Controlled release hydrocodone formulations

WO 01/32148 PCT/US00/29953

CONTROLLED RELEASE HYPROCODONE FORMULATIONS

BACKGROUND OF THE INVENTION

Due to the difficulties presented by the pharmacotherapy of pain, particularly chronic pain, opioid analgesics are ideal drugs to be administered as controlled release formulations. The present invention relates to a solid, controlled-release oral dosage form for use in the treatment of pain.

It is the intent of all controlled (slow) release formulations to provide a longer period of pharmacological action after administration than is ordinarily obtained after administration of immediate-release dosage forms. Such longer periods of response provide for many therapeutic benefits that are not achieved with corresponding short acting, immediate release preparations. Thus, therapy may be continued without interrupting the sleep of the patient, which is of special importance, for example, when treating a patient for moderate to severe pain (e.g., a post-surgery patient, a cancer patient, etc.), or for those patients who experience migraine headaches on awakening, as well as for the debilitated patient for whom sleep is essential.

Unless conventional rapid acting drug therapy is carefully administered at frequent intervals to maintain effective steady state plasma concentrations of the drug, peaks and valleys in the plasma level of the active drug occurs because of the rapid absorption, systemic excretion of the compound and through metabolic inactivation, thereby producing special problems in maintenance therapy of the patient. A further general advantage of longer acting drug preparations is improved patient compliance resulting from the avoidance of missed doses through patient forgetfulness.

Il is known in the pharmaceutical art to prepare compositions which provide for controlled release of pharmacologically active substances contained in the compositions after oral administration to humans and animals. Such slow release compositions are used to delay absorption of a medicament until it has reached certain portions of the alimentary tract. Such controlled release of a medicament in the alimentary tract further maintains a desired concentration of said medicament in the blood stream for a longer duration than would occur if conventional rapid release dosage forms are administered.

The prior art teaching of the preparation and use of compositions providing the controlled release of an active compound from a carrier is basically concerned with the release of the active 1 WO 01/32148 PCT/US00/29953 substance into the physiologic fluid of the alimentary tract. However, it is generally recognized that the mere presence of an active substance in the gastrointestinal fluids does not, by itself, ensure bioavailability.

In order to be absorbed, the active drug substance must be in solution. The time required for a given proportion of an active substance from a unit dosage form is determined as the proportion of the amount of active drug substance released from a unit dosage form over a specified time base by a test method conducted under standardized conditions. The physiologic fluids of the gastrointestinal tract are the media for determining dissolution time. The present state of the art recognizes many satisfactory test procedures to measure dissolution time for pharmaceutical compositions, and these test procedures are described in official compendia worldwide.

Although there are many diverse factors which influence the dissolution of a drug substance from its carrier, the dissolution time determined for a pharmacologically active substance from the specific composition is relatively constant and reproducible. Among the different factors which may affect the dissolution time are the surface area of the drug substance presented to the dissolution solvent medium, the pH of the solution, the solubility of the substance in the specific solvent medium, and the driving forces of the saturation concentration of dissolved materials in the solvent medium. Thus, the dissolution concentration of an active drug substance is dynamically modified in its steady state as components are removed from the dissolution medium through absorption across the tissue site. Under physiologic conditions, the saturation level of the dissolved materials is replenished from the dosage form reserve to maintain a relatively uniform and constant dissolution concentration in the solvent medium providing for a steady state absorption.

The transport across a tissue absorption site of the gastrointestinal tract is influenced by the Donnan osmotic equilibrium forces on both sides of the membrane since the direction of the driving force is the difference between the concentrations of active substance on either side of the membrane, i.e., the amount dissolved in the gastrointestinal fluids and the amount present in the blood. Since the blood concentrations are constantly being modified by dilution, circulatory changes, tissue storage, metabolic conversion and systemic excretion, the flow of active materials is directed from the gastrointestinal tract into the blood stream.

Various techniques have been used to prepare controlled release dosage forms. Specially coated pellets, tablets and capsules wherein the slow release of the active medicament is brought about through selective breakdown of the coating of the preparation or through compounding 2 WO 01/32148 209703/2 PCT/US00/29953 with a special matrix to affect the release of a drug are known in the art. Certain controlled release formulations provide for related sequential release of a single dose of an active compound at predetermined periods after administration.

Specific examples of controlled release opioid formulations reported in the patent literature include, for example, those disclosed in U.S. Patent Nos. 4,990,341 and 4,844,909 (Goldie, et al.), both assigned to the assignee of the present invention? describe hydromorphone compositions wherein the dissolution rate in-vitro of the dosage form, when measured by the USP Paddle or Basket Method at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C, is between 12.5 and 42.5% (by wt) hydromorphone released after 1 hour, between 25 and 55% (by wt) released after 2 hours, between 45 and 75% (by wt) released after 4 hours and between 55 and 85% (by wt) released after 6 hours, the in-vitro release rate being independent of pH between pH 1.6 and 7.2 and chosen such that the peak plasma concentration of hydromorphone obtained in-vivo occurs between 2 and 4 hours after administration of the dosage form. At least 12 hours of pain relief is obtained with these hydromorphone formulations.

It is considered highly desirable to provide controlled-release dosage formulations of other opioid analgesic drugs which can be used for moderate pain. It is further considered highly desirable to provide such controlled-release formulations with pharmacokinetic properties which provide the most effective pain management inpatients in need of pain therapy.

SUMMARY OF THE INVENTION

It is an object ofthe present invention to substantially improve the efficiency and quality of pain management in human patients experiencing moderate pain.

It is an object of the present invention to provide bioavailable hydrocodone formulations that substantially improve the efficiency and quality of pain management.

It is yet another obj ect of the present invention to provide bioavailable controlled-release hydrocodone formulations which provide a substantially increased duration of effect as compared to immediate release hydrocodone formulations, but which provide an early onset of analgesia.

It is a further object of the invention to provide orally administrable controlled release opioid formulations suitable for twice-a-day administration which provide an early onset of therapeutic effect and which, after rising to a maximum concentration during the dosage interval, provide a relatively flat serum plasma profile, meaning that the plasma level of the opioid 3 WO 01/32148 PCT/USO0/29953 provides a ratio of 0.55 to 0.85, and which provides effective pain relief to the patient.

In alternate embodiments, the dosage form provides a ratio of 0.65 to 0.75

The above objects and others are attained by virtue of the present invention, which in certain embodiments, provides a solid oral controlled-release dosage form comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof and a sufficient amount of a controlled release material to render the dosage form suitable for twice-a-day administration, the dosage form after single administration to a human patient or a population of patients, providing a time to peak plasma concentration of hydrocodone in-vivo, preferably at from about 2 to about 8 hours (Tmax), and after attaining a maximum concentration, providing a C^/C^ ratio of 0.55 to 0.85.

In certain preferred embodiments, the controlled release dosage form provides an in-vitro release of from 18% to about 42.5% by weight of the hydrocodone or salt thereof from the dosage form at one hour when measured by the USP Basket Method at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) for 55 minutes at 37°C and thereafter switching to 900 ml of Simulated Intestinal Fluid (SIF) at 37°C.

In certain preferred embodiments, the dissolution rate in-vitro of the hydrocodone dosage form when measured by the USP Basket method at 100 rpm in 900 ml aqueous buffer at a pH of 1.2 and 7.5 at 37°C is from about 25 to about 65% by weight of the hydrocodone or salt thereof released after 2 hours, from about 45 to about 85% by weight of the hydrocodone or salt thereof released after 4 hours, and greater than about 60% by weight of the hydrocodone or salt thereof released after 8 hours. Although the in-vitro release rate may be either pH-independent or pH-dependent as desired, in preferred embodiments of the invention the release of hydrocodone is pH-independent.

In certain preferred embodiments, there is provided a controlled release dosage form comprising a therapeutically effective amount of hydrocodone wherein the dosage form provides a hydrocodone plasma plasma concentration of at least 5 or 6 ng/ml, at 12 hours after administration and provides a plasma plasma concentration of at least about 8 ng/ml at from about 2 to about 8 hours after administration.

In other preferred embodiments of the invention, there is provided a twice-a-day oral controlled release dosage form of hydrocodone which provides a Cmax of hydrocodone which is less than about 50% of the Cmax of an equivalent dose of an immediate release hydrocodone reference formulation (e.g. Lortab®), and which provides effective analgesia during the 12 hour dosage interval. 4 WO 01/32148 PCT/US00/29953

In other preferred embodiments of the invention, there is provided a twice-a-day controlled release dosage form of hydrocodone wherein the dosage form provides a time to 80% Cmax which is from about 90% to about 150%, preferably from about 90% to about 110%, of the time to 80% Cmax of an equivalent dose of immediate release hydrocodone reference formulation (e.g. Lortab). Preferably, the time to 80% Cmax of hydrocodone for the controlled release dosage form being from about 0.5 to about 1.5 hours, most preferably from about 0.8 to about 1.2 hours. In alternate embodiments, the time to 80% Cmax of hydrocodone for the controlled release dosage form is from about 0.75 to about 2.0 hours, most preferably from about 0.9 to about 1.5 hours.

In other preferred embodiments of the invention, there is provided a twice-a-day controlled release dosage form of hydrocodone wherein the dosage form provides a time to 90% Cmax which is about 150% to about 400%, preferably from about 150% to about 250%, of the time to 90% Cmax of an equivalent dose of immediate release hydrocodone reference formulation. Preferably, the time to 90% Cmax of hydrocodone for the controlled release dosage form is from about 1.5 to about 2.5 hours, most preferably from about 1.8 to about 2.2 hours. In alternate embodiments, the time to 90% Cmax of hydrocodone for the controlled release dosage form is from about 1.5 to about 4.0 hours, most preferably from about 1.8 to about 2.5 hours .

In other preferred embodiments of the invention, there is provided a twice-a-day controlled release dosage form of hydrocodone wherein the dosage form maintains a plasma concentration within 80% of Cmax from about 0.5 to 10 hours, preferably from about 1 to about 9 hours or from about 4 to about 8 hours.

In other preferred embodiments of the invention, there is provided a twice-a-day controlled release dosage form of hydrocodone which maintains a plasma plasma concentration of hydrocodone within 90% of Cmax from about 1 to 6.5 hours, preferably from about 2 to about 5 hours or from about 2 to about 6.5 hours.

In other preferred embodiments of the invention, there is provided a twice-a-day controlled release dosage form of hydrocodone which provides a mean in-vivo absoiption rate from administration to Tmax from about 1.5 mg/hour to about 5 mg/hour and provides a mean rate of absorption from Tmax to the end of the dosing interval which is less than about 0.5 mg/hour based on oral administration of a dosage form containing 15 mg hydrocodone bitaitrate. Preferably, the dosage form provides a mean in-vivo absorption rate from administration to Tmax from about 2 mg/hour to about 4 mg/hour and provides a mean in-vivo absorption rate Tmax to the end of the 12 hour dosing interval which is from about 0.08 mg/hour to about 0.4 5 WO 01/32148 209703/2 FCT/US00/29953 mg/hour based on oral administration of a dosage form containing 15 mg hydrocodone bitartrate.

In other preferred embodiments of the invention, there is provided a twice-a-day oral controlled release hydrocodone dosage form which provides a rate of absorption during the time period from Tmax to about 12 hours after oral administration of the dosage form which is from about 55% to about 85% of the rate of elimination during the same time period.

The above embodiments of the invention, as well as other embodiments, preferably provide a time to Tmax at a time point 3 to 4 times later than the Tmax provided by an equivalent dose of an immediate release hydrocodone reference. Preferably, the Tmax provided by the sustained release formulation occurs at from about 2 to about 8 hours, from about 3 to about 7 hours or from about 4 to about 6 hours after oral administration.

The present invention is further directed to hydrocodone formulations which provide a Cmax of hydrocodone which is less than about 50%, preferably less than about 40% of the Cmax provided by an equivalent dose of an immediate release reference product.

For example, it was surprisingly discovered that when hydrocodone is formulated in the delivery system as disclosed in U.S. Patent Nos: 4,861,598 and 4,970,075, the Cmax of hydrocodone provided by the delivery system as a percentage of the Cmax of an immediate release reference product was considerably lower than the same calculation for oxycodone formulated in the same delivery system. This phenomena is evident, regardless of the fact that the controlled release oxycodone and hydrocodone formulations exhibited similar in-vitro dissolution parameters.

When the present invention is formulated using the delivery systems U.S. Patent Nos: 4,861,598 and 4,970,075, the Cmax of the delivery system as a percentage of the Cmax of the immediate release reference product is less than about 50%, and less than 40% in preferred embodiments, whereas oxycodone, exhibits a calculation of greater than 50%. ‘Hydrocodone" is defined for purposes of the invention as including hydrocodone free base, as well as pharmaceutically acceptable salts and complexes of hydrocodone.

The term “USP Paddle or Basket Method" is the Paddle and Basket Method described, e.g„ in U.S. Pharmacopoeia XXII (1990).

The term “pH-dependent” for purposes of the present invention is defined as having characteristics (e.g. dissolution) which vary according to environmental pH.

The term “pH-independent” for purposes of the present invention is defined as having characteristics (e.g., dissolution) which are substantially unaffected by pH.

The term "bioavailability” is defined for purposes of the present invention as the extent to 6 WO 01/32148 PCT/USOO/29953 which the drug (e.g., hydrocodone) is absorbed from the unit dosage forms.

The term "controlled-release" is defined for purposes of the present invention as the release of the drug (e.g., hydrocodone) at such a rate that blood (e.g., plasma) concentrations are maintained within the therapeutic range but below toxic concentrations over a period of time of about 12 hours or longer.

The term “Cmax” denotes the maximum plasma concentration obtained during the dosing interval.

The term “Tmax” denotes the time to maximum plasma concentration (Cmax).

The term T I a (abs) denotes the amount of time necessary for one-half of the absorbable dose of opioid to be transferred to plasma.

The term "steady state" means that a plasma concentration for a given drug has been achieved and which is maintained with subsequent doses of the drug at a concentration which is at or above the minimum effective therapeutic concentration and is below the minimum toxic plasma concentration for a given drug. For opioid analgesics, the minimum effective therapeutic concentration will be a partially determined by the amount of pain relief achieved in a given patient. It will be well understood by those skilled in the medical art that pain measurement is highly subjective and great individual variations may occur among patients.

The terms "maintenance therapy" and "chronic therapy" are defined for purposes of the present invention as the drug therapy administered to a patient after a patient is titrated with an opioid analgesic to a steady state as defined above.

The term “minimum effective analgesic concentration” or “MEAC” with respect to concentrations of opioids such as hydrocodone is very difficult to quantify. However, there is generally a minimally effective analgesic concentration of plasma hydrocodone below which no analgesia is provided. While there is an indirect relationship between, e.g., plasma hydrocodone levels and analgesia, higher and prolonged plasma levels are generally associated with superior pain relief. There is a lag time or hysteresis, between the time of peak plasma hydrocodone levels and the time of peak drug effects. This holds true for the treatment of pain with opioid analgesics in general.

The term “mean resonance time" (MRT) is defined as the average time a drug molecule stays in the body. This calculation, which is a function of absorption, distribution and elimination, is dependent in part, on the dosage form containing the active ingredient. 7 WO 01/32148 PCT/US00/29953

For purposes ofthe invention, unless further specified, the term "a patient11 means that the discussion (or claim) is directed to the pharmacokinetic parameters of an individual patient or subject.

The term “population of patients” means that the discussion (or claim) is directed to the mean pharmacokinetic parameters of at least two patients or subjects.

The term “breakthrough pain" means pain which the patient experiences despite the fact that the patient is being administered generally effective amounts of the sustained release solid oral dosage forms of the invention containing hydromorphone.

The term “rescue" refers to a dose of an analgesic which is administered to a patient experiencing breakthrough pain.

The term “effective pain management" means an obj ective evaluation of a human patient’s response (pain experienced versus side effects) to analgesic treatment by a physician as well as subjective evaluation of therapeutic treatment by the patient undergoing such treatment. One skilled in the art will understand that effective analgesia will vary according to many factors, including individual patient variability.

The term “immediate release hydrocodone reference formulation” for purposes of the present invention, is an equivalent amount of the hydrocodone portion of Lortab®, commercially available from UCB Pharma, Inc, or a pharmaceutical product that provides an immediate release of hydrocodone or a salt thereof.

For purposes of the invention, the controlled release formulations disclosed herein and the immediate release control formulations are dose proportional. In such formulations, the pharmacokinetic parameters (e.g. AUC and Cmax) increase linearly from one dosage strength to another. Therefore the pharmacokinetic parameters of a particular dose can be inferred from the parameters of a different dose of the same formulation.

For purposes of the invention, unless otherwise specified, the pharmacokinetic parameters disclosed herein are based on the administration of a single dose of a hydrocodone formulation to an individual patient. Pharmacokinetic parameters based on a patient population will be specified as “mean” data.

The term “first administration” means a single dose of the present invention at the initiation of therapy to an individual patient or a patient population.

The controlled-release oral solid dosage forms ofthe present invention surprisingly may be opioid-sparing. It is possible that the controlled-release oral solid dosage forms of the present invention may be dosed at a substantially lower daily dosage in comparison to conventional 8 WO 01/32148 209703/2 PCT/US00/29953 immediate-release products, with no difference in analgesic efficacy. At comparable daily dosages, greater efficacy may result with the use of the controlled-release oral solid dosage forms of the present invention in comparison to conventional immediate-release products.

BRIEF DESCRIPTION OF THE DRAWINGS

The figures attached herewith are illustrative of embodiments of the invention and are not meant to limit the scope of the invention as encompassed by the claims.

Figure 1 is a graphical representation of the mean hydrocodone plasma concentration of Example 1, Example 2, Example 3 and an equivalent dose of immediate release hydrocodone.

Figure 2 is a graphical representation of the mean plasma concentration of Example 1, Example 2 and Example 3, against different samples of controlled release oxycodone manufactured in accordance with the procedures of Example 4, and different samples of controlled release morphine manufactured in accordance with the procedures of Example 5.

Figure 3 is a graphical representation of the % fraction hydrocodone absorbed over time of Example 1, Example 2, Example 3 and an equivalent dose of immediate release hydrocodone.

DETAILED DESCRIPTION

The above embodiments of the invention can be provided by a wide variety of controlled release formulations known to those skilled in the art. For example, suitable controlled release dosage forms are disclosed in U.S. Patent Nos: 4,861,598 and 4,970,075.

In certain embodiments of the present invention, an effective amount of opioid in immediate release form is included in the formulation. The immediate release form of the opioid is included in an amount which is effective to shorten the time to maximum concentration of the opioid in the blood (e.g., plasma), such that the T„„ is shortened to a time of, e.g., from about 2 to about 5 hours, or from about 2 to about 4 hours. It has been discovered that by including such an effective amount of immediate release opioid in the unit dose, the experience of relatively higher levels of pain in patients is significantly reduced. In such embodiments, an effective amount of the opioid in immediate release form may be coated onto the substrates of the present invention. For example, where the extended release opioid from the formulation is due to a controlled release coating, the immediate release layer would be overcoated on top of the 9 WO 01/32148 PCT/US00/29953 controlled release coating. On the other hand, the immediate release layer may be coated onto the surface of substrates wherein the opioid is incorporated in a controlled release matrix. Where a plurality of the sustained release substrates comprising an effective unit dose ofthe opioid (e.g., multiparticulate systems including pellets, spheres, beads and the like) are incorporated into a hard gelatin capsule, the immediate release portion ofthe opioid dose may be incorporated into the gelatin capsule via inclusion of the sufficient amount of immediate release opioid as a powder or granulate within the capsule. Alternatively, the gelatin capsule itself may be coated with an immediate release layer of the opioid. One skilled in the art would recognize still other alternative manners of incorporating the immediate release opioid portion into the unit dose. Such alternatives are deemed to be encompassed by the appended claims.

One advantage of the opioid dosage forms of the present invention is that therapeutic concentrations are generally achieved substantially without significant increases in the intensity and/or degree of concurrent side effects, such as nausea, vomiting, or drowsiness, which are often associated with high blood concentrations of opioids. There is also evidence to suggest that the use of the present dosage forms lead to a reduced risk of drug addiction.

ACTIVE AGENT

The controlled release oral dosage forms of the present invention preferably include from about 0.5 mg to about 1250 mg hydrocodone or an equivalent amount of a pharmaceutically acceptable salt thereof. In more preferred embodiments, the dosage form can include from about 5 mg to about 60 mg, e.g. 15 mg. Suitable pharmaceutically acceptable salts of hydrocodone include hydrocodone bitartrate, hydrocodone bitartrate hydrate, hydrocodone hydrochloride, hydrocodone p-toluenesulfonate, hydrocodone phosphate, hydrocodone thiosemicarbazone, hydrocodone sulfate, hydrocodone trifluoroacetate, hydrocodone hemipentahydrate, hydrocodone pentafluoropropionate, hydrocodone p-nitrophenylhydrazone, hydrocodone o-methyloxime, hydrocodone semicarbazone, hydrocodone hydrobromide, hydrocodone mucate, hydrocodone oleate, hydrocodone phosphate dibasic, hydrocodone phosphate monobasic, hydrocodone inorganic salt, hydrocodone organic salt, hydrocodone acetate trihydrate, hydrocodone bis(heptafuorobutyrate), hydrocodone bis(methylcarbamate), hydrocodone bis(pentafluoropropionate), hydrocodone bis(pyridine carboxylate), hydrocodone bis(trifluoroacetate), hydrocodone chlorhydrate, and hydrocodone sulfate pentahydrate. Preferably, the hydrocodone is present as the bitartrate salt. 10 WO 01732148 209703/2 PCTZUSOO/29953

The dosage forms of the present invention may further include one or more additional drugs which may or may not act synergistically with the hydrocodone analgesics of the present invention. Examples of such additional drugs include non-steroidal anti-inflammatory agents, including ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, caiprofen, oxaprozin, pramoprofen, muroprofen, trioxapro-fen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and the like. Such non-steroidal anti-inflammatory agents also include cyclo-oxygenase inhibitors such as celecoxib (SC-58635), DUP-697, flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid (6-MNA), Vioxx (MK-966), nabumetone (prodrug for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, and T-614. as amantadine (1-aminoadamantine), and memantine (3,5 dimethylaminoadamantone), their mixtures and pharmaceutically acceptable salts thereof.

Other additional drugs include nontoxic NMDA receptor antagonists such dextrorphan, dextromethorphan, 3-(l-naphthalennyl)-5-(phosphonomethyl)-L-phenylaIanine, 3-(1-naphthalenyl)-5-(phosphonomethyl)-DL-phenylalanine, 1 -(3,5-dimethylphenyl)naphthalene, and 2-(3,5-dimethylphenyl) naphthalene, 2SR,4RS-4-(((lH-Tetrazol-5-yl)methyl)oxy)piperidine-2-carboxylic acid; 2SR,4RS-4-((((lH-Tetrazol-5-yl)methyl)oxy)methyl)piperidine-2-carboxylic acid; E and Z 2SR-4-(0-(lH-Tetrazol-5-yl)methyl)ketoximino)piperidine-2-carboxylic acid; 2SR,4RS-4-((lH-Tetrazol-5-yl)thio)piperidine-2-carboxylicacid; 2SR,4RS-4-((lH-Tetrazol-5-yl)thio)piperidine-2-carboxyIic acid; 2SR,4RS-4-(5-mercapto-lH-Tetrazol-l-yl)piperidine-2-carboxylic acid; 2SR,4RS-4-(5-mercapto-2H-Tetrazol-2-yl)piperidine-2-carboxylic acid; 2SR,4RS-4-(5-mercapto-lH-Tetrazol-l-yl)piperidine-2-carboxylic acid; 2SR,4RS-4-(5-mercapto-2H-Tetrazol-2-yl)piperidine-2-caiboxyiic acid; 2SR,4RS-4-(((lH-Tetrazol-5-yl)thio)methyl)piperidine-2-carboxylic acid; 2SR,4RS-4-((5-mereapto-lH-Tetrazol-l-yl)methyl)piperidine-2-carboxylic acid; or 2SR,4RS-4-((5-mercapto-2H-Tetrazol-2-yl)methyl)piperidine-2-carboxylic acid, their mixtures and pharmaceutically acceptable salts thereof.

Other suitable additional drugs which may be included in the dosage forms of the present invention include acetaminophen, aspirin, neuro-active steroids (such as those disclosed in U.S. Serial No. 6,048,848 issued on April 11,2000) andothernon- 11

WO 01Z3214S PCTfUSOO/29953 opioid analgesics.

For example, if a second (non-opioid) drug is included in the formulation, such drug may be included in contro lied release form or in immediate release form. The additional drag may be incorporated into the controlled release matrix along with the opioid; incorporated into the controlled release coating; incorporated as a separated controlled release layer or immediate release layer; or may be incorporated as a powder, granulation, etc., in a gelatin capsule with the substrates of the present invention.

In certain preferred embodiments of the present invention, an effective amount of hydrocodone in immediate release form is included in the controlled release unit dose hydrocodone formulation to be administered. The immediate release form ofthe hydrocodone is included in an amount which is effective to shorten the time to Cmax of the hydrocodone in the blood (e.g., plasma). In such embodiments, an effective amount ofthe hydrocodone in immediate release form may be coated onto the substrates of the present invention. For example, where the extended release hydrocodone from the formulation is due to a controlled release coating, the immediate release layer would be overcoated on top of the controlled release coating. On the other hand, the immediate release layer may be coated onto the surface of substrates wherein the hydrocodone is incorporated in a controlled release matrix. Where a plurality of the sustained release substrates comprising an effective unit dose of the hydrocodone (e.g., multiparticulate systems including pellets, spheres, beads and the like) are incorporated into a hard gelatin capsule, the immediate release portion of the opioid dose may be incorporated into the gelatin capsule via inclusion of the sufficient amount of immediate release hydrocodone as a powder or granulate within the capsule. Alternatively, the gelatin capsule itself may be coated with an immediate release layer of the hydrocodone. One skilled in the art would recognize still other alternative manners of incorporating the immediate release hydromorphone portion into the unit dose. Such alternatives are deemed to be encompassed by the appended claims. It has been discovered that by including such an effective amount of immediate release hydrocodone in the unit dose, the experience of relatively higher levels of pain in patients is significantly reduced.

DOSAGE FORMS

The controlled-release dosage form may optionally include a controlled release material which is incorporated into a matrix along with the hydrocodone, or which is applied as a sustained release coating over a substrate comprising the drug (the term “substrate” 12 WO 01/32148 PCT/USOO/29953 encompassing beads, pellets, spheroids, tablets, tablet cores, etc). The controlled release material may be hydrophobic or hydrophilic as desired. The oral dosage form according to the invention may be provided as, for example, granules, spheroids, pellets (hereinafter collectively referred to as “multiparticulates”). An amount of the multiparticulates which is effective to provide the desired dose of opioid over time may be placed in a capsule or may be incorporated in any other suitable oral solid form, e.g., compressed into a tablet. On the other hand, the oral dosage form according to the present invention may be prepared as a tablet core coated with a controlled-release coating, or as a tablet comprising a matrix of drug, controlled release material, and optionally other pharmaceutically desirable ingredients (e.g., diluents, binders, colorants, lubricants, etc.).

CONTROLLED RELEASE MATRIX FORMULATIONS

In certain preferred embodiments of the present invention, the controlled-release formulation is achieved via a matrix (e.g, a matrix tablet) which includes a controlled-release material as set forth above. A dosage form including a controlled-release matrix provides in-vitro dissolution rates of the opioid within the preferred ranges and that releases the opioid in a pH-dependent or pH-independent manner. The materials suitable for inclusion in a controlled-release matrix will depend on the method used to form the matrix. The oral dosage form may contain between 1 % and 80% (by weight) of at least one hydrophilic or hydrophobic controlled release material. A non-limiting list of suitable controlled-release materials which may be included in a controlled-release matrix according to the invention include hydrophilic and/or hydrophobic materials, such as gums, cellulose ethers, acrylic resins, protein derived materials, waxes, shellac, and oils such as hydrogenated castor oil, hydrogenated vegetable oil. However, any pharmaceutically acceptable hydrophobic or hydrophilic controlled-release material which is capable of imparting controlled-release of the opioid may be used in accordance with the present invention. Preferred controlled-release polymers include alkylcelluloses such as ethylcellulose, acrylic and methacrylic acid polymers and copolymers, and cellulose ethers, especially hydroxyalkylcelluloses (especially hydroxypropylmethylcellulose) and carboxyalkylcelluloses. Preferred acrylic and methacrylic acid polymers and copolymers include methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, amino alkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid 13 WO 01/32148 PCT/US00/299S3 alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. Certain preferred embodiments utilize mixtures of any of the foregoing controlled-release materials in the matrices of the invention.

The matrix also may include a binder. In such embodiments, the binder preferably contributes to the controlled-release of the hydrocodone from the controlled-release matrix.

Preferred hydrophobic binder materials are water-insoluble with more or less pronounced hydrophilic and/or hydrophobic trends. Preferably, the hydrophobic binder materials useful in the invention have a melting point from about 30 to about 200°C, preferably from about 45 to about 90°C. When the hydrophobic material is a hydrocarbon, the hydrocarbon preferably has a melting point of between 25° and 90°C. Of the long chain (C8-C50) hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The oral dosage form may contain up to 80% (by weight) of at least one digestible, long chain hydrocarbon.

Preferably, the oral dosage form contains up to 80% (by weight) of at least one polyalkylene glycol. Specifically, the hydrophobic binder material may comprise natural or synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fatty acids, including but not limited to fatty acid esters, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic aid, stearyl alcohol and hydrophobic and hydrophilic materials having hydrocarbon backbones. Suitable waxes include, for example, beeswax, glycowax, castor wax and camauba wax. For purposes of the present invention, a wax-like substance is defined as any material which is normally solid al room temperature and has a melting point of from about 30 to about 100°C.

Preferred hydrophobic binder materials which may be used in accordance with the present invention include digestible, long chain (C8-C5O, especially C ,2-C ^), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils, natural and synthetic waxes and polyalkylene glycols. Hydrocarbons having a melting point of between 25° and 90°C are preferred. Of the long- chain hydrocarbon binder materials, fatty (aliphatic) alcohols are preferred in certain embodiments. The oral dosage form may contain up to 80% (by weight) of at least one digestible, long chain hydrocarbon.

In certain preferred embodiments, a combination of two or more hydrophobic binder materials are included in the matrix formulations. If an additional hydrophobic binder material is included, it is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures of the same. Examples include beeswax, camauba wax, stearic acid and stearyl 14 WO 01/32148 PCT/USOO/29953 alcohol. This list is not meant to be exclusive.

One particular suitable controlled-release matrix comprises at least one water soluble hydroxyalkyl cellulose, at least one C!2-C36, preferably C14-C22, aliphatic alcohol and, optionally, at least one polyalkylene glycol. The hydroxyalkyl cellulose is preferably a hydroxy (C, to C6) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose. The amount of the at least one hydroxyalkyl cellulose in the present oral dosage form will be determined, inter alia, by the precise rate of opioid release required. The aliphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In particularly preferred embodiments of the present oral dosage form, however, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The amount of the aliphatic alcohol in the present oral dosage form will be determined, as above, by the precise rate of opioid release required. It will also depend on whether at least one polyalkylene glycol is present in or absent from the oral dosage form. In the absence of at least one polyalkylene glycol, the oral dosage form preferably contains between 20% and 50% (by wt) of the aliphatic alcohol. When a polyalkylene glycol is present in the oral dosage form, then the combined weight of the aliphatic alcohol and the polyalkylene glycol preferably constitutes between 20% and 50% (by wt) of the total dosage.

In one preferred embodiment, the ratio of, e.g., the at least one hydroxyalkyl cellulose or acrylic resin to the at least one aliphatic alcohol/ polyalkylene glycol determines, to a considerable extent, the release rate of the opioid from the formulation. A ratio of the hydroxyalkyl cellulose to the aliphatic alcohol/poly alkylene glycol of between 1:2 and 1:4 is preferred, with a ratio of between 1:3 and 1:4 being particularly preferred.

The polyalkylene glycol may be, for example, polypropylene glycol or, which is preferred, polyethylene glycol. The number average molecular weight of the at least one polyalkylene glycol is preferred between 1,000 and 15,000 especially between 1,500 and 12,000.

Another suitable controlled-release matrix comprises an alkylcellulose (especially ethylcellulose), a C,2 to C36 aliphatic alcohol and, optionally, a polyalkylene glycol.

In addition to the above ingredients, a controlled-release matrix may also contain suitable quantities of other materials, e.g., diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art.

In order to facilitate the preparation of a solid, controlled-release oral dosage form according to this invention there is provided, in a further aspect of the present invention, a process for the preparation of a solid, controlled-release oral dosage form according to the present 15 209703/2 PCT/USOO/29953 WO 01/32148 invention comprising incorporating opioids or a salt thereof in a controlled-release matrix. Incorporation in the matrix may be effected, for example, by (a) forming granules comprising at least one hydrophobic and/or hydrophilic material as set forth above (e.g., a water soluble hydroxyalkyl cellulose) together with the hydrocodone; (b) mixing the at least one hydrophobic and/or hydrophilic material- containing granules with at least one Ct2-C36 aliphatic alcohol, and (c) optionally, compressing and shaping the granules.

The granules may be formed by any of the procedures well-known to those skilled in the art of pharmaceutical formulation. For example, in one preferred method, the granules may be formed by wet granulating hydroxyalkyl cellulose/opioid with water. In a particularly preferred embodiment of this process, the amount of water added during the wet granulation step is preferably between 1.5 and 5 times, especially between 1.75 and 3.5 times, the dry weight of the opioid.

The matrices of the present invention may also be prepared via a melt pellitization technique. In such circumstance, the opioid in finely divided form is combined with a binder (also in particulate form) and other optional inert ingredients, and thereafter the mixture is pelletized, e.g., by mechanically working the mixture in a high shear mixer to form the pellets (granules, spheres). Thereafter, the pellets (granules, spheres) may be sieved in order to obtain pellets of the requisite size. The binder material is preferably in particulate form and has a melting point above about 40° C. Suitable binder substances include, for example, hydrogenated castor oil, hydrogenated vegetable oil, other hydrogenated fats, fatty alcohols, fatty acid esters, fatty acid glycerides, and the like.

Controlled-release matrices can also be prepared by, e.g., melt-granulation or melt-extrusion techniques. Generally, melt-granulation techniques involve melting a normally solid hydrophobic binder material, e.g. a wax, and incorporating a powdered drug therein. To obtain a controlled release dosage form, it may be necessary to incorporate a hydrophobic controlled release material, e.g. ethylcellulose or a water-insoluble acrylic polymer, into the molten wax hydrophobic binder material. Examples of controlled-release formulations prepared via melt-granulation techniques are found, e.g., in U.S. Patent No. 4,861,598, assigned to the Assignee of the present invention.

The additional hydrophobic binder material may comprise one or more water-insoluble wax-like thermoplastic substances possibly mixed with one or more wax-like thermoplastic substances being less hydrophobic than said one or more water-insoluble wax-like substances. In 16 209703/2 PCTZUS00/29953 WO 0102148 order to achieve controlled release, the individual wax-like substances in the formulation should be substantially non-degradable and insoluble in gastrointestinal fluids during the initial release phases. Useful water-insoluble wax-like binder substances may be those with a water-solubility that is lower than about 1:5,000 (w/w).

In addition to the above ingredients, a controlled release matrix may also contain suitable quantities of other materials, e.g., diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art in amounts up to about 50% by weight of the particulate if desired. The quantities of these additional materials will be sufficient to provide the desired effect to the desired formulation.

Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms are described in the Handbook of Phannaceutical Excipients, American Pharmaceutical Association (1986).

The preparation of a suitable melt-extruded matrix according to the present invention may, for example, include the steps of blending the opioid analgesic, together with a controlled release material and preferably a binder material to obtain a homogeneous mixture. The homogeneous mixture is then heated to a temperature sufficient to at least soften the mixture sufficiently to extrude the same. The resulting homogeneous mixture is then extruded, e.g., using a twin-screw extruder, to form strands. The extrudate is preferably cooled and cut into multiparticulates by any means known in the art. The strands are cooled and cut into multiparticulates. The multiparticulates are then divided into unit doses. The extrudate preferably has a diameter of from about 0.1 to about 5 mm and provides controlled release of the therapeutically active agent for a time period of from about 8 to about 24 hours.

An optional process for preparing the melt extrusioned formulations of the present invention includes directly metering into an extruder a hydrophobic controlled release material, a therapeutically active agent, and an optional binder material; heating the homogenous mixture; extruding the homogenous mixture to thereby form strands; cooling the strands containing the homogeneous mixture; cutting the strands into particles having a size from about 0.1 mm to about 12 mm; and dividing said particles into unit doses. In this aspect of the invention, a relatively continuous manufacturing procedure is realized.

Plasticizers, such as those described hereinabove, may be included in melt-extruded matrices. The plasticizer is preferably included as from about 0.1 to about 30% by weight of the matrix. Other phannaceutical excipients, e.g., talc, mono or poly saccharides, colorants, flavorants, lubricants and the like may be included in the controlled release matrices of the 17 209703/2 PCT/US00/29953 WO 01/32148 present invention as desired. The amounts included will depend upon the desired characteristic to be achieved.

The diameter of the extruder aperture or exit port can be adjusted to vary the thickness of the extruded strands. Furthermore, the exit part of the extruder need not be round; it can be oblong, rectangular, etc. The exiting strands can be reduced to particles using a hot wire cutter, guillotine, etc. A melt extruded multiparticulate system can be, for example, in the form of granules, spheroids or pellets depending upon the extruder exit orifice. For purposes of the present invention, the terms "melt-extruded multiparticulate(s)" and "melt-extruded multiparticulate system(s)" and "melt-extruded particles" shall refer to a plurality of units, preferably within a range of similar size and/or shape and containing one or more active agents and one or more excipients, preferably including a hydrophobic controlled release material as described herein. Preferably the melt-extruded multiparticulates will be of a range of from about 0.1 to about 12 mm in length and have a diameter of from about 0.1 to about 5 mm. In addition, it is to be understood that the melt-extruded multiparticulates can be any geometrical shape within this size range, such as, simply by way of example, beads, seeds, pellets, etc. Alternatively, the extrudate may simply be cut into desired lengths and divided into unit doses of the therapeutically active agent without the need of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared that include an effective amount of melt-extruded multiparticulates within a capsule. For example, a plurality of the melt-extruded multiparticulates may be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by gastric fluid.

In another preferred embodiment, a suitable amount of the multiparticulate extrudate is compressed into an oral tablet using conventional tableting equipment using standard techniques. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980),

In yet another preferred embodiment, the extrudate can be shaped into tablets as set forth in U.S. Patent No. 4,957,681 (Klimesch, et. al.), described in additional detail above

Optionally, the controlled-release matrix multiparticulate systems or tablets can be coated, or the gelatin capsule can be further coated, with a controlled release coating such as the controlled release coatings described above. Such coatings preferably include a sufficient amount of hydrophobic and/or hydrophilic controlled-release material to obtain a weight gain 18 WO 01/32148 PCT/US00/29953 level from about 2 to about 25 percent, although the overcoat may be greater depending upon, e.g., the physical properties of the particular opioid analgesic used and the desired release rate, among other things.

The dosage forms of the present invention may further include combinations of melt-extruded multiparticulates containing one or more opioid analgesics. Furthermore, the dosage forms can also include an amount of an immediate release therapeutically active agent for prompt therapeutic effect. The immediate release therapeutically active agent may be incorporated, e.g., as separate pellets within a gelatin capsule, or may be coated on the surface of, e.g., beads or melt extruded multiparticulates. The unit dosage forms of the present invention may also contain a combination of, e.g., controlled release beads and matrix multiparticulates to achieve a desired effect.

The controlled-release formulations ofthe present invention preferably slowly release the therapeutically active agent, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids. The controlled-release profile of the melt-extruded formulations of the invention can be altered, for example, by varying the amount of controlled-release material, by varying the amount of plasticizer relative to other matrix constituents, hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc.

In other embodiments of the invention, melt-extruded formulations are prepared without the inclusion of the therapeutically active agent, which is added thereafter to the extrudate. Such formulations typically will have the therapeutically active agent blended together with the extruded matrix material, and then the mixture would be tableted in order to provide a slow release formulation. Such formulations may be advantageous, for example, when the therapeutically active agent included in the formulation is sensitive to temperatures needed for softening the hydrophobic material and/ or the retardant material.

Typical melt-extrusion production systems suitable for use in accordance with the present invention include a suitable extruder drive motor having variable speed and constant torque control, start-stop controls, and ammeter. In addition, the production system will include a temperature control console which includes temperature sensors, cooling means and temperature indicators throughout the length ofthe extruder. In addition, the production system will include an extruder such as twin-screw extruder which consists of two counter-rotating intermeshing screws enclosed within a cylinder or barrel having an aperture or die at the exit thereof. The feed materials enter through a feed hopper and are moved through the barrel by the screws and are forced through the die into strands which are thereafter conveyed such as by a continuous 19 WO 01/32148 PCT/USOO/29953 movable belt to allow for cooling and being directed to a pelletizer or other suitable device to render the extruded ropes into the multiparticulate system. The pelletizer can consist of rollers, fixed knife, rotating cutter and the like. Suitable instruments and systems are available from distributors such as C.W. Brabender Instruments, Inc. of South Hackensack, New Jersey. Other suitable apparatus will be apparent to those of ordinary skill in the art. A further aspect of the invention is related to the preparation of melt-extruded multiparticulates as set forth above in a manner which controls the amount of air included in the extruded product. By controlling the amount of air included in the extrudate, it has been surprisingly found that the release rate of the therapeutically active agent from the, e.g., multiparticulate extrudate, can be altered significantly. In certain embodiments, it has been surprisingly found that the pH dependency of the extruded product can be altered as well.

Thus, in a further aspect of the invention, the melt-extruded product is prepared in a manner which substantially excludes air during the extrusion phase of the process. This may be accomplished, for example, by using a Leistritz extruder having a vacuum attachment. It has been surprisingly found that extruded multiparticulates prepared according to the invention using the Leistritz extruder under vacuum provides a melt-extruded product having different physical characteristics. In particular, the extrudate is substantially non-porous when magnified, e.g., using a scanning electron microscope which provides an SEM (scanning electron micrograph). Contrary to conventional thought, it has been found that such substantially non-porous formulations provide a faster release of the therapeutically active agent, relative to the same formulation prepared without vacuum. SEMs of the multiparticulates prepared using an extruder under vacuum appear very smooth, and the multiparticulates tend to be more robust than those multiparticulates prepared without vacuum. It has been observed that in at least certain formulations, the use of extrusion under vacuum provides an extruded multiparticulate product which is more pH-dependent than its counterpart formulation prepared without vacuum.

PROCESSES FOR PREPARING MATRIX BEADS

Controlled-release dosage forms according to the present invention may also be prepared as matrix beads formulations. The matrix beads include a spheronising agent and the hydrocodone. 20 WO 01/32148 PCT/USOO/29953

The hydrocodone preferably comprises from about 0.01 to about 99 % by weight of the matrix bead by weight. It is preferable that the hydrocodone is included as about 0.1 to about 50 % by weight of the matrix bead.

Spheronising agents which may be used to prepare the matrix bead formulations of the present invention include any art-known spheronising agent. Cellulose derivatives are preferred, and microcrystaliine cellulose is especially preferred. A suitable microcrystaliine cellulose is, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Corporation). The spheronising agent is preferably included as about 1 to about 99% of the matrix bead by weight.

In addition to the active ingredient and spheronizing agent, the spheroids may also contain a binder. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water soluble hydroxy lower alkylcellulose, such as hydroxypropylcellulose, are preferred.

In addition to the opioid analgesic and spheronising agent, the matrix bead formulations of the present invention may include a controlled release material such as those described hereinabove. Preferred controlled-release materials for inclusion in the matrix bead formulations include acrylic and methacrylic acid polymers or copolymers, and ethylcellulose. When present in the formulation, the controlled-release material will be included in amounts of from about 1 to about 80% of the matrix bead, by weight. The controlled-release material is preferably included in the matrix bead formulation in an amount effective to provide controlled release of the opioid analgesic from the bead.

Pharmaceutical processing aids such as binders, diluents, and the like may be included in the matrix bead formulations. Amounts of these agents included in the formulations will vary with the desired effect to be exhibited by the formulation.

The matrix beads may be overcoated with a controlled-release coating including a controlled-release material such as those described hereinabove. The controlled-release coating is applied to a weight gain of from about 5 to about 30 %. The amount of the controlled-release coating to be applied will vary according to a variety of factors, e.g., the composition of the matrix bead and the chemical and/or physical properties of the opioid analgesic (i.e., hydrocodone).

Matrix beads are generally prepared by granulating the spheronising agent together with the opioid analgesic, e.g. by wet granulation. The granulate is then spheronized to produce the matrix beads. The matrix beads are then optionally overcoated with the controlled release coating by methods such as those described hereinabove. 21 WO 01/32148 PCT/USOO/29953

Another method for preparing matrix beads, for example, by (a) forming granules comprising at least one water soluble hydroxyalkyl cellulose and opioid or an opioid salt; (b) mixing the hydroxyalkyl cellulose containing granules with at least one C12 - C16 aliphatic alcohol; and (c) optionally, compressing and shaping the granules. Preferably, the granules are foimed by wet granulating the hydroxyalkyl cellulose/opioid with water. In a particularly preferred embodiment of this process, the amount of water added during the wet granulation step is preferably between 1.5 and 5 times, especially between 1.75 and 3.5 times, the dry weight of the opioid.

In yet other alternative embodiments, a spheronizing agent, together with the active ingredient can be spheronized to form spheroids. Microcrystalline cellulose is preferred. A suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Corporation). In such embodiments, in addition to the active ingredient and spheronizing agent, the spheroids may also contain a binder. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water soluble hydroxy lower alkyl cellulose, such as hydroxy propyl cellulose, are preferred. Additionally (or alternatively) the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose. In such embodiments, the sustained-release coating will generally include a water insoluble material such as (a) a wax, either alone or in admixture with a fatty alcohol; or (b) shellac or zein.

CONTROLLED RELEASE BEAD FORMULATIONS

In one especially preferred embodiment, the oral dosage form comprises an effective number of controlled release spheroids contained within a gelatin capsule.

In another preferred embodiment of the present invention, the controlled-release dosage form comprises spheroids containing the active ingredient coated with a controlled-release coating including a controlled release material. The term spheroid is known in the pharmaceutical art and means, e.g., a spherical granule having a diameter of between 0.1 mm and 2.5 mm, especially between 0.5 mm and 2 mm.

The spheroids are preferably film coated with a controlled release material that permits release of the opioid (or salt) at a controlled rate in an aqueous medium. The film coat is chosen so as to achieve, in combination with the other stated properties, the in-vitro release rate outlined 22 WO 01/32148 PCT/US00/29953 above (e.g., at least about 12.5% released after 1 hour). The controlled-release coating formulations of the present invention preferably produce a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack-free.

COATINGS

The dosage forms of the present invention may optionally be coated with one or more coatings suitable for the regulation of release or for the protection of the formulation. In one embodiment, coatings are provided to permit either pH-dependent or pH-independent release, e.g., when exposed to gastrointestinal fluid. When a pH-independent coating is desired, the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid, e.g., the GI tract. Other preferred embodiments include a pH-dependent coating that releases the opioid in desired areas of the gastro-intestinal (GI) tract, e.g., the stomach or small intestine, such that an absorption profile is provided which is capable of providing at least about twelve hour and preferably up to twenty-four hour analgesia to a patient. It is also possible to formulate compositions which release a portion of the dose in one desired area of the GI tract, e.g., the stomach, and release the remainder of the dose in another area of the GI tract, e.g,, the small intestine.

Formulations according to the invention that utilize pH-dependent coatings may also impart a repeat-action effect whereby unprotected drug is coated over an enteric coat and is released in the stomach, while the remainder, being protected by the enteric coating, is released further down the gastrointestinal tract. Coatings which are pH-dependent may be used in accordance with the present invention include a controlled release materia] such as, e.g., shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate, and methacrylic acid ester copolymers, zein, and the like.

In another preferred embodiment, the present invention is related to a stabilized solid controlled dosage form comprising an opioid coated with a hydrophobic controlled release material selected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof. The coating may be applied in the form of an organic or aqueous solution or dispersion.

In certain preferred embodiments, the controlled release coating is derived from an aqueous dispersion of the hydrophobic controlled release material. The coated substrate containing the opioid(s) (e.g., a tablet core or inert pharmaceutical beads or spheroids) is then 23 WO 0102148 209703/2 PCT/US00Z29953 cured until an endpoint is reached at which the substrate provides a stable dissolution. The curing endpoint may be determined by comparing the dissolution profile (curve) of the dosage form immediately after curing to the dissolution profile (curve) of the dosage form after exposure to accelerated storage conditions of, e.g., at least one month at a temperature of 40°C and a relative humidity of 75%. These formulations are described in detail in U.S. Patent Nos. 5,273,760 and 5,286,493, assigned to the Assignee of the present invention? ' Other examples of controlled-release formulations and coatings which may be used in accordance with the present invention include Assignee's U.S. Patent Nos. 5,324,351; 5,356,467, and 5,472,712,

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

In certain embodiments, it is necessary to overcoat the substrate comprising the opioid analgesic with a sufficient amount of the aqueous dispersion of e.g,, alkylcellulose or acrylic polymer, to obtain a weight gain level from about 2 to about 50%, e.g., about 2 to about 25% in order to obtain a controlled-release formulation. The overcoat may be lesser or greater depending upon the physical properties of the therapeutically active agent and the desired release rate, the inclusion of plasticizer in the aqueous dispersion and the manner of incorporation of the same, for example.

ALKYLCELLULOSE POLYMERS

Cellulosic materials and polymers, including alkylcelluloses are controlled release materials well suited for coating the substrates, e.g., beads, tablets, etc. according to the invention. Simply by way of example, one preferred alkylcellulosic polymer is ethylcellulose, although the artisan will appreciate that other cellulose and/or alkylcellulose polymers may be readily employed, singly or on any combination, as all or part of a hydrophobic coatings according to the invention.

One commercially-available aqueous dispersion of ethylcellulose is Aquacoat® (FMC Corp., Philadelphia, Pennsylvania, U.S.A.). Aquacoat® is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, die organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not incorporated in the pseudolatex during the manufacturing phase. Thus, prior to using the 24 WO 01/32148 PCT/US00/29953 same as a coating, it is necessary to intimately mix the Aquacoat® with a suitable plasticizer prior to use.

Another aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc., West Point, Pennsylvania, U.S.A.). This product is prepared by incorporating plasticizer into the dispersion during the manufacturing process. A hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates.

ACRYLIC POLYMERS

In other preferred embodiments of the present invention, the controlled release material comprising the controlled-release coating is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. in certain preferred embodiments, the acrylic polymer is comprised of one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.

In order to obtain a desirable dissolution profile, it may be necessary to incorporate two or more ammonio methacrylate copolymers having differing physical properties, such as different molar ratios of the quaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparing pH-dependent coatings which may be used in accordance with the present invention. For example, there are a family of copolymers synthesized from diethylaminoethyl methacrylate and other neutral methacrylic esters, also known as methacrylic acid copolymer or polymeric methacrylates, commercially available as Eudragit® from Rohm Tech, Inc. There are several different types of Eudragit®. For example, Eudragit E is an example of a methacrylic acid copolymer which swells and dissolves in acidic media. Eudragit L is a methacrylic acid copolymer which does not swell 25 WO 01/32148 PCT/US00/29953 at about pH < 5.7 and is soluble at about pH > 6. Eudragit S does not swell at about pH < 6.5 and is soluble at about pH > 7. Eudragit RL and Eudragit RS are water swellable, and the amount of water absorbed by these polymers is pH-dependent, however, dosage forms coated with Eudragit RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D, respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. The mean molecular weight is about 150,000. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixed together in any desired ratio in order to ultimately obtain a controlled-release formulation having a desirable dissolution profile. Desirable controlled-release formulations may be obtained, for instance, from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Of course, one skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, Eudragit® L.

PLASTICIZERS

In embodiments of the present invention where the coating comprises an aqueous dispersion of a hydrophobic controlled release material, the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic material will further improve the physical properties of the controlled-release coating. For example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is preferable to incorporate a plasticizer into an ethylcellulose coating containing controlled-release coating before using the same as a coating material. Generally, the amount of plasticizer included in a coating solution is based on the concentration ofthe film-former, e.g., most often from about 1 to about 5 0 percent by weight of the film-former. Concentration of the plasticizer, however, can only be properly determined after careful experimentation with the 26 WO 01/32148 PCT/USOO/29953 particular coating solution and method of application.

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

Examples of suitable plasticizers for the acrylic polymers of the present invention include, but are not limited to citric acid esters such as tri ethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. Other plasticizers which have proved to be suitable for enhancing the elasticity of the films formed from acrylic films such as Eudragit® RL/RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacelin. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.

It has further been found that the addition of a small amount of talc to the controlled release coating reduces the tendency of the aqueous dispersion to stick during processing, and acts as a polishing agent.

PREPARATION OF COATED BEAD FORMULATIONS

When an aqueous dispersion of hydrophobic material is used to coat substrates, e.g., inert pharmaceutical beads such as nu pariel 18/20 beads, a plurality of the resultant stabilized solid controlled-release beads may thereafter be placed in a gelatin capsule in an amount sufficient to provide an effective controlled-release dose when ingested and contacted by an environmental fluid, e.g., gastric fluid or dissolution media.

The stabilized controlled-release bead formulations of the present invention slowly release the opioid analgesic, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids. The controlled-release profile of the formulations of the invention can be altered, for example, by varying the amount of overcoating with the aqueous dispersion of hydrophobic controlled release material, altering the manner in which the plasticizer is added to the aqueous dispersion of hydrophobic controlled release material, by varying the amount of plasticizer relative to hydrophobic controlled release material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc. The dissolution profile of the ultimate product may also be modified, for example, by increasing or decreasing the 27 WO 01/32148 PCT/US00/29953 thickness of the controlled release coating.

Substrates coated with a therapeutically active agent are prepared, e.g. by dissolving the therapeutically active agent in water and then spraying the solution onto a substrate, for example, nu panel 18/20 beads, using a Wuster insert. Optionally, additional ingredients are also added prior to coating the beads in order to assist the binding of the opioid to the beads, and/or to color the solution, etc. For example, a product which includes hydroxypropyl methylcellulose, etc. with or without colorant (e.g., Opadry®, commercially available from Colorcon, Inc.) may be added to the solution and the solution mixed (e.g., for about 1 hour) prior to application of the same onto the substrate. The resultant coated substrate may then be optionally overcoated with a barrier agent, to separate the therapeutically active agent from the hydrophobic controlled-release coating.

An example of a suitable barrier agent is one which comprises hydroxypropyl methylcellulose. However, any film-former known in the art may be used. Il is preferred that the barrier agent does not affect the dissolution rate of the final product.

The substrates may then be overcoated with an aqueous dispersion of the hydrophobic controlled release material. The aqueous dispersion of hydrophobic controlled release material preferably further includes an effective amount of plasticizer, e.g. triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose, such as Aquacoat® or Surelease®, may be used. If Surelease® is used, it is not necessary to separately add a plasticizer. Alternatively, pre-formulated aqueous dispersions of acrylic polymers such as Eudragit® can be used.

The coating solutions of the present invention preferably contain, in addition to the film-former, plasticizer, and solvent system (i.e., water), a colorant to provide elegance and product distinction. Color may be added to the solution of the therapeutically active agent instead, or in addition to the aqueous dispersion of hydrophobic material. For example, color can be added to Aquacoat® via the use of alcohol or propylene glycol based color dispersions, milled aluminum lakes and opacifiers such as titanium dioxide by adding color with shear to water soluble polymer solution and then using low shear to the plasticized Aquacoat®. Alternatively, any suitable method of providing color to the formulations of the present invention may be used. Suitable ingredients for providing color to the formulation when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and color pigments, such as iron oxide pigments. The incorporation of pigments, may, however, increase the retard effect of the coating.

The plasticized aqueous dispersion of hydrophobic controlled release material may be applied onto the substrate comprising the therapeutically active agent by spraying using any 28 WO 01/32148 209703/2 PCT/USOO/29953 suitable spray equipment known in the art. In a preferred method, a Wurster fluidized-bed system is used in which an air jet, injected from underneath, fluidizes the core material and effects drying while the acrylic polymer coating is sprayed on. A sufficient amount of the aqueous dispersion of hydrophobic material to obtain a predetermined controlled-release of said therapeutically active agent when said coated substrate is exposed to aqueous solutions, e.g. gastric fluid, is preferably applied, taking into account the physical characteristics of the therapeutically active agent, the manner of incorporation of the plasticizer, etc. After coating with the hydrophobic controlled release material, a further overcoat of a film-former, such as Opadry®, is optionally applied to the beads. This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads.

The release of the therapeutically active agent from the controlled-release formulation of the present invention can be further influenced, i.e., adjusted to a desired rate, by the addition of one or more release-modifying agents, or by providing one or more passageways through the coating. The ratio of hydrophobic controlled release material to water soluble material is determined by, among other factors, the release rate required and the solubility characteristics of the materials selected.

The release-modifying agents which function as pore-formers may be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use. The pore-formers may comprise one or more hydrophilic materials such as hydroxypropylmethylcellulose.

The controlled-release coatings of the present invention can also include erosion-promoting agents such as starch and gums.

The controlled-release coatings of the present invention can also include materials useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain.

The release-modifying agent may also comprise a semi-permeable polymer. In certain preferred embodiments, the release-modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing.

The controlled-release coatings of the present invention may also include an exit means comprising at least one passageway, orifice, or the like. The passageway may be formed by such methods as those disclosed in U.S. Patent Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864.

The passageway can have any shape such as round, triangular, square, elliptical, irregular, etc. 29 WO 01/32148 209703/2 PCT/US00/29953

Another method of producing controlled release bead formulations suitable for about 24-hour administration is via powder layering. U.S. Patent No. 5,411,745, assigned to the Assignee of the present invention, teaches preparation of 24-hour morphine formulations prepared via powder layering techniques utilizing aprocessing aid consisting essentially of hydrous lactose impalpable. The powder-layered beads are prepared by spraying an aqueous binder solution onto inert beads to provide a tacky surface, and subsequently spraying a powder that is a homogenous mixture of morphine sulfate and hydrous lactose impalpable onto the tacky beads. The beads are then dried and coated with a hydrophobic material such as those described hereinabove to obtain the desired release of drug when the final formulation is exposed to environmental fluids. An appropriate amount of the controlled release beads are then, e.g. encapsulated to provide a final dosage form which provides effective plasma concentrations of morphine for about 12 hours.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the present invention. They are not meant to be construed to limit the claims in any manner whatsoever.

Example 1

Hydrocodone sustained release tablets were produced with the formula set forth in Table 1 below:

Table 1

Ingredients Amt/Unit (mg) Amount/Batch (gm) Hydrocodone Bitartrate 15.0 150.0 Spray Dried Lactose 56.0 560.0 Povidone 4.0 40.0 Eudragit RS30D (solids) 10.0 100.0 Triacetin 2.0 20.0 Stearyl Alcohol 20.0 200.0 Talc 2.0 20.0 Magnesium Stearate 1.0 10.0 Total 110.0 1100.0

According to the following procedure: 1. Retardant dispersion: Blend Eudragit RS30D and Triacetin using a lightnin mixer. 2. Melt Stearyl Alcohol. 3. Spray retardant dispersion onto Hydrocodone Bitartrate, Spray Dried Lactose, and 30 WO 01/32148 PCT/USOO/29953

Povidone using a fluid bed granulator. 4. Dry batch on a stainless steel tray for 15 minutes, or till constant weight. 5. Incorporate the melted Stearyl Alcohol into the batch using a Hobart mixer. 6. Dry waxed granulation on a stainless steel tray for 30 minutes, or temperature of granulation reaches 3 5 °C or less. 7. Mill the cooled granulation through a CoMil. 8. Lubricate the granulation with talc and magnesium stearate using a Hobart Mixer. 9. Compress the granulation into tablets using a tablet press.

The tablets were then tested for dissolution using the following procedure: 1. Apparatus: USP Method I (basket), 100 rpm. 2. Medium: 700 ml SGF for 55 min, thereafter 900 ml of SIF without enzyme 3. Sampling time: 1,2,4,8 and 12 hours. 4. Analytical: High Performance Liquid Chromatography.

The dissolution parameters are set forth in Table II below:

Table II

Time (Hours) % Dissolved 1 39.7 2 51.5 4 67.4 8 86.4 12 96.1

The Cmax and Tmax were then obtained for Example 1 and an immediate release reference standard in a bioavailability study comparing hydrocodone 15 mg administered as an immediate release formulation (Lortab 7.5 mg X 2) to the above CR formulation in healthy human subjects, as set forth in Table III below:

Table III

Pharmacokinetic data Hydrocodone Bitartrate Cmax (ng/ml) IR reference product 35.4 Cmax (ng/ml) CR product 13.4 Cmax (CR)/Cmax (IR) 38% Tmax (hr) IR reference product 1.32 Tmax( hr) CR product 4.07 31

Example 2

Hydrocodone sustained release tablets were produced with the formula set forth in

Table IV below: WO 01/32148 PCT/USOO/29953

Table IV

Ingredients Amt/Unit (mg) Amt/Batch (g) Hydrocodone Bitartrate 15.0 150.0 Spray Dried Lactose 51.0 510.0 Povidone 4.0 40.0 Eudragit RS30D (solids) 10.0 100.0 Triacetin 2.0 20.0 Stearyl Alcohol 25.0 250.0 Talc 2.0 20.0 Magnesium Stearate 1.0 10.0 1 Total 110.0 i 1100.0 according to the procedure of Example 1.

The dissolution parameters were then obtained using the procedure of Example 1. The results are set forth in table V below:

Table V

Time (Hours) % Dissolved 1 36 2 45.8 4 60.5 8 78.9 12 90.4

Example 3

Hydrocodone sustained release capsules were produced with the formula set forth in Table VI below:

Table VI

Ingredients Amt/Unit (mg) Amt/Batch (g) Hydrocodone Bitartrate 15.0 320.0 Eudragit RSPO 76.0 1520.0 Eudragit RLPO 4.0 80.0 Stearyl Alcohol 25.0 500.0 Total 120.0 2400.0 32 WO 01/32148 PCT/USOO/29953

According to the following procedure: 1. Blend milled Stearyl Alcohol, Eudragit RLPO, Hydrocodone Bitartrate, and Eudragit RSPO using a Hobart Mixer. 2. Extrude the granulation using a Powder Feeder, Melt Extruder(equipped with the 6 x 1 mm die head), Conveyor, Lasermike, and Pelletizer under the following conditions:

Zone 1 10°C Zone 2 20°C Zone 3 120°C Zone 4 120°C Zone 5 120°C Zone 6 120°C Zone 7 95°C Zone 8 95°C MGA 120°C Die 117°C

Powder feed rate-40g/min; screw speed-185 rpm; vacuum—980 mBar Conveyor-such that diameter of extrudate is 1mm Pelletizer-such that pellets are cut to 1mm in length 3. Screen pellets using #16 mesh and #20 mesh screens. Collect material that passes through the # 16 mesh screen and is retained on the #20 mesh screen. 4. Fill size #2 clear gelatin capsules with the pellets. Range: NLT 114 mg and NMT 126 mg.

The dissolution parameters were then obtained using the procedure of Example 1. The results are set forth in table VII below:

Table VII

Time (Hours) % Dissolved 1 23.9 2 34.7 4 51.7 8 74.6 12 85.2

Example 4

Oxycodone sustained release tablets were produced with the formula set forth in Table VIII below: 33 WO 01/32148 PCT/USOO/29953

Table VIII

Ingredients Amt/Unit (mg) Amount/Batch (gm) Oxycodone HCl 20.0 22.0 Spray Dried Lactose 59.25 65.175 Povidone 5.0 5.5 Eudragit RS30D (solids) 10.0 11.0 ! Triacetin 2.0 2.2 i Stearyl Alcohol 25.0 27.5 Talc 2.5 2.75 Magnesium Stearate 1.25 1.375 Opadry Pink Y-S-14518A 4.0 4.26 Total 129.0 141.76

According to the following procedure: 1. Granulation: Spray the Eudragit/Triacetin dispersion onto the Oxycodone HCl, Spray Dried Lactose and Povidone using a fluid bed granulator. 2. Milling: Discharge the granulation and pass through a mill. 3. Waxing: Melt the stearyl alcohol and add to the milled granulation using a mixer. Allow to cool. 4. Milling: Pass the cooled granulation through a mill. 5. Lubrication: Lubricate the granulation with talc and magnesium stearate using a mixer. 6. Compression: Compress the granulation into tablets using a tablet press. 7. Film coating: Apply an aqueous film coat to the tablets.

The tablets were then tested for dissolution using the following procedure: 1. Apparatus: USP Type II (paddle), 150 rpm.

2. Medium: 700 ml SGF for First hour, thereafter made 900 ml with phosphate buffer to pH 7.5. 3. Sampling time: 1,2,4,8,12, 18 and 24 hours. 4. Analytical: High Performance Liquid Chromatography.

The dissolution parameters are set forth in Table IX below:

Table IX

Time (hrs) % Dissolved 1 45 2 55 4 70 8 87 12 96 18 101 24 102

The Cmax and Tmax were then obtained for Example 4 and an immediate release reference standard in a bioavailability study, as set forth in Table X below: 34 WO 01/32148 PCT/USOO/29953

Table X

Pharmacokinetic data Oxycodone HCl Cmax (ng/ml) IR reference product 38.2 Cmax (ng/ml) CR product 21.7 Cmax (CR)/Cmax (IR) 57% Tmax (hr) IR reference product 1.10 Tmax( hr) | CR product 2.62

Example 5

Morphine sustained release tablets were produced with the formula set forth in Table XI below:

Table XI

Ingredients Amount/unit (mg) Amount/batch (kg) Morphine sulfate 30.0 138.0 Spray Dried Lactose 70.0 322.0 Hydroxyethyl cellulose 10.0 46.0 Cetostearyl alcohol 35.0 161.0 Talc 3.0 13.8 I Magnesium stearate 2.0 9.2 | Opadrv YS-1-4729 5.0 23.0 1 ToOtal 155.0 713.0

According to the following procedure: 1. Granulation: Add water to the Morphine sulfate, Spray Dried Lactose and Hydroxyethyl cellulose in a mixer and dry using a fluid bed granulator. 2. Screening: Discharge the granulation and pass through a sieve. 3. Waxing: Melt the cetostearyl alcohol and add to the nulled granulation using a mixer. Allow to cool. 4. Screening: Pass the cooled granulation through a sieve. 5. Lubrication: Lubricate the granulation with talc and magnesium stearate using a mixer, 6. Compression: Compress the granulation into tablets using a tablet press. 7. Film coating: Apply an aqueous film coat to the tablets.

The tablets were then tested for dissolution using the following procedure: 1. Apparatus: USP Method I (Basket), 50 rpm

2. Medium: 900 ml of Purified Water, 37°C 3. Sampling time: 1,2, 3, 4, and 6 hours. 4. Analytical: UV detection, 285 nm and 305 nm, 2-point method using 5-cm cell. 35 WO 01/32148 PCT/US00/29953

The dissolution parameters are set forth in Table XII below:

Table XII

Time (Hours) % Dissolved 1 34.2 2 49.9 3 64.2 4 75.5 6 90.3

The Cmax and Tmax were then obtained for Example 5 and an immediate release reference standard in a bioavailability study, as set forth in Table ΧΠΙ below:

Table XIII

Pharmacokinetic data Morphine Sulphate Cmax (ng/ml) IR reference product 22.1 Cmax (ng/ml) CR product 12 Cmax (CR)/Cmax (IR) 54% Tmax (hr) IR reference product 0.98 Tmax( hr) CR product 2.09

Example 6

The pharmakokinetic parameters of Example 1, Example 4 and Example 5 were compared to each other. It was surprisingly found that even though the dissolution of the hydrocodone HCI controlled release tablets of example 1 were very similar to the dissolution of the controlled release oxycodone tablets of example 4 and the moiphine sulfate controlled release tablets of example 5, the Cmax ratio of CR to IR for the hydrocodone formulation is 38%, whereas the oxycodone tablets and morphine tablets are over 50%. The comparative results are set forth in Table XIV below:

Table XIV

Pharmacokinetic data Hydrocodone Bitartrate Oxycodone HCI Morphine Sulphate Cmax (ng/ml) IR reference product 35.4 38.2 22.1 Cmax (ng/ml) CR product 13.4 21.7 12 Cmax (CR)/Cmax (IR) 38% 57% 54% 36 WO 01/32148 PCT/US00/29953

Tmax (hr) IR reference product 1,32 1.10 0.98 Tmax( hr) CR product 4.07 2.62 2.09

Example 7 A single dose, four treatment, open label, pharmacokinetic comparison of controlled release hydrocodone formulations of Example 1, Example 2, Example 3 and two immediate release hydrocodone bitartrate 7.5 mg/Acetaminophen 500mg tablets (IR Example) in fasted normal volunteers was conducted. The plasma concentrations for these formulations are set forth in tables 15-18 below: 37

Subject 0.5

Table 15

Hydrocodone Plasma Concentration (ng/mL) after administration of one (1) Conlrolled-RBlease Hydrocodone Bitarlrate 15 mg tablet-FomiulaUon A

Time (hours) -0.08 1 0.00 2 0.00 3 0.00 4 0 00 5 0.00 6 0.00 7 0.00 8 0.00 9 0.00 10 0.00 11 0.00 12 0.00 13 0.00 14 0.00 MEAN 0.00 SD 0.00 %CV 0.00 4.55 7 81 4.63 3.46 1.43 4.69 0.56 3.68 8.06 3.63 3.64 3.07 1.95 2.21 3.83 2.13 21.7 0.75 ΤΓΤ 8.76 7.66 9.48 4.25 7.60 1.B6 7.61 9.79 5.71 5.20 6.14 3.82 4 56 6.68 2.62 39 2 2 3 4 6 9 12 9.11 15.8 15.5 17.4 15.4 14.5 12.1 9.20 11.3 14.8 15.5 14.5 10.5 9.30 8.95 15.9 15.6 16.9 16.3 12.3 9 41 9.11 10,7 11.9 13.0 12.4 10.7 B.96 7.20 12.8 13.5 13,0 12.5 9.62 7 01 10.5 12.8 13.9 13.3 15.1 12.3 8.59 3.65 7.54 8.26 8.18 8.90 6.23 4.56 11.5 12.4 13.2 127 12.5 9 10 7,09 9.98 11.4 10.7 11,4 11.9 7 66 5.98 7.84 8.49 10.8 11.6 11.5 8.02 6.70 8.00 10 3 11.8 12.5 10.8 7.44 7.84 8.51 14.3 15.0 14.9 14.7 12.1 7.75 4.47 9.55 9.15 6.31 8.05 5.85 3.93 7.33 11 2 12 9 13.3 13.2 10.6 8.41 8.25 11.7 12.6 13.0 12.7 9.78 7.69 2.10 2.48 2 31 2.70 2.41 2.54 2.09 25.5 21.2 183 20.8 19 0 26.0 27.2 18 24 30 38 6.33 3.58 2.25 1.29 5.40 3.39 2.10 0 921 6.55 4.10 2.38 0 986 5 22 3.08 1.56 0.558 4.38 3.26 1.93 1.01 4 52 3 11 1.59 0.702 2.99 1.61 0.752 0.D0 4.33 2.93 1.24 0.509 3.85 2.10 1.12 0.573 3.34 2.33 1.31 0.00 4.75 2.21 1.11 0.00 4.34 2.52 1.69 0.859 2.45 7.68 1.35 1.07 4.68 3.11 2.35 0.978 4.51 3.22 1.62 0.675 1.15 1.44 0.513 0.425 25.5 44.7 31.7 63.0 WO 01/32148 PCT/USOO/29953

Table 16

Hydrocodone Plasma Concentration (ng/mL) after administration of one (1) Controlled-Release Hydrocodone Bltartrate 15 mg lablel-Formulalion B

Subject --- Time (hours) 4).08 0.5 0.75 1 2 3 4 6 9 12 IB X4 1 0.00 3.18 5.64 11.8 11.4 12.4 13.5 14.3 11.4 9.20 5.69 3.23 2.23 1.10 2 0.00 2.61 7.04 8.53 10.7 124 11 5 13.6 11.4 9.25 6.43 4.13 2.59 1,35 3 0.00 5.49 7 57 9.67 13.5 15.6 15.7 14.4 12.6 9 41 7.83 5.19 3.45 1.77 4 0.00 2.71 5.67 6.35 Θ.Θ0 11.3 13.7 12.0 8.72 8.10 5.50 4.33 2.63 1.26 GJ 5 0.00 3.98 6.59 7.38 10.6 11.0 11.6 9.42 6.75 4.81 5.28 3.67 2.43 1.25 to 6 0.00 0.711 2.85 7.98 12.9 13.6 13 13.0 10.1 8.04 5.17 3.71 2.33 0.940 7 0.00 1.B2 3.03 3.97 7.22 0 04 0.05 7,07 5.97 3 77 2 53 2.12 1.94 1.19 fl 0.00 2.47 3.99 6.03 10.9 13.2 13.0 12.6 9.49 7.60 6.11 4.74 2.38 0.056 g 0.00 5.02 10.4 8.48 9.06 9.90 9.88 7.96 4 70 3.99 377 3 42 1.53 0.005 10 0.00 3.20 0.17 10.7 9.0Θ 10.7 11.0 11.2 9 06 6.20 330 2.75 1.04 0.672 11 0.00 4.20 6.86 6.36 9.97 11 3 11.3 10.2 7.79 5.00 4 30 2.67 1.53 0.815 12 0.00 4.73 7.Z1 9.40 11.9 15.1 16.5 15.5 13.2 0.09 4.50 3.60 2.67 2.12 13 0.00 1.56 2.87 3.09 6.31 7.43 7.07 7.64 7.01 5.34 3.57 2.12 1.35 1.41 14 0.00 0.663 2.20 3.06 8.74 14.7 15.0 15.3 136 10.7 6.84 4.47 2.39 1.59 MEAN 0 3,02 5 76 7.46 10.1 12 12.4 11.8 9.42 7.10 5.00 3.5B 2.24 1.22 SD 0 1.53 2.45 2.53 2.03 2.45 2.61 2.81 2.77 2.27 1.48 0.943 0.556 0.400 %CV 0 50.7 42.5 33.9 20.1 20.4 21 23.8 29.4 31.6 29 1 26.3 24.0 33 4 WO 01/32148 PCT/US00/29953

Table 17

Hydrocodone Plasma Concentration (ng/mL) after administration of two (2) Immediate-Release Hydrocodone 7.5 mgf Acetaminophen 500 mg lablets-Formulation C

Subject -0.08 0.5 0.75

Time (hours) 3 4 6 9 1 0.00 2 0.00 3 0.00 4 0.00 5 0.00 6 0.00 7 0.00 8 0.00 9 0.00 10 0.00 11 0.00 12 0.00 13 0.00 14 0.00 40.6 41.6 44.3 50.7 17.6 42.3 21.2 43 3 37.4 39 3 3.17 8.67 0.900 6.76 2.97 13.7 50.0 39 3 0.627 14.8 8.46 13.3 30.6 44.4 3.73 12.2 18.0 29.7 45.4 32.1 26.3 40 1 28.6 23.3 42.6 37.8 35.4 36.5 26,9 23.5 36.1 27.9 22.4 16.3 17.5 16.9 14.7 18.3 17.1 22.2 32.4 28.8 33.7 24.2 20.1 25.2 22.4 173 29 3 31.3 24.8 44.4 40.0 30.8 17.9 19.1 19.8 35.3 30.7 26.6 22.7 15.2 9 95 20.2 15.6 9.46 31.2 21.0 130 20.7 15.4 9 39 18.1 14.1 7.91 13.8 11.3 6.52 14.1 9.66 5.52 24.2 18.3 10.9 17.0 13.0 6.84 16.5 10.9 5.90 21.0 14.0 9.43 29.1 19.9 11.3 163 13.9 8.72 23.4 16.1 9 20 12 1B 24 30 36 6 08 2.58 1.20 0.585 0.00 6 08 2.96 1.68 0.872 0.00 7 79 3.12 1.77 0.665 0.00 5.09 2.27 1.17 0.523 0 00 4.98 2.37 1.07 0.546 0.00 4.22 1.71 0.703 0.00 0.00 3.32 1.21 000 0.00 0.00 6.46 2.17 1.02 0.00 0.00 4.01 1.47 0.565 0.00 0.00 3.15 1.05 0.00 0.00 0.00 6.04 2.62 1.14 0.00 0.00 6.B6 3.15 1.47 0.634 0.00 5.43 2.51 0.706 0.00 0.00 6.24 2.60 1.27 0.556 0.00 MEAN 0.00 20.0 28.6 31.4 27.8 23.8 20.6 14.9 886 5.41 2.27 0.983 0.314 0.00 SD 0.00 17.7 16.0 10.6 6.93 5.48 5.21 3.26 2.15 1.36 0.676 0.541 0.336 0.00 %cv 0.00 88.5 55.9 33.8 24.9 23.0 25.3 21.9 24.3 25.1 29.8 55.0 107 0.00 WO 01/32148 PCT/US00/299S3

Table 1β

Hydrocodone Plasma Concentration (ng/mL) after administration οΓ one (1) Controlled-Release Hydrocodone Bitartrate 15 mg capsula-Formulatlon D

Subject -0.08 0.5 0.75 1

Time (hours) 4 6 9 12 10 24 30 36 1 0.00 2 0 00 3 0.00 4 0.00 5 0.00 6 0.00 7 0.00 8 0.00 9 0.00 10 0.00 11 o.oo 12 0.00 13 0.00 1.76 4.07 5.17 2.76 4.B3 5.13 2.91 4.25 6.01 1.69 5.93 6.26 0.616 2 74 4.47 0.663 2.40 4.07 0.00 1.55 2.32 1.26 3.03 5.15 3,36 3.63 6.30 0.692 2.91 2.95 1.11 2.87 3.28 2.25 3.31 4.72 0.00 1.29 2.71 0.33 6.17 10.1 0.29 8.58 7.50 4.61 7.26 0.31 5.11 6.02 Θ.03 5.51 9.72 10.4 12.3 8 37 9.16 10.1 6.3Θ 8.00 0.04 6.09 9.69 11.4 6.67 11.1 14.0 13.6 10.6 13.5 11.8 12.0 14.8 13.5 8.06 10.5 8.91 8.60 10.1 0.66 11.7 13.0 11.5 7,22 7.41 6.75 8.81 9.34 9.07 8.20 9 55 8 26 7.37 7,11 6 33 10.3 12.0 12 2 11.2 12.1 11.0 6.92 8.44 7.13 11.7 8.7B 6.14 3.91 1.97 10.1 6.57 3.71 2.57 1.34 11.4 7.40 4.16 2.65 1.46 0.70 4.58 2 61 1.63 0.536 6.64 4.72 257 2.05 0.986 0.30 5.38 3.88 2.39 1.25 4.02 3.10 1.72 0.984 0.578 9.28 6.81 3 31 1.93 1.25 6.49 3.72 2.25 1.92 0.901 5.67 3.76 2.76 1.43 0.573 8.81 5.76 3.25 2.10 1.08 9.75 5.64 3.51 2.71 1.34 7.01 3.99 2.41 1.04 0.8S8 14 0.00 1,02 294 4.53 8.82 105 11.7 14.1 13.0 10.2 6,37 3.56 1.93 1.61 MEAN 0.00 1.44 327 4.57 7.39 9.12 9.70 11.1 10 1 0.49 5.47 3.27 2.09 1.12 SD 0.00 1.06 1.23 1.31 1.57 1.Θ6 1.71 2.57 2 55 2.11 1.61 1.00 0,754 0.419 V.CV 0.00 73.6 37.6 28.7 21.2 20.4 17.6 23.2 25 2 24.9 29.4 33.0 36.1 37.4 WO 01/32148 PCT/US00/29953

The pharmacokinetic parameters are set forth in Table 19 below:

Table 19 WO 01/32148 PCT/USOO/29953

Mean* %Ratiobc 90%Clb Parameter Ex. 1 IREx. Ex. 1/TR Ex. Fasted Fasted Fasted Lower Upper AUC(0, last) (ng«hr/mL) 200.95 216.35 93.36 86.96 100.23 Cmax (ng/mL) 13.16 33.37 39.48 35.26 44.20 Tmax (hr) 4.07 1.32 208.11 257.17 357.80 W50 (hr) 13.41 4.67 287.38 265.91 314.15 T1/2(abs) (hr) 1.64 0.69 237.65 197.73 284.44 TVaielim) (hr) 6.44 3.09 208.78 184.43 234.20 Ex. 2 IREx. Ex. 2/IR Ex. Fasted Fasted Fasted Lower Upper AUC(0,last) (ng»hr/mL) 201.57 216.35 93.21 86.82 100.07 Cmax (ng/mL) 12.42 33.37 37.36 33.37 41.83 Tmax (hr) 4.20 1.32 317.57 262.19 362.83 W50 (hr) 13.08 4.67 280.31 257.03 305.26 T1/2(abs) (hr) 1.57 0.69 227.91 183.84 270.55 T1/z(elim) (hr) 7.86 3.09 254.85 231.54 281.31 Ex. 3 IR. Ex. Ex. 3/IR Ex. Fasted Fasted Fasted Lower Upper AUC(0,last) (ng»hr/mL) 194.40 216.35 90.28 84.09 96.92 Cmax (ng/mL) 10.93 33.37 32.69 29.20 36.60 Tmax (hr) 5.93 1.32 448.65 398.87 499.51 W50 (hr) 16.30 4.67 349.21 328.68 376.92 TVz(abs) (hr) 2.98 0.69 431.26 395.95 482.67 | TY2(elim) (hr) 6.96 3.09 225.61 200.49 250.26 ’Geometric means for AUC (0, last) and Cmax and arithmetic means for Tmax, W50, TVz(abs), and TV2(elim). bRatio and 90% Cl are based on least square means. ‘Ratio (%): (Test mean / Reference mean) x 100, based on least square means

Example 8

Hydrocodone sustained release tablets were produced with the formula set forth in Table XX below: 42 WO 01/32148 PCT/L'SOO/29953

Table XX

Ingredient — mg/tab kg/batch Hydrocodone bitartrate 15 15.0 Dibasic calcium phosphate 31 31.0 Glyceryl behenate 10 10.0 Stearyl alcohol 22 22.0 Microcrystalline cellulose 31 31.0 Magnesium stearate 1.0 1.0 Opadry Purple YS-1-10371-A 5.0 5.0 Purified water N/A1 28.33' I 115.0 mg 115.0 kg 1 Evaporates during processing and is not part of finished product.

According to the following procedure: 1. Milling: Pass stearyl alcohol flakes through a mill. 2. Blending: Mix The Hydrocodone bitartrate, Dibasic calcium phosphate, Glyceryl behenate, Stearyl alcohol and Microcrystalline cellulose with a suitable blender 3. Extrusion: Continuously feed the blended material into a twin screw extruder at an elevated temperature to soften and form an extrudate. 4. Cooling: Allow the extrudate to cool on a Conveyor. 5. Milling: Pass the cooled extrudate through a mill to obtain a suitable particle size granulation 6. Blending: Blend the milled extrudate with the magnesium stearate. 7. Compression: Compress the resultant granulation using a tablet press. 8. Coating: Prepare a film coating solution by dispersing the Opadry in Purified Water and applying it to the tablet cores.

The tablets were then tested for dissolution using the following procedure: 1. Apparatus: USP Type I (basket), 100 rpm. 2. Medium: 700 ml SGF (without enzymes) for first 55 minutes, thereafter made 900 ml with phosphate buffer to pH 7.5. 3. Sampling time: 1,2,4,8, and 12 hours. 4. Analytical: High Performance Liquid Chromatography. 43 WO 01/32148 PCT/USOO/29953

The dissolution parameters are set forth in Table XXI below:

Table XXI

Time (hrs) % Dissolved 1 22 2 37 4 58 8 84 12 99

Example 9 A 3 way crossover, pharmacokinetic comparison study of a single dose of 15 mg Hydrocodone Controlled Release Tablets (Example 8) in Fed and Fasted and of 15 mg Hydrocodone Immediate Release (2 x 7.5 mg tablets) was given over two Q6H doses in fasted normal volunteers.

The Cmax and Tmax were then obtained for Example 8 and an immediate release reference standard in a bioavailability study, as set forth in Table XXII and XXIII below:

Table XXII

Pharmacokinetic data (Fasted State) Hydrocodone Bitartrate Cmax (ng/ml) IR reference product (Dose adjusted) 43.16 Cmax (ng/ml) CR product 17.87 Cmax (CR)/Cmax (IR) 41% Tmax (hr) IR reference product 6.42 Tmax( hr) CR product 4.04 44 WO 01/32148 PCT/US00/29953

Table XXXIII

Pharmacokinetic data Hydrocodone Bitartrate CR 15 mg Tablets (Fasted) Hydrocodone Bitartrate CR 15 mg Tablets (Fed) Hydrocodone I Bitartrate IR 2 x 7.5 mg Tablets (Fasted) Cmax (ng/ml) 17.87 19.23 21.58 Cp hmtr 11.06 12.84 i C,,hnilI/Cmax 62% 67% j Tmax( hr) 4.04 4.81 6.42 1 AUC 267.43 277.58 229.33 45