ensure physical stability.

Heat treatment can be performed in a convection oven, in an open oven, undervacuum, in the coating drum using conventional heat, microwave and any othersources of heat. Heat treatment in a coating drum can be preferred. If thepharmaceutical compositions comprise a prolonged release coating either alone or inaddition to a controlled release matrix, heat treatment of such prolonged releasecoatings is also designated as curing which helps coalescence of e.g. polymercoatings.

Prolonged release pharmaceutical compositions in accordance with some aspects ofthe invention may comprise a prolonged release matrix and/or coating which ensuresprolonged release of the active ingredients and/or they may alternatively rely on acoating for imparting controlled release properties. In case of a prolonged release WO 2011/141488 PCT/EP2011/057566 -50- coating, the actives may be disposed on bead-like structures such as non pareil beadsor granules or they may be incorporated into extruded granules or spheroids which assuch do not provide prolonged release. The prolonged release coating is then layeredthereon.

If a prolonged release coating is used it may be layered on individual prolongedrelease matrices such as granules or mini-tablets or it may layered on a monolithicformulation such as tablets or mini-tablets which are obtained by compressingprolonged release matrix granules.

If prolonged release coating is used the prolonged release composition may beoptionally cured in order to enhance coalescence of the coating and thus to improvestability and intactness of the coating. The curing conditions may be the same asdescribed above for coatings. Curing can further slow down the release properties. Acuring step of about 20 minutes to 30 minutes at about 50° to 100° may be sufficientto slow down the release such that it won't substantially changes after storage understressed conditions as the coating’s properties will not substantially change anymore.

Pharmaceutical compositions in accordance with the invention may also comprise aprolonged release matrix with one or more prolonged release coatings thereon.

In addition prolonged release compositions comprising a prolonged release matrix orprolonged release coating may comprise e.g. a fraction of at least one or both of thepharmaceutically active agents in immediate release form. Such an immediate releasephase which may account for up to 30% of the overall amount of thepharmaceutically active agent(s) being present in the composition can ensure an earlyonset of therapeutic efficacy. WO 2011/141488 PCT/EP2011/057566 -51 -

The prolonged release compositions in accordance with the invention may beformulated into different dosage forms. For example, prolonged release compositionsmay take the form of tablets or mini-tablets. Tablets may be a monolithic tabletcomprising e.g. a continuous prolonged release matrix. However, tablets or mini-tablets may be also be made from multiparticulates which are compressed intotablets. Such multiparticulates may e.g. comprise a prolonged release matrixoptionally with an immediate release phase or active loaded beads with a prolongedrelease coating and optionally an immediate release phase thereon. The dosage formmay also take the form of such multiparticulates, e.g. granules or mini-tablets whichmay be filled into a capsule.

The in vitro release rates of the prolonged release pharmaceutical compositions willbe chosen such that a therapeutic efficacy in vivo is achieved over preferably at leasttwelve hours and in some instance even up to twenty four hours. Such compositionsmay be described as “twice a day” or “once a day” formulations as they may beadministered on such a regimen. A preferred embodiment of all embodiments and aspects as described above (inparticular of the embodiments of the first, second, third, fourth and fifth aspect of theinvention), the pharmaceutical compositions may comprise a prolonged releasematrix and a prolonged release coating. These pharmaceutical compositionsaccording to the first to fifth aspect may comprise hydromorphone and naloxone orthe pharmaceutically acceptable salt or derivatives thereof in the above mentionedratios and amounts. In the embodiments of the above mentioned aspects of theinvention, hydromorphone or a pharmaceutically acceptable salt or derivative thereofand naloxone or a pharmaceutically acceptable salt or derivative thereof may thus becombined with a prolonged release material such that a prolonged release matrix isformed on which a prolonged release coating is then disposed. The prolonged release WO 2011/141488 PCT/EP2011/057566 -52- coating may be disposed on individual prolonged release matrix formulations so thata multiparticulate formulation is obtained. These multi-particulates may be directlyfilled into capsules or blended with other excipients to obtain a dosage form. In otherembodiments, the prolonged release matrix formulation may take the form of e.g.granules which are compressed into mini-tablets or a monolithic dosage from such astablets on which the prolonged release coating is then disposed. The manufacture ofthe prolonged release matrix may preferably be undertaken using an anhydrousmethod as described below. Manufacturing a prolonged release matrix in ananhydrous manner will have a beneficial effect on chemical stability as expressede.g. by a substantially same in vitro release profile after storage under stressedconditions. Heat treatment will beneficially influence physical stability. Amultiparticulate nature may have positive effects of food effects upon administration.

The prolonged release material may be any material that is known to be capable ofimparting controlled release properties on the active agent when being formulatedinto a prolonged release matrix.

Such materials may be hydrophilic and/or hydrophobic materials such as gums,cellulose ethers, acrylic polymers, protein-derived materials etc.

Prolonged materials may also include fatty acids, fatty alcohols, glyceryl esters offatty acids, polyethylene glycols, mineral and oils and waxes. Fatty acids and fattyalcohols preferable are those with a Cio to C30 chain, preferably with a C12 to C24chain and more preferably with a C14 to C20 chain or a Ci6 to C20 chain. Materialssuch as stearyl alcohol, cetostearyl alcohol, cetyl alcohol, myristyl alcohol andpolyalkylene glycols may be preferred. Waxes may be selected from natural andsynthetic waxes such as beeswax, carnauba wax. Oils may be vegetable oils andinclude for example castor oil. WO 2011/141488 PCT/EP2011/057566 -53-

The prolonged release matrix materials which may be considered in the context ofthe present invention may also be selected from cellulose ethers.

The term “cellulose ethers” comprises cellulose-derived polymers derivatized with atleast alkyl and/or hydroxyalkyl groups which may be hydrophilic or hydrophobic.

For example, the prolonged release matrix material may be a hydrophilic hydroxyalkyl cellulose such as a hydroxy (Cl - C6) alkyl celluloses such as hydroxypropylcellulose, hydroxypropylmethyl cellulose and particularly preferably hydroxy ethylcellulose.

Examples of hydrophobic cellulose ethers include e.g. ethyl cellulose. The use ofethyl cellulose may be preferred. Hydrophobic cellulose ethers such as ethylcellulose may be particularly suitable for imparting alcohol resistance topharmaceutical compositions. A particularly suitable material for prolonged release matrix formulations inaccordance with the present invention may be selected from the group of acrylicresins. Such acrylic resins may be made from (meth)acrylic acid (co) polymers.

There are various types of (meth)acrylic acid (co)polymers available which may becharacterised according to the nature of their residues such as neutral (meth)acrylicacid (co)polymers, (meth)acrylic acid (co)polymers with anionic residues or(meth)acrylic acid ester copolymers with cationic residues.

Neutral (meth)acrylic acid (co)polymers include polymers having 95 to 100% byweight of polymerised monomers having neutral residues. Monomers with neutral WO 2011/141488 PCT/EP2011/057566 -54- residues can be C1-C4 alkyl esters of acrylic or methacrylic acid such asmethylmethacrylate, ethylmethacrylate, butylmethacrylate, methylacrylate,ethylacrylate and butylacrylate. For example, neutral (meth)acrylic acid(co)polymers may comprise 20 to 40 % by weight ethylacrylate and 60 to 80 % byweight methylmethacrylate. Such polymers are e.g. available under the trade nameEudragit® NE which is a copolymer of 30 % by weight ethylacrylate and 70 % byweight methylmethacrylate. This polymer is usually provided in the form of a 30 %or 40% aqueous dispersion (Eudragit® NE 30 D, Eudragit® NE 40 D or Eudragit®NM 30 D). (Meth)acrylic acid (co)polymers with functional anionic residues may be(meth)acrylic acid (co)polymers having 25 to 95 % by weight of radicallypolymerised Ci to C4 alkyl esters of acrylic or methacrylic acid and 5 to 75 % byweight of methacrylate monomers with an anionic group in the alkyl residue. Ci toC4 alkyl esters of acrylic or methacrylic acid are again methylmethacrylate, ethylmethacrylate, butylmethacrylate, methylacrylate, ethylacrylate and butylacrylate. A(meth)acrylate monomer with an anionic group in the alkyl residue may be forexample acrylic acid and preferably methacrylic acid. Such methacrylic acidcopolymers with an anionic functional group may comprise e.g. 40 to 60 % byweight methacrylic acid and 60 to 40 % by weight methylmethacrylate or 60 to 40 %by weight ethyl acrylate. These types of polymers are available as Eudragit® LI 00 /Eudragit® L 12.5 or Eudragit® L 100-55 / Eudragit® L 30 D-55, respectively.

For example, Eudragit® L 100 is a copolymer of 50 % by weight methylmethacrylateand 50 % by weight methacrylic acid. It is also provided as a 12.5% solution(Eudragit® L 12.5). Eudragit® L 100-55 is a copolymer of 50 % by weightethylacrylate and 50 % by weight methacrylic acid. It is also provided as 30 %dispersion (Eudragit® L 30 D-55). WO 2011/141488 PCT/EP2011/057566 -55- (Meth)acrylic acid (co)polymers with an anionic functional group may also comprise20 to 40 % by weight methacrylic acid and 80 to 60 % by weightmethylmethacrylate. These types of polymers are usually available under the tradename Eudragit® S. It is also provided as a 12. 5 % solution (Eudragit® S 12.5).Another type of methacrylic acid copolymers with an anionic functional group isavailable under the trade name Eudragit® FS which typically comprises 10 to 30 %by weight methylmethacrylate, 50 to 70 % by weight methylacrylate and 5 to 15 %by weight methacrylic acid. Thus, Eudragit®FS may be a polymer of 25 % by weightmethylmethacrylate, 65 % by weight methylacrylate and 10 % by weight methacrylicacid. It is usually provided as 30 % dispersion (Eudragit® FS 30 D). (Meth)acrylic acid (co)polymers with functional cationic groups may be methacrylicacid copolymers with tertiary amino groups. Such polymers may comprise 30 % to 80 % by weight of radically polymerised C1-C4 alkyl esters of acrylic acid ormethacrylic acid and 70 to 20 % by weight methacrylate monomers with a tertiaryamino group in the alkyl rest.

Suitable monomers with a functional tertiary amino group are disclosed e.g. in US4,705,695, column 3, line 64 to column 4, line 13. They include for exampledimethylaminoethyl acrylate, 2-dimethylaminopropyl acrylate, dimethylaminopropylmethacrylate, dimethylaminobenzyl acrylate, dimethylaminobenzyl methacrylate, (3-dimethylamino-2,2-dimethyl)propyl acrylate, dimethylamino-2,2-dimethylpropylmethacrylate, (3-diethylamino-2,2-dimethyl)propyl acrylate anddiethylamino-2,2-dimethylpropylmethacrylate. Particularly suitable isdimethylaminoethyl methacrylate. The amount of monomers with a tertiary aminogroup in the copolymer may vary between 20 to 70 %, between 40 to 60 %. Theamount of Ci to C4 alkyl esters of acrylic or methacrylic acid may be within 70 to 30 WO 2011/141488 PCT/EP2011/057566 -56- % by weight. Ci to C4 alcohol esters of acrylic or methacrylic acid includemethylmethacrylate, ethylmethacrylate, butylmethacrylate, methylacrylate,ethylacrylate and butylacrylate. A common (meth)acrylic acid (co)polymer with atertiary amino group may comprise 20 to 30 % by weight methylmethacrylate, 20 to30 % by weight butylmethacrylate and 60 to 40 % by weight dimethylaminoethylmethacrylate. For example the commercially available Eudragit® E 100 comprises25 % by weight methylmethacrylate, 25 % by weight butylmethacrylate and 50 % byweight dimethylaminoethyl methacrylate. Another common commercially availablepolymer, Eudragit®E PO comprises copolymers of methylmethacrylate,butylmethacrylate and dimethylaminoethyl methacrylate in a ratio of 25:25:50.

Another type of (meth)acrylic acid (co)polymers with functional cationic groups is(meth)acrylic acid (co)polymers with a quaternary amino group. This type of(meth)acrylic acid (co)polymers typically comprises 50 to 70 % of radicallypolymerised methylmethacrylate, 20 to 40 % by weight of ethylacrylate and 12 to 2% by weight of 2-trimethylammoniumethyl methacrylate chloride. Such polymersare e.g. available under the trade names Eudragit®RS or Eudragit®RL.

For example, Eudragit®RS comprises radically polymerised units of 65 % by weightmethylmethacrylate, 30 % by weight ethylacrylate and 5 % by weight 2-trimethylamoniumethyl methacrylate chloride. Eudragit®RL comprises radicallypolymerised units of 60 % by weight methylmethacrylate, 30 % by weightethylacrylate and 10 % by weight 2-trimethylamoniumethyl methacrylate chloride.

Prolonged release matrix materials which are particularly suitable for the presentinvention are e.g. the neutral (meth)acrylic acid (co)polymers or the (meth)acrylicacid (co)polymers with anionic functional groups. One may for example usemixtures of these types of polymers. WO 2011/141488 PCT/EP2011/057566 -57-

For example, one may use Eudragit®NE as a neutral (meth)acrylic acid (co)polymerand Eudragit®RSPO as a (meth)acrylic acid (co)polymer with an anionic functionalgroup. One may also use a mixture of these types of polymers.

However, one may also use a mixture of (meth)acrylic acid (co)polymers and otherprolonged release matrix materials such as cellulose ethers. For example, one mayuse a mixture of a neutral (meth)acrylic acid (co)polymer and a hydrophobiccellulose ether. A particularly suitable example is the combination of a Eudragit®NEtogether with ethyl cellulose. Another prolonged release material which may be usedfor the present invention may be polymers such as polyethylene oxide.

As regards polyethylene oxides, particularly those polyethylene oxides with amolecular weight in the range of 1 x 105 - 5 x 105 may be used.

Prolonged release materials which are particularly suitable for the present inventionare e.g. the neutral (meth)acrylic acid (co)polymers or the (meth)acrylic acid(co)polymers with anionic functional groups. One may for example use mixtures ofthese types of polymers.

For example, one may use Eudragit®NE as a neutral (meth)acrylic acid (co)polymerand Eudragit®RSPO as a (meth)acrylic acid (co)polymer with an anionic functionalgroup. One may also use a mixture of these types of polymers.

The use of (meth)acrylic acid (co)polymers can be particularly suitable for increasinghardness/breaking strength upon heat treatment. WO 2011/141488 PCT/EP2011/057566 -58-

However, one may also use a mixture of (meth)acrylic acid (co)polymers and otherprolonged release matrix materials such as cellulose ethers. For example, one mayuse a mixture of a neutral (meth)acrylic acid (co)polymer and a hydrophobiccellulose ether. A particularly suitable example is the combination of aEudragit®NE together with ethyl cellulose. Another example is a mixture ofcellulose ether such as hydrophobic cellulose ethers (e.g. ethyl cellulose) with a fattyalcohol (e.g. stearyl alcohol). A mixture of (meth)acrylic acid (co)polymers such asneutral (meth)acrylic acid (co)polymer (e.g. Eudragit®NE) and cellulose ethers suchas hydrophobic cellulose ethers (e.g. ethyl cellulose) may also comprise a fattyalcohol (such as stearyl or cetostearyl alcohol) as a further prolonged release matrixmaterial. Such mixtures may allow combining beneficial characteristics such asalcohol resistance and increased hardness and improved stability upon heattreatment.

The amount of prolonged release material(s) in the prolonged release formulationmay be of about 5 to 90 % by weight, of about 10 to 70% by weight, of about 20 to60 % by weight, of about 20% to about 55% by weight, of about 25% to about 50%by weight, of about 25% to about 45% by weight and preferably of about 30 to about40% by weight based on the weight of the pharmaceutical composition. The amountof prolonged release material that is incorporated into the composition can be oneway of adjusting the prolonged release properties. For example, if the amount ofprolonged release material is increased, the release can be further prolonged. Theaforementioned amounts refer to the overall content of prolonged release materials ina pharmaceutical composition. These amounts may thus refer to a mixture of variousprolonged release materials such as a neutral (meth)acrylic acid (co)polymer, ahydrophobic cellulose ether and/or a fatty alcohol. WO 2011/141488 PCT/EP2011/057566 -59-

If cellulose ether is among the prolonged release materials, it will typically bepresent in an amount of about 5% to about 50% by weight, of about 5% to about45% by weight, of about 5% to about 40% by weight, of about 5% to about 35% byweight, of about 5% to about 30% by weight, of about 5% to about 25% by weight,of about 5% to about 20% by weight such as of about 5% by weight, of about 7% byweight, of about 10% by weight, of about 15% by weight, of about 18% by weight orof about 20% by weight based on the weight of the pharmaceutical composition.

If fatty alcohol is among the prolonged release materials, it will typically be presentin an amount of about 5% to about 50% by weight, of about 5% to about 45% byweight, of about 5% to about 40% by weight, of about 5% to about 35% by weight,of about 10% to about 30% by weight, of about 10% to about 25% by weight such asof about 10% by weight, of about 15% by weight, of about 20% by weight or about25% by weight based on the weight of the pharmaceutical composition.

If (meth)acrylic acid (co)polymer is among the prolonged release materials, it willtypically be present in an amount of about 5% to about 50% by weight, of about 5%to about 45% by weight, of about 5% to about 40% by weight, of about 5% to about35% by weight, of about 10% to about 30% by weight, of about 10% to about 25%by weight such as of about 10% by weight, of about 15% by weight, of about 20% byweight or about 25% by weight based on the weight of the pharmaceuticalcomposition.

The pharmaceutical compositions in accordance with the invention may also includepharmaceutically acceptable excipients such fillers, lubricants, binders, release ratemodifiers,, anti-tacking agents etc. WO 2011/141488 PCT/EP2011/057566 -60-

Fillers which may also be designated as diluents may include e.g. lactose, preferablyanhydrous lactose, glucose or saccharose, starches, their hydrolysates,microcrystalline cellulose, cellatose, sugar alcohols such as sorbitol or mannitol,polysoluble calcium salts like calcium hydrogen phosphate, dicalcium- or tricalciumphosphate and combinations of two or more of the above fillers..

It has been observed that the combination of hydromorphone and naloxone can bemoisture sensitive in particular if cellulose ethers are used as prolonged releasematerial. In view of this situation it can be preferred to use fillers which do notimport moisture e.g. in the form of water. In preferred embodiments one may thususe anhydrous fillers such as anhydrous lactose.

Lubricants can include highly dispersed silica, talcum, com starch, magnesium oxideand magnesium- or calcium stearate, fats like hydrated castor oil, sodium stearylfumarate and combinations of two or more of the above lubricants.

It can be preferred to use a combination of magnesium stearate and talcum aslubricants. It has been found that if appropriate amounts of these lubricants arechosen, one can e.g. improve flow properties of granules used for compressing.

It thus can be preferred to use a lubricant amount of about 0.5% to about 4% byweight, of about 0.7% to about 3% by weight, of about 1% to about 2% by weightsuch as of about 1.0% by weight, of about 1.1 % by weight, of about 1.2 % byweight, of about 1.3 % by weight, of about 1.4 % by weight, of about 1.5 % byweight, of about 1.6% by weight, of about 1.7 % by weight, of about 1.8% byweight, of about 1.9 % by weight or of about 2.0 % by weight based on the weight ofthe pharmaceutical composition. An amount of about 0.75% to about 1.25% byweight based on the weight of the pharmaceutical composition can be preferred, WO 2011/141488 PCT/EP2011/057566 -61 - particularly if magnesium stearate and talc are used. The aforementioned amountsrefer to the amount of all lubricants (i.e. including mixtures) in the composition.

Binders can include hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose, polyvinyl pyrollidone, carbopol, and combinations thereof.

It can be preferred to use HPC as a binder as this may positively influence thehardness of the tablets.

It thus can be preferred to use a binder amount of about 1% to about 10% by weight,of about 2% to about 9% by weight, of about 3% to about 7% by weight, of about3% to about 6% by weight, of about 4% to about 5% by weight such as of about 4.0% by weight, of about 4.1 % by weight, of about 4.2 % by weight, of about 4.3 % byweight, of about 4.4 % by weight, of about 4.5 % by weight, of about 4.6% byweight, of about 4.7 % by weight, of about 4.8 % by weight, of about 4.9 % byweight or of about 5.0 % by weight based on the weight of the pharmaceuticalcomposition. An amount of about 4.4% to about 5.0% by weight based on the weightof the pharmaceutical composition can be preferred, particularly of HPC is used asbinder. The aforementioned amounts refer to the amount of all binders (i.e. includingmixtures) in the composition.

It can be preferred to not use povidone as a binder.

Release rate modifiers are pharmaceutically acceptable excipients which may beused to tune the release which otherwise would be obtained using the prolongedrelease materials, e.g. to accelerate the release or to further slow it down. Suchrelease modifiers may be hydrophilic substances such as polyethylenglycols,hydroxypropylmethlycellulose, hydroxyethylcellulose, and the like or hydrophobic WO 2011/141488 PCT/EP2011/057566 -62- substances such as oils, waxes and the like. Other release modifiers may includesome the aforementioned (meth)aycrylic acid(co)polymers such as polymers of theEudragit® RLPO type or gums such as xanthan gum.

Release rate modifiers such as polymers of the Eudragit/®RLPO type, low molecularweight hydroxypropylmethlycellulose such Hypromellose KI OOM or xanthan gummay be preferred.

Such release rate modifiers may be present in an amount of about 1% to about 20%by weight, of about 2% to about 19% by weight, of about 3% to about 18% byweight, of about 4% to about 17% by weight, of about 5% to about 15% by weightsuch as of about 5 % by weight, of about 6% by weight, of about 7% by weight, ofabout 8% by weight, of about 9% by weight, of about 10% by weight, of about 11%by weight, of about 12% by weight, of about 13% by weight, of about 14% byweight or of about 15% by weight based on the weight of the pharmaceuticalcomposition. The aforementioned amounts refer to the amount of all release ratemodifiers (i.e. including mixtures) in the composition.

It is to be understood that the functions of pharmaceutically acceptable excipientsmay be overlapping. For example, a spheronising agent such as microcrystallinecellulose can also be used as filler if appropriate amounts are chosen. Further, HPMCmay not only act as release rate modifying agent but also as binder if e.g. used inprolonged release formulation with a coating.

Prolonged release coatings may be made from materials which are common in theart. WO 2011/141488 PCT/EP2011/057566 -63-

They may thus be selected from e.g. prolonged release materials selected e.g. from (i) an alkylcellulose; (ii) an acrylic polymer; (iii) polyvinylalcohol or (iv) mixturesthereof. Hydrophobic representatives of the afore-mentioned groups can be preferred.The coating may be applied in the form of an organic or aqueous solution ordispersion.

In some embodiments, the controlled release coating is derived from an aqueousdispersion of the hydrophobic controlled release material. The coated compositioncan then be cured.

In preferred embodiments, the controlled release coatings include a plasticizer suchas those described herein below.

In certain embodiments, one may coat with an amount of coating material which issufficient to obtain a weight gain level from about 2 to about 20%, e.g., about 2 toabout 15% and preferably about 5 to about 10% such as 6%, 7%, 8% or 9% in orderto obtain sufficiently prolong the release from the formulation..

Cellulosic materials and polymers, including alkyl celluloses are prolonged releasematerials well suited for coating substrates, e.g., beads, granules, tablets, etc.according to the invention. Simply by way of example, one preferred alkyl cellulosicpolymer is ethyl cellulose

One commercially available aqueous dispersion of ethyl cellulose is Aquacoat® suchas Aquacoat® ECD30 (FMC Corp., Philadelphia, Pennsylvania, U.S.A.). Aquacoatis prepared by dissolving the ethyl cellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactant and a WO 2011/141488 PCT/EP2011/057566 -64- stabilizer. After homogenization to generate submicron droplets, the organic solventis evaporated under vacuum to form a pseudo latex.

Another aqueous dispersion of ethyl cellulose is commercially available asSurelease® (Colorcon, Inc., West Point, Pennsylvania, U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during the manufacturingprocess. A hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleicacid) is prepared as a homogeneous mixture, which is then diluted with an alkalinesolution to obtain an aqueous dispersion which can be applied directly ontosubstrates.

In other of the present invention, the prolonged release coating material is apharmaceutically acceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethylmethacrylates, cynaoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamide copolymer, poly(methyl methacrylate),polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride) and glycidylmethacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised of one or moreammonium methacrylate copolymers. Ammonium methacrylate copolymers are wellknown in the art, and are described as fully polymerized copolymers of acrylic andmethacrylic acid esters with a low content of quaternary ammonium groups. Typicalexamples include Eudragit® RS30D which is a low permeability ammoniummethacrylate polymer and Eudragit®RL30D which is a high permeabilityammonium methacrylate polymer. Eudragit RL and Eudragit RS are water swellable, WO 2011/141488 PCT/EP2011/057566 -65- and the amount of water absorbed by these polymers is pH-dependent, however,dosage forms coated with Eudragit RL and RS are pH-independent.

The acrylic coatings may comprise a mixture of two acrylic resin lacquerscommercially available from Rohm Pharma under the Trade namesEudragit®RL30D and Eudragit®RS30D, respectively. The Eudragit®RL/RSdispersions of the present invention may be mixed together in any desired ration inorder to ultimately obtain a prolonged-release formulation having a desirabledissolution profile.

Other polymers which can be used as a prolonged release coating materials if theyare applied at sufficient amounts are e.g. hydrophilic polymers such ashyrdoxypropylmethylcellulose.

The above mentioned coatings may also be applied in combination. Further it ispossible to influence the release properties of a dosage form by increasing theamount of the coating material and thus the thickness of the coating.

In embodiments of the present invention where the coating comprises an aqueousdispersion of a hydrophobic controlled release material, the inclusion of an effectiveamount of a plasticizer in the aqueous dispersion of hydrophobic material mayfurther improve the physical properties of the prolonged release coating. Forexample, because ethyl cellulose has a relatively high glass transition temperatureand may not form flexible films under normal coating conditions, it can be preferredto incorporate a plasticizer into an ethyl cellulose coating containing prolongedrelease coating before using the same as a coating material. Generally, the amount ofplasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 % by weight of the film-former. WO 2011/141488 PCT/EP2011/057566 -66-

Examples of suitable plasticizers for ethyl cellulose include water insolubleplasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate,and triacetin, although it is possible that other water-insoluble plasticizers (such asacetylated monoglycerides, phthalate esters, castor oil, etc.) may be used. Triethylcitrate is an especially preferred plasticizer for the aqueous dispersions of ethylcellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of the present inventioninclude, but are not limited to citric acid esters such as triethyl citrate NF XVI,tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. Otherplasticizers which have proved to be suitable for enhancing the elasticity of the filmsformed from acrylic films such as Eudragit®RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin.

In the following it is described how a prolonged release matrices which may be usedfor all aspects and variations of the invention may be composed.

The invention for all its aspects and variations thus considers as a first option an oralprolonged release pharmaceutical composition comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE asprolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) the hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 -67- derivative thereof is combined with said prolonged release material toform a prolonged release matrix.

The invention for all its aspects and variations thus considers as a second option anoral prolonged release pharmaceutical composition comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) the hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof is combined with said prolonged release material toform a prolonged release matrix.

The invention for all its aspects and variations thus considers as a third option an oralprolonged release pharmaceutical composition comprising at least: a) at least one fatty alcohol as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) the hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix.

The invention for all its aspects and variations thus considers as a fourth option anoral prolonged release pharmaceutical composition comprising at least: WO 2011/141488 PCT/EP2011/057566 -68- a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one cellulose ether, preferably at least one hydrophobic celluloseether such as ethyl cellulose as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) the hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix.

The invention for all its aspects and variations thus considers as a fifth option an oralprolonged release pharmaceutical composition comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one fatty alcohol as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) the hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix.

The invention for all its aspects and variations thus considers as a sixth option whichmay be particularly preferred, an oral prolonged release pharmaceutical compositioncomprising at least: WO 2011/141488 PCT/EP2011/057566 -69- a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose and at least one fatty alcohol asprolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) the hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix.

The invention for all its aspects and variations thus considers as a seventh option anoral prolonged release pharmaceutical composition comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE, at leastone cellulose ether, preferably at least one hydrophobic cellulose ethersuch as ethyl cellulose and at least one fatty alcohol as prolongedrelease materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) the hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix.

The prolonged release materials may be used in the amounts mentioned above. WO 2011/141488 PCT/EP2011/057566 -70-

In a first embodiment of the first to seventh option, the pharmaceutical compositionis heat treated as described above.

In addition or alternatively to this first embodiment of the first to seventh option, thepharmaceutical composition may comprise an anhydrous filler such as anhydrouslactose.

In addition or alternatively to this first and second embodiment of the first to seventhoption, the pharmaceutical composition may comprise magnesium stearate and/ortalc in the above mentioned amounts.

In addition or alternatively to this first, second and third embodiment of the first toseventh option, the pharmaceutical composition may comprise HPC in the abovementioned amounts.

In addition or alternatively to this first, second, third and fourth embodiment of thefirst to seventh option, the pharmaceutical composition may comprise HPC in theabove mentioned amounts.

In addition or alternatively to this first, second, third, fourth and fifth embodiment ofthe first to seventh option, the pharmaceutical composition may comprise anadditional prolonged release coating. Such a coating may comprise preferably ethylcellulose as prolonged release coating material.

These pharmaceutical compositions according to the first to seventh option maycomprise hydromorphone and naloxone or a pharmaceutically acceptable salt orderivatives thereof in the above mentioned ratios and amounts. They may furtherprovide the above mentioned in vitro release data and alcohol resistance as described WO 2011/141488 PCT/EP2011/057566 -71 - above. Further, these compositions may provide storage stability. They may also beof a multiparticulate nature. They may further provide the pharmacokineticparameters as mentioned herein.

Of one attempts to realize specific in vitro release rates, one can use combinations ofthe above mentioned measures. For example, if the release from a prolonged releasematrix is deemed too fast one may apply a prolonged release coating in addition. Inaddition or alternatively, one may add additional prolonged release matrix materialssuch as hydrophobic polymers, with ethyl cellulose being preferred and/or fattyalcohols to granules which already comprise a prolonged release matrix and to thencompress these granules together with the additional prolonged release matrixmaterials into e.g. tablets. In a preferred embodiment, such prolonged release matrixformulations which are coated with such prolonged release matrix formulations andthen are used as a multiparticulate formulation.

The pharmaceutical compositions in accordance with the invention as describedherein may be formulated to provide a mean AUCt of about 1162 h*pg/ml to about2241 h*pg/ml and preferably of about 1328 to about 2075 h*pg/ml per mgadministered amount of hydro morphone and a mean Cmax of about 122 pg/ml toabout 234 pg/ml and preferably of about 139 to about 218 pg/ml per mg administeredamount of hydromorphone and mean tmax of about lh to about 4.5h, preferably ofabout 1,5h to about 4h and more preferably of about 1,5h to about 3h. These valuesrefer preferably to single dose administration to healthy subjects. Preferably,administration is in the fasted state. The mean values of Cmax, AUCt and tmax referto the geometric mean.

The “Cmax value” indicates the maximum blood plasma concentration of the activeagent hydromorphone. WO 2011/141488 PCT/EP2011/057566 -72-

The “tmax value” indicates the time point at which the Cmax value is reached. Inother words, tmax is the time point of the maximum observed plasma concentration.

The “AUC (Area Under the Curve)” value corresponds to the area of theconcentration curve. The AUC value is proportional to the amount of the activeagent absorbed into the blood circulation in total and is hence a measure for thebioavailability.

The “AUCt value” is the value for the area under the plasma concentration-timecurve from the time of administration to the last measurable concentration. AUCtvalues are usually calculated using the linear trapezoidal method.

If pharmacokinetic parameters such as mean tmax, cmax and AUCt are measured forhealthy subjects which may be healthy human, they are typically obtained bymeasuring the development of blood plasma values over time in a test population ofapproximately 16 to 24 healthy human subjects. Regulatory bodies such as theEuropean Agency for the Evaluation of Medicinal Products (EMEA) or the Food andDrug Administration (FDA) will usually accept data obtained from e.g. 16 or 24 testpersons. However, initial trials involving fewer participants such as 8 to 16participants may also be acceptable.

The term “healthy” subjects in this context refers to a typical male or female ofusually Caucasian origin with average values as regards height, weight andphysiological parameters such as blood pressure etc. Healthy human subjects for thepurposes of the present invention are selected according to inclusion and exclusioncriteria which are based on and in accordance with recommendations of theInternational Conference for Harmonization of Clinical Trials (ICH). For the WO 2011/141488 PCT/EP2011/057566 -73- purposes of the present invention, healthy subjects may be identified according to theinclusion and exclusion criteria as outlaid in Example 7.

Thus, inclusion criteria comprise e.g. an age between &gt;18 and &lt;45 years; a BMIwithin the range 19-29 kg/m2, and within the weight range 60 - 100 kg for malesand 55 - 90 kg for females; that females must be non-nursing, non-pregnant, andprovide a negative urine β-hCG pregnancy test within 24 hours before receiving thestudy medication; generally good health, evidenced by a lack of significantlyabnormal findings on medical history, physical examination, clinical laboratory tests,vital signs, and ECG etc.

Exclusion criteria comprise e.g. exposure to any investigational drug or placebowithin 3 months of the first dose of study medication, any significant illness withinthe 30 days before the first dose of study medication, any clinically significantabnormalities identified at prestudy screening for medical history, physicalexamination or laboratory analyses, use of any prescription medication (except HRTfor postmenopausal females and contraceptive medication) in the 21 days, or over thecounter medication including acid controllers, vitamins, herbal products and/ormineral supplements in the 7 days, before first dose of study medication, concurrentmedical condition known to interfere with gastrointestinal drug absorption (e.g.delayed gastric emptying, mal absorption syndromes), distribution (e.g. obesity),metabolism or excretion (e.g. hepatitis, glomerulonephritis), history of or concurrentmedical condition, which in the opinion of the investigator would compromise theability of the subject to safely complete the study, history of seizure disorders forwhich subjects required pharmacologic treatment, current history of smoking morethan 5 cigarettes a day, subjects with evidence of active or past history of substanceor alcohol abuse according to DSM-IV criteria, subjects who reported regularconsumption of 2 or more alcoholic drinks per day or have blood alcohol levels of WO 2011/141488 PCT/EP2011/057566 -74- &gt;0.5% at screening, donation of more than 500 mL of blood or blood products orother major blood loss in the 3 months before first dose of study medication, anypositive results in the prestudy screen for ethanol, opiates, barbiturates,amphetamines, cocaine metabolites, methadone, propoxyphene, phencyclidine,benzodiazepines, and cannabinoids in the specimen of urine collected at screening,known sensitivity to hydromorphone, naloxone, or related compounds etc.

The afore-mentioned pharmacokinetic data may preferably be obtainable with aprolonged release pharmaceutical composition comprising at least hydromorphone ora pharmaceutically acceptable salt or derivative thereof or naloxone or apharmaceutically acceptable salt or derivative thereof and at least one prolongedrelease material which is preferably combined with these pharmaceutically activeagents to form a prolonged release matrix; wherein the amount of hydromorphone ora pharmaceutically acceptable salt or derivative thereof or naloxone or apharmaceutically acceptable salt or derivative thereof released in vitro in 500 or 900ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddle method at 100 rpmat 37° C is: at 1 h: 25 to 55% by weight of the pharmaceutically active agents, at 2 h: 45 to 75% by weight of the pharmaceutically active agents, at 3 h: 55 to 85% by weight of the pharmaceutically active agents, at 4 h: 60 to 90% by weight of the pharmaceutically active agents, at 6 h: 70 to 100% by weight of the pharmaceutically active agents, at 8 h: more than 85% by weight of the pharmaceutically active agents, at 10 h: more than 90% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HCI andnaloxone HCI being preferred. The prolonged release pharmaceutical composition WO 2011/141488 PCT/EP2011/057566 -75- may comprise these actives in the above indicated amounts and weight ratio of about2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter.

The afore-mentioned pharmacokinetic data may even more preferably be obtainablewith a prolonged release pharmaceutical composition comprising at leasthydromorphone or a pharmaceutically acceptable salt or derivative thereof ornaloxone or a pharmaceutically acceptable salt or derivative thereof and at least oneprolonged release material which is preferably combined with these pharmaceuticallyactive agents to form a prolonged release matrix; wherein the amount ofhydro morphone or a pharmaceutically acceptable salt or derivative thereof ornaloxone or a pharmaceutically acceptable salt or derivative thereof released in vitroin 500 or 900 ml of Simulated Gastric Fluid, pH 1.2 using the Ph. Eur. paddlemethod at 100 rpm at 37° C is: at 1 h: 30 to 50% by weight of the pharmaceutically active agents, at 2 h: 50 to 70% by weight of the pharmaceutically active agents, at 3 h: 60 to 80% by weight of the pharmaceutically active agents, at 4 h: 65 to 85% by weight of the pharmaceutically active agents, at 6 h: 75 to 95% by weight of the pharmaceutically active agents, at 8 h: more than 90% by weight of the pharmaceutically active agents, at 10 h: more than 100% by weight of the pharmaceutically active agents.

The pharmaceutically active agents may preferably be hydromorphone HCl andnaloxone HCl being preferred. The prolonged release pharmaceutical compositionmay comprise these actives in the above indicated amounts and weight ratio of about WO 2011/141488 PCT/EP2011/057566 -76- 2:1, about 1:1, about 1:2 or about 1:3. The composition may be alcohol resistant asdescribed hereinafter.

Prolonged release pharmaceutical compositions as mentioned hereinafter can beobtained using a method of manufacturing comprising at least the steps of: a) producing granules comprising at least one prolonged release material,at least hydromorphone or a pharmaceutically acceptable or derivativesalt thereof and at least naloxone or a pharmaceutically acceptable saltor derivative thereof, b) optionally selecting granules of step a) of substantially uniform size; c) optionally adding additional prolonged release materials; d) compressing said granules of step a), step b) or step c) to obtain anoral prolonged release pharmaceutical composition in the form of atablet, e) optionally heat treating said compressed granules of step d); f) optionally disposing a prolonged release coatings either on thegranules of step a), b) or c) or on the monolithic composition obtainedin step d) or e); g) optionally curing the obtained composition.

It is to be understood that at least the compression step c) produces an oral prolongedrelease pharmaceutical composition in the form of a tablet which comprises aprolonged release matrix. However, the granules obtained in step a) may alsoalready comprise a prolonged release matrix.

Prolonged release pharmaceutical compositions as mentioned hereinafter can also beobtained using a method of manufacturing comprising at least the steps of: a) producing granules comprising at least one prolonged release material,at least hydromorphone or a pharmaceutically acceptable or WO 2011/141488 PCT/EP2011/057566 -77- derivative salt thereof and at least naloxone or a pharmaceuticallyacceptable salt or derivative thereof, b) optionally selecting granules of step a) of substantially uniform size; c) optionally heat treating said granules of step a) or step); d) optionally disposing a prolonged release coatings either on thegranules of step a), b) or or c); e) optionally curing the obtained composition.

The person skilled in the art is aware of different means and methods for producinggranules according to step a).

In one embodiment, such granules may be produced by wet or dry granulation.Thus, for producing granules, step a) may comprise the following steps: aa) blending a prolonged release material with at least hydromorphoneor a pharmaceutically acceptable or derivative salt thereof and atleast naloxone or a pharmaceutically acceptable salt or derivativethereof and optionally with a pharmaceutically acceptableexcipient, ab) wet or dry granulating said blend of step aa) to obtain granules, andoptionally spheronising them, ac) drying said granules of step ab).

The pharmaceutically acceptable excipients may include the fillers, binders,lubricants, release rate modifiers, spheronising agents, anti-tacking agents, etc. asmentioned above. However, some of these excipients such as e.g. lubricants may beadded at a later stage (see below). WO 2011/141488 PCT/EP2011/057566 -78-

Different technology is available to obtain such granules. One may use e.g. drumgranulation or fluidized bed granulation.

Alternatively and/or additionally granules according to step a) may be producedcomprising the steps of: aa) blending a prolonged release matrix material with at leasthydromorphone or a pharmaceutically acceptable or derivative saltthereof and at least naloxone or a pharmaceutically acceptable saltor derivative thereof and optionally with a pharmaceuticallyacceptable excipient, ab) extruding said blend of step aa) to obtain granules, ac) drying said granules of step ab).

The pharmaceutically acceptable excipients may include the fillers, binders,lubricants, release rate modifiers, spheronising agents, anti-tacking agents, etc. asmentioned above. However, some of these excipients such as e.g. lubricants may beadded at a later stage (see below).

Different extruder technology is available to obtain extruded granules. For example,one may use a single screw or twin screw extruder. For twin screw extruders, onemay use counter-rotating or co-rotating screws having optionally paddle means.

As mentioned above, the granules which may be produced by wet granulationextrusion may be dried before being mixed with the at least one pharmaceuticallyactive agent.

Typically, drying takes place at humidity in the range of about 0.5 % to about 5.0 %at a temperature in the range of about 20°C to about 90°C and for a time in the range WO 2011/141488 PCT/EP2011/057566 -79- of about 10 min to about 3 hours. Drying at ambient humidity at a temperature in therange of about 40°C to about 90°C and for a time in the range of about 15 min toabout 2 hours can be preferred.

The granules may then be optionally screened in order to select granules ofsubstantially uniform size. Selecting granules of substantially uniform size beforecompressing them may improve the prolonged release properties of the finalprolonged release pharmaceutical composition as the active and the granules are thenassumed to be more uniformly distributed which may prevent irregularities in therelease profile. Granules for which at least about 70%, preferably at least about 80%,more preferably at least about 90% are of about the same mean size will typically beconsidered as being of substantially uniform size.

Preferably, granules are selected of a mean size in the range of about 100 pm toabout 2 mm, more preferably in the range of about 100 pm to about 1 mm, and evenmore preferably in the range of about 100 pm to about 600 pm. Selection may beperformed using a sieve with an appropriate mesh size.

In some embodiments the granules may be milled before selecting them for theirsize. Milling may both increase the yield of the selection step and improve thegranules’ suitability for the subsequent compression step. For milling one may usefor example a rotary hammer mill or top/bottom driven conical mill.

Even though granules may be produced by wet granulation, anyhdrousmanufacturing steps and methods such as anhydrous extrusion may be preferred, atleast where hydromorphone and naloxone or its pharmaceutically acceptable salts orderivatives thereof are to be included in a prolonged release matrix. The preferencefor anhydrous manufacturing steps and methods when making a prolonged release WO 2011/141488 PCT/EP2011/057566 - 80- matrix is that this has a beneficial impact on the chemical stability of hydro morphoneor naloxone or its pharmaceutically acceptable salts or derivatives. Once the activeagents have been included in such a prolonged release matrux, the optional additionalapplication of e.g. a prolonged release coating does not have be in an anhydrousmanner. It is to be understood that the term “anhydrous manufacturing” indicates thatthe process that leads to a prolonged release matrix may be performed in the absenceof substantial amounts of water. This does not mean that the components which areused do not comprise molecular bound water. Thus, even where the process isperformed in an anhydrous manner such as extrusion, naloxone hydrochloride maye.g. be provided as a dihydrate and fillers such as lactose may be provided as lactosemonohydrate even though anhydrous lactose can be preferred.

For compressing the pharmaceutically active agent(s) with the granules, one may usetypical tabletting equipment such as Example Fette or Kilian press.

When compressing granules and active(s), one may also include pharmaceuticallyacceptable excipients as they are commonly used in the art. For example, one mayadd lubricants, anti-tacking agents, binders and the like. For lubricants, the use ofmagnesium stearate and/or talc in the aforementioned amounts can be of advantage.

As mentioned above, prolonged release pharmaceutical dosage forms in accordancewith the invention may be additionally subjected to a heat treatment step as has beendescribed above.

The prolonged release coating may be produced by methods common in the art sucha fluidized bed spraying.

As described above, the invention relates in some embodiments to oral prolongedrelease pharmaceutical compositions comprising hydromorphone or a WO 2011/141488 PCT/EP2011/057566 - 81 - pharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt of derivative thereof comprising hydromorphone ora pharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt of derivative thereof in weight rations in a range of5 about 2:1 to about 1:3, preferably of about 2:1, 1:1, 1:2 or 1:3. It is to be understoodthat particularly for these embodiments, hydromorphone or a pharmaceuticallyacceptable salt or derivative thereof and naloxone of a pharmaceutically acceptablesalt or derivative thereof can be comprised within distinct pharmaceuticalcompositions which can then be administered simultaneously or sequentially to 10 provide the benefits of such a fixed ratio.

The invention is now illustrated with respect to specific examples. These examplesare, however, not to be construed as limiting. WO 2011/141488 PCT/EP2011/057566 - 82-

EXAMPLES

Example 1:

Tablets of the composition as shown in Table 1 were manufactured.

Tablets F880/99 F880/105 F893/31 Ingredient Amount(mg) Amount(mg) Amount(mg) Hydromorphone HCI 2.0 2.0 2.0 Naloxone HCI 4.0 4.0 4.0 Stearyl alcohol 25.0 25.0 25.0 Ethyl cellulose N45 20.0 20.0 ___ Lactose anhydrous 76.4 76.4 76.4 Eudragit RSPO* — — 20.0 Sodium stearylfumarate 2.6 2.6 2.6 Hypromellose KI OOM 20.0 — 20.0 Xanthan Gum ‘extra’ — 12.0 — Total 150.0 142.0 150 *The amount indicated refers to the amount of solids used. 10 Hydromorphone HCI and naloxone HCI were mixed with lactose anhydrous, stearylalcohol and either ethyl cellulose N45 or Eudragit RSPO as a prolonged releasepolymer in a double cone mixer for 10 min.

Subsequently the blend was melt extruded using a heated twin screw extruder.. 15 WO 2011/141488 PCT/EP2011/057566 - 83 -

The temperature profile for the extruder was as follows:

Extruder type twin screw Heating zone 1 (feedingzone) 25°C Heating zone 2 50-55°C Heating zone 3 73-83°C Heating zones 5-10 70-80°C Die head 50-55

The feeder rate was 10-15kg/h. The screw speed was set at 150-250rpm. The dieplate design allowed for multiple strand extrusion. Compressed air was used to coolthe extruded strands on conveyor belt.

Subsequently, the strands were milled to obtain granules. For milling, a Retsch millwith a 1.25 mm screen was used. This gave a substantially unimodal size distributionof the granules mainly in the range 100 to 600 pm.

The granules were then blended with sodium stearyl fumarate which was included asa lubricant. In addition, Hypromellose KI 00M was included as a release modifier.These components were blended for an additional 5 min. The granules were thencompressed into tablets using a Kilian press.

Tablets F880/99, F880/105 and F893/31 were then analyzed as regards in vitrorelease behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HCI with pH 1.2). Aliquotsof the dissolution media are withdrawn at the respective time points and analyzed byHPLC at 220 nm. WO 2011/141488 PCT/EP2011/057566 - 84-

The in vitro release are indicated as percentage (based on the label content of activetested) in table 2.

Table 2

Tablets Dissolutionmedium 0.1 N HCl pH 1.2 0.1 N HCl pH 1.2 0.1 N HCl pH 1.2 Active tested Hm Nal Hm iliiiiiil Hm 0.5h 25 24 29 28 25 23 lh 37 35 41 40 36 33 2h 55 53 59 56 53 49 3h 68 66 71 68 65 62 4h 78 77 79 77 75 71 5h 88 86 86 83 83 79 6h 94 92 91 88 89 85 7h 97 96 93 91 92 89 8h 99 97 96 94 95 92 9h 99 98 97 96 97 95 lOh 99 98 98 97 97 96 llh 99 98 99 98 97 96 12h 99 98 99 98 97 96

Hm = hydromorphone HC1, Nal = naloxone HC1, 0.1 N HC1 w/o 40% EtOH = 0.1 N HC1 pH 1.2 without 40% ethanol; Values are averages of 6 measurements.

The tablets were further evaluated with respect to their alcohol resistance. To this 10 end in vitro release rates were determined using the Ph. European paddle method at75 rpm in 500 simulated gastric fluid (SGF) dissolution medium (0.1 N HC1 with pH1.2) with 40% EtOH. Aliquots of the dissolution media are withdrawn at therespective time points and analyzed by HPLC at 220 nm. 15 The in vitro release rates are indicated as percentage (based on the label content ofactive tested) in table 3. WO 2011/141488 PCT/EP2011/057566 - 85 -

Table 3

Tablet F880/99 Dissolutionmedium 0.1 N HC1 w 40% EtOH 0.1 N HC1 w 40% EtOH 0.1 N HCI w 40% EtOH Active tested Hm Nal Hm iiiiiii Hm Nal 15min 0 0 0 0 0 0 30 min 12 11 9 9 12 11 45 min 16 16 23 21 17 16 60 min 21 20 39 36 21 20 90 min 25 24 63 59 25 23 120min 31 30 83 77 31 29

Hm = hydromorphone HC1, Nal = naloxone HC1, 0.1 N HC1 w 40% EtOH = 0.1 N HC1 pH 1.2 with40% ethanol, Values are averages of 6 measurements.

Example 2

Tablets of the composition as shown in Table 4 were manufactured. 10 Table 4

Tablets F880/77 F880/83 F893/89 Ingredient Amount(mg) Amount(mg) Amount(mg) Hydromorphone HCI 2.0 2.0 2.0 Naloxone HCI 4.0 4.0 4.0 Stearyl alcohol 25.0 25.0 15.0 Ethyl cellulose N45 20.0 20.0 20 Lactose anhydrous 76.4 76.4 76.4 Sodium stearylfumarate 2.6 2.6 2.6 Hypromellose K100M”Extra” 20.0 7.5 12.5 Total 150 142.5 137.5 WO 2011/141488 PCT/EP2011/057566 - 86-

Hydromorphone HCI and naloxone HCI were mixed with lactose anhydrous, stearylalcohol and ethyl cellulose as a prolonged release polymer in a double cone mixer for10 min.

Subsequently the blend was melt extruded using a heated twin screw extruder.

The temperature profile for the extruder was as follows:

Extruder type twin screw Heating zone 1 (feedingzone) 25°C Heating zone 2 50-55°C Heating zone 3 73-83°C Heating zones 5-10 70-80°C Die head 50-55

The feeder rate was 10-15kg/hr. The screw speed was set at 150-250rpm. The dieplate design allowed for multiple strand extrusion. Compressed air was used to coolthe extruded strands on a conveyor belt.

Subsequently, the strands were milled to obtain granules. For milling, a Retsch millwith a 1.25 mm screen was used. This gave a substantially unimodal size distributionof the granules mainly in the range 100 to 600 pm.

The granules were then blended with sodium stearyl fumarate which was included asa lubricant. In addition, Hypromellose KI 00M was included as a release modifier.These components were blended for an additional 5 min. The granules were thencompressed into tablets using a Kilian press. WO 2011/141488 PCT/EP2011/057566 - 87-

Tablets F880/77, F880/83 and F880/89 were then analyzed as regards in vitro releasebehavior using the Ph. European paddle method at 75 rpm in 500 ml simulatedgastric fluid (SGF) dissolution medium (0.1 N HC1 with pH 1.2). Aliquots of the 5 dissolution media are withdrawn at the respective time points and analyzed by HPLCat 220 nm.

Tablets F880/77, F880/83 and F880/89 were further evaluated with respect to theiralcohol resistance. To this end in vitro release rates were determined using the Ph. 10 European paddle method at 75 rpm in 500 ml simulated gastric fluid (SGF)dissolution medium (0.1 N HC1 with pH 1.2) with 40% EtOH. Aliquots of thedissolution media are withdrawn at the respective time points and analyzed by HPLCat 220 nm. 15 The in vitro release data is indicated as percentage (based on the label content ofactive tested) in tables 5 to 6. WO 2011/141488 PCT/EP2011/057566 -88-

Table 5

Tablets iiiiiiiiiiliililiiiiiiiiii Dissolutionmedium 0.1 N HCI pH 1.2 0.1 N HCI pH 1.2 0.1 N HCI pH 1.2 Active tested Hm Nal Hm iiiiiiii Hm Nal 0.5h 16 14 25 24 23 20 lh 24 22 40 39 35 33 2h 38 35 68 67 51 49 3h 50 45 87 86 65 63 4h 59 54 96 96 78 76 5h 68 62 99 99 87 86 6h 76 70 100 100 95 93 7h 82 77 100 100 96 95 8h 87 82 101 100 96 95 9h 92 86 101 101 97 96 lOh 95 90 101 100 96 96 llh 97 93 101 101 97 96 12h 99 94 102 101 97 96

Hm = hydromorphone HC1, Nal = naloxone HC1; Values are averages of 6 measurements. 5 Table 6

Tablets F880/77 F880/83 F880/89 Dissolutionmedium 0.1 N HCI w40% EtOH 0.1 N HCI w40% EtOH 0.1 N HCI w 40% EtOH Active tested Hm iliiiiiiiiiii Hm Nal Hm Nal 15 min 15 14 12 10 10 8 30 min 25 22 19 17 16 14 45 min 37 34 24 23 21 20 60 min n.d. n.d. 29 28 25 23 90 min n.d. n.d. 37 35 32 30 120 min n.d. n.d. 43 42 38 36

Hm = hydromorphone HC1, Nal = naloxone HC1, 0.1 N HC1 w 40% EtOH = 0.1 N HC1 pH 1.2 with 40% ethanol, n.d. = not determined; Values are averages of 6 measurements. 10 WO 2011/141488 PCT/EP2011/057566 - 89-

Example 3:

Granules of the composition as shown in table 7 were manufactured. 5 Table 7

Tablets PN3450 iiiiiiii iiiiiiii Ingredient Amount (mg) Amount(mg) Amount(mg) Hydromorphone HCI 4.0 4.0 4.0 Naloxone HCI 8.0 8.0 8.0 Hydroxypropylcellulose 5.0 5.0 5.0 Stearyl alcohol 17.5 25.0 25.0 Ethyl cellulose N45 7.5 10.0 15.0 Lactose anhydrous 46.0 46.0 46.0 Magnesium stearate 1.25 1.25 1.25 Talc 0.75 0.75 0.75 Total 90 100 105

Hydromorphone HCI and naloxone HCI were mixed with lactose anhydrous, stearyl10 alcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.

Subsequently the blend was melt extruded using a heated twin screw extruder. 15 The temperature profile was as follows: WO 2011/141488 PCT/EP2011/057566 -90-

Extruder type twin screw Heating zone 1 (feedingzone) 25°C Heating zone 2 50-55°C Heating zone 3 73-83°C Heating zones 5-10 70-80°C Die head 50-55

The feeder rate was 10-15kg/hr. The screw speed was set at 150-250rpm. The dieplate design allowed for multiple strand extrusion. Compressed air was used to coolthe extruded strands on a conveyor belt.

The granules were milled and the milled granules were blended with magnesiumstearate and talc in a tumbler mixer. Subsequently, the blended granules werecompressed into tablets and heat treated for 30 minutes at 55°C.

Figure 1 shows for e.g. for the case of PN3450 that heat treatment of the prolongedmatrix improves the physical stability of the formulation, e.g. in that the appearanceof cracks is reduced and the intactness of the tablet is improved. Similar observationswere made for the other heat treated tablets mentioned herein. This may positvelyinfluence the in vitro release properties of the formulation, particularly in an in vivosetting as cracks may e.g. affect the release properties in an unpredictable mannerdue to e.g. a sudden change in the surface of the tablet. Furthermore, the hardness ofthe tablets is increase by usually 6 kP to 10 to 11 kP.

Tablets PN3450, PN3451 and PN3452 were then analyzed as regards in vitro releasebehavior using the Ph. European paddle method at 75 rpm in 500 ml simulatedgastric fluid (SGF) dissolution medium (0.1 N HC1 with pH 1.2). Aliquots of the WO 2011/141488 PCT/EP2011/057566 -91 - dissolution media are withdrawn at the respective time points and analyzed by HPLCat 220 nm.

The in vitro release data is indicated as percentage (based on the label content of5 active tested) in table 9.

Table 9

Tablets PN3450 iiiiieiiiiiiiii Dissolutionmedium 0.1 N HCl pH 1.2 0.1 N HCl pH 1.2 0.1 N HCl pH 1.2 Active tested Hm Nal Hm iiiiii Hm Nal lh 51,50 50,80 40,54 39,69 33,22 32,31 2h 68,10 67,60 54,82 53,92 45,89 45,04 3h 78,50 78,30 64,22 63,54 54,80 54,05 4h 85,50 85,60 71,72 71,11 61,85 61,21 5h 90,50 90,70 77,74 77,28 67,57 67,06 6h 93,90 94,30 82,11 81,72 72,22 71,97 7h 95,90 96,60 85,82 85,65 76,29 75,94 8h 96,90 97,90 89,19 89,24 79,75 79,63 9h 97,50 98,50 91,82 91,93 82,81 82,73 lOh 97,50 98,60 93,71 94,04 85,24 85,59 llh 97,00 98,30 95,19 95,72 87,60 87,83 12h 97,20 98,40 96,54 97,26 89,43 89,91

Hm = hydromorphone HCl, Nal = naloxone HCl; Values are averages of 6 measurements. 10 Subsequently, tablets PN350, PN3451 and PN3452 were placed in PVC blisters andstored for 3 months at 25°C and 60% RH or for 1, 2 and 3 months at 40°C and 75%RH.

All tablets were tested either initially or after storage for total related substances. 15 WO 2011/141488 PCT/EP2011/057566 -92-

The results are shown in table 10.

Table 10

Tablets PN3450 PN3450 iiiiiiiii iiiiiiiii iilBliliii iiiiiiiiii Container iiiiiiiii iHiiiiii iiiiiiiii iiiiiiiiiii iiiiiiiiiii: iiiiiiiiiiiii Storage iiitiiiii % RH iiitiiiii % RH iiitiiiii % RH iiitiiiii % RH iiiiiiiii % RH tlitiili RH Initial 0,15% 0.15% 0.15% 0.15% 0.16% 0.16% 1 month ___ 0.26% ___ 0.31% ___ 0.33% 2 months — 0.28% — 0.39% — 0.29% 3 months 0.33% 0.24% 0.34% 0.24% 0.36% 0.32%

Example 4:

Granules of the composition as shown in Table 11 were manufactured. 10

Table 11

Tablets F923/16 Ingredient Amount(mg) Hydromorphone HC1 4.0 Naloxone HC1 8.0 Hydroxypropylcellulose 5.0 Stearyl alcohol 25.0 Ethyl cellulose N45 10.0 Lactose anhydrous 46.0 Total 98 WO 2011/141488 PCT/EP2011/057566 -93-

Hydromorphone HC1 and naloxone HC1 were mixed with lactose anhydrous, stearylalcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.

Subsequently the blend was melt extruded using a heated twin screw extruder. Thegranules were milled and the milled granules were blended with magnesium stearateand talc in a tumbler mixer. Subsequently, the blended granules were compressedinto tablets.

Tablets F923/16 were heat treated for 15 min at 55°C. The heat treated tablets werelabeled F922/58A.

Tablets F923/16 were heat treated for 30 min at 55°C. The heat treated tablets werelabeled F922/58B.

Tablets F923/16 were heat treated for 45 min at 55°C. The heat treated tablets werelabeled F922/58C.

Tablets F923/16 as well as their heat treated counterparts were then analyzed asregards in vitro release behavior using the Ph. European paddle method at 75 rpm in500 ml simulated gastric fluid (SGF) dissolution medium (0.1 N HC1 with pH 1.2).Aliquots of the dissolution media are withdrawn at the respective time points andanalyzed by HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 12. WO 2011/141488 PCT/EP2011/057566 -94-

Table 12

Tablets F923/16 iiiliiiiilliii iiiiiiiiiiiiiii iiiiiiiiiiiiiii Dissolutionmedium 0.1 N HClpH 1.2 0.1 N HClpH 1.2 0.1 N HClpH 1.2 0.1 N HClpH 1.2 Active tested Hm iii Hm Nal Hm Nal Hm iiili lh 48 47 40,06 39,10 39,12 38,17 38,31 37,54 2h 64 64 53,93 52,15 53,47 52,68 52,43 51,04 3h 75 74 63,75 62,68 63,79 62,34 62,19 61,07 4h 82 82 71,05 70,47 70,74 69,86 69,53 68,41 5h 86 87 78,03 77,01 76,58 75,71 75,37 76,35 6h 91 92 81,42 81,27 81,27 80,61 79,94 79,05 7h 94 94 84,75 84,56 85,59 82,89 83,97 83,26 8h 95 96 87,70 87,62 88,74 88,42 87,17 86,71 9h 96 97 91,27 90,97 90,86 90,71 89,67 88,92 lOh 96 97 92,80 92,86 92,88 92,73 92,80 92,34 llh 96 97 94,14 94,45 94,32 94,42 93,73 91,82 12h 98 97 95,16 95,46 96,33 95,58 94,60 94,55

Hm = hydromorphone HCl, Nal = naloxone HCl; Values are averages of 6 measurements. 5 Example 5:

Tablets with a prolonged release matrix and of comparable composition as inexample 3 but comprising 20 mg ethyl cellulose were prepared. These tablets werethen subjected to different heat treatments. 10

F922/70C: heat treated for 45 min at 55°C F922/70D: heat treated for 60 min at 55°C F922/70E: heat treated for 75 min at 55°C 15 Tablets F922/70C, F922/70D and F922/70E were then analyzed as regards in vitrorelease behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HCl with pH 1.2). Aliquots WO 2011/141488 PCT/EP2011/057566 -95- of the dissolution media are withdrawn at the respective time points and analyzed byHPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content of 5 active tested) in table 13.

Table 13

Tablets F922 /70C iiliiiiiiliiii iiiiililiiillii Dissolutionmedium 0.1 N HCIpH 1.2 pH 1.2 pH1.2 Active tested Hm Nal Hm Hm Nal lh 23,09 21,44 22,56 20,95 21,89 20,37 2h 33,32 31,48 31,65 29,87 31,24 29,27 3h 41,16 38,85 38,90 36,71 38,24 36,14 4h 47,38 45,14 44,50 42,18 44,05 41,80 5h 52,37 49,95 49,65 47,36 49,11 46,87 6h 57,11 54,79 53,72 51,77 53,39 51,11 7h 60,75 59,23 57,67 55,57 57,25 55,11 8h 65,12 62,84 61,13 59,31 60,78 58,65 9h 68,15 66,50 64,27 62,44 63,93 61,81 lOh 71,75 69,40 67,47 65,21 66,76 64,95 llh 74,02 72,26 70,10 68,42 69,53 67,72 12h 76,49 75,01 72,82 70,86 71,83 70,16

Hm = hydromorphone HCI, Nal = naloxone HCI; Values are averages of 6 measurements.

Example 6

Tablets F906/46 with a prolonged release matrix and of comparable composition asin example 3 but comprising 20 mg ethyl cellulose were prepared. These tablets were15 then subjected to different heat treatments.

F906/95B: F906/46 heat treated for 15 min at 55°C F906/95C: F906/46 heat treated for 45 min at 55°C WO 2011/141488 PCT/EP2011/057566 -96-

Tablets F906/46, F906/95B and F906/95C were then analyzed as regards in vitrorelease behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HCI with pH 1.2). Aliquots5 of the dissolution media are withdrawn at the respective time points and analyzed by HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 14. 10

Table 14

Tablets F906/46 F9906/95B F906/95C Dissolutionmedium 0.1 N HCIpH 1.2 0.1 N HCI 0.1 N HCI Active tested Hm iiiii Hm iiiii Hm iliiiii lh 42,23 41,72 35.2 34,1 35.9 34,8 2h 57,26 57,35 48,8 47,8 49,8 48,9 3h 68,41 69,12 58,1 57,4 59,4 58,7 4h 89,71 89,87 64,5 64,0 65,4 65,0 5h 95,66 96,01 71,6 71,4 71,4 71,3 6h 96,21 96,69 77,2 77,3 77,8 77,8 7h 96,24 96,80 80,6 80,7 82,6 82,5 8h 96,29 96,70 85,6 85,7 85,6 85,5 9h 96,24 96,75 88,1 88,2 89,7 89,6 lOh 96,27 96,88 91,6 91,7 90,6 90,4 llh 96,38 96,87 93,4 93,7 93,1 93,4 12h 96,26 96,85 94,7 95,2 93,9 94,3

Hm = hydromorphone HCI, Nal = naloxone HCI; Values are averages of 6 measurements. 15 Example 7

Tablets of the composition as shown in table 15 were manufactured. WO 2011/141488 PCT/EP2011/057566 -97-

Table 15

Tablets Iliiiilll F933/69 liiiiiiil Iiiiiiii Ingredient Amount (mg) Amount(mg) Amount(mg) Amount (mg) Hydromorphone HCI 2.0 4.0 4.0 4.0 Naloxone HCI 4.0 2.0 4.0 12.0 Hydroxypropylcellulose 5.0 5.0 5.0 5.0 Stearyl alcohol 25.0 25.0 25.0 25.0 Ethyl cellulose N45 10.0 10.0 10.0 10.0 Lactose anhydrous 52.0 52.0 50.0 42.0 Talc 1.25 1.25 1.25 1.25 Magnesium Stearate 0.75 0.75 0.75 0.75 Total 100 100 100 100

Hydromorphone HCI and naloxone HCI were mixed with lactose anhydrous, stearyl5 alcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.Subsequently the blend was melt extruded using a heated twin screw extruder asdescribed above. 10 The granules were milled and the milled granules were blended with magnesiumstearate and talc in a tumbler mixer. Subsequently, the blended granules werecompressed into tablets. The tablets were then heat treated for 30 min at 55°C.

Tablets F933/67, F933/69, F933/71 and F933/73 were then analyzed as regards in 15 vitro release behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HCI with pH 1.2). Aliquots WO 2011/141488 PCT/EP2011/057566 -98- of the dissolution media are withdrawn at the respective time points and analyzed by HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content of 5 active tested) in table 16.

Table 16

Tablets iiiiiiliiiiliiii iiiiiiliiiiliiii iiiiiiliiiiliiii iiiiiiliiiiliiii Dissolutionmedium 0.1 N HClpH 1.2 pH 1.2 iiiiiiliiiiliiiipH 1.2 0.1 N HClpH 1.2 Activetested Hm Nal Hm iiiiii Hm iiiii Hm Nal lh 38,16 37,43 38,24 37,75 39,15 38,22 42,14 40,53 2h 52,62 51,72 53,18 52,23 53,69 52,54 57,09 55,52 3h 62,53 61,83 63,45 62,35 63,42 62,60 67,91 66,23 4h 70,09 69,43 71,23 70,26 70,94 70,02 75,35 73,88 5h 76,18 75,56 77,48 76,50 76,89 75,93 81,10 79,68 6h 81,03 80,48 82,50 81,63 81,66 80,68 85,90 84,79 7h 84,93 84,74 86,70 85,77 85,49 84,77 89,59 88,81 8h 88,38 88,30 89,90 88,98 88,63 87,76 92,33 91,74 9h 91,30 91,17 92,81 91,81 91,11 90,31 94,21 93,78 lOh 93,48 93,63 94,97 94,13 93,16 92,53 96,13 95,87 llh 95,36 95,66 96,71 96,03 94,67 93,84 97,31 97,29 12h 96,88 97,32 98,06 97,47 95,98 95,37 98,78 99,08

Hm = hydromorphone HCl, Nal = naloxone HCl; Values are averages of 6 measurements.

Example 8

Tablets F918/109 with a similar composition as in examples 1 to 7 weremanufactured and cured for 60 minutes at 55°C. They were stored for 1 month at 15 25°C and 60° relative humidity (RH) or for 1 month at 40°C and 75% RH. WO 2011/141488 PCT/EP2011/057566 -99-

Tablets F919/77 with a similar composition as in examples 1 to 7 were manufacturedcured for 30 minutes at 55°C. They were stored for 1 or 2 months at 40°C and 75%RH. 5 Tablets F918/109 and F919/77 were then analyzed either initially or after storage asregards in vitro release behavior using the Ph. European paddle method at 75 rpm in500 simulated gastric fluid (SGF) dissolution medium (0.1 N HCl with pH 1.2).Aliquots of the dissolution media are withdrawn at the respective time points andanalyzed by HPEC at 220 nm. 10

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in tables 17 and 18.

Table 17

Tablets F918/109 F918/109 F918/109 Storage 1 month,25°C, 60% RH 1 month,40°C\ 75%RH Dissolutionmedium 0.1 N PH HCl 0.1 N HClpH 1.2 0.1 N HClpH 1.2 Active tested Hm iiiiiii Hm iiiiii Hm Nal lh 32,11 31,09 32,85 31,47 35,03 33,83 2h 44,68 43,47 45,64 44,07 47,77 46,49 3h 53,86 52,54 54,62 52,89 56,80 55,47 4h 60,84 59,48 61,71 59,87 63,65 62,30 5h 66,90 65,53 67,71 65,84 69,30 67,88 6h 71,81 70,44 72,41 70,53 74,05 72,68 7h 75,90 74,65 76,58 74,83 78,18 76,77 8h 79,41 78,30 80,24 78,49 81,63 80,26 9h 82,63 81,70 83,33 81,67 84,72 83,36 lOh 85,28 84,41 85,86 84,19 87,31 86,03 llh 87,67 86,88 88,37 86,72 89,39 88,21 12h 89,71 89,22 90,14 88,69 91,13 90,18

Hm = hydromorphone HCl, Nal = naloxone HCl; Values are averages of 6 measurements. WO 2011/141488 PCT/EP2011/057566 - 100 -

Table 18

Tablets F919/77 F919/77 F919/77 Storage 1 month,40°C, 75%RH 1 month,40°C, 75%RH Dissolutionmedium 0.1 N PH HCl 0.1 N HClpH 1.2 0.1 N HClpH 1.2 Active tested Hm ililll Hm iiii Hm Nal lh 30,29 29,36 30,49 29,50 31,07 30,12 2h 42,41 41,49 41,88 40,81 42,69 41,64 3h 51,14 50,30 50,08 48,95 50,93 49,78 4h 58,01 57,25 56,59 55,39 57,40 56,41 5h 63,64 63,05 61,98 60,72 62,60 61,78 6h 68,66 68,05 66,43 65,29 67,16 66,22 7h 72,77 72,37 70,28 69,16 71,10 70,16 8h 76,30 76,10 73,60 72,66 74,52 73,49 9h 79,47 79,32 76,55 75,72 77,38 76,63 lOh 82,27 82,18 79,24 78,34 79,95 79,19 llh 84,62 84,57 81,50 80,82 82,36 81,72 12h 86,68 86,83 83,43 82,82 84,36 84,07

Hm = hydromorphone HC1, Nal = naloxone HC1; Values are averages of 6 measurements.

Example 9

Tablets F899/29, F899/39 and F908/93 were produced similarly to examples 1 to 8. 10 Subsequently, tablets F899/29 and F899/39 were placed in Duma fos containers andstored for 1, 2 or 5 months at 25°C and 60% RH or at 40°C and 75% RH. TabletsF908/93 were placed either in PVC containers or in PVC coated PVdC blisters andstored for 1, 2 or 5 months at 25°C and 60% RH or at 40°C and 75% RH. 15 All tablets were tested either initially or after storage for total related substances. WO 2011/141488 PCT/EP2011/057566 - 101 -

The results are shown in tables 19 and 20.

Table 19

Tablets F899/29 F899/29 iiilllliiiiiiiil F899/29 Container Duma fos Duma fos Duma fos Duma fos Storage 25°C/60% RH 40°C/75% RH ilitSil·! 40°C/75% RH Initial 0,05% 0.05% 0.16% 0.16% 1 month — 0.09% — 0.17% 2 months ___ 0.26% ___ 0.24% 5 months 0.17% 0.30% 0.10% 0.24%

Table 20

Tablet F908/93 F908/93 F908/93 F908/93 Container PVC PVC PVS/PVdC PVCVPVdC Storage 25°C/60% RH 40°C/75% RH 25°C/60% RH 40°C/75% RH Initial 0,10% 0.10% 0.10% 0.10% 1 month 0.21% 0.24% 0.40% 0.31% 2 months 0.25% 0.30% 0.65% 0.46% 5 months — 0.49% — 0.64%

Example 10

Tablets of the composition as shown in Table 21 were manufactured. WO 2011/141488 PCT/EP2011/057566 - 102 -

Table 21

Tablets 933/I07B F929/85B F929/79B Ingredient Amount(mg) Amount(mg) Amount (mg) Amount(mg) Hydromorphone HCI 4.00 4.00 4.00 4.00 Naloxone HCI 8.00 8.00 8.00 8.00 Hydroxypropylcellulose 5.00 5.00 5.00 5.00 Ethyl cellulose N45 15.0 15.0 15.0 15.0 Stearyl alcohol 25.0 25.0 25.0 25.0 Lactose anhydrous 46.0 46.0 46.0 46.0 Magnesium Stearate 1.25 1.25 1.25 1.25 Talcum 0.75 0.75 0.75 0.75 Total 105 105 105 105 Surelease E7-7050* 7.00 5.00 3.75 Opadry II brown* 2.30 2.50 3.75 Purified water** 28.0 20.0 15.0 Total 105 114.3 112.5 112.5 *The amount indicated refers to the amount of solids used. ** Evaporated during coating 5

Hydromorphone HCI and naloxone HCI were mixed with lactose anhydrous, stearylalcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.Subsequently the blend was melt extruded using a heated twin screw extruder as10 described above. The milled granules were blended with magnesium stearate and talcin a tumbler mixer. Subsequently, the blended granules were compressed into tablets.The tablets were then heat treated for 45 min at 55°C. Subsequently the coatingswere applied. WO 2011/141488 PCT/EP2011/057566 - 103 -

Tablets F933/107B, F929/73B, F929/85B and F929/79B were then analyzed asregards in vitro release behavior using the Ph. European paddle method at 75 rpm in500 ml simulated gastric fluid (SGF) dissolution medium (0.1 N HC1 with pH 1.2).Aliquots of the dissolution media are withdrawn at the respective time points and 5 analyzed by HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 22. 10 Table 22

Tablets F933/107B F929/73B F929/85B F929/79B Dissolutionmedium iiiiiiiOiiiipH 1.2 0.1 N HCIpH 1.2 0.1 N HCIpH 1.2 0.1 N PH HCI Active tested Hm iiiii Hm Nal Hm Nal Hm Nal lh 41,11 40,19 0,13 0,19 8,61 7,26 29,21 27,74 2h 56,10 55,15 0,81 0,65 17,89 15,80 43,70 41,98 3h 66,02 64,99 1,58 1,27 25,06 22,59 54,21 52,41 4h 73,90 73,07 2,55 1,97 31,14 28,42 62,18 60,40 5h 79,71 79,18 3,45 2,65 36,34 33,38 68,94 67,27 6h 84,28 83,60 5,08 3,95 41,15 38,09 74,37 72,63 7h 88,19 87,84 6,76 5,45 45,75 42,60 78,62 77,05 8h 91,29 91,03 8,56 7,05 50,55 47,25 82,91 81,37 9h 93,91 93,62 10,18 8,51 54,51 51,28 86,11 84,57 lOh 95,95 95,91 11,92 10,05 58,50 55,34 88,67 87,31 llh 97,67 98,06 13,56 11,62 61,91 58,80 91,23 90,11 12h 98,57 98,74 15,37 13,27 65,24 62,11 92,91 91,70

Hm = hydromorphone HC1, Nal = naloxone HC1; Values are averages of 6 measurements.

Example 11 15

Tablets of the composition as shown in Table 23 were manufactured. WO 2011/141488 PCT/EP2011/057566 - 104 -

Table 23

Tablets F941/07B F929/91C F929/97C Ingredient Amount(mg) Amount(mg) Amount(mg) Hydromorphone HCI 4.00 4.00 4.00 Naloxone HCI 4.00 4.00 4.00 Hydroxypropylcellulose 5.00 5.00 5.00 Ethyl cellulose N45* 7.50 7.50 7.50 Stearyl alcohol 17.5 17.5 17.5 Lactose anhydrous 50.0 50.0 50.0 Magnesium Stearate 1.25 1.25 1.25 Talcum 0.75 0.75 0.75 Total 90 90 90 Surelease E7-7050* 7.50 10.0 Opadry II brown* 5.00 5.00 Purified water** 30.0 40.0 Total 90 102.5 105 *The amount indicated refers to the amount of solids used. ** Evaporated during coating 5

Hydromorphone HCI and naloxone HCI were mixed with lactose anhydrous, stearylalcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.Subsequently the blend was melt extruded using a heated twin screw extruder as10 described above. The milled granules were blended with magnesium stearate and talcin a tumbler mixer. Subsequently, the blended granules were compressed into tablets.The tablets were then heat treated for 45 min at 55°C. Subsequently the coatingswere applied. WO 2011/141488 PCT/EP2011/057566 - 105 -

Tablets F941/07B, F929/91C and F929/97C were then analyzed as regards in vitrorelease behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HC1 with pH 1.2). Aliquots5 of the dissolution media are withdrawn at the respective time points and analyzed by HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 24. 10

Table 24

Tablets F941/07B, F929/91C iiiiiiiiiiiiiii Dissolutionmedium 0.1 N HOpH 1.2 0.1 N HC1 0.1 N HC1 Active tested Hm iiiii Hm iiiii Hm iliiiii lh 48,75 47,97 12,07 11,02 1,30 0,97 2h 65,20 64,34 25,71 24,46 4,46 3,51 3h 75,96 75,05 35,83 34,48 7,82 6,46 4h 83,03 82,25 44,13 42,68 11,81 10,09 5h 88,29 87,64 51,32 49,85 18,08 16,14 6h 92,21 91,60 57,86 56,41 28,52 26,46 7h 94,81 94,48 63,60 62,18 35,81 33,71 8h 96,53 96,01 68,42 66,99 41,92 39,79 9h 97,31 97,11 72,85 71,44 47,04 44,85 lOh 97,54 97,46 76,94 75,72 51,46 49,24 llh 97,75 97,82 79,73 78,48 55,40 53,22 12h 97,70 97,71 82,77 81,59 58,87 56,65

Hm = hydromorphone HC1, Nal = naloxone HC1; Values are averages of 6 measurements. 15 Tablets F929/91C and F929/97C were further evaluated with respect to their alcoholresistance. To this end in vitro release rates were determined using the Ph. Europeanpaddle method at 75 rpm in 500 ml simulated gastric fluid (SGF) dissolution medium WO 2011/141488 PCT/EP2011/057566 - 106 - (0.1 N HCI with pH 1.2) with 40% EtOH. Aliquots of the dissolution media arewithdrawn at the respective time points and analyzed by HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content of 5 active tested) in table 25.

Table 25

Tablets F929/91C F929/97C Dissolutionmedium 11··] HCI wEtOH 0.1 N 40% ICI w EtOH Active tested Nal Hm Nal 15 min 1,16 0,78 0,00 0,00 30 min n.d. n.d. n.d. n.d. 45 min n.d. n.d. n.d. n.d. 60 min 12,07 11,02 1,30 0,97 90 min n.d. n.d. n.d. n.d. 120 min 25,71 24,46 4,46 3,51

Hm = hydromorphone HCI, Nal = naloxone HCI, 0.1 N HCI w 40% EtOH = 0.1 N HCI pH 1.2 with10 40% ethanol, n.d. = not determined

Example 12

Tablets of the composition as shown in Table 26 were manufactured. 15 WO 2011/141488 PCT/EP2011/057566 - 107 -

Table 26

Tablets F941/60B F945/06 F944/86 F945/30 Ingredient Amount (mg) Amount(mg) Amount (mg) Amount(mg) Hydromorphone HCl 4.00 4.00 4.00 4.00 Naloxone HCl 2.00 2.00 8.00 8.00 Hydroxypropylcellulose 5.00 5.00 5.00 5.00 Ethyl cellulose N45 15.0 15.0 10.00 10.00 Stearyl alcohol 25.0 25.0 25.0 25.0 Lactose anhydrous 52.0 52.0 46.0 46.0 Magnesium Stearate 1.25 1.25 1.25 1.25 Talcum 0.75 0.75 0.75 0.75 Total 105 105 100 100 Surelease E7-7050* 12.0 7.50 Opadry II brown* 0.0 5.00 Purified water** 48.0 30.0 Total 105 117 100 112.5 *The amount indicated refers to the amount of solids used. ** Evaporated during coating 5

Hydromorphone HCl and naloxone HCl were mixed with lactose anhydrous, stearylalcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.Subsequently the blend was melt extruded using a heated twin screw extruder as10 described above. The milled granules were blended with magnesium stearate and talcin a tumbler mixer. Subsequently, the blended granules were compressed into tablets.Tablets F941/60B were heat treated for 45 min at 55°C. Tablets F944/86 were heattreated for 30 min at 55°C. Subsequently the coatings were applied. WO 2011/141488 PCT/EP2011/057566 - 108 -

Tablets F941/60B, F945/06, F944/86 and F945/30 were then analyzed as regards invitro release behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HCI with pH 1.2). Aliquotsof the dissolution media are withdrawn at the respective time points and analyzed by5 HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 27. 10 Table 27

Tablets F941/60B F945/06 F944/86 F945/30 Dissolutionmedium pH 1.2 0.1 N HCIpH 1.2 0.1 N HCIpH1.2 Illi HCI 2 Active tested Hm Nal Hm Nal Hm Nal Nal lh 31,91 31,30 0,07 0,24 42,34 41,05 10,12 8,50 2h 44,71 44,11 0,00 0,00 57,27 55,66 22,45 20,08 3h 53,54 52,76 0,00 0,15 67,40 65,71 31,05 28,40 4h 60,84 59,92 0,00 0,00 75,13 73,49 37,72 34,87 5h 66,54 65,73 0,00 0,00 80,39 79,05 43,69 40,70 6h 71,65 70,74 0,00 0,45 85,16 83,78 49,07 45,90 7h 75,81 74,88 0,00 0,86 88,91 87,48 53,65 50,47 8h 79,32 78,62 0,00 1,15 91,74 90,58 58,14 54,82 9h 82,63 81,74 0,00 1,31 94,30 93,04 61,81 58,69 lOh 85,47 84,67 0,00 1,50 96,59 95,76 65,50 62,36 llh 87,92 87,17 0,00 1,68 97,14 96,57 69,01 65,70 12h 89,64 88,92 0,00 1,87 97,82 97,39 72,00 68,89

Hm = hydromorphone HCI, Nal = naloxone HCI; Values are averages of 6 measurements.

Example 13 15 WO 2011/141488 PCT/EP2011/057566 - 109 -

Tablets of the composition as shown in Table 28 were manufactured.

Table 28

Tablets F941/07B F944/49 F929/103 Ingredient Amount(mg) Amount(mg) Amount(mg) Hydromorphone HCI 4.00 4.00 4.00 Naloxone HCI 4.00 4.00 4.00 Hydroxypropylcellulose 5.00 5.00 5.00 Ethyl cellulose N45 7.50 7.50 7.50 Stearyl alcohol 17.5 17.5 17.5 Lactose anhydrous 50.0 50.0 50.0 Magnesium Stearate 1.25 1.25 1.25 Talcum 0.75 0.75 0.75 Total 90 90 90 Eudragit RL30D* 5.00 14.0 Eudragit RS30D* 5.00 0.00 Talc 5.00 7.00 Triethyl citrate 2.00 2.80 Purified water** 44.8 62.6 Total 90 107 113.8 *The amount indicated refers to the amount of solids used.** Evaporated dining coating

Hydromorphone HCI and naloxone HCI were mixed with lactose anhydrous, stearyl10 alcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.Subsequently the blend was melt extruded using a heated twin screw extruder asdescribed above. The milled granules were blended with magnesium stearate and talc WO 2011/141488 PCT/EP2011/057566 - 110- in a tumbler mixer. Subsequently, the blended granules were compressed into tablets.Tablets were then heat treated for 45 min at 55°C. Subsequently the coatings wereapplied. 5 Tablets F941/07B, F944/49 and F929/103 were then analyzed as regards in vitrorelease behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HCI with pH 1.2). Aliquotsof the dissolution media are withdrawn at the respective time points and analyzed byHPLC at 220 nm. 10

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 29.

Table 29

Tablets F941/07B iiiiiillglliiiii iiiiililiiiiiii Dissolutionmedium llliiiliHiliiipH 1.2 iiiilMBiiiiipH 1.2 iiiiii:l»ifiiipH 1.2 Active tested Hm iiiii Hm iiiii Hm iiiii lh 48,75 47,97 6,04 4,60 14,54 12,42 2h 65,20 64,34 24,83 21,75 39,00 35,75 3h 75,96 75,05 49,18 46,69 57,55 54,52 4h 83,03 82,25 61,94 59,94 70,09 67,76 5h 88,29 87,64 71,03 69,11 78,89 77,01 6h 92,21 91,60 78,22 76,31 85,20 83,57 7h 94,81 94,48 83,60 81,83 89,78 88,43 8h 96,53 96,01 87,96 86,66 93,23 92,16 9h 97,31 97,11 91,56 90,05 95,60 94,58 lOh 97,54 97,46 93,89 92,84 97,08 96,33 llh 97,75 97,82 95,84 95,06 98,16 97,36 12h 97,70 97,71 97,07 96,61 98,46 98,01

Hm = hydromorphone HCI, Nal = naloxone HCI; Values are averages of 6 measurements.

Example 14 WO 2011/141488 PCT/EP2011/057566 - Ill -

Tablets of the composition as shown in Table 30 were manufactured.

Table 30 5

Tablets F944/90 F944/101D Ingredient Amount(mg) Amount(mg) Hydromorphone HCI 4.00 4.00 Naloxone HCI 8.00 8.00 Hydroxypropylcellulose 5.00 5.00 Ethyl cellulose N45 7.50 7.50 Stearyl alcohol 17.5 17.5 Lactose anhydrous 46.0 46.0 Magnesium Stearate 1.25 1.25 Talcum 0.75 0.75 Total 90 90 Sure lease E7-7050* 7.50 Advantia Preferred*(Aquarius HPMC) 5.00 Purified water** 30.0 Total 90 102.5 *The amount indicated refers to the amount of solids used. ** Evaporated during coating

Hydromorphone HCI and naloxone HCI were mixed with lactose anhydrous, stearyl 10 alcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.Subsequently the blend was melt extruded using a heated twin screw extruder asdescribed above. The milled granules were blended with magnesium stearate and talcin a tumbler mixer. Subsequently, the blended granules were compressed into tablets. WO 2011/141488 PCT/EP2011/057566

Tablets were then heat treated for 30 min at 55°C. Subsequently the coatings wereapplied.

Tablets F944/90 and F944/101D were then analyzed as regards in vitro release 5 behavior using the Ph. European paddle method at 75 rpm in 500 ml simulatedgastric fluid (SGF) dissolution medium (0.1 N HCI with pH 1.2). Aliquots of thedissolution media are withdrawn at the respective time points and analyzed by HPLCat 220 nm. 10 The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 31.

Table 31

Tablets F944/90 F944/101D Dissolutionmedium 0.1 N HCIpH 1.2 0.1 N HCI pH 1.2 Active tested Hm Nal Hm Nal lh 51,08 49,95 21,88 20,12 2h 68,55 67,18 38,23 36,15 3h 79,32 77,97 50,93 48,65 4h 86,47 85,26 60,36 58,15 5h 91,63 90,53 67,82 65,77 6h 94,86 94,04 74,74 72,72 7h 96,95 96,34 79,32 77,41 8h 97,90 97,48 83,90 82,14 9h 98,56 98,27 87,03 85,47 lOh 98,97 98,72 90,14 88,73 llh 98,86 98,71 92,32 91,10 12h 98,87 98,76 94,09 93,11 15 Hm = hydromorphone HCI, Nal = naloxone HCI; Values are averages of 6 measurements.

Tablets similar to F994/101D were manufactured. In tablets F994/101B, the weightgain by coating was about 5 mg. Tablets F994/101E were the same as tablets WO 2011/141488 PCT/EP2011/057566 - 113 - F994/101D except that they had been cured 30 minutes at 55°C after the coating hadbeen applied. These tablets were also tested for their in vitro release.

The in vitro release data is indicated as percentage (based on the label content of 5 active tested) in table 32.

Table 32

Tablets F944/I01B F944/10ID F944/101E Dissolutionmedium iiiitliililiiipH 1.2 iiiiiiliBiliiiipH 1.2 iiiiiiliBiliiiipH 1.2 Active tested Hm iiili Hm iiili Hm iiili lh 33,91 32,23 21,88 20,12 15,55 13,05 2h 50,66 48,53 38,23 36,15 31,17 28,20 3h 62,06 59,71 50,93 48,65 42,66 39,67 4h 70,64 68,21 60,36 58,15 52,68 49,67 5h 77,57 75,20 67,82 65,77 60,06 56,91 6h 82,52 80,46 74,74 72,72 67,14 64,15 7h 86,96 84,87 79,32 77,41 72,70 69,83 8h 90,51 88,57 83,90 82,14 77,78 75,03 9h 92,75 90,85 87,03 85,47 82,36 79,77 lOh 94,99 93,44 90,14 88,73 85,18 82,76 llh 95,81 94,56 92,32 91,10 87,84 85,55 12h 97,02 95,83 94,09 93,11 90,58 88,36

Hm = hydromorphone HCI, Nal = naloxone HCI; Values are averages of 6 measurements.

Example 15

Tablets of the composition as shown in Table 33 were manufactured. 15 WO 2011/141488 PCT/EP2011/057566

Table 33

Tablets PN3450 iiliiiii F944/82 F945/69 Ingredient Amount(mg) Amount(mg) Amount (mg) Amount(mg) Amount (mg) Hydromorphone HCI 4.0 4.00 4.0 4.00 4.00 Naloxone HCI 8.0 8.00 8.0 8.00 8.00 Hydroxypropylcellulose 5.0 5.00 5.0 5.00 5.00 Stearyl alcohol 17.5 17.5 25.0 25.0 25.0 Ethyl cellulose N45 7.5 7.5 10.0 10.0 10.0 Lactose anhydrous 46.0 46.0 46.0 46.0 46.0 Talc 1.25 1.25 1.25 1.25 1.25 Magnesium Stearate 0.75 0.75 0.75 0.75 0.75 Total 90 90 100 100 100 Stearyl alcohol(extragranular) 15.00 15.00 0.00 Ethylcellulose N45(extragranular) 0.00 0.00 15.00 Total 90 105 100 115 115

Hydromorphone HCI and naloxone HCI were mixed with lactose anhydrous, stearyl5 alcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min.Subsequently the blend was melt extruded using a heated twin screw extruder asdescribed above. 10 The milled granules were blended with magnesium stearate and talc and theadditional amount of extragranular stearyl alcohol or ethyl cellulose in a tumblermixer. Subsequently, the blended granules were compressed into tablets. The tabletswere then heat treated for 30 min at 55°C. WO 2011/141488 PCT/EP2011/057566 - 115 -

Tablets PN3450, PN3451, F944/78, F944/82 and F945/69 were then analyzed asregards in vitro release behavior using the Ph. European paddle method at 75 rpm in500 ml simulated gastric fluid (SGF) dissolution medium (0.1 N HCl with pH 1.2). 5 Aliquots of the dissolution media are withdrawn at the respective time points andanalyzed by HPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 34. 10

Table 34

IlihiOi llieisilll |||||9|g||||||| Ι||β1|1||| BllllBiSlBBlB F945.69 Disso- 0.1 N HClpH 1.2 :ι:ι:ιι:νβιιββ: Β|ΒΙΟί:ί|Β|Β( 0.1 N HClpH 1.2 0.1 N HClpH 1.2 Active |ii||| Hm llllllll Hm |li||| Hm IfilBll Hm Ilillll lh 51,50 50,80 43,94 42.52 40,54 39,69 30,89 29,56 38,94 37,56 2h 68,10 67,60 59,69 57,94 54,82 53,92 42,72 41,12 53,24 55,65 3h 78,50 78,30 70,31 68,46 64,22 63,54 51,12 49,36 62,95 61,61 4h 85,50 85,60 77,61 75,77 71,72 71,11 57,95 56,13 70,34 68,94 5h 90,50 90,70 83,81 82,16 77,74 77,28 63,21 61,38 76,28 75,05 6h 93,90 94,30 88,25 86,65 82,11 81,72 67,88 65,91 81,31 80,03 7h 95,90 96,60 91,83 90,29 85,82 85,65 71,76 69,85 85,10 84,05 8h 96,90 97,90 94,57 93,06 89,19 89,24 75,34 73,46 88,53 87,47 9h 97,50 98,50 96,50 95,28 91,82 91,93 78,37 76,52 91,35 90,32 lOh 97,50 98,60 98,34 97,37 93,71 94,04 81,07 79,29 93,67 92,44 llh 97,00 98,30 99,36 98,52 95,19 95,72 83,52 81,76 95,31 94,47 12h 97,20 98,40 99,58 98,93 96,54 97,26 85,64 83,97 96,61 95,71

Hm = hydromorphone HCl, Nal = naloxone HCl; Values are averages of 6 measurements. 15

Example 16

Tablets of the composition as shown in Table 35 were manufactured. WO 2011/141488 PCT/EP2011/057566

Table 35

Tablets PN3642 PN3643 iilliiiiii PN3645 Ingredient Amount(mg) Amount(mg) Amount(mg) Amount (mg) Hydromorphone HCl 4.00 4.00 4.00 4.00 Naloxone HCl 8.00 8.00 8.00 8.00 Hydroxypropylcellulose 5.00 5.00 5.00 5.00 Ethyl cellulose N45 7.50 7.50 15.0 15.0 Stearyl alcohol 17.5 17.5 25.0 25.0 Lactose anhydrous 52.0 52.0 46.0 46.0 Magnesium Stearate 0.75 0.75 0.75 0.75 Talcum 1.25 1.25 1.25 1.25 Total 90 90 105 105 Sure lease E7-19030* 5.00 6.00 5.00 9.00 Opadry II brown* 5.00 4.00 5.00 6.00 Purified water** 20.0 24.0 20.0 36.0 Total 100 100 115 120 *The amount indicated refers to the amount of solids used. 5 ** Evaporated during coating

Hydromorphone HCl and naloxone HCl were mixed with lactose anhydrous, stearylalcohol, hydroxypropyl cellulose and ethyl cellulose N45 as a prolonged releasepolymer. These components were blended in a double cone mixer for 10 min. 10 Subsequently the blend was melt extruded using a heated twin screw extruder asdescribed above. The milled granules were blended with magnesium stearate and talcin a tumbler mixer. Subsequently, the blended granules were compressed into tablets.The tablets were then heat treated for 60 min at 55°C. Subsequently the coatingswere applied with Manesty air atomised spray fitted with a 1.2 mm nozzle adjusted 15 to give an even spray pattern and located approximately 15 cm from tablet bed. WO 2011/141488 PCT/EP2011/057566 - 117 -

Atomising air pressure 1.8 bar

Fan width air pressure 2.0 bar

Inlet air temperature 52° C

Outlet air temperature 40-45°C

Air flow 350 m3/hr

Drum speed 20 rpm

Spray rate ca. 6-10 g/min

Cabinet depression -50

Wall thickness of silicon tubing 1.6mm

Bore of silicon tubing 4.8mm

Tablets PN3642, PN3643, PN 3644 and PN3645 were then analyzed as regards invitro release behavior using the Ph. European paddle method at 75 rpm in 500 mlsimulated gastric fluid (SGF) dissolution medium (0.1 N HCI with pH 1.2). Aliquotsof the dissolution media are withdrawn at the respective time points and analyzed byHPLC at 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 36. WO 2011/141488 PCT/EP2011/057566

Table 36

Tablets PN3642 PN3643 PN3644 PN3645 Dissolutionmedium 0.1 N HClpH 1.2 0.1 N HClpH 1.2 0.1 N HClpH 1.2 0.1 N HClpH 1.2 Active tested Hm Nal Hm Nal Hm Nal Hm Nal lh 30,14 28,16 16,15 13,62 23,29 21,81 12,70 10,75 2h 49,65 47,91 35,51 32,66 38,00 36,72 26,59 24,45 3h 63,09 61,54 48,58 45,95 48,11 46,87 36,40 34,25 4h 72,95 71,53 58,85 56,36 55,98 54,76 44,48 42,37 5h 80,56 79,42 67,19 64,83 62,40 61,34 51,12 49,13 6h 86,32 85,32 74,14 71,99 68,00 67,04 56,94 54,86 7h 90,74 89,90 79,91 77,93 72,67 71,84 62,26 60,16 8h 93,79 93,27 84,68 82,84 76,69 76,04 66,72 64,85 9h 95,94 95,81 88,57 87,10 80,26 79,73 70,73 68,92 lOh 97,59 97,63 91,68 90,47 83,28 82,73 74,08 72,62 llh 98,31 98,63 94,10 93,30 86,00 85,59 77,48 75,82 12h 98,77 99,28 96,05 95,31 88,08 87,94 80,30 78,70

Hm = hydromorphone HCl, Nal = naloxone HCl. Values are averages of 6 measurements.

Tablets PN3642, PN3643, PN3644, PN3645 were further evaluated with respect totheir alcohol resistance. To this end in vitro release rates were determined using thePh. European paddle method at 75 rpm in 500 ml simulated gastric fluid (SGF)dissolution medium (0.1 N HCl with pH 1.2) with 40% EtOH. Aliquots of the 10 dissolution media are withdrawn at the respective time points and analyzed by HPLCat 220 nm.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 37. 15 WO 2011/141488 PCT/EP2011/057566

Table 37

Tablets PN3642 PN3643 PN3644 PN3645 Dissolutionmedium 0.1 N HCIpH 1.2 0.1 N HCIpH 1.2 0.1 N HCIpH 1.2 0.1 N HCIpH 1.2 Active tested Hm Nal Hm Nal Hm Nal Hm Nal 15 min 3.8 2.7 1.8 1.4 4.0 2.7 1.4 0.7 30 min 10.2 8.6 5.6 4.5 9.5 8.2 2.1 1.9 45 min 16.7 14.6 9.9 8.3 15.3 13.8 4.6 3.8 60 mi 22.4 20.1 14.1 10.7 20.3 18.5 7.3 6.1 90 min 31.8 29.3 21.9 17.6 27.9 26.1 12.8 11.0 120 min 39.5 36.8 29.4 25.6 34.1 32.4 18.0 15.8

Hm = hydromorphone HCI, Nal = naloxone HCI, 0.1 N HCI w 40% EtOH = 0.1 N HCI pH 1.2 with5 40% ethanol, n.d. = not determined; Values are averages of 6 measurements.

Subsequently, tablets PN3642, PN3643, PN3644 and PN3645 were placed in PVC blisters and stored for 1, 2 and 3 months at 40°C and 75% RH. 10 All tablets were tested either initially or after storage for total related substances.

The results are shown in table 38.

Table 38

Tablets iiiiiiiii iiliiiilii iiiiiiiii iieiiiiii Container PVC iliiiiiiiiii iiiillliiii iiiiiiiiiii Storage liitiillll % RH iiiiiiiii% RH iiiiiiiii % RH liitiiiiii % RH Initial 0.00% 0.00% 0.00% 0.08% 1 month 0.00% 0.05% 0.05% 0.00% 2 months 0.05% 0.00% 0.00% 0.00% 3 months 0.05% 0.05% 0.00% 0.05% WO 2011/141488 PCT/EP2011/057566 - 120 -

All tablets were tested either initially or after storage also for known relatedsubstances. These were noroxymorphone, hydromorphone N-oxide,pseudohydromorphone, naloxone N-oxide, pseudonaloxone. All known substanceswere either less than limit of detection or less than limit of quantification. 5

Example 17

Tablets corresponding to tablets of PN3462 were tested in an open label, single-dosestudy in 15 healthy subjects in the fasted state. The mean AUCt /h*pg/ml was 10 7675.9, the mean Cmax (pg/ml) was 664.6, the mean tmax was 1,9h.

Example 18

Formulations with a prolonged release coating were produced having the 15 composition of Table 39.

Table 39

Formulation A B Ingredient amount per capsule (mg) amount per capsule (mg) Microcrystallinecellulose (MCC) spheres 44.89 44.83 Hydromorphonehydrochloride 3.00 3.00 Naloxone hydrochloridedihydrate 1.65 1.65 Hydroxypropylmethylcellulose,polyethylene glycol filmcoating concentrate(Opadry YS-1 -7006,Clear) HS 1.63 1.68 WO 2011/141488 PCT/EP2011/057566 - 121 -

Aqueous ethylcellulosedispersion (Surelease) 4.66 6.04 Polyvinyl alcohol-polyethylene glycol graftcopolymer (Kollicoat IR)HS 0.34 0.45 Silicon dioxide NF(Syloid 244FP) NF 0.00 0.29 Purified Water USP q.s. q.s. Total -56 -58

For Formulation A, a solution is produced from hydromorphone and naloxonedissolved in water, Opadry Clear ® YS-1-7006. This solution is then sprayed on to amicrocrystalline cellulose (MXX) beads in a fluid bed dryer with a Wurster column.This produces an immediate-release (IR) bead. The IR bead is then sprayed withSure lease dispersion and Kollicoat IR in a fluid bed dryer with a Wurster column, aprolonged release bead is thus formed. The prolonged release beads are then sprayedwith Opadry Clear ® YS-1-7006 aqueous solution. Opadry protects the beads fromagglomeration. The beads are then encapsulated.

For Formulation B, a solution is produced from hydromorphone and naloxonedissolved in water, Opadry Clear ® YS-1-7006. This solution is then sprayed on to amicrocrystalline cellulose (MXX) beads in a fluid bed dryer with a Wurster column.This produces an immediate-release (IR) bead. The IR bead is then sprayed withSure lease dispersion and Kollicoat IR in a fluid bed dryer with a Wurster column, aprolonged release bead is thus formed. The prolonged release beads are then sprayedwith Opadry Clear ® YS-1-7006 aqueous solution. Opadry protects the beads fromagglomeration. The beads are then cured in a fluid bed dryer at 60°C outlettemperature with water spraying for 2 hours. The cured beads are then coated withOpadry Clear coating and mixed with silicon dioxide before encapsulation. WO 2011/141488 PCT/EP2011/057566 - 122-

Formulations A and B were then analyzed as regards in vitro release behavior usingthe USP basket method at 100 rpm in 000 ml simulated gastric fluid (SGF)dissolution medium (0.1 N HCI with pH 1.2) without enzyme. Aliquots of thedissolution media are withdrawn at the respective time points and analyzed byHPLC/UV.

The in vitro release data is indicated as percentage (based on the label content ofactive tested) in table 40. The values in the brackets indicate the range observedwhen measuring six tablets.

Table 40

Formulation A B Dissolutionmedium 0.1 N HCI pH 1.2 0.1 N HCI pH 1.2 Activetested Hm Nal Hm Nal lh 3 (2-3) 4 (3-5) 14(13-15) 15 (14-17) 2h 6 (5-7) 7 (7-8) 40 (39-42) 42 (41-43) 4h 20 (19-22) 12 (12-14) 68 (68-69) 69 (68-69) 8h 67 (65-68) 65 (63-66) 90 (89-90) 89 (88-90) 12h 87 (87-88) 85 (84-86) 97 (97-98) 97 (96-97) 16h 96 (95-96) 94 (93-95) 100 (99-101) 100 (99-101) 24h 102 (101-102) 101 (100-101) 103 (101-104) 103 (101-104)

Hm = hydromorphone HCI, Nal = naloxone HCI; values are the average of 6 measurements, values inthe brackest indicate the observed ranges.

The controlled release bead dosage forms form Formulation A and Formulation Bwere tested against Hydromorph Contin™ in single-dose pK study conducted underfasted conditions. A summary of the results is shown in Figure 2.

The results showed that all three formulations are bioequivalent. Formulation A ispreferred since it resulted in a tmax closest to that of the reference formulation. WO 2011/141488 PCT/EP2011/057566 - 123 -

Thus, when the dosage form according to the invention is in the form of a controlledrelease bead dosage form, it can be preferred that: (i) it is not subjected to a curingstep during manufacture, and (ii) it contains a weight ratio of hydromorphone tonaloxone of 2:1 (this was confirmed in a randomized, double-blind, placebo- 5 controlled, dose-ranging crossover study evaluating the effect of naloxone onintravenous hydromorphone abuse potential in healthy, non-dependent, opioid-experienced recreational drug users).

Example 19 10

This example shows an aqueous method of manufacturing. Granules of thecomposition as shown in Table 41 were manufactured.

Table 41 15

Granules F888/49 iilBliiiiili Ingredient Amount(mg) Amount (mg) Hydromorphone HCI 2.0 Naloxone HCI 4.0 Ethyl cellulose 32.0 32.0 Eudragit NE 40 D* 23.0 23.0 Lactose Anhydrous 29.7 29.7 Purified Water** 11.5 11.5 Glycerol Monostearate 40-55% 2.3 2.3 Hypromellose 5.2mPas*** 0.23 0.23 Talc 5.8 5.8 Total*** 95.0 97.0 *The amount indicated refers to the amount of solids used**Water was removed from the granules by drying ***The amount refers to the weight of the granules without waterThe amounts refer to Hydromorphone HCI and Naloxone HCI. WO 2011/141488 PCT/EP2011/057566 - 124-

To obtain granules, Hypromellose 5.2 mPas was mixed with purified water untilfully dissolved using a Silverson high shear mixer. Then, whilst heating to 60°C andmaintaining mixing, glycerol monostearate 40-55% was added. When the mixturereached 60°C, heating was discontinued the mixture was cooled to &lt;54°C withmixing being continued. Talc was added to the Eudragit NE 40 D dispersion whilestirring with a Heidolph paddle stirrer until fully dispersed. Then thehypromellose/glycerol monostearate dispersion was added to the Eudragit NE 40 D /talc dispersion with paddle stirring until a homogenous mixture was obtained.Stirring was maintained.

Ethyl cellulose, lactose, and hydromorphone hydrochloride or naloxonehydrochloride were placed into an Aeromatic Fielder S2 fluid bed granulator.

The conditions for fluidised bed granulation were as follows:

Apparatus: Aeromatic-Fielder S2 fluid bed granulator

Nozzle diameter:1.8mm

Spraying pressure: filter chamber

Air velocity (m/s):4-6

Inlet Air temperature (°C):30-40

Spray rate (g/minxkg): 30-50

Spray time (min):120

Product temperature (°C):24-26

The granules were then dried in the fluidized bed granulator at &lt;28°C for 20-30minutes until the moisture content was below 2% w/w. The granules were then WO 2011/141488 PCT/EP2011/057566 - 125 - sieved using a Demi Finex sieve shakerwith a mesh size of 1mm. Subsequently thegranules were milled using a Quadro Comil 197S.

Granules were then pressed into tablets (see Table 42). 5

Table 42

Tablets iiiiiiii iiiiiiiii Ingredient Amount(mg) Amount(mg) Hydromorphone HCI Granules F888/49 95.0 Naloxone HCI Granules F888/55 97.0 Hydromorphone HCI 2.0 Naloxone HCI 4.0 Magnesiumstearate 1.0 1.0 Total 100 100

The amounts refer to Hydromorphone HCI and Naloxone HCI. 10 For obtaining the tablets, granules were blended with hydromorphone HCI, ornaloxone HCI and magnesium stearate using an Apex cone blender. Tablets wereobtained by compressing the blend using a Kilian rotary tablet press at a tablet speedof up to 50,000 tablets /hr. 15 Tablet F888/72 was cured in a convection oven at 60°C for 1 h. The cured tablet waslabeled F892/15.

Tablet F888/83 was cured at 60°C for 1 h. The cured tablet was labeled F892/16. WO 2011/141488 PCT/EP2011/057566 - 126 -

Tablets F892/15 and F892/16 were further subjected to prolonged storage under ICHstressed conditions, namely storage at 25°C/60%RH for 7 months.

For F892/15 the amount of total related substances was 0.28%. The amount ofhydromorphone N-oxide was 0.18%.

For F892/16 the amount of total related substances was 0.56%. The amount ofhydromorphone N-oxide was 0.14%. The amount of noroxymorphone was 0.10%.The amount of naloxone N-oxide was 0.06%.

Some embodiments of the invention relate to: 1. An oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and c) wherein the prolonged release pharmaceutical composition is heattreated. 2. A pharmaceutical composition according to 1, wherein the at least oneprolonged release material and hydromorphone or a pharmaceutically acceptable saltor derivative thereof and naloxone or a pharmaceutically acceptable salt or derivativethereof are combined such that a prolonged release matrix is formed. 3. A pharmaceutical composition according to 1 or 2, wherein a prolongedrelease coating is disposed on the active ingredients hydromorphone or a WO 2011/141488 PCT/EP2011/057566 - 127 - pharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof 4. A pharmaceutical composition according to 1, 2 or 3, wherein hydro morphone or a pharmaceutically acceptable salt or derivative thereof andnaloxone or a pharmaceutically acceptable salt or derivative thereof are present in thepharmaceutical composition in a weight ratio of about 2:1, about 1:1, about 1:2 orabout 1:3. 5. Pharmaceutical composition according to 1, 2, 3 or 4, wherein the prolongedrelease material is selected from the group comprising hydrophobic or hydrophilicpolymers, protein-derived material, gums, substituted or unsubstituted hydrocarbons,digestible carbohydrates, fatty acids, fatty alcohols, glyceryl esters of fatty acids,natural and synthetic oils and waxes. 6. Pharmaceutical composition according to 5, wherein the prolonged releasematerial is a cellulose ether, a (meth)acrylic based (co)polymer and/or a fattyalcohol. 7. Pharmaceutical composition according to 6, wherein prolonged releasematerial is a neutral (meth)acrylic based (co)polymer, a hydrophobic cellulose etherand/or a fatty alcohol. 8. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6 or 7comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE asprolonged release material; WO 2011/141488 PCT/EP2011/057566 - 128 - b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix 9. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6 or 7,comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 10. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6 or 7,comprising at least: a) at least one fatty alcohol as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 - 129 - derivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 11. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6 or 7,comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one cellulose ether, preferably at least one hydrophobic celluloseether such as ethyl cellulose as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 12. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6 or 7,comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one fatty alcohol as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 - 130- derivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 13. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6 or 7,comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose and at least one fatty alcohol asprolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 14. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6 or 7,comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE, at leastone cellulose ether, preferably at least one hydrophobic cellulose ethersuch as ethyl cellulose and at least one fatty alcohol as prolongedrelease materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 - 131 - derivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 15. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, wherein the pharmaceutical composition comprises additionally atleast one filler, at least one lubricant, at least one binder, at least one release ratemodifiers, at least one spheronising agent and/or at least one anti-tacking agent 16. Pharmaceutical composition according to 15, wherein said filler is anhydrouslactose. 17. Pharmaceutical composition according to 15 or 16, wherein magnesiumstearate and/or talc are used as lubricants. 18. Pharmaceutical composition according to 15, 16 or 17, whereinhydroxypropyl cellulose is used as binder. 19. Pharmaceutical composition according to 15, 16, 17 or 18, whereinhydroxypropylmethyl cellulose, an anionic (meth)acrylic acid (co)polymer such asEudragit RSPO and/or Xanthan gum are used release rate modifiers. 20. Pharmaceutical composition according to 15, 16, 17, 18 or 19, whereinmicrocrystalline cellulose is used as spheronising agent. 21. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 , wherein heat treatment takes place at atemperature in the range of about 30°C to about 95°C and for a time in the range ofabout 10 min to about 3 hours.. WO 2011/141488 PCT/EP2011/057566 - 132- 22. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21, wherein the composition releases thepharmaceutically active agents with the following in vitro release rate whenmeasured using the Ph. Eur. paddle method in 500 or 900 ml of Simulated GastricFluid at 75 or 100 rpm at 37 degrees C°: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agents, at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents. 23. Pharmaceutical composition according to any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22, wherein the ratio of the amount of thepharmaceutically active agents released after 0.5, 1 or 2 hours of in vitro dissolutionof the dosage form in 500 ot 900 ml of Simulated Gastric Fluid with up to 40%ethanol using the Ph. Eur. paddle method at 100 rpm at 37 degrees C° compared tothe amount of the active agents released after 0.5, 1 or 2 hours of in vitro dissolutionof the dosage form in 500 or 900 ml of Simulated Gastric Fluid with 0% ethanolusing the Ph. Eur. paddle method at 75 or 100 rpm at 37 degrees C° is about 2:1 orless, is about 1.5:1 or less, is about 1:1 or less, about 1:1.2 or less, about 1:1.4 or less,about 1:1.6 or less, about 1:1.8 or less, about 1:2 or less, about 1:2.5 or less about 1:3or less or about 1:5 or less. WO 2011/141488 PCT/EP2011/057566 - 133 - 24. Pharmaceutical composition according to to any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21,22 or 23, comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions releases the pharmaceutically active agents withsubstantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions. 25. Pharmaceutical composition according to to any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 composition comprising atleast: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions has less than 3% of total substances related tohydromorphone or a pharmaceutically acceptable salt or derivativethereof and/or related to naloxone or a pharmaceutically acceptablesalt or derivative thereof 26. An oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable salt WO 2011/141488 PCT/EP2011/057566 - 134- or derivative thereof with hydromorphone or a pharmaceuticallyacceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof being present inthe pharmaceutical composition in a weight ratio in a range of about2:1 to about 1:3, preferably of about 2:1, about 1:1, about 1:2 or about1:3. 27. Pharmaceutical composition according to 26, wherein the prolonged releasepharmaceutical composition is heat treated. 28. Pharmaceutical composition according to 26 or 27, wherein the at least oneprolonged release material and hydromorphone or a pharmaceutically acceptable saltor derivative thereof and naloxone or a pharmaceutically acceptable salt or derivativethereof are combined such that a prolonged release matrix is formed. 29. Pharmaceutical composition according to 26, 27 or 28, wherein a prolongedrelease coating is disposed on the active ingredients hydromorphone or apharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof. 30. Pharmaceutical composition according to 26, 27, 28 or 29, wherein theprolonged release material is selected from the group comprising hydrophobic orhydrophilic polymers, protein-derived material, gums, substituted or unsubstitutedhydrocarbons, digestible carbohydrates, fatty acids, fatty alcohols, glyceryl esters offatty acids, natural and synthetic oil and waxes. WO 2011/141488 PCT/EP2011/057566 - 135 - 31. Pharmaceutical composition according to 30, wherein the prolonged releasematerial is a cellulose ether, a (meth)acrylic based (co)polymer and/or a fattyalcohol. 32. Pharmaceutical composition according to 31, wherein prolonged releasematerial is a neutral (meth)acrylic based (co)polymer, a hydrophobic cellulose etherand/or a fatty alcohol. 33. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31 or 32,comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE asprolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix 34. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31 or 32,comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein WO 2011/141488 PCT/EP2011/057566 - 136- c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 35. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31 or 32,comprising at least: a) at least one fatty alcohol as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 36. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31 or 32,comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one cellulose ether, preferably at least one hydrophobic celluloseether such as ethyl cellulose as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 - 137- derivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 37. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31 or 32,comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one fatty alcohol as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 38. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31 or 32,comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose and at least one fatty alcohol asprolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. WO 2011/141488 PCT/EP2011/057566 - 138- 39. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31 or 32,comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE, at leastone cellulose ether, preferably at least one hydrophobic cellulose ethersuch as ethyl cellulose and at least one fatty alcohol as prolongedrelease materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 40. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 or 39, wherein the pharmaceutical composition comprisesadditionally at least one filler, at least one lubricant, at least one binder, at least onerelease rate modifiers, at least one spheronising agent and/or at least one anti-tackingagent 41. Pharmaceutical composition according to 40, wherein said filler is anhydrouslactose. 42. Pharmaceutical composition according to 40 or 41, wherein magnesiumstearate and/or talc are used as lubricants. WO 2011/141488 PCT/EP2011/057566 - 139- 43. Pharmaceutical composition according to 40, 41 or 42, whereinhydroxypropyl cellulose is used as binder. 44. Pharmaceutical composition according to 40, 41, 42 or 43, whereinhydroxypropylmethyl cellulose, an anionic (meth)acrylic acid (co)polymer such asEudragit RSPO and/or Xanthan gum are used release rate modifiers. 45. Pharmaceutical composition according to 40, 41, 42, 43 or 44, whereinmicrocrystalline cellulose is used as spheronising agent. 46. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 39, 40, 41, 42, 43, 44 or 45, wherein heat treatment takesplace at a temperature in the range of about 30°C to about 95°C and for a time in therange of about 10 min to about 3 hours. 47. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 39, 40, 41, 42, 43, 44, 45 or 46, wherein the compositionreleases the pharmaceutically active agents with the following in vitro release ratewhen measured using the Ph. Eur. paddle method in 500 or 900 ml of SimulatedGastric Fluid at 75 or 100 rpm at 37 degrees C°: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agents, at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents. WO 2011/141488 PCT/EP2011/057566 - 140 - 48. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 39, 40, 41, 42, 43, 44, 45, 46 or 47, wherein the ratio of theamount of the pharmaceutically active agents released after 0.5, 1 or 2 hours of invitro dissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid withup to 40% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37 degreesC° compared to the amount of the active agents released after 0.5, 1 or 2 hours of invitro dissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid with0% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37 degrees C° isabout 2:1 or less, is about 1.5:1 or less, is about 1:1 or less, about 1:1.2 or less, about1:1.4 or less, about 1:1.6 or less, about 1:1.8 or less, about 1:2 or less, about 1:2.5 orless about 1:3 or less or about 1:5 or less. 49. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 39, 40, 41, 42, 43, 44 ,45, 46, 47 or 48, comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions releases the pharmaceutically active agents withsubstantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions. 50. Pharmaceutical composition according to any of 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 38, 39, 40, 41, 42, 43, 44 ,45, 46, 47, 48 or 49, comprising atleast: a) at least one prolonged release material; WO 2011/141488 PCT/EP2011/057566 - 141 - b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions has less than 3% of total substances related tohydromorphone or a pharmaceutically acceptable salt or derivativethereof and/or related to naloxone or a pharmaceutically acceptablesalt or derivative thereof 51. An oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the at least one prolonged release material and hydromorphone or apharmaceutically acceptable salt or derivative thereof and naloxone ora pharmaceutically acceptable salt or derivative thereof are combinedsuch that a prolonged release matrix is formed. 52. A pharmaceutical composition according to 51, wherein the prolonged releasepharmaceutical composition is heat treated. 53. A pharmaceutical composition according to 51 or 52, wherein a prolonged release coating is disposed on the active ingredientshydro morphone or a pharmaceutically acceptable salt or derivative thereof andnaloxone or a pharmaceutically acceptable salt or derivative thereof. WO 2011/141488 PCT/EP2011/057566 - 142- 54. A pharmaceutical composition according to 51, 52 or 53, whereinhydro morphone or a pharmaceutically acceptable salt or derivative thereof andnaloxone or a pharmaceutically acceptable salt or derivative thereof are present in thepharmaceutical composition in a weight ratio of about 2:1, about 1:1, about 1:2 orabout 1:3. 55. Pharmaceutical composition according to 51, 52, 53 or 54 wherein theprolonged release material is selected from the group comprising hydrophobic orhydrophilic polymers, protein-derived material, gums, substituted or unsubstitutedhydrocarbons, digestible carbohydrates, fatty acids, fatty alcohols, glyceryl esters offatty acids, natural and synthetic oil and waxes. 56. Pharmaceutical composition according to 55, wherein the prolonged releasematerial is a cellulose ether, a (meth)acrylic based (co)polymer and/or a fattyalcohol. 57. Pharmaceutical composition according to 56, wherein prolonged releasematerial is a neutral (meth)acrylic based (co)polymer, a hydrophobic cellulose etherand/or a fatty alcohol. 58. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56 or 57comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE asprolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein WO 2011/141488 PCT/EP2011/057566 - 143 - c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix 59. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57 or58 comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 60. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57 or58 comprising at least: a) at least one fatty alcohol as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. WO 2011/141488 PCT/EP2011/057566 - 144- 61. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57 or58 comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one cellulose ether, preferably at least one hydrophobic celluloseether such as ethyl cellulose as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 62. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57 or58 comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one fatty alcohol as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. WO 2011/141488 PCT/EP2011/057566 - 145 - 63. Pharmaceutical composition according to any of 49, 50, 51, 52, 53, 54 or 55,comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose and at least one fatty alcohol asprolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 64. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57 or58 comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE, at leastone cellulose ether, preferably at least one hydrophobic cellulose ethersuch as ethyl cellulose and at least one fatty alcohol as prolongedrelease materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. WO 2011/141488 PCT/EP2011/057566 - 146- 65. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63 or 64 wherein the pharmaceutical composition comprisesadditionally at least one filler, at least one lubricant, at least one binder, at least onerelease rate modifiers, at least one spheronising agent and/or at least one anti-tackingagent 66. Pharmaceutical composition according to 65, wherein said filler is anhydrouslactose. 67. Pharmaceutical composition according to 65 or 66, wherein magnesiumstearate and/or talc are used as lubricants. 68. Pharmaceutical composition according to 65, 66 or 67, whereinhydroxypropyl cellulose is used as binder. 69. Pharmaceutical composition according to 65, 66, 67 or 68, whereinhydroxypropylmethyl cellulose, an anionic (meth)acrylic acid (co)polymer such asEudragit RSPO and/or Xanthan gum are used release rate modifiers. 70. Pharmaceutical composition according to 65, 66, 67, 68, 6 8or 69, whereinmicrocrystalline cellulose is used as spheronising agent. 71. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 or 70, wherein heat treatment takesplace at a temperature in the range of about 30°C to about 95°C and for a time in therange of about 10 min to about 3 hours. WO 2011/141488 PCT/EP2011/057566 - 147- 72. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 or 71, wherein the compositionreleases the pharmaceutically active agents with the following in vitro release ratewhen measured using the Ph. Eur. paddle method in 500 or 900 ml of SimulatedGastric Fluid at 75 or 100 rpm at 37 degrees C°: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agents, at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents. 73. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 or 72 wherein the ratio of theamount of the pharmaceutically active agents released after 0.5, 1 or 2 hours of invitro dissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid withup to 40% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37 degreesC° compared to the amount of the active agents released after 0.5, 1 or 2 hours of invitro dissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid with0% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37 degrees C° isabout 2:1 or less, is about 1.5:1 or less, is about 1:1 or less, about 1:1.2 or less, about1:1.4 or less, about 1:1.6 or less, about 1:1.8 or less, about 1:2 or less, about 1:2.5 orless about 1:3 or less or about 1:5 or less. 74. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72 or 73, comprising at least: WO 2011/141488 PCT/EP2011/057566 - 148 - a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions releases the pharmaceutically active agents withsubstantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions. 75. Pharmaceutical composition according to any of 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73 or 74, compositioncomprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions has less than 3% of total substances related tohydromorphone or a pharmaceutically acceptable salt or derivativethereof and/or related to naloxone or a pharmaceutically acceptablesalt or derivative thereof 76. An oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, and wherein c) the pharmaceutical composition provides alcohol resistance. WO 2011/141488 PCT/EP2011/057566 - 149 - 77. A pharmaceutical composition according to 76, wherein the prolonged releasepharmaceutical composition is heat treated. 78. A pharmaceutical composition according to 76 or 77, wherein the at least oneprolonged release material and hydromorphone or a pharmaceutically acceptable saltor derivative thereof and naloxone or a pharmaceutically acceptable salt or derivativethereof are combined such that a prolonged release matrix is formed. 79. A pharmaceutical composition according to 76, 77 or 78, wherein a prolongedrelease coating is disposed on the active ingredients hydromorphone or apharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof 80. A pharmaceutical composition according to 76, 77, 78 or 79, whereinhydro morphone or a pharmaceutically acceptable salt or derivative thereof andnaloxone or a pharmaceutically acceptable salt or derivative thereof are present in thepharmaceutical composition in a weight ratio of about 2:1, about 1:1, about 1:2 orabout 1:3. 81. Pharmaceutical composition according to 76, 77, 78, 79 or 80 wherein theprolonged release material is selected from the group comprising hydrophobic orhydrophilic polymers, protein-derived material, gums, substituted or unsubstitutedhydrocarbons, digestible carbohydrates, fatty acids, fatty alcohols, glyceryl esters offatty acids, natural and synthetic oil and waxes. WO 2011/141488 PCT/EP2011/057566 - 150 - 82. Pharmaceutical composition according to 81, wherein the prolonged releasematerial is a cellulose ether, a (meth)acrylic based (co)polymer and/or a fattyalcohol. 83. Pharmaceutical composition according to 82, wherein prolonged releasematerial is a neutral (meth)acrylic based (co)polymer, a hydrophobic cellulose etherand/or a fatty alcohol. 84. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82 or83, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE asprolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix 85. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82 or83, comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein WO 2011/141488 PCT/EP2011/057566 - 151 - c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 86. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82 or83, comprising at least: a) at least one fatty alcohol as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 87. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82 or83, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one cellulose ether, preferably at least one hydrophobic celluloseether such as ethyl cellulose as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 - 152 - derivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 88. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82 or83, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one fatty alcohol as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 89. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82 or83, comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose and at least one fatty alcohol asprolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. WO 2011/141488 PCT/EP2011/057566 - 153 - 90. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82 or83, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE, at leastone cellulose ether, preferably at least one hydrophobic cellulose ethersuch as ethyl cellulose and at least one fatty alcohol as prolongedrelease materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 91. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90 wherein the pharmaceutical composition comprisesadditionally at least one filler, at least one lubricant, at least one binder, at least onerelease rate modifiers, at least one spheronising agent and/or at least one anti-tackingagent 92. Pharmaceutical composition according to 91, wherein said filler is anhydrouslactose. 93. Pharmaceutical composition according to 91 or 92, wherein magnesiumstearate and/or talc are used as lubricants. WO 2011/141488 PCT/EP2011/057566 - 154- 94. Pharmaceutical composition according to 91, 92 or 93, whereinhydroxypropyl cellulose is used as binder. 95. Pharmaceutical composition according to 91, 92, 93 or 94, whereinhydroxypropylmethyl cellulose, an anionic (meth)acrylic acid (co)polymer such asEudragit RSPO and/or Xanthan gum are used release rate modifiers. 96. Pharmaceutical composition according to 91, 92, 93, 94 or 95, whereinmicrocrystalline cellulose is used as spheronising agent. 97. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 or 96 wherein heat treatment takesplace at a temperature in the range of about 30°C to about 95°C and for a time in therange of about 10 min to about 3 hours. 98. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96 or 97, wherein the compositionreleases the pharmaceutically active agents with the following in vitro release ratewhen measured using the Ph. Eur. paddle method in 500 or 900 ml of SimulatedGastric Fluid at 75 or 100 rpm at 37 degrees C°: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agent at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents. WO 2011/141488 PCT/EP2011/057566 - 155 - 99. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97 or 98, wherein the ratio of theamount of the pharmaceutically active agents released after 0.5, 1 or 2 hours of invitro dissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid withup to 40% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37 degreesC° compared to the amount of the active agents released after 0.5, 1 or 2 hours of invitro dissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid with0% ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37 degrees C° isabout 2:1 or less, is about 1.5:1 or less, is about 1:1 or less, about 1:1.2 or less, about1:1.4 or less, about 1:1.6 or less, about 1:1.8 or less, about 1:2 or less, about 1:2.5 orless about 1:3 or less or about 1:5 or less. 100. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99, comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions releases the pharmaceutically active agents withsubstantially the same release rate as before subjecting thepharmaceutical composition to stressed conditions. 101. Pharmaceutical composition according to any of 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100, comprising atleast: a) at least one prolonged release material; WO 2011/141488 PCT/EP2011/057566 - 156 - b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein c) the pharmaceutical composition after storage under stressedconditions has less than 3% of total substances related tohydromorphone or a pharmaceutically acceptable salt or derivativethereof and/or related to naloxone or a pharmaceutically acceptablesalt or derivative thereof 102. An oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein the c) pharmaceutical composition after storage under stressed conditionsreleases the pharmaceutically active agents with substantially thesame release rate as before subjecting the pharmaceutical compositionto stressed conditions. 103. A pharmaceutical composition according to 102, wherein the prolongedrelease pharmaceutical composition is heat treated. 104. A pharmaceutical composition according to 102 or 103, wherein the at leastone prolonged release material and hydromorphone or a pharmaceutically acceptablesalt or derivative thereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined such that a prolonged release matrix is formed. WO 2011/141488 PCT/EP2011/057566 - 157 - 105. A pharmaceutical composition according to 102, 103 or 104, wherein aprolonged release coating is disposed on the active ingredients hydromorphone or apharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof. 106. A pharmaceutical composition according to 102, 103, 104 or 105, whereinhydro morphone or a pharmaceutically acceptable salt or derivative thereof andnaloxone or a pharmaceutically acceptable salt or derivative thereof are present in thepharmaceutical composition in a weight ratio of about 2:1, about 1:1, about 1:2 orabout 1:3. 107. Pharmaceutical composition according to 102, 103, 104, 105 or 106, whereinthe prolonged release material is selected from the group comprising hydrophobic orhydrophilic polymers, protein-derived material, gums, substituted or unsubstitutedhydrocarbons, digestible carbohydrates, fatty acids, fatty alcohols, glyceryl esters offatty acids, natural and synthetic oil and waxes. 108. Pharmaceutical composition according to 107, wherein the prolonged releasematerial is a cellulose ether, a (meth)acrylic based (co)polymer and/or a fattyalcohol. 109. Pharmaceutical composition according to 108, wherein prolonged releasematerial is a neutral (meth)acrylic based (co)polymer, a hydrophobic cellulose etherand/or a fatty alcohol. 110. Pharmaceutical composition according to any of 102, 103, 104, 105, 106, 107, 108 or 109, comprising at least: WO 2011/141488 PCT/EP2011/057566 - 158 - a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE asprolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix 111. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108 or 109, comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 112. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108 or 109, comprising at least: a) at least one fatty alcohol as prolonged release material; WO 2011/141488 PCT/EP2011/057566 - 159 - b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 113. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108 or 109, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one cellulose ether, preferably at least one hydrophobic celluloseether such as ethyl cellulose as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 114. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108 or 109, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one fatty alcohol as prolonged release materials; WO 2011/141488 PCT/EP2011/057566 - 160 - b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 115. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108 or 109, comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose and at least one fatty alcohol asprolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 116. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108 or 109, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE, at leastone cellulose ether, preferably at least one hydrophobic cellulose ethersuch as ethyl cellulose and at least one fatty alcohol as prolongedrelease matrix materials; WO 2011/141488 PCT/EP2011/057566 - 161 - b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 117. Pharmaceutical composition according to any of 102, 103, 104, 105, 106, 107, 108, 109, 111, 112, 113, 114, 115 or 116 wherein the pharmaceuticalcomposition comprises additionally at least one filler, at least one lubricant, at leastone binder, at least one release rate modifier, at least one spheronising agent and/orat least one anti-tacking agent 118. Pharmaceutical composition according to 117, wherein said filler isanhydrous lactose. 119. Pharmaceutical composition according to 117 or 118, wherein magnesiumstearate and/or talc are used as lubricants. 120. Pharmaceutical composition according to 117, 118 or 119, whereinhydroxypropyl cellulose is used as binder. 121. Pharmaceutical composition according to 117, 118, 119 or 120, whereinhydroxypropylmethyl cellulose, an anionic (meth)acrylic acid (co)polymer such asEudragit RSPO and/or Xanthan gum are used release rate modifiers. WO 2011/141488 PCT/EP2011/057566 - 162 - 122. Pharmaceutical composition according to 117, 118, 119, 120 or 121, whereinmicrocrystalline cellulose is used as spheronising agent. 123. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 or 122,wherein heat treatment takes place at a temperature in the range of about 30°C toabout 95°C and for a time in the range of about 10 min to about 3 hours. 124. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122 or123, wherein the composition releases the pharmaceutically active agents with thefollowing in vitro release rate when measured using the Ph. Eur. paddle method in500 or 900 ml of Simulated Gastric Fluid at 75 or 100 rpm at 37 degrees C°: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agents, at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents. 125. Pharmaceutical composition according to any of 102, 103, 104, 105, 106,107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123or 124, wherein the ratio of the amount of the pharmaceutically active agentsreleased after 0.5, 1 or 2 hours of in vitro dissolution of the dosage form in 500 or900 ml of Simulated Gastric Fluid with up to 40% ethanol using the Ph. Eur. paddlemethod at 75 100 rpm at 37 degrees C° compared to the amount of the active agents WO 2011/141488 PCT/EP2011/057566 - 163 - released after 0.5, 1 or 2 hours of in vitro dissolution of the dosage form in 500 or900 ml of Simulated Gastric Fluid with 0% ethanol using the Ph. Eur. paddle methodat 75 or 100 rpm at 37 degrees C° is about 2:1 or less, is about 1.5:1 or less, is about1:1 or less, about 1:1.2 or less, about 1:1.4 or less, about 1:1.6 or less, about 1:1.8 orless, about 1:2 or less, about 1:2.5 or less about 1:3 or less or about 1:5 or less. 126. Pharmaceutical composition according to any of 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123,124 or 125, comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein the c) pharmaceutical composition after storage under stressed conditionshas less than 3% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or related tonaloxone or a pharmaceutically acceptable salt or derivative thereof 127. An oral prolonged release pharmaceutical composition comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein the c) pharmaceutical composition after storage under stressed conditionshas less than 3% of total substances related to hydromorphone or apharmaceutically acceptable salt or derivative thereof and/or related tonaloxone or a pharmaceutically acceptable salt or derivative thereof WO 2011/141488 PCT/EP2011/057566 - 164 - 128. Pharmaceutical composition according to 127, wherein the prolonged releasepharmaceutical composition is heat treated. 129. A pharmaceutical composition according to 127 or 128, wherein the at leastone prolonged release matrix material and hydromorphone or a the at least oneprolonged release material and hydromorphone or a pharmaceutically acceptable saltor derivative thereof and naloxone or a pharmaceutically acceptable salt or derivativethereof are combined such that a prolonged release matrix is formed. 130. A pharmaceutical composition according to 127, 128 or 129, wherein aprolonged release coating is disposed on the active ingredients hydromorphone or apharmaceutically acceptable salt or derivative thereof and naloxone or apharmaceutically acceptable salt or derivative thereof 131. A pharmaceutical composition according to 127, 128, 129 or 130, whereinhydro morphone or a pharmaceutically acceptable salt or derivative thereof andnaloxone or a pharmaceutically acceptable salt or derivative thereof are present in thepharmaceutical composition in a weight ratio of about 2:1, about 1:1, about 1:2 orabout 1:3. 132. Pharmaceutical composition according to 127, 128, 129, 130 or 131, whereinthe prolonged release material is selected from the group comprising hydrophobic orhydrophilic polymers, protein-derived material, gums, substituted or unsubstitutedhydrocarbons, digestible carbohydrates, fatty acids, fatty alcohols, glyceryl esters offatty acids, natural and synthetic oil and waxes. WO 2011/141488 PCT/EP2011/057566 - 165 - 133. Pharmaceutical composition according to 132, wherein the prolonged releasematerial is a cellulose ether, a (meth)acrylic based (co)polymer and/or a fattyalcohol. 134. Pharmaceutical composition according to 133, wherein prolonged releasematerial is a neutral (meth)acrylic based (co)polymer, a hydrophobic cellulose etherand/or a fatty alcohol. 135. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133 or 134, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE asprolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix 136. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133 or 134, comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein WO 2011/141488 PCT/EP2011/057566 - 166 - c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 137. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133 or 134, comprising at least: a) at least one fatty alcohol as prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialto form a prolonged release matrix. 138. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133 or 134, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one cellulose ether, preferably at least one hydrophobic celluloseether such as ethyl cellulose as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt or WO 2011/141488 PCT/EP2011/057566 - 167 - derivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 139. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133 or 134, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE and atleast one fatty alcohol as prolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 140. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133 or 134, comprising at least: a) at least one cellulose ether, preferably at least one hydrophobiccellulose ether such as ethyl cellulose and at least one fatty alcohol asprolonged release materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. WO 2011/141488 PCT/EP2011/057566 - 168 - 141. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133 or 134, comprising at least: a) at least one (meth)acrylic acid (co)polymer, preferably at least oneneutral (meth)acrylic acid (co)polymer such as Eudragit®NE, at leastone cellulose ether, preferably at least one hydrophobic cellulose ethersuch as ethyl cellulose and at least one fatty alcohol as prolongedrelease materials; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof, wherein c) hydromorphone or a pharmaceutically acceptable salt or derivativethereof and naloxone or a pharmaceutically acceptable salt orderivative thereof are combined with said prolonged release materialsto form a prolonged release matrix. 142. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133, 134, 135, 136, 137, 138, 139, 140, or 141 wherein the pharmaceuticalcomposition comprises additionally at least one filler, at least one lubricant, at leastone binder, at least one release rate modifier, at least one spheronising agent and/orat least one anti-tacking agent 143. Pharmaceutical composition according to 142, wherein said filler isanhydrous lactose. 144. Pharmaceutical composition according to 142 or 143, wherein magnesiumstearate and/or talc are used as lubricants. WO 2011/141488 PCT/EP2011/057566 - 169 - 145. Pharmaceutical composition according to 142, 143 or 144, whereinhydroxypropyl cellulose is used as binder. 146. Pharmaceutical composition according to 142, 143, 144 or 145, whereinhydroxypropylmethyl cellulose, an anionic (meth)acrylic acid (co)polymer such asEudragit RSPO and/or Xanthan gum are used release rate modifiers. 147. Pharmaceutical composition according to 142, 143, 144, 145 or 146, whereinmicrocrystalline cellulose is used as spheronising agent. 148. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, or 147wherein heat treatment takes place at a temperature in the range of about 30°C toabout 95°C and for a time in the range of about 10 min to about 3 hours 149. Pharmaceutical composition according to any of 127, 128, 129, 130, 131,132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147 or148, wherein the composition releases the pharmaceutically active agents with thefollowing in vitro release rate when measured using the Ph. Eur. paddle method in500 or 900 ml of Simulated Gastric Fluid at 75 or 100 rpm at 37 degrees C°: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agents, at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents. WO 2011/141488 PCT/EP2011/057566 - 170 - 150. Pharmaceutical composition according to any of 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148or 149 wherein the ratio of the amount of the pharmaceutically active agents releasedafter 0.5, 1 or 2 hours of in vitro dissolution of the dosage form in 500 or 900 ml ofSimulated Gastric Fluid with up to 40% ethanol using the Ph. Eur. paddle method at75 or 100 rpm at 37 degrees C° compared to the amount of the active agents releasedafter 0.5, 1 or 2 hours of in vitro dissolution of the dosage form in 500 or 900 ml ofSimulated Gastric Fluid with 0% ethanol using the Ph. Eur. paddle method at 75 or100 rpm at 37 degrees C° is about 2:1 or less, is about 1.5:1 or less, is about 1:1 orless, about 1:1.2 or less, about 1:1.4 or less, about 1:1.6 or less, about 1:1.8 or less,about 1:2 or less, about 1:2.5 or less about 1:3 or less or about 1:5 or less. 151. Pharmaceutical composition according to any of 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148,149 or 150, comprising at least: a) at least one prolonged release material; b) at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and naloxone or a pharmaceutically acceptable saltor derivative thereof; and wherein the c) pharmaceutical composition after storage under stressed conditionsreleases the pharmaceutically active agents with substantially thesame release rate as before subjecting the pharmaceutical compositionto stressed conditions. 152. Pharmaceutical dosage form according to any of 1 to 151, whereinhydromorphone hydrochloride and naloxone hydrochloride are used. WO 2011/141488 PCT/EP2011/057566 - 171 - 153. Pharmaceutical dosage form according to any of 1 to 152, wherein about 1mg, about 2 mg, about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 24 mg,about 32 mg, about 40 mg, about 48 mg or about 64 mg hydromorphonehydrochloride are used. 154. Pharmaceutical dosage form according to any of 1 to 153 wherein about 1mg, about 2 mg, about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 24 mg,about 32 mg, about 48 mg, about 64 mg, about 96 mg, about 128 or about 256 mg ofnaloxone hydrochloride are used. 155. Method of manufacturing an oral prolonged release pharmaceuticalcomposition according to any of 1 to 154 comprising at least the steps of: a) producing granules comprising at least one prolonged release material,at least hydromorphone or a pharmaceutically acceptable salt orderivative thereof and at least naloxone or a pharmaceuticallyacceptable salt or derivative thereof, b) optionally selecting granules of step a) of substantially uniform size; c) optionally adding additional prolonged release material, d) compressing said granules of step a), b) or c) to obtain an oralprolonged release pharmaceutical composition in the form of a tablet; e) optionally heat treating said compressed granules; f) optionally disposing a prolonged release coatings either on thegranules of step a), b) or c) or on the monolithic composition obtainedin step d) or e); g) optionally curing the obtained composition. 156. Method according to 155, wherein step a) comprises the following steps: WO 2011/141488 PCT/EP2011/057566 - 172- aa) blending a prolonged release material with at least hydromorphoneor a pharmaceutically acceptable salt or derivative thereof and atleast naloxone or a pharmaceutically acceptable salt or derivativethereof and optionally with a filler, a lubricant, a binder, a releaserate modifier, a spheronising agent and/or an anti-tacking agent; ab) wet or dry granulating said blend of step aa) to obtain granules; ac) drying said granules of step ab). 157. Method according to 156, wherein at least step ab) is performed by rotary pangranulation or fluidized bed granulation. 158. Method according to 155, wherein step a) comprises the following steps: aa) blending a prolonged release material with at least hydromorphoneor a pharmaceutically acceptable salt or derivative thereof and atleast naloxone or a pharmaceutically acceptable salt or derivativethereof and optionally with a spheronising agent, a filler, alubricant, a binder, a release rate modifier, and/or an anti-tackingagent; ab) extruding said blend of step aa) to obtain granules; and optionallyspheronising said granules of step ab); ac) drying said granules of step ab). 159. Method according to any of 155 to 158, wherein drying in step ac) takes placeat humidity in the range of about 0.5 % to about 5.0 % at a temperature in the rangeof about 20°C to about 90°C and for a time in the range of about 10 min to about 3hours. WO 2011/141488 PCT/EP2011/057566 - 173 - 160. Method according to any of 155 to 159, wherein granules of a mean size inthe range of about 100 gm to about 2 mm are selected in step b). 161. Method according to any of 155 to 160, wherein heat treatment takes place ata temperature in the range of about 30°C to about 95°C and for a time in the range ofabout 10 min to about 3 hours. 162. Method according to any of 155 to 160, wherein the prolonged releasematerial is selected from the group comprising hydrophobic or hydrophilic polymers,protein-derived material, gums, substituted or unsubstituted hydrocarbons, digestiblecarbohydrates, fatty acids, fatty alcohols, glyceryl esters of fatty acids, natural andsynthetic oil and waxes. 163. Method according to 162, wherein the prolonged release material is acellulose ether, a (meth)acrylic based (co)polymer and/or a fatty alcohol. 164. Method according to 163, wherein prolonged release material is a neutral(meth)acrylic based (co)polymer, a hydrophobic cellulose ether and/or a fattyalcohol. 165. Method according to any of claims 155 to 164, wherein the pharmaceuticalcomposition comprises additionally at least one filler, at least one lubricant, at leastone binder, at least one release relate modifier, at least one spheronising and at leastone anti-tacking agent. 166. Method according to any of 155 to 165, wherein said filler is anhydrouslactose. WO 2011/141488 PCT/EP2011/057566 - 174- 167. Method according to any of 155 to 166, wherein magnesium stearate and/ortalc are used as lubricants. 168. Method according to any of 155 to 167, wherein hydroxypropyl cellulose isused as binder. 169. Method according to any of 155 to 168, wherein hydroxypropylmethylcellulose, an anionic (meth)acrylic acid (co)polymer such as Eudragit RSPO and/orXanthan gum are used release rate modifiers. 170. Method according to any of 155 to 169, wherein microcrystalline cellulose isused as spheronising agent. 171. Method according to any of 155 to 170, wherein the composition releases thepharmaceutically active agents with the following in vitro release rate whenmeasured using the Ph. Eur. paddle method in 500 or 900 ml of Simulated GastricFluid at 75 or 100 rpm at 37 degrees C°: at 1 h: 5 to 45% by weight of the pharmaceutically active agents, at 2 h: 15 to 55% by weight of the pharmaceutically active agents, at 3 h: 30 to 70% by weight of the pharmaceutically active agents, at 4 h: 35 to 75% by weight of the pharmaceutically active agents, at 6 h: 40 to 80% by weight of the pharmaceutically active agents, at 8 h: 50 to 90% by weight of the pharmaceutically active agents, at 10 h: 60 to 100% by weight of the pharmaceutically active agents, at 12 h: 65 to 100% by weight of the pharmaceutically active agents. 172. Method according to any of 155 to 171, wherein the ratio of the amount of thepharmaceutically active agents released after 0.5, 1 or 2 hours of in vitro dissolution WO 2011/141488 PCT/EP2011/057566 - 175 - of the dosage form in 500 or 900 ml of Simulated Gastric Fluid with up to 40%ethanol using the Ph. Eur. paddle method at 75 or 100 rpm at 37 degrees C°compared to the amount of the active agents released after 0.5, 1 or 2 hours of invitro dissolution of the dosage form in 500 or 900 ml of Simulated Gastric Fluid with0% ethanol using the Ph. Eur. paddle method at 100 rpm at 37 degrees C° is about2:1 or less, is about 1.5:1 or less, is about 1:1 or less, about 1:1.2 or less, about 1:1.4or less, about 1:1.6 or less, about 1:1.8 or less, about 1:2 or less, about 1:2.5 or lessabout 1:3 or less or about 1:5 or less. 173. Method according to any of 155 to 172, wherein hydromorphonehydrochloride and naloxone hydrochloride are used. 174. Method according to any of 155 to 172, wherein about 1 mg, about 2 mg,about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 24 mg, about 32 mg, about40 mg, about 48 mg or about 64 mg hydromorphone hydrochloride are used. 175. Method according to any of 155 to 172, wherein about 1 mg, about 2 mg,about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 24 mg, about 32 mg, about48 mg, about 64 mg, about 96 mg, about 128 or about 256 mg of naloxonehydrochloride are used. 176. Pharmaceutical composition obtainable by a method according to any ofclaims 155 to 175.