Untitled record

Tamper-resistant oral pharmaceutical dosage forms comprising an opioid analgesic

Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic

Full description

Background of the invention:

The present invention relates to pharmaceutical dosage forms, e.g., a tamper-resistant dosage form comprising an opioid analgesic, processes of manufacture, uses, and methods for using them in therapy.

Pharmaceutical products are sometimes subject to misuse. For example, a given dose of an opioid agonist may be more effective when given parenterally than the same dose when given orally. Some formulations may be manipulated to provide an opioid agonist contained in these formulations for illicit use. Metered-release formulations containing an opioid agent are sometimes crushed or subjected to extraction with solvents (such as ethanol) by drug users to provide the opioid within these formulations for rapid release for oral administration. Orally or parenteral injection.

Metered-release opioid agonist dosage forms that have the ability to release a portion of the opioid when exposed to ethanol can also result in a patient receiving the dose sooner than intended if they ignore the directions for use and use alcohol simultaneously with the dosage form. dosage form.

Hence, the field still needs oral dosage forms that include an opioid cofactor without significantly altering opioid release properties upon contact with alcohol and/or with resistance to crushing.

General description of the invention:

Certain embodiments of the present invention are intended to provide an extended release oral dosage form comprising an active agent such as an opioid analgesic and being tamper resistant.

An objective of specific embodiments of the present invention is to provide an extended-release oral dosage form comprising an active agent such as an opioid analgesic and characterized by crush resistance.

An objective of specific embodiments according to the present invention is to provide an extended-release oral dosage form comprising an active agent such as an opioid analgesic and characterized by resistance to alcohol extraction and elimination of the dose when used concomitantly with or in contact with alcohol.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation in the form of a tablet or multiple particulates, wherein the tablet or individual multiparticles can Become at least flat without breaking, and are characterized by the disc or individual particulates having a thickness after flattening that corresponds to no more than about 60% of the thickness of the disc or individual particulates. Prior to flattening, such that the flattened tablet or individual particulates provide a dissolution rate in vitro, when measured with a USP Type 1 (basket) device at 100 rpm in 900 mL of simulated gastric fluid ( SGF) without enzymes at 37°C, characterized by a percentage of the amount active released at 0.5 h of dissolution that deviates by no more than about 20% points from the corresponding in vitro dissolution rate of a non-flat reference tablet non-flattened or reference multi particulates.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation in the form of a tablet or multiple particulates, wherein the tablet or individual multi particulates can Become at least flattened without breaking, and are characterized by the individual disc or particulate having a thickness after flattening that corresponds to no more than about 60% of the thickness of the disc or particulate. Individual multiple before flattening, whereby a flattened or non-flattened tablet or individual flattened or flattened microparticle provides an in vitro dissolution rate, when measured with a USP Type 1 (basket) device at 100 rpm at 900 ml of simulated gastric fluid (SGF) containing 40% ethanol at 37°C, characterized by a percentage of the amount active released at 0.5 h of dissolution that deviates by no more than about 20% points from the rate Corresponding in vitro dissolution, measured using USP type 1 (basket) at 100 rpm in 900 mL of simulated gastric fluid without enzymes at 37°C without ethanol, for a flattened or non-flattened reference tablet or reference particulates reference multiple particulates flat and non-flat, respectively.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation, wherein the extended-release matrix formulation includes a composition consisting of at least:

At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; and at least one active agent; And

The composition contains at least about 80% (by weight) of polyethylene oxide.

In accordance with the specific embodiments, the active agent is oxycodone hydrochloride, and the composition comprises more than about 5% (by weight) of oxycodone hydrochloride.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release template formulation, wherein the extended-release template formulation includes a composition consisting of at least one active agent;

At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

At least one polyethylene oxide has an approximate molecular weight, based on rheological measurements, of less than 1,000,000.

In certain embodiments, the present invention is directed to a process for preparing an extended-release solid oral pharmaceutical dosage form,

It includes the following steps:

Merge at least

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000, and

(2) at least one active agent,

To create a composition;

(b) Formation of the composition to form an extended release matrix formulation; And

(c) Curing said extended-release template formulation, comprising at least a processing step of exposing said extended-release template formulation to a temperature at least the ductility temperature of said polyethylene oxide for a period of at least about one minute.

In specific embodiments, the present invention is directed to the preparation of an extended-release solid oral pharmaceutical dosage form, comprising at least the following steps:

(a) Combine at least:

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000, and

(2) at least one active agent,

To create a composition;

(b) forming the composition to form an extended-release template formulation; And

(c) Curing matrix formulation of said extended release, comprising at least a curing step such that said polyethylene oxide is at least partially melted.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release block formulation comprising an active agent in the form of a tablet or multi particulates, wherein the tablet or multiparticles The individual multi particulate can become at least flattened without breaking, and is characterized by the fact that the tablet or individual multiparticle has a thickness after flattening corresponding to no more than about 60%. of the thickness of the tablet or individual flattened PM prior to flattening, wherein said flat disk or flattened individual PM provides the in vitro dissolution rate, when measured with a USP Type 1 (basket) device at 100 rpm in 900 mL of liquid Simulated gastric fluid (SGF) without enzymes at 37°C, characterized by the percentage amount active released at 0.5 h of dissolution that deviates by no more than about 20% points from the corresponding dissolution rate dissolution rate in the laboratory for a non-flat reference tablet or non-flat reference particulates, respectively.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release block formulation comprising an active agent in the form of a tablet or multiple particulates, wherein the tablet or multiparticles The individual can at least become flat without breaking, and is characterized by the individual disk or particle having a thickness after flattening that corresponds to no more than about 60% of the thickness of the tablet or particle. Individualization prior to flattening, whereby said flattened tablet or flattened multi particulates and non-flattened reference tablet or flattened multi particulates provide the dissolution rate in the laboratory, when measured with a USP type device 1 (basket) at 100 rpm in 900 ml of simulated gastric fluid (SGF) without enzymes at 37°C, between about 5 and about 40% (by weight) of the agent Effectively released after 0.5 hours.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation comprising an active agent in the form of a tablet or multiple particulates, wherein A tablet or individual microparticle can at least become flattened without breaking, and is characterized by a tablet or individual microparticle having a thickness after flattening corresponding to no more than about 60% of the thickness. Thickness of the individual tablet or microparticle before flattening, such that the flattened or flattened tablet or the flattened or flattened polyparticle provides an in vitro dissolution rate, when measured with a USP Type 1 (basket) device at 100 rpm at 900 ml of simulated gastric fluid (SGF) without enzymes containing 40% ethanol at 37°C, characterized by a percentage of the amount of active agent released at 0.5 h of dissolution that deviates by no more than about a 20% point from the dissolution rate In vitro counterpart, measured using USP type 1 (basket) at 100 rpm in 900 mL of simulated gastric fluid (SGF) without enzymes and without ethanol at 37°C, for a flat and non-flat reference tablet. flattened or reference multi particulates and non-flat, respectively.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation comprising an active agent in the form of a tablet or multiple particulates, wherein the tablet or Individual PMs can become at least flattened without breaking, and the tablet or individual PM has a thickness after flattening that corresponds to no more than about 60% of Thickness of an individual tablet or particle before flattening. A flattened or flattened tablet or flattened or flattened multiple particle provides the in vitro dissolution rate, when measured with a USP Type 1 (basket) device at 100 rpm In 900 ml of simulated gastric fluid (SGF) without enzymes containing 40% or 20% ethanol at 37°C, between about 5 and about 40% (by weight) of the active agent is released after 0.5 hours.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation, wherein the extended-release template formulation includes

A composition consisting of at least:

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

(2) at least one active agent selected from opioid analgesics; And

Whereas, the composition includes at least about 80% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release template formulation, wherein the extended-release template formulation includes:

A composition consisting of at least:

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

(2) 10 mg of oxycodone hydrochloride; And

Whereas, the composition includes at least about 85% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation, wherein the extended-release matrix formulation comprises:

A composition consisting of at least:

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

(2) 15 or 20 mg of oxycodone hydrochloride; And

Whereas, the composition includes at least about 80% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release template formulation, wherein the extended-release template formulation includes:

A composition consisting of at least:

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

(2) 40 mg of oxycodone hydrochloride; And

Whereas, the composition includes at least about 65% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release template formulation, wherein the extended-release template formulation includes a composition consisting of at least:

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

(2) 60 mg or 80 mg of oxycodone hydrochloride; And

Whereas, the composition includes at least about 60% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation, wherein the extended-release matrix formulation includes:

A composition consisting of at least:

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And the:

(2) 8 mg of oxycodone hydrochloride; And

Whereas, the composition includes at least about 94% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release template formulation, wherein the extended-release template formulation includes:

A composition consisting of at least:

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

(2) 12 mg of oxycodone hydrochloride; And

Whereas, the composition includes at least about 92% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation, wherein the extended-release matrix formulation includes a composition consisting of at least:

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And the:

(2) 32 mg of oxycodone hydrochloride; And

Whereas, the composition includes at least about 90% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release template formulation, wherein the extended-release template formulation includes a composition consisting of at least:

(1) At least one active agent selected from an opioid analgesics;

(2) at least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

(3) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of less than 1,000,000.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation, wherein the extended-release matrix formulation includes a composition consisting of at least:

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

(2) at least one active agent selected from an opioid analgesics; And

Whereas, the composition includes at least about 80% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release template formulation, wherein the extended-release template formulation includes a composition consisting of at least:

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

(2) at least one active agent; And

When the extended-release die formulation is subjected to an indentation test, it has a cracking force of 110 Newtons.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation, wherein the extended-release matrix formulation includes a composition consisting of at least:

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

(2) at least one active agent; And

When the extended-release die formulation is subjected to an indentation test, it has an “incision depth distance” of 1.0 mm.

In certain embodiments, the present invention is directed to a treatment method whereby a dosage form according to the invention comprising an opioid analgesic is administered to treat pain in a patient in need.

In certain embodiments, the present invention directs the use of a dosage form according to the present invention comprising an opioid analgesic to manufacture a drug for the treatment of pain.

In certain embodiments, the present invention is directed to the use of high molecular weight polyethylene oxide, having an approximate molecular weight of at least 1,000,000 based on urological measurements, in the form of a matrix comprising an active agent selected from opioids To give the extended release solid oral dosage form resistant to alcohol extraction.

In certain embodiments, the invention is directed to a process for preparing an extended-release solid oral pharmaceutical dosage form, comprising at least the following steps:

(a) Merge at least

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000, and

(2) at least one active agent,

To create a composition;

(b) Formation of the composition to form an extended release matrix formulation; And

(c) Processing said extended-release template formulation, comprising at least a processing step of exposing the extended-release template formulation to a temperature that is at least the polyethylene oxide softening temperature for a period of at least 5 minutes.

According to certain embodiments of the invention, the dosage form of the sustained-release solid pharmaceutical is suitable for use as a suppository.

The term “extended release” is defined for the purposes of the present invention to refer to products that are formulated to deliver the drug over an extended period after ingestion, allowing for a reduction in dose times compared to a drug delivered in a conventional dosage form (e.g. as a solution or solution). Image of immediate release dose.

The term “immediate release” is defined for the purposes of the present invention to refer to products that are formulated to allow the drug to dissolve in gastrointestinal contents without intending to delay or prolong the dissolution or absorption of the drug.

The term “solid oral extended-release dosage form” refers to a dosage form that includes a unit dose of the active agent in an extended-release form such as an “extended release matrix formulation” and optionally other adjuvants Common additives and conventional preservatives such as a protective coating, capsule, etc., and optionally any other additional properties or ingredients used in the dosage form. If not specifically stated, the term “solid oral extended-release dosage form” refers to said dosage form in its intact form, more specifically before any manipulation. The extended-release dosage form may be, for example, a tablet containing the extended-release formulation or a capsule containing the extended-release formulation in the form of multiple particulates. The term “solid oral extended-release dosage form” can include part of an active agent in an extended-release form and part of an active agent in an immediate-release form, for example as an immediate release layer of an active agent. Surrounding the dosage form or immediate-release component included in the dosage form.

The term “extended release matrix formulation” is defined for the purposes of the present invention as a solid form of a formulation comprising at least one active agent and at least one extended release property such as an extended release matrix such as high molecular weight polyethylene oxide. The composition may optionally include more than these two components; That is, it may include other active agents, additional retardants and/or other substances including, but not limited to, low molecular weight polyethylene oxides, other adjuvants and conventional additives familiar in the art.

The term “bioequivalent” for the purposes of the present invention is defined to refer to a dose profile that provides the geometric mean of the Cmax, AUCt, and AUCinf values ​​for an active agent, with the 90% confidence intervals based on the ratio (test/reference) ranging from 80.00 % to 125.00%. It is preferable that the average values ​​of Cmax, AUCt, and AUCinf range from 80.00% to 125.00% as determined in cases of eating and fasting.

For the purposes of the present invention, the term “polyethylene oxide” is defined as having a molecular weight of at least 25,000, measured to the best of knowledge in the art, and preferably a molecular weight of at least 100,000. Lower molecular weight structures are usually referred to as polyethylene glycols.

The term "high molecular weight polyethylene oxide" is defined for the purposes of the present invention as having an approximate molecular weight of at least 1,000,000. To serve the purpose of the present invention, the approximate molecular weight is based on rheological measurements. Polyethylene oxide is considered to have an approximate molecular weight of 1,000,000 when a 2% (by weight) aqueous solution of said polyethylene oxide is demonstrated using a Brookfield RVF viscometer, No. 1 spindle, at 10 rpm, at temperature 25°C, viscosity range ranges from 400 to 800 MPa per second (centipoise cP). Polyethylene oxide is considered to have an approximate molecular weight of 2,000,000 when a 2% (by weight) aqueous solution of said polyethylene oxide using a Brookfield RVF viscometer, spindle number 3, at 10 rpm, at a temperature of 25°C, shows Viscosity range is 2000 to 4000 MPa/s (centipoise). Polyethylene oxide is considered to have an approximate molecular weight of 4,000,000 when a 1% (by weight) aqueous solution of said polyethylene oxide using a Brookfield model RVF viscometer, No. 2 spindle, at 2 rpm, at 25°C, shows a range Viscosity ranges from 1650 to 5500 MPa per second (centipoise cP). Polyethylene oxide is considered to have an approximate molecular weight of 5,000,000 when a 1% (by weight) aqueous solution of said polyethylene oxide is demonstrated using a Brookfield RVF viscometer, spindle No. 2, at 2 rpm, at Temperature 25°C, viscosity range ranges from 5500 to 7500 MPa per second (centipoise). Polyethylene oxide is considered to have an approximate molecular weight of 7,000,000 when a 1% (by weight) aqueous solution of said polyethylene oxide using a Brookfield RVF viscometer, No. 2 spindle, at 2 rpm, at 25°C, shows a range Viscosity ranges from 7,500 to 10,000 MPa per second (centipoise). Polyethylene oxide is considered to have an approximate molecular weight of 8,000,000 when a 1% (by weight) aqueous solution of said polyethylene oxide using a Brookfield RVF viscometer, No. 2 spindle, at 2 rpm, at 25°C, shows a range Viscosity ranges from 10,000 to 15,000 MPa per second (centipoise).

Regarding polyethylene oxides with low molecular weight; Polyethylene oxide is considered to have an approximate molecular weight of 100,000 when a 5% (by weight) aqueous solution of said polyethylene oxide using a Brookfield model RVF viscometer, No. 1 spindle, at 50 rpm, at 25°C, shows a viscosity range of From 30 to 50 MPa per second (centipoise), polyethylene oxide is considered to have an approximate molecular weight of 900,000 when a 5% (by weight) aqueous solution of said polyethylene oxide Using a Brookfield viscometer model RVF, No. 2 shaft, at 2 rpm, at 25°C, viscosity range from 8,800 to 17,600 MPa s (centipoise).

The term "low molecular weight polyethylene oxide" is defined for the purposes of the present invention as having an approximate molecular weight of less than 1,000,000 based on the rheological measurements specified above.

For the purposes of the present invention, the term “direct compression” is defined to refer to a tablet making process whereby the tablet or other compressed dosage form is manufactured following a process comprising the steps of mixing the compounds by drying, and compressing the dry mixture to form the dosage form, for example using diffusion blend and/or convection mixing process, for example:

guidance for industry, supac-ir/mr: immediate release and modified release solid oral dosage forms, manufacturing equipment addendum.

The term “bed of free-flowing tablets” is defined for the purposes of the present invention as a batch of tablets kept in motion relative to each other, for example in a packing vessel set at a suitable rotational speed or in a fluidized bed of tablets. . The free flowing tablets coating reduces or prevents the tablets from sticking together.

The term “flattening” and related terms when used in the context of making tablets or other dosage forms flat according to the present invention means that a tablet is subjected to a force applied from a direction substantially perpendicular to the diameter, and substantially in line with the thickness of the tablet. tablet for example. It is possible to apply force using a carver-type bench press (unless otherwise specified) to the point where target flatness/reduced thickness is necessary. According to specific embodiments of the invention, flattening does not break the tablet into small pieces, but edge spits and cracks can occur. Flatness is described in terms of the thickness of a flat disc compared to the thickness of a flat disc, expressed as a percentage of thickness, based on the thickness of the flat disc. In addition to tablets, flattening can be applied to any dosage form, such that the force is applied from a direction that is closely aligned with the smallest diameter (more specifically thickness) of the dosage form when the form is not spherical and from any direction when it is spherical. Flatness is then described in terms of the thickness/smallest diameter of the flat shape compared to the thickness/smallest diameter of the non-flat shape expressed as a percentage of thickness, based on the thickness/smallest diameter of the non-flat shape when the initial shape is spherical, or percentage thickness, based on the diameter Not flat when the initial shape is spherical. Thickness is measured using a thickness gauge (eg, digital thickness gauge). Figures 4 through 6 show tablets that have been flattened using a Carver bench press. The initial appearance of the tablets is shown in Figures 1 through 3 to the left of the image.

In certain embodiments according to the invention, in addition to using a bench press, a hammer may be used to flatten tablets/dose images. In such a flattening process, a hammer is used manually and the blows are delivered from a direction that is closely aligned with the thickness of the disc, for example. Flatness is then also described in terms of the thickness/smallest diameter of the flat shape compared to the non-flat shape expressed as a thickness percentage, based on the thickness/smallest diameter of the non-flat shape when the initial shape is non-spherical, or the thickness percentage , based on the non flattened diameter when the initial shape is spherical. Thickness measured is measured using a thickness gauge (for example, a digital thickness gauge).

On the other hand, when carrying out the fracture strength or hardness test according to what is mentioned in the reference:

remingtons pharmaceutical sciences, 18th edition, 1990, chapter 89 oral solid dosage forms, pages 1633-1665.

The contents of which are included by reference herein, using a Schleuniger device, the tablet/dose form is placed between a pair of flat plates arranged in parallel, and is compressed by the two flat plates so that the force is applied perpendicularly to an extent Large in thickness and largely aligned with the diameter of the tablet, thus reducing the diameter in this direction.

This reduced diameter is expressed as a percentage of the diameter, based on the diameter of the disc before the breaking strength test was performed. Tablet hardness is defined as the force at which the tablet under test/dose form breaks. Tablets/dosage forms that do not break but are deformed by the applied force are considered to be resistant to breakage at that specified force.

Another test to measure tablet strength/dosage profiles is the indentation test using a texture analyzer such as the TA-XT2 Texture Analyzer (from:

texture technologies corp., 18 fairview road, scarsdale, ny 10583). In this method, the tablets/dose images are placed on top of a stainless stand equipped with a slightly concave surface, and then accessed with a descending probe for the texture analyzer, such as a stainless steel ball probe with a diameter of 1/8 of the TA type. -8A. Before the measurement begins, the disks are stacked directly under the probe, so that the descending probe will penetrate the disks axially, meaning that it will penetrate to the center of the disk, and so that the force of the descending probe is applied largely perpendicular to the diameter, and in parallel with Significantly with the thickness of the disc. First, the structure analyzer probe begins moving toward the disk sample at the pre-test speed. When the probe contacts the surface of the disc, and then reaches the operating force set, the probe continues to move at the test speed, and penetrates into the disc. For each penetration depth of the probe, which will later be referred to as a “distance,” the corresponding force will be measured, and data will be collected. When the probe reaches the maximum penetration depth required, it changes direction, moving backwards at post-test speed, while additional data can be collected. The cracking force is defined as the first local maximum force reached in the corresponding force/distance diagram, and is calculated using for example the Texture Analyzer software, version 2.64 English. To avoid being bound by any theory, it is believed that at this point some structural damage to the tablet occurs in the form of fracture. However, the broken tablets/dosage forms according to specific embodiments of the present invention remain intact as indicated by continued resistance to the descending probe. The distance corresponding to the first local maximum is referred to herein as the “slit depth distance”.

For the purposes of specific embodiments according to the present invention, the term “breaking strength” refers to the hardness of tablets/dose forms preferably measured using a Schleuniger device, while the term “cracking force” reflects the strength of the tablets/dose forms that It is best measured in an indentation test using a texture analyzer.

There is an additional variable for extended release die formulas that can be obtained from the notch test as mentioned above, which is the work to which the extended release die formula is subjected to in the notch test as mentioned above. The value of work corresponds to the complement of the force over the distance.

For the purposes of certain embodiments of the present invention, the term “resistant crushing” is defined to refer to dosage forms that can at least be flattened using a bench press as stated above without being crushed to no more than 60% thickness, preferably no Not more than 50% fish, preferably not more than 40% fish, even preferably not more than 30% fish, and most preferably not more than 20% fish, or 10% fish, or 5% fish.

To serve the purpose of specific embodiments according to the present invention, dosage forms are considered “resistant to axial extraction,” when the corresponding dosage form provides an in vitro dissolution rate, when measured with a USP Type 1 device (basket) at 100 rpm in 900 mL of enteral fluid Simulated gastric fluid (SGF) without enzymes containing 40% ethanol at 37°C, characterized by % amount active released at 0.5 h, preferably at 0.5 and 0.75 h, more preferably at 0.5 and 0.75 h One, more preferable when 0.5, 0.75, 1 and 1.5 hours, most preferably at 0.75, 1, 1.5 and 2 hours of dissolution which deviates by no more than about 20% points or preferably by no more than 15% points at each of the time points mentioned from the corresponding dissolution rate rate in vitro measured using USP type 1 (basket) at 100 rpm in 900 ml of simulated intestinal fluid without enzymes and without ethanol at 37°C.

The term “tamper resistant” for purposes of the present invention refers to dosage forms that provide at least crushing resistance and resistance to alcohol extraction, and preferably resistance to both crushing and alcohol extraction, as defined above. It can also include other tamper-resistant features.

To serve the purpose of the present invention, the term “active agent” is defined as a pharmaceutically active substance including, but not limited to, opioid sedatives and opioid analgesics.

For the purposes of the present invention, the term “opioid analgesic” includes single compounds and combinations of compounds selected from a group of opioids and which provide an analgesic effect such as a single opioid agonist or a combination of opioid cofactors. , one single mixed opioid adjuvant or a combination of mixed opioid adjuvant-antagonists, or one single opioid partial adjuvant or a combination of opioid partial adjuvants and combinations of adjuvants Opiates and mixed agonists Opiates and partial opioid antagonists with one or more opioid antagonists, stereoisomers, ether or ester, salts, hydrates, and solvates thereof, combinations of any of the foregoing, and the like.

The present invention disclosed herein is specifically intended to include the use of an opioid analgesic in the form of any pharmaceutically acceptable salt thereof.

Pharmaceutical acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like, and amino acid salts such as arginate, asparginate, glutamate, and the like; And mineral salts metal salts such as sodium salt, potassium salt, cesium salt, and the like; And organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like.

The opioids used according to the present invention may contain one or more asymmetric centers, and may be a source of enantiomers, diastereomers, or other stereoisomers. It is also intended that the present invention includes the use of all such possible forms as well as racemic and analyte forms and combinations thereof. When compounds described here contain olefinic double bonds or other centers with geometric asymmetry, they are intended to contain both geometric isomers E and Z. All tautomers are intended to be included in the present invention as well.

As used herein, the term “stereoisomers” is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. The term includes enantiomers and isomers of compounds that contain more than one chiral center and are characterized as mirror images of each other (diastereomers).

The term "chiral center" refers to a carbon atom to which four different groups are bonded.

The term "enantiomer" or "enantiomeric enantiomer" refers to a molecule that is not superimposed on its mirror image, and is therefore optically active, as the enantiomer rotates around the plane of polarized light in one direction, and its mirror image rotates around the plane of light. The polarizer is in the opposite direction.

The term "racemic" refers to a mixture of equal parts of optically inactive enantiomers.

The term "resolution" refers to the separation, concentration, or depletion of one of the two isoforms of a molecule.

The opioid cofactors useful in the present invention include, but are not limited to:

Alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, and dipipanone, heptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazine, etorphine, dihydroetorphine, fentanyl and its derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, and phenadoxone , phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, and properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, hydrates and solvents thereof, mixtures of any of the above, and the like.

Opioid antagonists useful in combination with opioid agonists as described above are, for example, naloxone, naltrexone, nalorphine or pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the above, and the like.

In certain embodiments, for example, a combination of oxycodone hydrochloride and naloxone hydrochloride in an amount of up to 2:1.

In certain embodiments, the opioid analgesic is selected from codeine, morphine, oxycodone, hydrocodone, hydromorphone, oxymorphone, pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing, and the like.

In certain embodiments, the opioid analgesic is oxycodone, hydromorphone, oxymorphone, or a salt thereof such as, for example, hydrochloride. The dosage form includes a ratio ranging from about 5 mg to about 500 mg of oxycodone hydrochloride, or from about 1 mg to about 100 mg of hydromorphone hydrochloride, or from about 5 mg to about 500 mg of oxymorphone hydrochloride. If other salts, derivatives, or forms are used, equimolar amounts of any pharmaceutically acceptable salt, derivative, or form may be used including, without limitation, hydrates, solvates, or free base. The dosage form includes, for example, 5 mg, 7.5 g, 10 g, 15 g, 20 g, 30 g, 40 g, 45 g, 60 g, 80 g, or 90 g, 120 mg, or 160 mg of oxycodone hydrochloride or equimolar amounts of any pharmaceutically acceptable salt, derivative, or other form including, without limitation, hydrates, solvates, or free bases. The dosage form includes, for example, 5 mg, 7.5 g, 10 g, 15 g, 20 g, 30 g, 40 g, 45 g, 60 g, 80 g, or 90 g , or 120 mg, or 160 mg of oxymorphone hydrochloride or equimolar amounts of any pharmaceutically acceptable salt, derivative, or other form including, without limitation, hydrates, solvates, or free bases. The dosage form includes, for example, 2 mg, 4 g, 8 g, 12 g, 16 g, 24 g, 32 g, 48 g, or 64 g of hydromorphone hydrochloride or equimolar amounts equimolar amounts of any pharmaceutically acceptable salt, derivative, or other form including, without limitation, hydrates, solubilities or free bases.

International Patent No. 097801/2005 1a, and US Patent Nos. 7,129,248 2b and 0173029/2006 1a, all three of which are incorporated herein by reference, describe a process for preparing oxycodone hydrochloride having a level of 14-hydroxycodeinone of less than about 25 ppm, preferably Less than about 15 ppm, or less than about 10 ppm, or less than about 5 ppm, preferably less than about 2 ppm, or less than about 1 ppm, or less than about 0.5 ppm per million, or less than about 0.25 ppm.

The abbreviation ppm used in this application means "parts per million". For 14-hydroxycodeinone, the term “ppm” means parts per million of 14-hydroxycodeinone in the product of a given sample. It is possible to determine the level of 14-hydroxycodeinone using any method known in the field, preferably using HPLC analysis using UV detection.

In certain embodiments according to the present invention, where the active agent is oxycodone hydrochloride, oxycodone hydrochloride is used having a level of 14-hydroxycodeinone less than about 25 ppm, preferably less than about 15 ppm, or less than about 10 ppm. per million, or less than about 5 ppm, preferably less than about 2 ppm, or less than about 1 ppm, or less than about 0.5 ppm, or less than about 0.25 ppm.

In certain other embodiments, other therapeutically active agents may be used in accordance with the present invention, either in combination with opioids or in place of opioids. Examples of such therapeutically effective agents include antihistamines (eg, dimenhydrinate, diphenhydramine, chlorpheniramine, and dexchlorpheniramine maleate), and non-steroidal anti-inflammatory agents (eg, naproxen, diclofenac, indomethacin, ibuprofen, sulindac, Cox inhibitors). -2, acetaminophen), anti-emetics agents (eg, metoclopramide, methylnaltrexone), and anti-epileptics (eg, phenytoin, meprobmate, and nitrazepam), vasodilators (eg, nifedipine, papaverine, diltiazem, and nicardipine), anti-tussive agents, expectorants (eg, codeine phosphate), and anti-asthmatics (eg, theophylline), antacids, seizures, anti-spasmodics (eg, atropine, scopolamine), antidiabetics (eg, insulin), and diuretics (eg, ethacrynic acid, bendrofluthiazide), blood pressure hypotensives (eg, clonidine, methyldopa), bronchodilators (eg, albuterol), steroids (eg, hydrocortisone, triamcinolone, prednisone), and antibiotics (eg, tetracycline), antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, and analgesics sedatives, decongestants (eg, pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine) as well as pharmaceutically acceptable salts, hydrates and solvates thereof themselves.

In certain embodiments, the invention directs the use of Cox-2 inhibitors as active agents, in combination with opioid analgesics or instead of opioid analgesics, for example using Cox-2 inhibitors such as:

meloxicam (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide).

As disclosed in US Patents 056.347/10 and 825.938/11, the contents of which are incorporated herein by reference, and:

nabumetone (4-(6-methoxy-2-naphthyl)-2-butanone), as disclosed in US Patent No. 056.348/10, the contents of which are incorporated herein by reference:

celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]enzenesulfonamide)

As disclosed in US Patent No. 698,394/11, the contents of which are incorporated herein by reference, nimesulide (N-(4-Nitro-2-phenoxyphenyl)methanesulfonamide), as disclosed in US Patent No. 057630/10 , the contents of which are incorporated herein by reference, and:

N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]methanesulfonamide as disclosed in US Patent No. 057.632/10, the contents of which are incorporated herein by reference.

The present invention is also directed to dosage forms using active agents such as benzodiazepines, barbiturates, or amphetamines. It can also be combined with corresponding antimaterials.

The term "benzodiazepines" refers to benzodiazepines and drugs derived from benzodiazepines that have the ability to depress the central nervous system. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, and methylphenid ​​ate, as well as pharmaceutically acceptable salts and hydrates Solvates and mixtures thereof. The benzodiazepines that may be used in the present invention include, but are not limited to, flumazenil as well as pharmaceutically acceptable salts, hydrates and solvates.

Barbiturates refer to sedative-hypnotic drugs derived from barbituric acid (2, 4, 6,-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, phenobarbital, and secobarbital, as well as pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof. The benzodiazepines that may be used in the present invention include, but are not limited to, amphetamines as well as pharmaceutically acceptable salts, hydrates and solutes.

Stimulants refer to medications that stimulate the central nervous system. Stimulants include, but are not limited to, amphetamines, such as amphetamine, dextroamphetamine resin complex, and:

dextroamphetamine, methamphetamine, and methylphenidate, as well as pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof. The stimulants that may be used in the present invention include, but are not limited to, benzodiazepines as well as pharmaceutically acceptable salts, hydrates and solutes as described herein.

Brief explanation of the drawings:

Figure 1 is a photograph of a top view of the tablets (along the thickness of the tablet) in Example 7-1 before (left side) and after (right side) a breaking strength test using a Schleuniger Model 6D.

Figure 2 is a top-view photograph of the tablets (along the thickness of the tablet) in Example 7-2 before (left side) and after (right side) fracture strength testing with the Schleuniger Model 6D.

Figure 3 is a top-view photograph of the tablets (along the thickness of the tablet) in Example 7-3 before (left side) and after (right side) fracture strength testing with the Schleuniger Model 6D.

Figure 4 is a photograph of a top view of the tablet (along the thickness of the tablet) in Example 7-1 after it has been flattened using a Carver manual bench press (hydraulic unit model 3912).

Figure 5 is a photograph of a top view of the disc (along the thickness of the disc) in Example 7-2 after it has been flattened using a Carver manual bench press (Hydraulic Unit Model No. 3912).

Figure 6 is a photograph of a top view of the disc (along the thickness of the disc) in Example 7-3 after it was flattened using a Carver manual bench press (Hydraulic Unit Model No. 3912).

Figure 7 is a photograph of a top view of the disc (along the thickness of the disc) in Example 7-1 after 10 hand strikes with the hammer.

Figure 8 is a photograph of a top view of the disc (along the thickness of the disc) in Example 7-2 after 10 hand strikes with the hammer.

Figure 9 is a photograph of a top view of the disc (along the thickness of the disc) in Example 7-3 after 10 hand strikes with the hammer.

Figure No. 10 is a diagram of the temperature curve of the curing process in Example No. 13-1.

Figure No. 11 is a diagram of the temperature curve of the curing process in Example No. 13-2.

Figure 12 is a plot of the temperature curve for the curing process in Example 13-3.

Figure 13 is a plot of the temperature curve of the curing process in Example 13-4.

Figure 14 is a plot of the temperature curve for the curing process in Example 13-5.

Figure 15 is a plot of the temperature curve of the curing process in Example 14-1.

Figure 16 is a plot of the temperature curve of the curing process in Example 14-2.

Figure 17 is a plot of the temperature curve for the curing process in Example 14-3.

Figure 18 is a plot of the temperature curve for the curing process in Example 14-4.

Figure 19 is a plot of the temperature curve for the curing process in Example 14-5.

Figure 20 is a diagram of the indentation test of Example 20 performed using Example 13-1 tablet (cured for 30 minutes, not coated).

Figure 21 is a diagram of the striation test of Example 20 performed with Example 13-2 tablet (cured for 30 minutes, not coated).

Figure 22 is a diagram of the striation test of Example 20 performed with Example 13-3 tablet (cured for 30 minutes, not coated).

Figure 23 is a diagram of the indentation test of Example 20 performed using the tablet of Example 13-4 (cured for 30 minutes, not coated).

Figure 24 is a diagram of the striation test of Example 20 performed with Example 13-5 tablet (cured for 30 minutes, not coated).

Figure 25 is a diagram of the notch test of Example 20 performed with Example 17-1 tablet (cured for 30 minutes at 37°C, not coated).

Figure 26 is a diagram of the notch test of Example 20 performed with Example 18-2 tablet (cured for 30 minutes at 37°C, not coated).

Figure 27 is a diagram of the notch test of Example 20 performed with Example 14-1 tablet (cured for 1 hour, coated).

Figure 28 is a diagram of the notch test of Example 20 performed with Example 14-2 tablet (cured for 1 hour, coated).

Figure 29 is a diagram of the notch test of Example 20 performed with Example 14-3 tablet (cured for 1 hour, coated).

Figure 30 is a diagram of the notch test of Example 20 performed with Example 14-4 tablet (cured for 1 hour, coated).

Figure 31 is a diagram of the notch test of Example 20 performed with Example 14-5 tablet (cured for 1 hour, coated).

Figure 32 is a diagram of the indentation test of Example 20 performed using Example 16-1 tablet (cured for 15 minutes, coated).

Figure 33 is a diagram of the striation test of Example 20 performed with Example 16-2 tablet (cured for 15 minutes, coated).

Figure 34 is a diagram of the striation tests of Example 21 performed with the Example 16-1 tablet (cured for 15 minutes, coated) and with a 60 g commercial OxycontinTM tablet.

Figure 35 is a diagram of the striation tests of Example 21 performed with the Example 16-2 tablet (cured for 15 minutes, coated) and with a commercial 80 g OxycontinTM tablet.

Figure 36 shows the average plasma oxycodone concentration versus time on a linear scale [Group: full analysis: (in case of eating food)] according to Example 26.

Figure No. 37 shows the average concentration versus time image on a linear scale [Group: Complete Analysis: (in case of eating food)] according to Example No. 26.

Figure No. 38 shows the average concentration versus time image on a linear scale [Group: Complete analysis: (in fasted state)] according to Example No. 26.

Figure 39 shows the average plasma oxycodone concentration versus time on a log-linear scale [Group: full analysis: (in fasted state)] according to Example 26.

Figure 40 shows representative images of the OxyContinTM 10 mg powder tablet and the Example 7-2 powder tablet, according to Example 27.

Figure 41 shows representative images of Example 7-2 and OxyContinTM 10 mg tablets crushed before and 45 minutes after dissolution, in accordance with Example 27.

Figure 42 shows dissolution profiles for crushed 7-2M tablets and crushed OxyContinTM 10 mg tablets, according to Example 27.

Figure 43 shows particle size distribution graphs for milled tablets (OxyContinTM 10 mg tablets, Examples 7-2 and Example 14-5), according to Example 27.

Detailed description:

In certain embodiments, the present invention is directed to a process for preparing an extended-release solid oral pharmaceutical dosage form,

It includes the following steps:

(a) Merge at least

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000, and

(2) at least one active agent,

To create a composition;

(b) Formation of the composition to form an extended release matrix formulation; And

(c) Curing said extended-release template formulation, comprising at least a processing step of exposing said extended-release template formulation to a temperature at least the ductility temperature of said polyethylene oxide for a period of at least about one minute.

The curing step is preferably carried out under atmospheric pressure.

In certain embodiments, the present invention relates to a process for preparing an extended-release solid oral pharmaceutical dosage form,

It includes the following steps:

(a) Merge at least

(1) At least one polyethylene oxide has a molecular weight, based on rheological measurements, of at least 1,000,000, and

(2) at least one active agent,

To create a composition;

(b) Formation of the composition to form an extended release matrix formulation; And

(c) Curing said extended-release template formulation, comprising at least a curing step of exposing said extended-release template formulation to a temperature at least the ductility temperature of said polyethylene oxide for a period of at least 5 minutes. The curing step is preferably carried out under atmospheric pressure.

In certain embodiments, the present invention is directed to a process for preparing an extended-release solid oral pharmaceutical dosage form,

It includes the following steps:

(a) Merge at least

(1) At least one polyethylene oxide has a molecular weight, based on rheological measurements, of at least 1,000,000, and

(2) at least one active agent,

To create a composition;

(b) forming the composition to form an extended-release template formulation; And

(c) Processing said extended release template formulation, comprising at least a curing step such that said polyethylene oxide is at least partially melted.

The curing step is preferably carried out under atmospheric pressure.

In certain models, the formulation in step (b) is formed to form an extended release matrix formulation in a tablet form. To form the extended-release block formulation into a tablet form, a direct compression process may be used. Direct compression is an effective and simple process for tablet formation by avoiding steps such as wet granulation. However, any other process known in the art can be used to manufacture tablets, such as wet granulation and subsequent compression of the granules to form tablets.

In one embodiment, the curing matrix formulation of the extended-release template in step (c) includes at least a curing step such that the high molecular weight polyethylene oxide in the extended-release template formulation at least partially melts. For example, at least about 20% or at least 30% of the high molecular weight polyethylene oxide in the extended-release template formulation melts. Preferably at least about 40% or at least 50%, preferably at least about 60% or at least about 75%, or at least about 90% of the high molecular weight polyethylene oxide in the extended-release template formulation. In a preferred embodiment, approximately 100% of the high molecular weight polyethylene oxide is melted.

In other embodiments, the process of curing the extended-release template formulation in step (c) includes at least a curing step where the extended-release template formulation is exposed to an elevated temperature for a specified period of time. In such embodiments, the temperature used in step (c), i.e. the curing temperature, is at least as high as the ductility temperature of the high molecular weight polyethylene oxide. Without being restricted by any theory, it is believed that curing at a temperature that is at least as high as the ductility temperature of high-molecular-weight polyethylene will cause the polyethylene oxide particles to at least stick together or coalesce. According to some embodiments, the curing temperature is at least about 60°C, at least about 62°C, or in a range from about 62°C to about 90°C, from about 62°C to about 85°C, from about 62°C to about 80°C, or from about 65°C to about 90°C. Or from about 65 AD to about 85 AD, or from about 65 AD to about 80 AD. It is preferable for the curing temperature to be in a range ranging from about 68°C to about 90°C, or from about 68°C to about 85°C, or from about 68°C to about 80°C, and more preferably from about 70°C to about 90°C, or from about 70°C to about 90°C, or from about 70 AD to about 85 AD or from about 70 AD to about 80 AD, and most preferably from about 72 AD to about 90 AD or from about 72 AD to about 85 AD or from about 72 AD to about 80 AD. The curing temperature can be at least about 60°C or at least about 62°C, but not less than about 90°C or less than about 80°C. It is preferable that it be in a range ranging from about 62 m to about 72 m, and especially from about 86 m to about 72 m. Preferably, the curing temperature should be at least as high as the lower end of the ductility temperature range for high molecular weight polyethylene oxide, or at least approximately 62°C or at least approximately 68°C. It is more preferable for the curing temperature to fall within the ductility temperature range of at least high molecular weight polyethylene oxide, or at least about 70°C. It is also more preferable for the curing temperature to be at least as high as the upper limit of the temperature range for high molecular weight polyethylene oxide ductility, or at least about 72°C. In an alternative embodiment, the curing temperature is above the upper limit of the high molecular weight polyethylene oxide ductility temperature range, for example the curing temperature is at least about 75°C or at least about 80°C.

In those embodiments, where the extended release curing matrix formulation in step (c) comprises at least a curing step wherein the extended release curing matrix formulation is exposed to an elevated temperature for a specified period of time, which period will be referred to as later in this application as “curing time”. To measure the processing time, a starting point and an end point for the processing step are determined. For the purposes of the present invention, the starting point of the curing step is defined as the point time at which the curing temperature is reached.

In certain embodiments, the temperature profile during the curing step shows a plateau-like form between the start point and the end point of curing. In such embodiments, the end point of the curing step is determined by the point in time at which heating is stopped or at least reduced, for example by terminating or reducing heating and/or by starting a subsequent cooling step, and the temperature is accordingly reduced below the curing temperature by more than about 10°C. and/or below the lower limit of the ductility temperature range for high molecular weight polyethylene oxide, for example below about 62°C. When the curing temperature is reached, and the curing step is started accordingly, deviations from the curing temperature can occur during the curing step. Such deviations can be tolerated as long as they do not exceed a value of about 10 m, preferably about 6 m, and more preferably about 3 m. For example, if a processing temperature of about 75°C is to be maintained, the measured temperature can be temporarily increased to a value of about 85°C, preferably around 81°C, more preferably around 78°C, and the measured temperature can also be temporarily decreased to a value of about 65°C , preferably around 69m, and more preferably around 72m. In cases of a larger increase in temperature and/or if the temperature drops below the lower limit of the ductility temperature range for high molecular weight polyethylene oxide, for example below about 62°C, the curing step is stopped, i.e. more specifically an end point is reached. It is possible to restart processing by reaching the processing temperature again.

In other embodiments, the temperature profile during the treatment step shows a parabolic or triangular form between the start and end points of the treatment. This means that after the starting point, more specifically the point time at which the curing temperature is reached, the temperature increases further to reach a maximum, and then decreases. In such embodiments, the end point of the curing step is defined as the point in time at which the temperature drops below the curing temperature.

In this context, it should be noted that depending on the device used for curing, which we will refer to later in this application as the curing device, different types of temperatures can be measured in the curing device to determine the curing temperature characteristics.

In certain embodiments, the curing step may be performed in an oven. In such models, the temperature inside the oven is measured. Based on that measurement, when a curing step is performed in a kiln, the curing temperature is defined as the target inside temperature of the kiln, and the starting point is defined as the time point at which the kiln's internal temperature reaches the curing temperature. The end point of the curing step is defined as (1) the point time at which heating is stopped or at least reduced, after which the temperature inside the furnace drops to more than about 10°C below the curing temperature and/or below the minimum For a high molecular weight polyethylene oxide ductility temperature range, for example below about 62°C, in the form of a near-planar temperature, or (2) the point in time at which the temperature inside the kiln falls below the curing temperature in the curve Temperature in the form of a parabola or triangle. It is preferable that the curing step begin when the temperature inside the oven reaches a curing temperature of at least about 62°C, or at least about 68°C, or at least about 70°C, and preferably at least about 72°C, or at least about 75°C. In preferred embodiments, the temperature profile during the curing step shows a nearly flat profile, where the curing temperature, ie, the internal temperature of the kiln, is preferably about 68°C, for example, about 70°C, about 72°C, or about 73°C, or In a range from about 70°C to about 75°C, and it is preferable for the treatment time to be in a range ranging from about 30 minutes to about 20 hours, or more preferably from about 30 minutes to about 15 hours, or from about 30 minutes to about 4 hours, or from About 30 minutes to approx Two hours. It is most preferable for the curing time to be in the range of about 30 minutes to about 90 minutes.

In certain other embodiments, curing is performed in airflow-heated curing devices, such curing devices comprising a heated air supply (inlet) and an exhaust pipe such as a coating pan or fluidized bed. Such curing methods will later be referred to as convection curing methods. In such curing devices, it is possible to measure the inlet air temperature, i.e., the temperature of the heated air entering the convection curing device, and/or the exhaust air temperature, i.e., the temperature of the air exiting the convective curing device. It is also possible to determine or at least evaluate the temperature of the formulations inside the curing medium during the curing step, for example by using infrared temperature measuring instruments, such as an IR gun, or by measuring the temperature using a temperature probe placed inside the curing medium. device near matrix formulations with extended release. Based on this, when the curing step is performed in a convection curing medium, the curing temperature can be determined, and the curing time can be measured as follows.

In one embodiment, where the curing time is measured in accordance with Method 1, the curing temperature is defined as the target inlet air temperature, and the start point of the curing step is defined as the time point at which the target inlet air temperature reaches the curing temperature. The end point of a treatment step is defined as (1) the point in time at which heating is stopped or at least reduced, after which the inlet air temperature falls below the treatment temperature by more than about 10°C and/or below the minimum For a high molecular weight polyethylene oxide ductility temperature range, eg below about 62°C, as a near-planar temperature, or (2) the point in time at which the inlet air temperature falls below the process temperature in a temperature curve looks like Parabolic parabola or triangular triangle. It is preferable to begin the treatment step according to Method No. 1 when the inlet air temperature reaches a treatment temperature of at least about 62°C, or at least about 68°C, or at least about 70°C, and preferably at least about 72°C, or at least about 75°C. In a preferred embodiment, the temperature curve during the treatment step shows a nearly flat picture, where the treatment temperature, meaning more specifically, the target inlet air temperature, is preferably about 72°C, for example about 75°C, and the treatment time measured in accordance with Method No. 1 To be in the range of about 15 minutes to about 2 hours, for example from about 30 minutes to about 1 hour.

In one embodiment, where the curing time is measured in accordance with Method 2, the curing temperature is defined as the target exhaust air temperature, and the starting point of the curing step is defined as the time point at which the exhaust air temperature reaches the curing temperature. . The end point of the treatment step is defined as (1) the point in time at which heating is stopped or at least reduced, after which the exhaust air temperature falls below the treatment temperature by more than about 10°C and/or below the lower end of the temperature range The temperature of ductility of high molecular weight polyethylene oxide, for example less than about 62 C, as a near-planar temperature, or (2) the point in time at which the exhaust air temperature drops below the process temperature in a temperature curve Heat on The shape of a parabolic parabola or triangular triangle. It is preferable to begin the treatment step according to Method No. 2 when the exhaust air temperature reaches a treatment temperature of at least about 62°C, or at least about 68°C, or at least about 70°C, and preferably at least about 72°C, or at least about 75°C. In preferred embodiments, the temperature curve during the treatment step shows a nearly flat picture, where the treatment temperature, i.e., the target exhaust air temperature, is preferably at least about 68°C, or at least about 70°C, or at least about 72°C, over For example, the target exhaust air temperature is about 68°C, or about 70°C, or about 72°C, or 75°C, or about 78°C. It is preferable for the treatment time, which is measured according to method No. 2, to be in a range ranging from about one minute to about two hours. More than about 5 minutes To about 90 minutes, for example the processing time is about 5 minutes, or about 10 minutes, or about 15 minutes, or about 30 minutes, or about 60 minutes, or about 70 minutes, or about 75 minutes, or about 90 minutes. In a more preferable embodiment, the curing time, measured according to Method 2, is in the range from about 15 minutes to about 1 hour.

In another embodiment, where the curing time is measured in accordance with Method 3, the curing temperature is defined as the target temperature for the extended release matrix formulations, and the starting point of the curing step is defined as the time point at which the temperature of the matrix formulations reached Extended release die, which can be measured for example with an IR gun, to the curing temperature. The end point of the curing step is defined as (1) the point in time at which heating is stopped or at least reduced, after which the temperature of the extended-release die formulations drops below the curing temperature by more than about 10°C and/or below the limit The lower end of the ductility temperature range for high molecular weight polyethylene oxide, for example below about 62°C, as a near-planar temperature, or (2) the point in time at which the temperature of the extended-release template formulations drops below Processing heat in a temperature curve in the form of a parabolic or triangular triangle. The curing step according to Method 1 should preferably begin when the temperature of the extended-release template formulations has reached a curing temperature of at least about 62°C, or at least about 68°C, or at least about 70°C, and preferably at least about 72°C, or at least about 75°C. the least.

In another embodiment, where the curing time is measured in accordance with Method 4, the curing temperature is defined as the target temperature measured using a temperature probe, such as a wire thermocouple, placed within the curing device near the mold formulations. Extended release, the starting point of the curing step is defined as the point in time at which the temperature measured using a temperature probe, placed inside the curing device near the die formulas, is reached. Extended release, to the curing temperature. The end point of the curing step is defined as (1) the point in time at which heating is stopped or at least reduced, after which the temperature measured using a temperature probe falls below the curing temperature by more than about 10°C and/or less of the lower limit of the temperature range of high molecular weight polyethylene oxide ductility, e.g. below about 62°C, as a near-planar temperature, or (ii) the point in time at which the temperature as measured using a temperature probe decreases temperature probe below the processing temperature in a temperature profile curve in the form of a parabolic or triangular triangle.

The curing step according to Method 4 should preferably begin when the temperature measured using a temperature probe, placed inside the curing device near the extended release matrix formulations, reaches a curing temperature of at least about 62°C. Or about 68 m at least, or about 70 m at least, and preferably about 72 m at least, or about 75 m at least. In a preferred embodiment, the temperature curve during the curing step shows a nearly flat profile, where the curing temperature, i.e., the target temperature measured using a temperature probe placed inside the curing medium near the extended-release die formulations, is preferred to be about At least 68°C, for example it is about 70°C, and the curing time, which is measured according to Method No. 4, should preferably be in a range ranging from about 15 minutes to about 2 hours. For example, the curing time is about 60 minutes or About 90 minutes.

If curing is performed in a convection curing device, the curing time may be measured by any of Methods 1, 2, 3, or 4. In a preferred embodiment, the curing time is measured using Method 2.

In certain embodiments, the curing temperature is defined as the target temperature range, for example, the curing temperature is defined as the inlet air temperature range or exhaust air temperature range. . In such embodiments, the starting point of the curing step is defined as the point in time at which the lower end of the target temperature range is reached, and the end point of the curing step is defined as the point in time at which heating is stopped or at least reduced, The temperature then drops to more than about 10°C below the lower limit of the target temperature range and/or below the lower limit of the high molecular weight polyethylene oxide ductility temperature range, for example less than about 62°C.

The curing time, i.e. more specifically the period of time during which the extended release matrix formulation is exposed, which can for example be measured according to methods 1, 2, 3 and 4 according to the above description, is about 1 minute or at least about 5 minutes . The treatment time can be changed from about 1 minute to about 24 hours, or from about 5 minutes to about 20 hours, or from about 10 minutes to about 15 hours, or from about 15 minutes to about 10 minutes, or from about 30 minutes to about 5 Hours based on specific composition, formulation, and processing temperature. The composition, curing time, and curing temperature variables are selected to achieve tamper resistant as described herein. Depending on specific models, the processing time varies from about 15 minutes to about 30 minutes. According to other embodiments, where the curing time is at least about 60 m, or at least about 62 m, and preferably at least about 68 m, or at least about 70 m, or at least about 72 m, or at least about 75 m, or varying from about 62 m to about 85 AD, or from about 65 AD to about 85 AD. It is preferable for the treatment time to be at least 15 minutes, at least 30 minutes, at least 60 minutes, at least 75 minutes, at least 90 minutes, or at least 120 minutes. In preferred embodiments, wherein the curing temperature is, for example, at least about 62°C, or at least about 68°C, or at least about 70°C, and preferably at least about 72°C, or at least about 75°C, or a range from about 62°C to About 80 AD, or from about 65 AD to about 80 AD, or from about 68 AD to about 80 AD, or from about 70 AD to about 80 AD, or from about 72 AD to about 80 AD. It is preferable for the treatment time to be at least about one minute or about 5 minutes. Preferably, the treatment time should be at least 15 minutes or at least 30 minutes. In such embodiments, the processing time can be chosen to be as short as possible while still achieving the required tamper resistant. For example, it is preferable for the treatment time not to exceed 5 hours, preferably not to exceed 3 hours, and most preferably not to exceed 2 hours. It is preferable for the treatment time to be in the range of about 1 minute to about 5 hours, from about 5 minutes to about 3 hours, from about 15 minutes to about 2 hours, and from about 15 minutes to about 1 hour. Any combination of curing temperatures and curing times as disclosed herein falls within the scope of the present invention.

In certain embodiments, the formulation is defined only to the curing temperature until the high molecular weight polyethylene oxide in the extended release matrix formulation reaches its ductility temperature and/or at least partially melts. In such specific embodiments, the processing time can be less than about 5 minutes, for example, the processing time can vary from about 0 minutes to about 3 hours, or from about 1 minute to about 2 hours, or from about 2 minutes to about 3 hours. About one hour. Instant curing can be performed by selecting a curing method that allows the high molecular weight polyethylene oxide in the extended release mold formulation to be immediately heated to at least its softening temperature, until the high molecular weight polyethylene oxide is at least partially melted. These treatment methods are, for example, microwave ovens, ultrasound devices, a light irradiation device such as a UV-irradiation device, or ultra-high frequency fields. frequeny (UHF), or any method known to those skilled in the field.

Those skilled in the art understand that the size of the extended release matrix formulation can determine the curing time and curing temperature required to achieve the desired tamper resistant. To avoid being bound by any theory, it is believed that in the case of a large continuous release block formulation, such as a large tablet, a longer processing time to conduct heat into the formulation is necessary than in the case of a corresponding smaller volume formulation. The higher temperature increases the thermal conductivity rate, thus reducing the required processing time.

Processing step (c) can be performed in an oven. Advantageously, curing step (c) occurs in a continuous-release free flowing matrix, such as a coating pan. The encapsulation vessel allows for an efficient batch processing step that can be followed by an encapsulation step without the need to transfer dosage forms, eg tablets. This process may include the following steps:

(a) Merge at least.

(1) At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000, and

(2) at least one active agent,

To create a composition;

(b) Forming said composition to form an extended release matrix formulation in the form of a direct compression tablet; And

(c) Treating the aforementioned curing tablet by:

- Expose a layer of free flowing discs to a temperature range of 62°C to about 90°C, preferably from about 70°C to about 90°C, for a period of time of at least about 1 minute or at least 5 minutes, preferably at least 30 minutes, in a container coating pan packaging, and

- Subsequent cooling of the layer of free flowing tablets to a temperature less than about 50°C.

And then:

(d) Packaging the dosage form in the aforementioned packaging container.

In certain embodiments, an additional curing step may be added after step (d) of encapsulating the dosage form. An additional dosing step may be performed as mentioned in processing step (c). In such specific embodiments, the curing temperature of the further curing step is preferably at least about 70 C, or at least about 72 C, or at least about 75 C. The curing time should preferably be in the range of about 15 minutes to about an hour, for example about 30 minutes.

In certain embodiments, an antioxidant is added, eg BHT (butylated hydroxytoluene).

In certain embodiments, the curing step (c) results in a reduction in the density matrix formulation of the extended release, such that the density of the annealed extended release formulation is less than the density of the extended-release matrix formulation prior to the curing step (c). It is preferable that the density of the hardened extended-release formulation be at least 0.5% less than the density of the non-hardening extended-release formulation. It is more preferable for the density of the sclerosing extended-release formulation to be reduced by at least 0.7%, at least 0.8%, at least 1.0%, at least 2.0%, or at least 2.5%. Without adhering to any theory, it is believed that the extended release mold formulation expands due to the absence of high pressure during processing step (c), which results in a decrease in density.

According to an additional feature of the invention, the density matrix formulation of the extended-release matrix formulation in the extended-release solid oral dosage form, preferably in a dosage form containing oxycodone hydrochloride as an active agent, is equal to or less than about 1.20 g /cm3. Preferably, it is equal to or less than about 1.19 g/cm3, or equal to or less than about 1.18 g/cm3, or equal to or less than about 1.17 g/cm3, or equal to or less than about. For example, the density of an extended-release template formulation is in the range from about 1.10 g/cm3 to about 1.20 g/cm3, or from about 1.11 g/cm3 to about 1.20 g/cm3, or from about 1.11 g/cm3 to about 1.19 g/cm3, more preferably from about 1.13 g/cm3 to about 1.18 g/cm3.

It is preferable to determine the density of the extended-release template formula by the Archimedes principle using a liquid with a known density (ρ0). The extended release matrix formulation is weighed in air, immersed in a liquid and weighed. From these two weights, the density of the extended release die formula ρ can be determined by the following equation:

<img file="SA2709B1_D0001.tif" />

Where ρ is the density of the extended-release formula, A is the weight of the extended-release formula in air, B is the weight of the extended-release formula when immersed in a liquid, and ρ0 is the density of the liquid at a given temperature. A suitable liquid with a known density ρ0 is, for example, hexane.

The density of an extended-release block formulation is preferably measured using a Top-loading Mettler Toledo instrument, Model No. AB 135-S/FACT, serial 1127430072, and Density Determination Kit 33360. The hexane is preferably used as a liquid hexane with a known density ρ0.

The density values ​​throughout this document correspond to the density of the extended-release die formulation at room temperature.

The density matrix formulation of extended release should preferably refer to the density of uncoated formulation, for example, the density of core tablet. In those embodiments, where the extended release matrix formulation is encapsulated, for example, where the extended release matrix formulation is subjected to an encapsulation step (d) after a curing step (c), it is preferable to measure the density of the matrix formulation Extended release before performing the encapsulation step, or by removing the encapsulation form from an extended release encapsulated template formulation and then measuring the density of the unencapsulated extended release template formulation.

In the embodiments described above, high molecular weight polyethylene oxide may be used having an approximate molecular weight that, based on rheological measurements, ranges from 2,000,000 to 15,000,000 or from 2,000,000 to 8,000,000. Specifically, polyethylene oxides may be used having an approximate molecular weight, based on rheological measurements, of 2,000,000, 4,000,000, 7,000,000, or 8,000,000. In particular, polyethylene oxides having an approximate molecular weight, based on rheological measurements, of 4,000,000 can be used.

In embodiments where the composition also includes at least one polyethylene oxide of low molecular weight, polyethylene oxides having an approximate molecular weight, based on rheological measurements, of 1,000,000 may be used, such as polyethylene oxides having an approximate molecular weight, based on rheological measurements, of 900,000. An additive such as low molecular weight polyethylene oxides can be used specifically to adjust the release rate such as enhancing the release rate of a formula that would otherwise provide a release rate to slow down the specific purpose. In such embodiments, at least one polyethylene oxide may be used having an approximate molecular weight, based on rheological measurements, of 100.00.

In such specific embodiments, wherein the composition includes at least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000, and at least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of less than 1,000 .000, wherein the composition includes at least 10% (by weight) or at least about 20% (by weight) of polyethylene oxide having an approximate molecular weight, based on rheological measurements, of less than 1,000,000. In such embodiments, the curing temperature is less than about 80°C or even less than about 77°C.

In certain embodiments, the total polyethylene oxide content in the composition is at least about 80% (by weight). Without being bound by any theory, it is believed that high polyethylene oxide contents provide resistance to tampering as stated herein, such as resistance to breakage and resistance to alcohol extraction. According to such specific embodiments, the active agent is oxycodone hydrochloride, and the composition includes more than about 5% (by weight) oxycodone hydrochloride.

In certain embodiments, the content in the composition of at least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000, is at least about 80% (by weight). In certain embodiments, the content in the composition of at least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000, is at least about 85% (by weight) or at least about 90% (by weight). In such embodiments, polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 4,000,000 or at least 7,000,000 may be used. In such embodiments, the active agent is oxycodone hydrochloride or hydromorphone hydrochloride, although other active agents may be used according to this aspect of the invention, and the composition includes more than about 5% (by weight) of oxycodone hydrochloride or hydromorphone hydrochloride.

In certain embodiments, where the amount of drug in the composition is at least 20% (by weight), the polyethylene oxide content can be as low as 75% (by weight). In another embodiment, the amount drug in the composition can be in the range from about 25% (by weight) to about 35% (by weight), and the polyethylene oxide content can be in the range from 65% (by weight) to about 75% (by weight). By weight). For example, in embodiments where the amount of drug in the composition is about 32% (by weight), the polyethylene oxide content can be about 67% (by weight).

In certain embodiments according to the invention, magnesium stearate is added during or after the curing process/curing step to avoid tablets sticking together. In such specific embodiments, magnesium stearate is added at the end of the curing process/curing step before or during cooling of the tablets. Other anti-adhesion agents that may be used: talc, fumed silica, colloidal silica dioxide, silica stearate, carnauba wax, long chain fatty alcohols and waxes, such as stearic acid, stearyl alcohol, mineral oil, Paraffin, micro crystalline cellulose, glycerin, propylene glycol, and polyethylene glycol. In addition or alternatively, encapsulation can be initiated at elevated temperature.

In certain embodiments, where curing step (c) is carried out in a coating pan, tablet sticking can be avoided or sticking tablets separated by increasing pan speed during or after the curing step, in the second case for example before Or while the discs are cooling. The bowl speed is increased to a speed at which all tablets are separated or no sticking occurs.

In certain embodiments of the invention, an initial film coating or part of a film coating is used before performing the curing step (c). A film coating provides an "overcoat" for extended-release matrix formulations or tablets to act as an anti-tacking agent, more specifically to avoid sticking of formulas or tablets to each other. In such specific embodiments, the film coating used prior to the curing step is an opadry film coating. After processing step (c), an additional film coating step can be performed.

The present invention also includes any extended release solid oral pharmaceutical dosage form that may be obtained by a process according to any process described above.

Independently, the present invention is directed to solid oral extended-release pharmaceutical dosage forms.

In certain embodiments, the present invention is directed to extended-release solid oral pharmaceutical dosage forms comprising an extended-release block formulation comprising an active agent in the form of a tablet or multiple particulates, wherein the tablet or individual multiparticles can They become at least flattened without breaking, and are characterized by a disc or individual particle having a thickness after flattening that corresponds to no more than about 60% of the thickness of the disc or particle. Individualization prior to flattening, whereby said flattened tablet or flattened multi particulates provide the in vitro dissolution rate, when measured with a USP type 1 device (basket) at 100 rpm in 900 ml of simulated enteric fluid Simulated gastric fluid (SGF) without enzymes at 37°C, characterized by a percentage of the amount of active agent released at 0.5 h, or at 0.5 and 0.75 h, or at 0.5, 0.75, and 1 h, or at 0.5, 0.75, 1, and 1. 5 hours, or at 0.5, 0.75, 1, 1.5 and 2 hours of dissolution that deviates by no more than about 20% at each of the time points mentioned from the corresponding dissolution rate in the laboratory for a non-flat reference tablet or non-flat reference particulates.

In such specific embodiments, the disc or individual multiple particles can become at least flattened without breaking, and the disc or individual multiple particles are characterized by having a thickness after flattening corresponding to no more than about 50% or 40%, or 30%. %, 20%, or 16% of the thickness of the tablet or individual polyparticle before flattening, wherein said flattened tablet or polyparticle provides an in vitro dissolution rate, when measured with a USP device Type 1 (basket) at 100 rpm in 900 ml of simulated gastric fluid (SGF) without enzymes at 37°C, characterized by a percentage of the amount active released at 0.5 h or at 0.5 and 0.75 h , or at 0.5, 0.75, and 1 hour, or at 0.5, 0.75, 1, and 1.5 hours, or at 0.5, 0.75, 1, 1.5, and 2 hours of melting that deviates by no more than about 20% points, or about 15% points at each From the time points mentioned from the corresponding dissolution rate in vitro for a reference tablet Non-flattened or non-flattened reference particles.

In certain embodiments, the present invention is directed to a solid oral extended-release pharmaceutical dosage form comprising an extended-release matrix formulation comprising an active agent in the form of a tablet or multiple particulates, wherein the tablet Or individual multiple particles can become at least flattened without breaking, and are characterized by the disc or individual multiple particles having a thickness after flattening that corresponds to no more than about 60% of the thickness of the disc or The individual multiparticle before flattening, where said flattened tablet or flattened multi particulates and the non-flattened reference tablet or reference non-flattened multi particulates provide the in vitro dissolution rate, when measured with a USP instrument Type 1 (basket) at 100 rpm in 900 ml of simulated gastric fluid (SGF) without enzymes at 37°C, ranging from about 5 to about 40% (by weight) of active agent released after 0.5 hours.

In such specific embodiments, the disc or individual multi particulates can at least become flattened without breaking, characterized by the disc or individual multiparticle having a thickness after flattening corresponding to no more than about 50% or 40%, or 30%, 20%, or 16% of the thickness of the tablet or single multiparticle before flattening, where the aforementioned flattened tablet or flattened multiparticle and the unflattened reference tablet or particulate are The non-flattened reference provides an in vitro dissolution rate, when measured with a USP Type 1 device (basket) at 100 rpm in 900 ml of simulated gastric fluid (SGF) without enzymes at 37°C, in the range From about 5 to about 40% (by weight) of the active agent released after 0.5 hours, or ranging from about 5 to about 30% (by weight) of the active agent released after 0.5 hours, or from about 5 to about 20 % (by weight) of the active agent released after 0.5 hour, or ranges from about 10 to about 18% (by weight) of the active agent released after 0.5 hour.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation comprising an active agent in the form of a tablet or multiple particulates, wherein the tablet or Individual polyparticles can become at least flattened without breaking, and the disc or individual particulate matter has a thickness after flattening that corresponds to no more than about 60% of the thickness. Individual tablet or particulates before flattening. A flattened or flattened tablet or flattened or non-flattened multiparticle provides an in vitro dissolution rate, when measured with a USP Type 1 (basket) device at 100 cycles per minute. minute in 900 ml of simulated gastric fluid (SGF) without enzymes and containing 40% ethanol at 37°C, characterized by a percentage of the amount active released at 0.5 hours or at 0.5 and 0.75 hours, or at 0.5, 0.75 and 1 hour, or at 0.5, 0.75, 1 and 1.5 hours, or at 0.5, 0.75, 1, 1.5 and 2 hours of melting which deviates by no more than about 20% points at each time point from the corresponding melting rate Corresponding dissolution rate in vitro, measured with a USP type 1 device (basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes and without ethanol at 37°C, for flat and non-flat reference tablet or reference multi particulates Flat and non-flat, respectively.

In such specific embodiments, the tablet or individual multiple particles can at least become flattened without breaking, and the tablet or individual multiple particles have a thickness after flattening corresponding to no more than about 60%, 50%, or 40%. Or 30%, 20%, or 16% of the thickness of the tablet or individual multi particulate before flattening. Flat provides an in vitro dissolution rate, when measured with a USP Type 1 (basket) device at 100 rpm in 900 mL of simulated gastric fluid (SGF) without enzymes and containing 40% ethanol at 37°C. As a percentage of the amount active released at 0.5 hours, or at 0.5 and 0.75 hours, or at 0.5, 0.75, and 1 hour, or at 0.5, 0.75, 1, and 1.5 hours, or at 0.5, 0.75, 1, and 1. 5 and two hours of dissolution which deviates no more than about 20% points or about 15% One point at each time point of the corresponding in vitro dissolution rate, measured with a USP type 1 device (basket) at 100 rpm in 900 ml of simulated gastric fluid (SGF) without enzymes and without ethanol at 37°C , for flat and non-flat reference tablet or flat and non-flat reference particles, respectively.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation comprising an active agent in the form of a tablet or multiple particulates, wherein the tablet or particulates The individual polyptych can at least become flattened without breaking, and is characterized by the disc or pipicle having a thickness after flattening that corresponds to no more than about 60% of the thickness of the disc or pipicle. Individual multi particulate before flattening, as a flattened or non-flattened tablet or flattened multi particulates provides a dissolution rate in the laboratory, when measured with a USP type 1 (basket) device at 100 rpm in 900 ml of simulated gastric fluid (SGF) without enzymes and comprising 40% ethanol or 0% ethanol at 37°C, ranging from about 5 to about 40% (by weight) of the agent The active agent is released after 0.5 hours.

In such specific embodiments, the disk or individual multiple particles can at least become flattened without breaking, characterized by the disk or individual multiple particles having a thickness after flattening corresponding to no more than about 50%, 40%, or 30%, or 20%, or 16% of the thickness of the tablet or individual microparticle before flattening, whereby the flattened or flattened tablet or flattened or non-flattened polyparticle provides an in vitro dissolution rate, when measured with a USP Type 1 device (basket) at 100 rpm in 900 ml of simulated intestinal fluid without enzymes and containing 40% or 0% ethanol at 37°C, ranging from about 5 to about 40% (by weight) of the active agent released after 0.5 h , or ranges from about 5 to about 30% (by weight) of the active agent released after 0.5 hours, or ranges from about 5 to about 20% (by weight) of the active agent released after 0.5 hours, or ranges from about 10 Up to about 18% (by weight) of the active agent is released after 0.5 hours.

Such dosage forms may be prepared as described above.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation, wherein the extended-release template formulation includes

A composition consisting of at least:

At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

At least one active agent, preferably selected from an opioid analgesics; And

The composition contains at least about 80% (by weight) of polyethylene oxide. The composition may also include at least about 85% or 90% (by weight) of polyethylene oxide. According to such embodiments, where the composition comprises at least about 80% (by weight) of polyethylene oxide, the active agent is oxycodone hydrochloride or hydromorphone hydrochloride, and the composition comprises more than about 5% (by weight) of oxycodone hydrochloride or hydromorphone hydrochloride. .

In such specific embodiments, the composition comprises at least about 80% (by weight) of polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation, wherein the extended-release template formulation includes

A composition consisting of at least:

At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

10 mg of oxycodone hydrochloride; And

The composition contains at least 85% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release template formulation, wherein the extended-release template formulation includes:

A composition consisting of at least:

At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

15 1 mg or 20 mg of oxycodone hydrochloride; And

The composition contains at least about 80% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation, wherein the extended-release template formulation includes

A composition consisting of at least:

At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

40 mg of oxycodone hydrochloride; And

The composition contains at least 65% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release template formulation, wherein the extended-release template formulation includes

A composition consisting of at least:

At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

60 mg or 80 mg of oxycodone hydrochloride; And

The composition contains at least about 60% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended release solid oral pharmaceutical dosage form comprising an extended release matrix formulation, wherein the extended release matrix formulation comprises

A composition consisting of at least:

At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

8 mg of oxycodone hydrochloride; And

The composition contains at least 94% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release template formulation, wherein the extended-release template formulation includes:

A composition consisting of at least:

At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

12 mg of oxycodone hydrochloride; And

The composition contains at least 92% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation, wherein the extended-release template formulation includes

A composition consisting of at least:

At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

32 mg of oxycodone hydrochloride; And

The composition contains at least about 90% (by weight) of polyethylene oxide.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release template formulation, wherein the extended-release template formulation includes:

A composition consisting of at least:

At least one active agent, preferably selected from an opioid analgesics;

At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of less than 1,000,000; In such specific embodiments, the composition comprises at least about 80% (by weight) polyethylene oxide. The composition may also comprise at least about 85% or 90% (by weight) of polyethylene oxide. According to such embodiments, where the composition comprises at least about 80% (by weight) of polyethylene oxide, the active agent is oxycodone hydrochloride or hydromorphone hydrochloride, and the composition comprises more than about 5% (by weight) of oxycodone hydrochloride or hydromorphone hydrochloride. . The composition may also include from 15 to 30% (by weight) of polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; From 65 to 80% (by weight) of polyethylene oxide has an approximate molecular weight, based on rheological measurements, of less than 1,000,000, or the composition may include at least about 20% (by weight), or about 30% (by weight) of The least, or at least about 50% (by weight) of polyethylene oxide, has a molecular weight, based on rheological measurements, of At least 1,000,000.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation, wherein the extended-release matrix formulation includes:

A composition consisting of at least:

At least one polyethylene oxide having a molecular weight, based on rheological measurements, of at least 800,000 or at least 900,000; And

At least one active agent selected from an opioid analgesics; And

The composition contains at least about 80% (by weight) of polyethylene oxide.

In certain embodiments of the invention, the extended release mold has a density less than or equal to about 1.20 g/cm3. In such embodiments, the density matrix formulation for extended release is less than or equal to about 1.19 g/cm3, preferably less than or equal to about 1.18 g/cm3, or less than or equal to about 1.17 g/cm3. For example, the density of an extended-release template formulation is in the range from about 1.10 g/cm3 to about 1.20 g/cm3, or from about 1.11 g/cm3 to about 1.20 g/cm3, or from about 1.11 g/cm3 to about 1.19 g/cm3. Preferably in a range from about 1.12 g/cm3 to about 1.19 g/cm3, or from about 1.13 g/cm3 to about 1.19 g/cm3, and more preferably from about 1.13 g/cm3 to about 1.18 g/cm3. It is preferable to determine density using the Archimedes principle, as described above.

In certain embodiments, the present invention is directed to an extended release solid oral pharmaceutical dosage form comprising an extended release matrix formulation, wherein the extended release matrix formulation comprises

A composition consisting of at least:

At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

At least one active agent; And

When the extended-release die formulation is subjected to an indentation test, it has a cracking force of approximately 110 Newtons.

In certain embodiments according to the invention, the extended-release die formulation has a cracking force of at least about 110 Newtons, preferably at least about 120 Newtons, at least 130 Newtons, at least 140 Newtons, and more preferably at least about 150 Newtons, Or at least 160 Newtons, or at least 170 Newtons, and more preferably at least about 180 Newtons, or at least about 190 Newtons, or at least about 200 Newtons.

In certain embodiments, the present invention is directed to an extended-release solid oral pharmaceutical dosage form comprising an extended-release matrix formulation, wherein the extended-release matrix formulation includes:

A composition consisting of at least:

At least one polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000; And

At least one active agent; And

When the extended-release die formulation is subjected to an indentation test, it has a “penetration depth to crack distance” of approximately 1.0 mm.

In certain embodiments according to the invention, the extended-release die formulation has a “slit depth distance” of at least about 1.0 mm, or at least about 1.2 mm, preferably at least about 1.4 mm, or at least about 1.5 mm, or at least about 1.6 mm. , more preferably at least about 1.8 mm, or at least about 1.9 mm, or at least about 2.0 mm, and most preferably at least about 2.2 mm, or at least about 2.4 mm, or at least about 2.6 mm.

In certain embodiments according to the invention, the extended-release die formulation has a cracking force of at least about 110 Newtons, preferably at least about 120 Newtons, at least 130 Newtons, at least 140 Newtons, and more preferably at least about 150 Newtons, or at least 160 N, or at least 170 N, more preferably at least about 180 N, or at least about 190 N, or at least about 200 N, and/or a “crack depth distance” of at least about 1.0 mm, or At least about 1.2 mm, preferably at least about 1.4 mm, or at least about 1.5 mm or at least about 1.6 mm, more preferably at least about 1.8 mm, or at least about 1.9 mm, or at least about 2.0 mm, more preferably at least about 2.2 mm, or at least about 2.4 mm, Or at least about 2.6 mm. Any combination of any of the foregoing values ​​of crushing force and "crack depth distance" is included within the scope of the invention.

In such specific embodiments, the extended release die formulation, when subjected to an indentation test, resists work of at least about 0.06 J, or at least about 0.08 J, and preferably at least about 0.09 J, or at least about 0.11 J, Or at least about 0.13 joules, and more preferably at least about 0.15 joules, or at least about 0.17 joules, or at least about 0.19 joules, and more preferably at least about 0.21 joules, or at least about 0.23 joules, or at least about 0.25 joules. .

The variables “cracking force,” “penetration depth to crack distance,” and “work” in an indentation test are determined as described above using a texture analyzer such as the TA-XT2 texture analyzer (from:

texture technologies corp., 18 fairview road, scarsdale, ny 10583). It is possible to determine the cracking force and/or “crack depth distance” using a matrix formulation, laminated or unlaminated with extended release. The crushing strength and/or “crack depth distance” are preferably determined using the extended release uncoated die formula. Without being bound by any theory, it is believed that an encapsulation layer, such as the coating performed in step (d) of the solid oral extended-release dosage form manufacturing process as described above, does not contribute significantly to the observed crushing strength and/or “Crack depth distance.” Therefore, the cracking force and/or crack depth distance determined for a specific extended release coated matrix formulation would not be expected to differ significantly from the values ​​determined for the corresponding uncoated matrix formulation.

In certain embodiments, the extended-release matrix formulation is in the form of a tablet or multiple particulates, the tablet or individual multiparticles being able to become at least flattened without breaking, characterized by the tablet or individual multiparticle having a thickness after flattening It corresponds to no more than about 60% of the thickness of the tablet or individual microparticle before flattening. It is preferable for the disc or individual multiple particles to become at least flat without breaking, and it is characterized that the disc or individual multiple particles has a thickness after flattening that does not exceed about 50%, 40%, 30%, 20%, or 16% of the thickness of the tablet or individual microparticle before flattening.

Flattening of tablets or individual particles is preferably done using a bench press, such as a Carver bench press, or using a hammer, as described above.

In such specific embodiments, the extended release template formulation is in the form of a tablet or multiple particles, the tablet or individual multi particulates can at least become flat without breaking, and the individual multiparticle tablet or particle is characterized by The thickness after flattening corresponds to no more than about 60% of the thickness of the disc or individual microparticle before flattening, as the aforementioned flattened tablet or multiparticle Flattened multi particulates provide a dissolution rate in vitro, when measured with a USP Type 1 (basket) device at 100 rpm in 900 ml of simulated gastric fluid (SGF) without enzymes at 37°C, with a Percentage of the amount active released at 0.5 h, or at 0.5 and 0.75 h, or at 0.5, 0.75, and 1 h, or at 0.5, 0.75, 1, and 1.5 h, or at 0.5, 0.75, 1, and 1.5 Two hours of dissolution, which deviates no more than about 20% point at Each of the time points given is from the corresponding dissolution rate in the laboratory for a non-flat reference tablet or non-flat reference particle. It is preferable for the tablet or individual multiple particles to become at least flat without breaking, and it is characterized that the tablet or individual multiple particles has a thickness after flattening that corresponds to no more than about 50%, 40%, 30%, 20%, or 16% of Thickness of tablet or individual polyparticle before flattening, whereby said flattened tablet or polyparticle provides the in vitro dissolution rate, when measured with a USP type 1 (basket) device at 100 cycles per minute in 900 ml of simulated gastric fluid (SGF) without enzymes at 37°C, characterized by a percentage of the amount active released at 0.5 h or at 0.5 and 0.75 h, or at 0.5, 0.75 and 1 h , or at 0.5, 0.75, 1, and 1.5 hours, or at 0.5, 0.75, 1, 1.5, and 2 hours of melting that deviates by no more than about 20% points or about 15% points at each of the time points mentioned from the corresponding melting rate. dissolution rate in vitro for a reference tablet other than Flat or non-flattened reference particles.

In certain embodiments, the invention is directed to an extended-release solid oral dosage form (EX). comprising an extended-release matrix formulation, wherein the extended-release template formulation is in the form of a tablet or multiparticle form particulates, and the disc or individual multi particulates can become at least flat without breaking, and is characterized by the fact that the disc or individual multi particulates has a thickness after flattening that corresponds to no more than Approximately 60% of the thickness of a single tablet or microparticle before flattening, as a flattened or flattened tablet or flattened or flattened multiparticle provides an in vitro dissolution rate, when measured with a USP Type 1 (basket) device at 100 cycles per minute in 900 ml of simulated gastric fluid (SGF) without enzymes and containing 40% ethanol at 37°C, characterized by a percentage of the amount active released at 0.5 h or at 0.5 and 0.75 h, or at 0.5 and 0.75 and 1 hour, or at 0.5, 0.75, 1 and 1.5 hours, or at 0.5, 0.75, 1, 1.5 and 2 hours of dissolution that deviates by no more than about 20% points at all time points from the corresponding dissolution rate Corresponding dissolution rate in vitro, measured with a USP type 1 device (basket) at 100 rpm in 900 ml of simulated gastric fluid without enzymes and without ethanol at 37°C, for a flat and non-flat reference tablet or flat and non-flat reference multi particulates Flat, in order. It is preferable for the tablet or multi particulates to become at least flattened without breaking, and it is characterized that the tablet or individual multi particulate has a thickness after flattening that does not exceed about 60%, 50%, 40%, or 30%, 20%, or 16% of the thickness of the individual tablet or particle before flattening, as the flattened or flattened tablet or flattened or nonflattened multiple particle provides a dissolution rate dissolution rate in vitro, when measured with a USP Type 1 device (basket) at 100 rpm in 900 mL of simulated gastric fluid (SGF) without enzymes and containing 40% ethanol at 37°C, characterized by a percentage of the amount of factor Effective amount active released at 0.5 hours, or at 0.5 and 0.75 hours, or at 0.5, 0.75, and 1 hour, or at 0.5, 0.75, 1, and 1.5 hours, or at 0.5, 0.75, 1, 1.5, and 2 hours of dissolution Which deviates no more than about 20% points or about 15% points at each of the time points Points given are from the corresponding dissolution rate in vitro, measured with a USP type 1 (basket) device at 100 rpm in 900 ml of simulated intestinal fluid without enzymes and without ethanol at 37°C, for a non-flat, non-flat reference tablet. Flat, non-flattened or reference multi particulates.

In such embodiments, the extended release matrix formulation does not break when subjected to a maximum force of about 196 N or about 439 N in a tablet hardness test.

It is preferable to perform a tablet hardness test to determine the resistance of extended-release die formulations to fracture using a Schleuniger device according to what was described above. For example, fracture strength is determined using a Schleuniger 2E/106 device, applying a maximum force of about 196 N, or using a Schleuniger Model 6D device, applying a maximum force of about 439 N.

It has been observed that the formulas according to the present invention are storage stable, whereby the extended-release template formula is stored at 25°C 60% relative humidity or 40°C 75% relative humidity for at least one month, preferably for at least two months, or At least 3 months, or at least 6 months, provides a dissolution rate, when measured with a USP Type 1 device (basket) at 100 rpm in 900 mL of simulated gastric fluid (SGF) without enzymes at 37m, characterized by a percentage of quantity The amount active agent released at 1 hour, or at 1 hour and 2 hours, or at 1 hour and 4 hours, or at 1 hour and 2 hours and 4 hours, or at 1 hour and 4 and 12 hours, or at 1 hour and 2 hours and 4 and 8 hours, or at 1 hour, 2 hours, 4, 8, and 12 hours of melting that deviates by no more than about 15% points, and preferably not more than 12% points, or not more than about 10% points, and preferably not more than about 8% points, or not more than about 6% points. It is most preferable that it does not exceed about 5% points at each of the mentioned time points The corresponding dissolution rate in the laboratory of a reference formula before storage. The extended-release block formulation is preferably stored in count bottles. Any combination of the above storage times, dissolution time points, and deviation limits are within the scope of the invention.

According to an additional characteristic of storage stability, the extended release matrix formulation has been stored at 25°C 60% relative humidity or 40°C 75% relative humidity for at least 1 month, preferably at least 2 months, or 3 At least 6 months, or at least 6 months, containing a % (by weight) amount of at least one active agent relative to that declared on the active agent label for the extended-release block formulation that deviates by not more than 10% points, preferably not more than 8% points or not more than 6% points, and more preferably not more than 5% points or not more than 4% points or not more than 3% points of the corresponding amount of the active agent in % (by weight) for To what is declared on the active agent label for an extended-release block formulation of a reference formulation prior to storage. An extended-release block formulation is preferably stored in count bottles, such as 100 count bottles. Any combination of storage times and deviation limits mentioned above is within the scope of the invention.

In such embodiments, the active agent is oxycodone hydrochloride.

It is preferable that the percentage (by weight) of at least one amount active relative to what is declared on the active agent label for the extended-release template formulation be determined by extracting at least one active agent from the extended-release template formulation and performing subsequent analysis using... High-performance liquid chromatography. In certain embodiments, where at least one active agent of oxycodone hydrochloride is specified, the percentage amount of oxycodone hydrochloride relative to that declared on the oxycodone hydrochloride label for the extended-release template formulation is preferred, by extracting the oxycodone hydrochloride from the extended-release template formulation using Mixture at 1: 2 of acetonitrile and simulated gastric fluid (SGF) without enzymes under constant magnetic stirring until the extended release matrix formulation is fully dispersed or overnight and subsequent analysis using high-performance liquid chromatography, preferably chromatography High performance reversed-phase fluid. In such embodiments, where the extended-release template formulation is in tablet form, the % (by weight) amount of oxycodone hydrochloride for the declared oxycodone hydrochloride for tablets is preferably determined by extracting oxycodone hydrochloride from two lots of ten tablets, each using 900 mL of Mixture at 1: 2 of acetonitrile and simulated gastric fluid (SGF) without enzymes under constant magnetic stirring until the extended-release template formulation is completely dispersed or overnight and subsequent analysis using a high-performance liquid chromatograph, preferably a reverse-phase high-performance liquid chromatograph . It is preferable that the test results be average values ​​in the two measurements.

In certain embodiments, the invention is directed to an extended-release solid oral pharmaceutical dosage form, wherein the dosage form provides a dissolution rate, when measured with a USP Type 1 device (basket) at 100 rpm in 900 ml of Simulated intestinal fluid without enzymes at 37°C, between 12.5 and 55% (by weight) of active agent released after 1 hour, between 25 and 65% (by weight) of active agent released after 2 hours, and between 45 and 85% (by weight) of active agent released After 4 hours, between 55 and 95% (by weight) of the active agent released after 6 hours, and optionally between 75 and 100% (by weight) of the active agent released after 8 hours. Preferably, the dosage form provides a dissolution rate, when measured with a USP Type 1 device (basket) at 100 rpm in 900 ml of simulated gastric fluid (SGF) without enzymes at 37°C, between 15 and 45 % (by weight) of the active agent released after 1 hour, between 30 and 60% (by weight) of the active agent released after 2 hours, between 50 and 80% (by weight) of the active agent released after 4 hours, and between 60 and 90 % (by weight) of active agent released after 6 hours, Optionally between 80 and 100% (by weight) of the active agent is released after 8 hours. It is more preferable that the dosage form provide a dissolution rate, when measured with a USP Type 1 device (basket) at 100 rpm in 900 mL of simulated enteric fluid without enzymes at 37°C, of ​​17.5 to 30% (by weight) of the active agent Which is released after 1 hour, and between 35 and 55% (by weight) of the active agent that is released after 2 hours, and between 55 and 75% (by weight) of the active agent that is released after 4 hours, and between 65 and 85% (by weight) of the active agent Which is released after 6 hours, and optionally between 85 and 100% (by weight) of the agent Effectively released after 8 hours.

In such embodiments, the active agent is oxycodone hydrochloride or hydromorphone hydrochloride.

These dosage forms may be prepared by following the process described herein.

In the above embodiments, the tablet may be formed by direct compression of the composition, cured by at least exposing said tablet to a temperature of at least about 60, at least about 62, at least about 68, at least about 70, or at least about 72 At least, or at least about 75 for a period of at least 1 minute, at least 5 minutes, or at least 15 minutes.

In certain embodiments according to the invention, the tablets described above may be further coated with a powder layer of polyethylene oxide by placing on the cured or uncured tablet a powder layer of polyethylene oxide surrounding the core, and treating the powder layer tablet as described above.

In certain embodiments according to the invention, a double-layered tablet or multiple layer is manufactured, wherein at least one layer contains an extended-release formulation as described above and at least one other layer contains an immediate-release formulation of the agent. The active agent included in the extended-release formulation or a second, different active agent. In such embodiments, the tablet is dual- or multi-layer, with one layer containing an extended-release formulation as described herein and one layer containing an immediate-release formulation. In such embodiments, particularly bi-layered tablets, opioid analgesics are included in the extended-release layer and non-opioid analgesics are also included in the immediate-release layer. Non-opioid analgesics can be non-steroidal anti-inflammatory agents, but also non-opioid analgesics such as acetaminophen. Acetaminophen may be used in combination with hydrocodone as an opioid analgesic. Such tablets may be prepared using certain tablet compression techniques called for compressing at least two compositions to form tablets with at least two distinct layers, each containing at least one of the two compositions. For example, such tablets could be manufactured in a tablet press by filling the compression tool with the first composition, compressing that first composition, then filling with the second composition on top of the first compressed composition, and then compressing both compositions to form the final two-layer tablet. The immediate-release formulation may be any formulation known in the art.

The invention also includes the use of high molecular weight polyethylene oxide having an approximate molecular weight, based on rheological measurements, of at least 1,000,000, in the form of a matrix in the manufacture of an extended-release solid oral dosage form comprising An active agent selected from opioids to give the extended-release solid oral dosage form resistant to alcohol extraction. Use may be accomplished as stated herein in connection with the described process, described formulas, or by any conventional method known in the art.

It has been observed that formulations according to the present invention comprising high molecular weight polyethylene oxide can be flattened to a thickness ranging from about 15 to about 18% of the non-flattened thickness, and that the flat tablet partially or substantially recovers its initial non-flat shape. Non flattened shape during dissolution, neglecting the swelling that occurs during dissolution. More specifically, the thickness of the disc increases and the diameter decreases significantly during dissolution. Without being bound by any theory, it is believed that high molecular weight polyethylene oxide has an image memory and the ability to recover the initial image after deformation, for example after flattening, in an environment that allows for recovery, such as an aqueous environment used in dissolution tests. This ability is believed to contribute to tamper resistant and, in particular, resistant alcohol extraction of dosage forms according to the present invention.

The invention also includes a treatment method where the dosage form is given to treat a specific disease or condition to a patient who needs treatment, especially treatment for pain, and the dosage form is used according to the invention to manufacture a medicine to treat a specific disease or condition or a patient who needs treatment, especially treatment for pain.

In one aspect of the present invention, an extended-release solid oral dosage form is provided to be administered twice daily, having an average tmax ranging from about 2 to about 6 hours, or from about 2.5 to about 5.5 hours, or from Approximately 2.5 to approximately 5 hours after administration at steady state or administered as a single dose to test subjects. The dosage form may include oxycodone or a salt thereof or hydromorphone or a salt thereof.

In one aspect of the present invention, a once-daily extended-release solid oral pharmaceutical dosage form is provided, having an average Tmax ranging from about 3 hours to about 10 hours, or from about 4 to about 9 hours, Or about 5 to about 8 hours after administration at steady state or given as a single dose to test subjects. The dosage form may include oxycodone or a salt thereof or hydromorphone or a salt thereof.

In another aspect according to the invention, an extended-release solid oral pharmaceutical dosage form is provided to be administered twice daily, wherein the dosage form comprises oxycodone or a salt thereof in an amount ranging from about 10 mg to about 160 mg, and wherein the dosage provides an average final plasma Cmax. of oxycodone reaches about 240 ng/mL or ranges from about 6 ng/mL to about 240 ng/mL after steady-state or single-dose administration to test subjects.

In another aspect according to the invention, an extended-release solid oral pharmaceutical dosage form is provided, wherein the dosage form comprises oxycodone or a salt thereof in an amount ranging from about 10 mg to about 40 mg, and wherein the dosage provides an average final plasma Cmax of oxycodone ranging from About 6 ng/mL to about 240 ng/mL after steady-state or single-dose administration to test subjects.

In another aspect according to the invention, an extended-release solid oral pharmaceutical dosage form is provided that is bioequivalent to the commercial product OxyContinTM.

In another aspect of the invention, an extended-release solid oral dosage form is provided that is bioequivalent to the commercial product PalladoneTM sold in the United States in 2005.

In another aspect of the invention, an extended-release solid oral pharmaceutical dosage form is provided, wherein the active agent is oxycodone hydrochloride, and wherein the dosage form comprising 10 mg of oxycodone hydrochloride when tested in a corresponding clinical study is equivalent Biologics of a reference tablet containing 10 mg of oxycodone hydrochloride in a matrix formulation containing:

(a) Oxycodone hydrochloride: 10.0 mg/tablet

(b) Lactose (spray-dried): 69.25 mg/tablet

(c) povidone: 5.0 mg/tablet

(d) Eudragit RS 30D (solids): 10.0 mg/tablet

(e) Triacetin: 2.0 mg/tablet

(f) stearyl alcohol: 25.0 mg/tablet

(g) talc: 2.5 mg/tablet

(h) magnesium stearate: 1.25 mg/tablet;

The reference tablet is prepared by following the following steps:

1. Eudragit RS 30D and Triacetin are combined while passing through a 250 micron screen sieve, and mixed under low shear for approximately 5 minutes or until uniform dispersion is observed.

2. Oxycodone hydrochloride, lactose, and povidone are placed in a granulator/dryer in the presence of a fluidized bed (FBD), and the suspension is sprayed onto the powder in the fluidized bed.

3. After spraying, granulation is passed through a #12 screen as necessary to reduce lumps.

4. Dry granulation is placed in a mixer.

5. Meanwhile, the required amount of stearyl alcohol is melted at a temperature of approximately 70°C.

6. Molten stearyl alcohol is included in the granulation during mixing.

7. The waxed granulation is transferred to the fluid bed granulator/dryer bowl in the presence of a fluidized bed or trays, and allowed to cool to room temperature or below.

8. The cooled granulation is then passed through a screen #12 sieve.

9. The waxed granulation is placed in a mixing medium and lubricated with the required amounts of talc and magnesium stearate for about 3 minutes.

10. The granulate product is compressed into 125 mg tablets using a suitable tableting machine.

Pharmacokinetic variables such as Cmax, tmax, AUCt, AUCinf etc. that describe the blood plasma curve can be obtained in clinical trials, by first administering a single dose of the active agent, eg oxycodone, to a group of test subjects, eg Cases from healthy humans. The blood plasma values ​​for the individual test subjects are then averaged, for example the average AUC, Cmax and tmax are obtained.

The Cmax value indicates the maximum concentration of the active agent in blood plasma. The tmax value indicates the time point at which the Cmax value is reached. In other words, the tmax value is the time point of the maximum observed plasma concentration.

The AUC value (i.e., area under the curve) indicates the area of ​​the concentration curve. The AUC value is proportional to the amount active absorbed into the blood circulation as a whole, and is therefore a measure of bioavailability.

The AUCt value indicates the area under the plasma concentration-time curve from the time of administration to the final measurable concentration of plasma, and is calculated using the trapezoidal rule: linear up/log down.

AUCinf is the area under the concentration curve-time of plasma that is deduced to infinity, and it is calculated using the following equation:

<img file="SA2709B1_D0002.tif" />

Where Ct is the last measurable plasma concentration, and lZ is the apparent terminal phase rate constant.

lZ is the apparent telophase rate constant, where lZ is the magnitude slope linear regression of log concentration versus time profile during telophase.

t1/2Z is ​​the apparent final phase half-life of the plasma, given as t1/2Z = (ln2)/lZ.

The delay time is determined by the time point preceding the first measurable plasma concentration value.

The term “healthy individuals” refers to males or females with average values, regards height, weight, physiological parameters, such as blood pressure, etc. Healthy test subjects for the purposes of the present invention are selected according to inclusion and exclusion criteria that are based on and consistent with the recommendations of the International Conference on Harmonization of Clinical Trials.

Hence, the inclusion principle includes males and females aged from 18 to 50 years, including a body weight ranging from 50 to 100 kg (49.98 kg to 99.79 kg), and a body mass index (BMI) of 18 and 34 (kg/m2), so that All test subjects who are healthy and free of significant abnormalities as determined by medical history, physical examination, vital signs, electrocardiogram, and females who are likely to give birth should use contraception. Sufficient and reliable, such as a barrier containing foam or jelly sufficient to kill spermicide, an intra-uterine device, a hormonal contraception method (hormonal contraceptives alone are not sufficient), and females must not be before menopause, but must One year postmenopausal, with high levels of follicle stimulating hormone (FSH), test subjects were willing to eat all the food provided to them during the study.

Another inclusion principle is that all subjects refrain from strenuous exercise during the entire study, and they should not start a new exercise program or engage in any exceptionally strenuous physical effort.

Exclusion criteria include pregnant females (positive beta test for human chorionic gonadotropin), lactating females, any history of drug abuse or alcohol for five years or current use, and a history or current conditions that may Interfering with absorption, distribution, metabolism, or excretion of the drug, and use of a drug containing an opioid in the last 30 years, a history of a known allergy to oxycodone, naltrexone, or related compounds, a history of frequent nausea or vomiting regardless of the aetiology, any history of seizures or head trauma for which there are current findings, and participation in a clinical drug study within the past 30 years. The last day before the initial dose in this study, any significant illness during the thirty days preceding the first dose in this study, and the use of any medication that includes treatment with thyroid hormones. thyroid hormone (permitting hormonal contraception) and/or vitamins and/or herbal and/or mineral supplements during the seven days preceding the first dose, and refusing to abstain from food for ten hours before administration and four hours after it or for four hours after administration. Study Drugs Abstaining from caffeine or xanthine completely during each restriction condition, and consumption of alcoholic beverages within 48 hours of study drug administration (or day) or at any time following administration first for the study drug, a history of smoking or using nicotine products within 45 days of administration of the study drug or a positive urine cotinine test, and donating donated blood or blood products within 30 days before administration of the study drugs or any time during the study except for a request This is in accordance with the clinical study protocol, positive results in a urine drug screen, an alcohol screen during a comprehensive examination at intervals, and a hepatitis B surface antigen. surface antigen (B), hepatitis B surface antibody (B) (unless immunized), hepatitis C antibody (C), a positive Naloxone HCl challenge test, and the presence of Gilberts Syndrome or Any hepatobiliary abnormalities, and the student believes that the human condition is unsuitable for a reason(s) not stated above.

Individuals who meet the inclusion principle and exceed the exclusion principle will be randomly assigned to the study.

The group that will be included in the study is the group of individuals who will give acknowledgment to the science.

A randomized safety group is the group of individuals who will be randomly assigned to the study, receive the study drug, and will receive at least one post-dose safety assessment.

The full analysis population for pharmacokinetic measurements will be the group of individuals who will be randomized into the study, receive the study drug, and have at least one valid pharmacokinetic measurement. It is possible to include test subjects who experience emesis within 12 hours after a dose based on visual inspection of PK profiles before closing the database. Individuals and curves/measurements excluded from the analysis will be documented in the statistical analysis plan.

For the Naloxone HCl challenge test, vital signs and pulse oximetry (SPO2) are obtained before the Naloxone HCl challenge test. The Naloxone HCl challenge can be given intravenously or subcutaneously subcutaneously. For the intravenous route, the needle or cannula must remain in the arm during administration. 0.2 mg of Naloxone HCl (0.5 ml) is given by intravenous injection. The test subject is observed for 30 seconds to confirm signs or symptoms of withdrawal. Then 0.6 mg of Naloxone HCl (1.5 mL) is given intravenously. The test individual is observed for 20 minutes to detect signs or symptoms of withdrawal. After observation for 20 minutes, vital signs and pulse oximetry (SPO2) are obtained before a Naloxone HCl challenge test.

Vital signs include systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, and oral temperature.

As for the question “How do you feel?”, a non-suggestive question of this type will be asked at each vital sign measurement, such as “Have there been any changes in your health condition since the examination/since the last time you were asked?” Each individual's answer will be evaluated to determine if there is an adverse event that should be reported. Individuals will be encouraged to tell volunteers about adverse events that occur to them at any time during the study.

Each test subject receiving an ingested treatment will receive a standard high-fat meal in accordance with “Industry Guidelines: Bioavailability Studies of Food Impact and Bioavailability in Ingested Conditions” (U.S. Department of Health and Human Services, Food Administration Drug Evaluation and Research Center, December 2002). The meal will be served 30 minutes before the dose, and will be consumed at a constant rate over a 25-minute period so that it is completed 5 minutes before administration.

Clinical laboratory evaluations in clinical studies include biochemistry (if at least ten hours of fasting), hematology, serology, urinalysis, screening for drugs of abuse, and additional tests.

Biochemical evaluations (in fasted state for at least ten hours) include determination of albumin, alkaline phosphatase, and

alanine aminotransferase (alanine transaminase, ALT), and

aspartate aminotransferase (aspartate transaminase, AST), and

Calcium, chloride, creatinine, glucose, inorganic phosphate, and

potassium, sodium, total bilirubin, total protein, urea, and

lactate dehydrogenase (LDH), direct bilirubin, and CO2.

Hematology evaluations include determination of hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell count, and white blood cell differential (% and absolute): basophils, eosinophils, lymphocytes, monocytes, and neutrophils.

Serology evaluations include identification of hepatitis B surface antigen (HBsAG), hepatitis B surface antibody (HBsAb), and hepatitis C antibody (anti-HCV).

Urinalysis evaluations include determining color, shape, pH, glucose, ketones, urobilinogen, nitrite, occult blood, protein, leukocyte esterase, microscopic and macroscopic evaluation, and specific gravity.

Screening for drugs of abuse includes a urine screen for opioids, amphetamines, cannabinoids, benzodiazepines, cocaine, cotinine, barbiturates, phencyclidine, methadone, and propoxyphene, and alcohol tests such as blood alcohol and alcohol testing.

Additional testing for females only includes a serum pregnancy test, serum pregnancy test, urine pregnancy test, and follicle stimulating hormone (FSH) serum test (for postmenopausal females who self-report hormone).

Detailed description of preferred models:

The present invention will now be given further elaboration with the accompanying examples. But it should be understood that the following description is for illustration only, and should not be considered a limitation of the invention in any way.

Example No. 1

In Example 1, a 200 mg tablet containing 10 mg of oxycodone hydrochloride is prepared using high molecular weight polyethylene oxide in combination with hydroxypropyl cellulose.

Composition:

Component

mg/unit

٪

oxycodone hydrochloride

10

5

polyethylene oxide

(Molecular weight: about 4,000,000;

PolyoxTM WSR-301)

160

80

hydroxypropyl cellulose

(KlucelTM HXF)

30

15

Total

200

100

Manufacturing process:

The processing steps to manufacture the tablets were as follows:

(1) Oxycodone hydrochloride, polyethylene oxide, and hydroxypropyl cellulose were mixed dry in a 1.5 cup capacity black &amp; decker handy chopper dual blade low/high shear blender.

(2) The Step 1 combination was pressed to the target weight using a Manesty F3 single-pass tablet press.

The tablets from step 2 were spread on a tray, and placed in a Hotpack oven model 435304 at 70°C for approximately 14.5 hours to cure the tablets.

Tests performed in the laboratory include tamper resistant (hammer and breaking strength test) and resistant alcohol extraction.

Tablets were tested in vitro using a USP type 2 device (paddle) at 50 rpm in 900 ml of simulated gastric fluid without SGF enzymes at 37°C, using a Perkin Elmer UV/VIS spectrometer lambda 20, Radiology UV at 230 nM. The results are presented in Table 1-1.

Untreated tablets, treated tablets, tampered tablets such as flat and treated tablets were tested. The flattening of treated tablets was flattened with a hammer using 7 hand hammer strokes to detect physical tampering. Tablet dimensions before and after flattening as well as dissolution profiles were evaluated using separate samples. The results are presented in Table 1-1.

As an additional test for tamper resistance, the treated discs were subjected to a breaking strength test with a maximum force of 196 Newtons using a Schleuniger 2E/106 device to evaluate breakage resistance. The results were also presented in Table 1-1.

In addition, the cured tablets were tested in vitro using ethanol/SGF media at 0%, 20%, and 40% ethanol concentrations to evaluate ethanol recovery potential. Testing was performed using a Perkin Elmer UV/VIS Spectrometer Lambda 20, UV at 230 nM. The sample time points included 0.5 hour and 1 hour. The results are presented in Table 1-1.

Processor

Intact, untreated

Salim

Flattening using 7 strokes of a hammer

Disc dimensions

Thickness (mm)

4.52 1

4.39 1

2.23 2

Diameter(mm)

-

7.56 1

10.27 2

Breaking strength (Newton)

-

196+ 3

-

Diameter (mm) after fracture resistance test

-

7.33 1

-

Dissolution

(which was launched%)

(n = 3 tablets per bowl)

0.5 hours

13

34

33

1 hour

18

46

45

2 hour

28

63

62

4 hour

43

81

83

8 hour

65

86

87

17 hour

85

86

87

1n = average of three measurements 2n = average of 5 measurements.

3 196+ means that by subjecting the discs to a maximum force of 196 N, they did not break, n = average of 3 measurements.

Dissolution

(which was launched%)

(n = 2 tablets per container)

Time

The ethanol concentration is 0% in SGF

Ethanol concentration of 20% in SGF

The ethanol concentration is 40% in SGF

Untreated

Processor

Untreated

Processor

Untreated

Processor

0.5

13

37

13

32

11

33

22

50

21

46

22

43

Example No. 2

In Example 2, three 200 mg tablets comprising 10 and 20 mg of oxycodone hydrochloride are prepared using high molecular weight polyethylene oxide in an optional combination with hydroxypropyl cellulose.

Composition:

Example 2.1

Example 2.2

Example 2.3

Component

mg/unit

mg/unit

mg/unit

oxycodone hydrochloride

10

20

10

polyethylene oxide

(Molecular weight: about 4,000,000

PolyoxTM WSR-301)

90

80

85

hydroxypropyl cellulose

(KlucelTM HXF)

0

0

5

Total

100

100

100

Manufacturing process:

The processing steps to manufacture the tablets were as follows:

(1) Oxycodone hydrochloride, polyethylene oxide, and hydroxypropyl cellulose were mixed dry in a 1.5 cup capacity Black &amp; Decker Handy Chopper dual blade low/high shear blender.

(2) The Step 1 combination was pressed to the target weight using a Manesty F3 single-pass tablet press.

(3) The tablets from step 2 were spread on a tray, and placed in a hotpack oven model 435304 at a temperature of 70°C to 75°C for 6 to 9 hours to cure the tablets.

Laboratory tests including tamper resistant testing and breaking strength test were performed as follows.

Cured tablets were tested in vitro using a USP Type 2 device (paddle) at 50 rpm in 500 ml of simulated gastric fluid without SGF enzymes at 37°C, using a Perkin Elmer UV/VIS Spectrometer Lambda 20, Radiology UV at 220 nM. Treated tablets and untreated tablets were tested. The flattening of tablets was flattened to 181.44/cm2 using a carver-type bench press to detect physical tampering. The results are presented in Table 2.

As an additional tamper-resistant test, the treated tablets were subjected to a breaking strength test with a maximum force of 196 Newtons using a Schleuniger 2E/106 to evaluate breakage resistance. The results are also presented in Table 2.

Example No. 2-1

Example No. 2-2

Example No. 2-3

Salim

(n=6)

Flattening with a bench press

Salim

(n=2)

Flattening with a bench press

Salim

(n=5)

Flattening with a bench press

Disc dimensions

Thickness (mm)

3.36

0.58

3.14

0.84

3.48

0.49

Diameter(mm)

6.48

12.80

6.58

13.44

6.46

12.86

Fish (%)

-

17.3

-

26.8

-

14.0

Breaking strength (Newton)

196+ 1

n/a

196+ 1

n/a

196 + 1

n/a

Dissolution

(which was launched%)

(n=1)

0.5 hours

34

46

42

50

40

56

1 hour

50

62

57

71

55

72

2 hour

72

78

78

91

77

89

4 hour

81

82

95

93

93

100

8 hour

82

82

95

93

94

100

12 hour

83

82

96

94

95

101

1 196+ means that by exposing the discs to a maximum force of 196 Newtons, they will not break.

Example No. 3:

In Example 3, a 200 mg tablet containing 10 mg of oxycodone hydrochloride and high molecular weight polyethylene oxide is prepared.

Composition:

Component

mg/unit

٪

oxycodone hydrochloride

10

5

polyethylene oxide

(Molecular weight: about 4,000,000;

PolyoxTM WSR301)

188

94

magnesium stearate

2

Total

200

100

Manufacturing process:

The processing steps to manufacture the tablets were as follows:

(1) Oxycodone hydrochloride, polyethylene oxide, and magnesium stearate were mixed in a 1.5 cup capacity Black &amp; Decker Handy Chopper dual blade low/high shear blender.

(2) The Step 1 combination was compressed to the target weight using a manesty F3 tablet press.

(3) The tablets from step 2 were spread on a tray, and placed in a Hotpack oven model 435304 at 70°C for 1 to 14 hours to cure the tablets.

Tests have been performed in the laboratory including tamper resistant testing (breaking strength test) as follows:

Tablets were tested in vitro using a USP Type 2 device (paddle) at 100 rpm in 900 ml of simulated gastric fluid without SGF enzymes at 37°C, using a Perkin Elmer UV/VIS Spectrometer Lambda 20, UV at 220 nM, after exposure to treatment for 2, 3, 4, 8, and 14 hours. Dimensions of treated and untreated tablets and dissolution results are shown in Table 3.

As an additional test for tamper resistance, the treated and untreated discs were subjected to a breaking strength test with a maximum force of 196 Newtons using a Schleuniger 2E/106 to evaluate breakage resistance. The results are also presented in Table 3.

Table No. 3

not

Processed2

Processing time (hours)

1 1

2 1

4 1

8 1

14 2

Disc dimensions

Weight(mg)

208

208

209

209

208

210

Thickness (mm)

4.74

5.17

5.25

5.17

5.17

4.85

Diameter(mm)

7.93

7.85

7.80

7.75

7.69

7.64

Breaking strength (Newton)

176

196+3

196+3

196+3

196+3

196+3

Solubility (% released) (n = 2)

0.5 hours

Not tested

Not tested

16

11

15

33

1 hour

23

18

23

50

2 hour

34

28

36

69

4 hour

54

45

58

87

8 hour

81

69

83

93

12 hour

96

83

92

94

1 Disk dimensions n = 4

2 Disk dimensions n = 10

196+3 means that by subjecting the discs to a maximum force of 196 Newtons, they did not break.

In Example 4, six 100 mg tablets (Examples 4-1 through 4-6) comprising 10 mg of oxycodone hydrochloride are prepared using high molecular weight polyethylene oxide in combination with hydroxypropyl cellulose.

Composition:

1-4

2-4

3-4

4-4

4-5

4-6

Component

mg/unit

mg/unit

mg/unit

mg/unit

mg/unit

mg/unit

oxycodone hydrochloride

10

10

10

10

10

10

polyethylene oxide

(Molecular weight: about 4,000,000;

(PolyoxTM WSR 301

89.5

79.5

69.5

89.0

0

0

polyethylene oxide

(Molecular weight: 100,000 approx.;

PolyoxTM N 10)

0

10

20

0

0

0

polyethylene oxide

(Molecular weight: about 2,000,000;

PolyoxTMN-60K))

0

0

0

0

0

89.5

polyethylene oxide

(Molecular weight: about 4,000,000;

(PolyoxTM WSR 301

0

0

0

0

89.5

0

hydroxytoluene to which a butylated group has been introduced (BHT)

0

0

0

0.5

0

0

magnesium stearate

0.5

0.5

0.5

0.5

0.5

0.5

Total

100

100

100

100

100

100

Blend volume (g)

125

125

125

125

157.5

155.5

Total blend volume (g)

(manufactured quantity)

250

250

250

250

157.5

155.5

The processing steps to manufacture the tablets were as follows:

(1) Oxycodone hydrochloride, polyethylene oxide (and butylated hydroxytoluene (BHT) when needed) were mixed by drying in a Black &amp; Decker Handy Chopper dual blade low/high shear mixer for 30 seconds.

(2) Magnesium stearate was added to the step 1 mixture and mixed for an additional 30 seconds.

(3) The Step 2 combination was compressed to the target weight using a Manesty F3 tablet press using standard round tooling (0.6746 cm) concave.

(4) Step 3 tablets were loaded into a 37.5 cm coating pan (LCDS Vector Laboratory Development Coating System) at 38 rpm equipped with a single baffle. A temperature probe (wire thermocouple) is placed inside the coating pan near the tablet layer to monitor the layer temperature. The layer of tablets was heated to a temperature ranging from about 70 to about 80°C (the temperature can be obtained from tablets 4-1 to 4-6 for each example) for a minimum of 30 minutes and a maximum of 2 hours. After that, the disk was cooled and vacuumed.

Tests were performed in the laboratory including tamper resistant testing (breaking strength test and hammer test) as follows:

Treated and untreated tablets were tested at 0.5, 1, and 2 hours of in vitro curing using a USP Type 2 device (paddle) at 100 rpm in 900 mL of simulated gastric fluid without SGF enzymes at 37°C, using a Perkin Elmer UV spectrophotometer. /VIS Spectrometer Lambda 20, UV at 220 nM. Tablet dimensions and dissolution results corresponding to the corresponding curing time and temperature are shown in Tables 4-1 to 4-6.

As an additional test for tamper resistance, the treated and untreated discs were subjected to a breaking strength test by applying a maximum force of 196 Newtons using a Schleuniger 2E/106 device to evaluate breakage resistance.

The results were also presented in Tables 4-1 to 4-6.

In addition, the tablets were flattened with a hammer using 10 hand strokes of the hammer to detect physical tampering (hammer test).

Table No. 4-1

Example No. 4-1

Untreated

(n = 10)

Processing time (hours) (n = 5)

0.5

1.0

1.5

2.0

Disc dimensions

Weight(mg)

108

109

108

107

107

Thickness (mm)

3.64

3.93

3.94

3.90

3.83

Diameter(mm)

6.74

6.62

6.57

6.55

6.52

Breaking strength (Newton)

94

196+2

196+2

196+2

196+2

Diameter(mm)

After breaking resistance test

(measured immediately after testing)

1 was crushed

5.15

5.38

5.23

5.44

Processing process

Disk layer temperature m

(temperature sensor inside the bowl)

0 minute

19.7

-

-

-

10 minute

-

66.2

-

-

-

20 minute

-

68.6

-

-

-

30 minute

-

73.5

-

-

-

40 minute

-

-

76.9

-

-

60 minute

-

-

78.9

-

-

90 minute

-

-

-

79.8

-

120 minute

-

-

-

-

80.2

n=

3

3

2

2

2

Dissolution

(which was launched%)

0.5 hours

19

21

18

18

19

1 hour

30

32

30

29

31

2 hour

47

49

46

46

50

4 hour

71

76

70

69

75

8 hour

93

96

91

89

93

12 hour

99

99

96

93

96

n=

After hammer test 3 (10 hand strikes with the hammer)

Thickness (mm)

n/a

1.70

2.18

2.37

2.09

2.31

2.06

2.26

2.39

2.66

2.28

1 The tablets were crushed and fragmented during the breaking strength test.

2 196+ means that the tablets do not break when exposed to a maximum force of 196.

3 The tablets were flattened when 10 hammer blows were applied to the tablets, but they did not break. The hammer strike caused some cracks in the edge.

Example No. 4-2

Untreated (n = 10)

Processing time (hours) (n = 5)

0.5

1.0

1.5

2.0

Disc dimensions

Weight(mg)

108

109

109

109

107

Thickness (mm)

3.65

3.90

3.92

3.87

3.74

Diameter(mm)

6.74

6.61

6.54

6.52

6.46

Breaking strength (Newton)

93

196 +3

196 +3

196 +3

196 +3

Diameter(mm)

After fracture strength test (measured immediately after testing)

Mashed 2

5.40

5.37

5.36

5.61

Diameter during relaxation(mm)

After the fracture resistance test (relaxation period not exceeding 15 minutes)

-

5.60

5.52

5.48

5.73

Processing process

Disk layer temperature m

(temperature sensor inside the bowl)

0 minute

20.2

-

-

-

10 minute

-

71.6

-

-

-

20 minute

-

74.9

-

-

-

30 minute

-

76.1

-

-

-

40 minute

-

-

79.8

-

-

60 minute

-

-

80.2

-

-

90 minute

-

-

-

76.4

-

120 minute

-

-

-

-

77.5

Dissolution

(which was launched%)

(n=3)

0.5 hours

-

20

20

-

29

1 hour

-

30

31

-

44

2 hour

-

47

47

-

66

4 hour

-

70

70

-

90

8 hour

-

89

91

-

95

12 hour

-

92

94

-

94

n=

After hammer test (10 hand strikes with hammer)

Thickness (mm)

n/a

1.98

2.00

1.80

1.62

1.96

1.76

2.06

1.95

1.99

1.79

1.98

1.53

2 The tablets were crushed and fragmented during the breaking strength test.

3 196+ means that the tablets do not break when exposed to a maximum force of 196.

Example No. 4-3

Untreated (n = 10)

Processing time (hours) (n = 5)

0.5

1.0

1.5

2.0

Disc dimensions

Weight(mg)

108

107

108

108

107

Thickness (mm)

3.63

3.85

3.82

3.78

3.72

Diameter(mm)

6.74

6.61

6.55

6.48

6.46

Breaking strength (Newton)

91

196 +3

196 +3

196 +3

196 +3

Diameter(mm)

After fracture strength test (measured immediately after testing)

It was crushed 2

5.58

5.60

5.56

5.72

Diameter during relaxation(mm)

After fracture resistance test (unfolding time not exceeding 15 minutes)

-

5.77

5.75

5.68

5.82

Processing process

Disk layer temperature m

(temperature sensor inside the bowl)

0 minute

20.3

-

-

-

10 minute

-

71.0

-

-

-

20 minute

-

74.1

-

-

-

30 minute

-

75.9

-

-

-

40 minute

-

-

76.5

-

-

60 minute

-

-

77.8

-

-

90 minute

-

-

-

76.0

-

120 minute

-

-

-

-

80.2

n=

3

3

2

Dissolution

(which was launched%)

0.5 hours

-

22

23

-

33

1 hour

-

32

35

-

52

2 hour

-

49

54

-

76

4 hour

-

70

80

-

93

8 hour

-

94

95

-

96

12 hour

-

96

96

-

96

n=

After hammer test (10 hand strikes with hammer)

Thickness (mm)

n/a

2.16

1.95

1.43

1.53

1.96

1.85

1.67

1.66

1.91

2.03

1.65

2.08

2 The tablets were crushed and fragmented during the breaking strength test.

3 196+ means that the tablets do not break when exposed to a maximum force of 196.

Example No. 4-4

Untreated (n = 10)

Processing time (hours) (n = 5)

0.5

1.0

1.5

2.0

Disc dimensions

Weight(mg)

101

101

101

101

101

Thickness (mm)

3.49

3.75

3.71

3.69

3.70

Diameter(mm)

6.75

6.59

6.55

6.55

6.52

Breaking strength (Newton)

81

96 + 3

96 + 3

96 + 3

96 + 3

Diameter(mm)

After the fracture strength test (measured immediately after the test

It was crushed 2

5.39

5.39

5.39

5.47

Flat diameter(mm)

After fracture resistance test (unfolding time not exceeding 15 minutes)

-

5.58

5.59

5.58

5.63

Processing process

Disk layer temperature m

(temperature sensor inside the bowl)

0 minute

37.3

5 minute

-

67.0

-

-

-

10 minute

-

71.8

-

-

-

20 minute

-

74.6

-

-

-

30 minute

-

76.2

-

-

-

40 minute

-

-

77.0

-

-

60 minute

-

-

78.7

-

-

90 minute

-

-

-

80.3

-

120 minute

-

-

-

-

79.3

Dissolution

(which was launched%)

(n=3)

0.5 hours

-

17

16

-

-

1 hour

-

26

25

-

-

2 hour

-

41

40

-

-

4 hour

-

63

59

-

-

8 hour

-

79

75

-

-

12 hour

-

82

80

-

-

n=

After hammer test (10 hand strikes with hammer)

Thickness (mm)

-

2.11

2.42

2.14

2.18

2.29

2.25

2.28

2.09

2.32

2.13

2.07

2.36

2 The tablets were crushed and fragmented during the breaking strength test.

3 196+ means that the tablets do not break when exposed to a maximum force of 196.

Example No. 4-5

Untreated (n = 10)

Processing time (hours) (n = 5)

0.5

1.0

1.5

2.0

Disc dimensions

Weight(mg)

108

108

107

107

107

Thickness (mm)

3.61

3.87

3.84

3.84

3.84

Diameter(mm)

6.74

6.69

6.63

6.61

6.59

Breaking strength (Newton)

116

196 +3

196 +3

196 +3

196 +3

Diameter (mm) after fracture strength test (measured immediately after the test

It was crushed 2

5.49

5.59

5.51

5.54

Diameter (mm) after fracture resistance test (unfolding time no more than 15 minutes)

-

5.67

5.76

5.67

5.68

Processing process

Disc layer temperature m (temperature probe inside the pan)

0 minute

19.8

5 minute

-

56.8

-

-

-

10 minute

-

70.0

-

-

-

20 minute

-

74.6

-

-

-

30 minute

-

76.2

-

-

-

40 minute

-

-

77.0

-

-

60 minute

-

-

78.2

-

-

90 minute

-

-

-

80.2

-

120 minute

-

-

-

-

80.3

Dissolution

(which was launched%)

(n=3)

0.5 hours

-

21

20

-

-

1 hour

-

33

32

-

-

2 hour

-

51

51

-

-

4 hour

-

75

76

-

-

8 hour

-

96

96

-

-

12 hour

-

100

100

-

-

n=

After hammer test (10 hand strikes with hammer)

Thickness (mm)

-

2.19

2.31

2.36

2.45

2.15

2.48

2.42

2.08

2.10

2.28

2.19

2.28

2 The tablets were crushed and fragmented during the breaking strength test.

3 196+ means that the tablets do not break when exposed to a maximum force of 196.

Example No. 4-6

Processing time (n = 5)

not

Treated (n = 6)

10 minute

20 minute

0.5 hours

1.0 hours

1.5 hours

2.0 hours

Disc dimensions

Weight(mg)

110

108

108

109

108

109

109

Thickness (mm)

3.65

3.93

3.89

3.89

3.87

3.85

3.85

Diameter(mm)

6.73

6.71

6.63

6.61

6.57

6.55

6.53

Breaking strength (Newton)

128

196 + 2

Diameter(mm)

After the fracture strength test (measured immediately after the test

1 was crushed

5.27

5.47

5.51

5.51

5.56

5.63

Diameter (mm) after fracture resistance test

(Diastasis period not exceeding 15 minutes)

-

5.48

5.60

5.67

5.66

5.69

5.76

Processing process

Disk layer temperature m

(temperature sensor inside the bowl)

0 minute

30.8

5 minute

-

70.5

-

-

-

-

-

10 minute

-

79.5

-

-

-

-

-

20 minute

-

-

79.9

-

-

-

-

30 minute

-

-

-

79.6

-

-

-

40 minute

-

-

-

-

80.0

-

-

60 minute

-

-

-

-

79.8

-

-

90 minute

-

-

-

-

-

80.2

-

120 minute

-

-

-

-

-

-

80.4

Dissolution

(which was launched%)

(n=3)

0.5 hours

-

-

-

19

20

-

-

1 hour

-

-

-

30

30

-

-

2 hour

-

-

-

48

51

-

-

4 hour

-

-

-

73

78

-

-

8 hour

-

-

-

99

99

-

-

12 hour

-

-

-

99

102

-

-

n=

After hammer test 3

(10 hand strikes with hammer)

Thickness (mm)

-

1.46

2.18

2.45

2.23

2.38

2.42

1.19

2.20

2.34

2.39

2.26

2.40

1.24

2.18

2.03

2.52

2.50

2.16

1 The tablets were crushed and fragmented during the breaking strength test.

2 196+ means that the tablets do not break when exposed to a maximum force of 196.

3 The tablets were flattened, but not broken. The hammer strike caused some cracks in the edge.

In Example 5 three other tablets containing 10% (by weight) of oxycodone hydrochloride are prepared.

Composition:

Example No. 5-1

Example No. 5-2

Example No. 5-3

schedule

mg/unit

(٪)

mg/unit (%)

mg/unit

(٪)

oxycodone hydrochloride

12

(10)

20

(10)

12

(10)

polyethylene oxide

(Molecular weight: about 4,000,000;

PolyoxTM WSR 301)

106.8

(89)

178

(89)

82.8

(69)

polyethylene oxide

(Molecular weight: approx. 100,000; PolyoxTM N 10)

0

0

24

(20)

magnesium stearate

1.2

(1)

2.0

(1)

1.2

(1)

Total

120

200

120

Total batch size (kg)

(manufactured quantity)

100

100

100

Encapsulation layer

mg/unit

mg/unit

mg/unit

Opadry white film coating concentration formula, Y-5-18024-A

3.6

(3)

6.0

(3)

3.

(3)

The processing steps to manufacture the tablets were as follows:

The polyethylene oxide was passed through a screen sweco sieve equipped with an 841 micron mesh into separate appropriate containers.

The Gemco “V” mixer (with I-bar) 0.107 cc is filled in the following order:

About half of that is polyethylene oxide WSR 301

oxycodone hydrochloride /

polyethylene oxide N10 (only example 5-3)

Residual polyethylene oxide WSR 301

Step 2 materials were mixed for 10 minutes (Example 5-1) or 20 minutes (Example 5-2) and 15 minutes (Example 5-3) with the I-rod running.

Magnesium stearate was fed to the Gemco V mixer.

Step 4 materials were mixed for 3 minutes with the I-rod off.

The Step 5 mixture was introduced into clean stainless steel equivalent weight containers.

The Step 5 mixture was compressed to the target weight using a 40-tablet press at 135,000 tablets per hour using a 22.9/81.3 cm standard round concave tooling.

The tablets from step 7 were loaded into a 121.9 cm Accela-Coat packaging hopper at 7 rpm with a hopper load of 98.6 kg (Example 5-1), 92.2 kg (Example 5-2), 96.9 kg (Example 5-3). ), the disc layer was heated using the exhaust air temperature to achieve an inlet temperature of approximately 80°C (Example No. 5-2 and Example No. 5-3) and 75°C, and was cured for an hour at the target inlet temperature.

The bowl speed was maintained at between 7 and 10 revolutions per minute, and the tablet bed was cooled using the exhaust air temperature to achieve an inlet temperature of 25°C until the bed temperature was between 30 and 34°C.

The disc layer was heated using an exhaust air temperature to achieve an inlet temperature of 55°C. Film coating was started as soon as the exit temperature approached 39°C, and continued until the target weight gain of 3% was achieved.

After the coating process was completed, the pan speed was set to 1.5 rpm, the exhaust temperature was set to 27°C, the air flow was maintained at the current setting, and the system was cooled to an exhaust temperature of 27 to 30°C.

The disks have been emptied.

Laboratory tests have been performed including tamper resistant (breaking strength test and hammer test) and resistant alcohol extraction as follows:

Cured tablets at 0.5 h, tablets cured at 1.0 h and coated tablets were tested in vitro using a USP type 2 device (paddle) at 100 rpm in 900 ml of simulated gastric fluid without SGF enzymes at 37°C, using a spectrophotometer Agilent UV/VIS Spectrometer Model HP8453, UV at 220 nM. Tablet dimensions and corresponding dissolution results for curing time, temperature, and analogues are shown in Tables 5-1 to 5-3.

Cured tablets at 1.0 hours and coated tablets were tested in vitro with 40% ethanol/SGF medium to evaluate alcohol extractability. Testing was performed using a USP Type 1 device (basket) at 100 rpm in 900 ml of simulated gastric fluid (SGF) without enzymes at 37°C, using an Agilent UV/VIS Spectrometer Model HP8453, UV Violet at 220 nM. The dissolution results are shown in Table 5-3.

As an additional tamper resistance test, the cured and uncured tablets were subjected to a breaking strength test with a maximum force of 439 Newtons using a Schleuniger Model 6 tamper resistance test. The results were presented in Tables 5-1 to 5-3.

In addition, the tablets were flattened using a hammer by applying 10 hand strikes with the hammer to detect physical tampering (hammer test).

Table No. 5-1

Example No. 5-1

Untreated

30 Minute processing

(n = 10)

1 Processing hour/envelope

(n = 10)

Disc dimensions

Weight(mg)

119.7 1

120

122

Thickness (mm)

3.63 2

3.91

3.88

Diameter(mm)

-

7.03

7.02

Breaking strength (Newton)

54 3

439 4

438 4

Diameter(mm)

After breaking resistance test

-

4.18

4.26

Processing process

Inlet temperature m

10 minute

-

75.8

75.8

20 minute

-

75.1

75.1

30 minute

-

76.0

76.0

40 minute

-

-

74.5

50 minute

-

-

73.5

60 minute

-

-

75.6

Dissolution

(which was launched%)

(n=3)

0.5 hours

-

19

19

1 hour

-

31

33

2 hour

-

47

50

4 hour

-

71

76

8 hour

-

93

97

12 hour

-

99

102

Hammer test

(10 hand strikes with hammer)

Measured disc thickness (mm) before and after testing (n = 3)

-

before

after

before

after

3.90

1.77

3.87

2.09

1 Fourteen current samples (40 tablets per sample) were taken, and the average of each sample was taken. The reported value is the average of the averages.

2n=39

3 n=130

4n = 10; The discs did not break when subjected to a maximum force of 438N/439N.

Table No. 5-2

Example No. 5-2

Untreated

30 Minute processing

(n = 10)

1 Processing hour/envelope

(n = 10)

Disc dimensions

Weight(mg)

200.4 1

201

206

Thickness (mm)

5.50 2

5.92

5.86

Diameter(mm)

-

7.03

7.01

Breaking strength (Newton)

85 3

439 4

439 4

Diameter(mm)

After breaking resistance

-

5.52

5.72

Processing process

Inlet temperature m

10 minute

-

79.7

79.7

20 minute

-

80.3

80.3

30 minute

-

79.3

79.3

40 minute

-

-

79.5

50 minute

-

-

80.9

60 minute

-

-

81.0

Dissolution

(which was launched%)

(n=3)

0.5 hours

-

14

15

1 hour

-

23

24

2 hour

-

36

38

4 hour

-

57

60

8 hour

-

83

85

12 hour

-

94

95

Hammer test

(10 hand strikes with hammer)

Measured disc thickness (mm) before and after testing (n = 3)

-

before

after

before

after

5.92

2.97

5.91

2.84

1 Nine current samples were taken (40 tablets per sample), and the average of each sample was taken. The reported value is the average of the averages.

2n = 27

3 n=90

4n = 10; The discs did not break when subjected to a maximum force of 438N/439N.

Example No. 5-3

Untreated

30 Minute processing

(n = 10)

1 Processing hour/envelope

(n = 10)

Disc dimensions

Weight(mg)

120.5 1

122

125

Thickness (mm)

3.64 2

3.85

3.77

Diameter(mm)

-

7.03

7.01

Breaking strength (Newton)

56 3

438 4

439 4

Diameter(mm)

After breaking resistance

-

3.96

4.28

Processing process

Inlet temperature m

10 minute

-

80.0

80.0

20 minute

-

82.3

82.3

30 minute

-

78.9

78.9

40 minute

-

-

79.5

50 minute

-

-

79.5

60 minute

-

-

80.7

SGF

SGF

40% ethanol

Dissolution

(which was launched%)

(n=3)

0.5 hours

-

20

23

21

1 hour

-

31

37

31

2 hour

-

50

58

50

4 hour

-

76

86

76

8 hour

-

95

100

99

12 hour

-

98

100

104

Hammer test

(10 hand strikes with hammer)

Measured disc thickness (mm) before and after testing (n = 3)

-

pre

post. post

pre

post. post

3.81

1.63

3.79

1.62

1 Twelve current samples were taken (40 tablets per sample), and the average of each sample was taken. The reported value is the average of the averages. And 2n = 33

3 n=130

4n = 10; The discs did not break when subjected to a maximum force of 438N/439N.

In Example 6, tablets containing Naltrexone HCl are prepared.

Composition:

disk

mg/unit

Naltrexone HCl

10

polyethylene oxide

(Molecular weight: about 4,000,000; PolyoxTM WSR301)

89.0

magnesium stearate

1.0

Total

100

Total batch size (kg)

(manufactured quantity)

20

mg/unit

Basal layer

Opadry Red film coating concentration formula, Y-5-1-15139

3.0

Special effects

epimembrane

Opadry FX Silver formula 62W28547

3.0

The tablets have been prepared

Example No. 7

Three additional examples involving 10 mg of oxycodone hydrochloride were prepared and tested.

Composition:

Example No. 7-1

Example No. 7-2

Example No. 7-3

schedule

mg/unit (%)

mg/unit (%)

mg/unit (%)

oxycodone hydrochloride

10 (5)

10 (6.67)

10 (10)

polyethylene oxide

(Molecular weight: about 4,000,000;

PolyoxTM WSR 301)

188 (94)

138.5 (92.3)

69 (69)

polyethylene oxide

(Molecular weight: 100,000 approx.;

PolyoxTM N 01)

0

0

20 (20)

magnesium stearate

2 (1)

1.5 (1)

1 (1)

Total

200

150

100

Total batch size (kg)

(manufactured quantity)

100

100

100

Film coating

mg/unit

mg/unit

mg/unit

The formula for the concentration of Opadry white film coating is Y-5-18024-A

6

4.5

3

The processing steps to manufacture the tablets were as follows:

The magnesium stearate was passed through a Sweco screen sieve equipped with an 841 micron mesh into separate appropriate containers.

The Gemco "V" mixer (with I-shaft) 0.283 m³ is filled in the following order:

About half of that is polyethylene oxide WSR 301

oxycodone hydrochloride /polyethylene oxide N10 (only Example 5-3)

Residual polyethylene oxide WSR 301

Step 2 materials were mixed for 10 minutes with the I-rod running.

Magnesium stearate was fed to the Gemco V mixer.

Step 4 materials were mixed for 3 minutes with the I-rod off.

The Step 5 mixture was introduced into clean stainless steel equivalent weight containers.

The Step 5 mixture was compressed to the target weight using a 40-tablet press at 135,000 tablets per hour using a 12.9/81.3 cm standard round concave tooling (Example 7-3).

The tablets from Step 7 were loaded into a 42-inch Accela-Coat packaging vessel at a vessel load of 97.388 kg (Example 7-1), 91.051 kg (Example 7-2), and 89.527 kg (Example 7-3).

The bowl speed was set to 7 rpm, and the tablet bed was heated by setting exhaust air temperature to achieve an inlet temperature of about 75°C. The tablets were processed at the target inlet temperature for 1 hour (Example 7-1 and Example 7-2) and 30 minutes (Example 7-3).

The bowl speed was maintained between 7 and 8 rpm, and the tablet bed was cooled using the exhaust air temperature to achieve an inlet temperature of 25°C until the bed temperature was achieved between 30 and 34°C.

The disc layer was heated using an exhaust air temperature to achieve an inlet temperature of 55°C. Film coating was started as soon as the exit temperature approached 39°C, and continued until the target weight gain of 3% was achieved.

After the coating process was completed, the pan speed was set to 1.5 rpm, the exhaust temperature was set to 27°C, the air flow was maintained at the current setting, and the system was cooled to an exhaust temperature of 27 to 30°C.

The disks have been emptied.

Tests have been performed in the laboratory including tamper resistant (breaking strength test, hammer test, flattened tablets), resistant alcohol extraction, and stability tests as follows:

Cured coated tablets (intact and flat) were tested in vitro using a USP Type 2 device (basket) at 100 rpm in 900 ml of simulated gastric fluid (SGF) without enzymes at 37°C. Samples were analyzed using high performance reverse-phase liquid chromatography (HPLC) using a Waters Atlantis dC 18 with dimensions of 3.0 150 mm, 3 µm column, using a mobile phase consisting of a mixture of acetonitrile and a non-basic potassium phosphate buffer solution ( pH 3), UV detector at 230 nM. Sample time points included 0.5, 0.75, 1.0, 1.5, and 2.0 hours. Additional sample time points included 1.0, 4.0, and 12 hours.

The coated (intact and flat) treated tablets were tested in vitro using ethanol/SGF medium containing 0% and 40% ethanol to evaluate alcohol extractability. The test was performed using a USP type 1 device (basket) at 100 rpm in 900 ml of simulated gastric fluid (SGF) without enzymes at 37°C.

Samples were analyzed using high performance reverse-phase liquid chromatography (HPLC) using a Waters Atlantis dC 18 with a dimension of 3.0 150 mm, 3 µm column, using a mobile phase consisting of a mixture of acetonitrile and a nonbasic potassium phosphate buffer solution (No. pH 3), UV detector at 230 nM. Sample time points included 0.5, 0.75, 1.0, 1.5, and 2.0 hours.

The treated discs were subjected to a breaking strength test by applying a maximum force of 439 Newtons using a Schleuniger Model 6 device to evaluate the resistance to breakage.

The treated tablets were subjected to high pressure using a Carver manual bench press (hydraulic unit model #3912) to detect physical tampering of flattening of tablets. The treated discs were subjected to an additional fracture resistance test by applying 10 hand strikes of a hammer to detect tamper resistant.

The treated, coated tablets were subjected to a stability test by storing them in 100 count bottles at different storage conditions (25°C/60% relative humidity or 40°C/75% relative humidity) for a specified period of time, and sequentially testing the tablets in the laboratory as described above. Storage time points include the initial sample (i.e. before storage), one month, two months, three months, and six months of storage. Sample time points for the dissolution test include 1.0, 4.0, and 12.0 hours.

The treated, coated tablets were subjected to an additional stability test by storing them in 100 count bottles at different storage conditions (25°C/60% relative humidity or 40°C/75% relative humidity) for a specified period of time, and sequentially subjecting the tablets to an assay test to determine the oxycodone content. Hydrochloride in tablet samples in percentage relative to that declared on the label. Sample time points in relation to storage include the initial sample (i.e. before storage), one month, two months, three months, and six months of storage. In the assay test, oxycodone hydrochloride was extracted from two batches of ten tablets each using 900 ml of a 1:2 mixture of acetonitrile and simulated gastric fluid without SGF enzymes under constant magnetic stirring in a 1000 ml volumetric flask until the tablets were completely dispersed or all night long. Sample solutions were diluted and analyzed using reversed-phase HPLC with a Waters Atlantis dC18 3.0 250 mm, 5 µm column, held at 60°C using a mobile phase consisting of acetonitrile and a buffer solution with monobasic potassium phosphate at pH. 3 with a UV detector at 280 nm.

The coated cured tablets were subjected to an additional stability test by storing them in 100 count bottles at different storage conditions (25°C/60% relative humidity or 40°C/75% relative humidity) for a specified period of time, and sequentially subjecting the tablets to the oxycodone-N-test. oxide (ONO) to determine the percentage content of the breakdown product oxycodone-N-oxide relative to that declared on the oxycodone hydrochloride label. Sample time points in relation to storage include the initial sample (i.e. before storage), one month, two months, three months, and six months of storage. In the ONO test, oxycodone hydrochloride and its degradation products were extracted from a batch of ten tablets using 900 mL of a 1:2 mixture of acetonitrile and simulated gastric fluid (SGF) enzymes under constant magnetic stirring in a beaker. Volume 1000 ml until the tablets are completely dispersed or overnight. Sample solutions were diluted and analyzed using reversed-phase HPLC with a Waters Atlantis dC18 3.0 250 mm, 5 µm column, held at 60°C using a mobile phase consisting of acetonitrile and a buffer solution with monobasic potassium phosphate at pH 3. With a UV detector at 206 nm.

The results are presented in Tables 7-1 to 7-3.

Table No. (7-1-1)

Example No. 7-1

Intact (n=10)

Flat (n=3)

(shed 6803.89 kg)

Disc dimensions

Weight(mg)

205

207

204

Thickness (mm)

5.95

1.01 1

0.96 1

% fish

17.0

16.1

Diameter(mm)

7.02

17.13 2

17.35 2

Breaking strength (Newton)

≤438 3

Diameter (mm) after fracture resistance test

5.84

Hammer test

before and after

Measured disc thickness(mm)

before

after

6.04

2.96

5.95

3.10

6.03

3.32

Salim

Salim

flat

flat

SGF

40% EtOH

SGF

40% EtOH

Dissolution

(which was launched%)

(n=3)

0.5 hours

11

9

17

13

0.75 hours

15

12

23

18

1.0 hours

20

16

28

21

1.5 hours

27

21

36

29

2.0 hours

34

27

44

35

Salim

Dissolution

(which was launched%)

(n=6)

0.5 hours

-

1 hour

22

2 hour

-

4 hour

57

8 hour

-

12 hour

97

1 3 measurements per disc.

2 Two measurements per disc

3 The discs did not break when subjected to a maximum force of 438 Newtons.

Table No. 7-1-2

Stability tests, Example No. 7-1

Storage conditions (m/RH%) and storage time1

Initial

Month

40/75

Two months

40/75

3 Months

25/60

3 Months

40/75

Solubility(released%)

(n=6)

SGF

1 hour

22

21

21

20

21

4 hour

57

57

58

56

58

12 hour

97

98

98

97

97

Assay test

%oxycodonehydrochloride2

Assay 1

96.6

96.2

97.3

97.1

95.0

Assay 2

95.3

97.2

95.7

98.7

96.0

Average

96.0

96.7

96.5

97.9

95.5

ONO test

(oxycodone N-oxide%)2

0.02

0.06

0.06

0.04

0.05

1 [month(s)]; 2 As advertised on the oxycodone hydrochloride label.

Table No. 7-2-1

Example No. 7-2

Intact (n = 10)

flat (n=3)

(9071.80 kg shed)

Disc dimensions

Weight(mg)

154

154

153

Thickness (mm)

4.68

0.75 1

0.77 1

% fish

16.0

16.5

Diameter(mm)

7.02

17.14 2

16.90 2

Breaking strength (Newton)

438 3

Diameter (mm) after fracture resistance test

4.93

Hammer test

before and after

Measured disc thickness(mm)

before

after

4.73

2.65

4.64

2.95

4.67

2.60

Salim

Salim

flat

flat

SGF