111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20040170680Al
`
`(19) United States
`(12) Patent Application Publication
`Oshlack et al.
`
`(10) Pub. No.: US 2004/0170680 Al
`Sep. 2, 2004
`( 43) Pub. Date:
`
`(54) ONCE-A-DAY OXYCODONE
`FORMULATIONS
`
`(76)
`
`Inventors: Benjamin Oshlack, New York, NY
`(US); Curtis Wright, Norwalk, CT
`(US); Derek Prater, Cambridge (GB)
`
`Correspondence Address:
`DAVIDSON, DAVIDSON & KAPPEL, LLC
`485 SEVENTH AVENUE, 14TH FLOOR
`NEW YORK, NY 10018 (US)
`
`(21) Appl. No.:
`
`10/476,409
`
`(22) PCT Filed:
`
`May 2, 2002
`
`(86) PCT No.:
`
`PCT/US02/14024
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/288,211, filed on May
`2,2001.
`
`Publication Classification
`
`(51)
`Int. Cl? ............................... A61K 9/52; A61K 9/22
`(52) U.S. Cl. ............................................ 424/457; 424/468
`
`ABSTRACT
`(57)
`The invention is directed to sustained release formulations
`containing oxycodone or a pharmaceutically acceptable salt
`thereof which provide a mean C24/Cmax oxycodone ratio of
`0.6 to 1.0 or 0.7 to 1 after oral administration at steady state
`to patients and methods thereof.
`
`KASHIV1026
`IPR of Patent No. 9,492,392
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`

`

`US 2004/0170680 Al
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`1
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`Sep.2,2004
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`ONCE-A-DAY OXYCODONE FORMULATIONS
`[0001] This application claims benefit of U.S. Provisional
`Application No. 60/288,211, filed May 2, 2001, the disclo-
`sure of which is hereby incorporated by reference.
`
`FIELD OF THE INVENTION
`[0002] The invention is directed to sustained release for-
`mulations containing oxycodone or a pharmaceutically
`acceptable salt thereof which is suitable for administration to
`a patient.
`
`BACKGROUND OF THE INVENTION
`[0003] Once-a-day sustained release opioid formulations
`are disclosed in U.S. Pat. Nos. 5,478,577; 5,672,360; 5,958,
`459; 6,103,261; 6,143,332; 5,965,161; 5,958,452 and 5,968,
`551. All documents cited herein, including the foregoing, are
`incorporated by reference in their entireties for all purposes.
`
`SUMMARY AND OBJECTS OF THE
`INVENTION
`It is an object of the present invention to provide an
`[0004]
`oxycodone formulation suitable for once daily administra-
`tion for effective pain management.
`It is an object of preferred embodiments of the
`[0005]
`present invention to provide a pharmaceutically acceptable
`dosage form for orally administering oxycodone to provide
`analgesic therapy beyond its relatively short half-life over an
`extended period of time, and having a duration of pain relief
`of at least 24-hours.
`[0006] The above objects and others are attained by the
`present invention, which is directed to a dosage form com-
`prising an analgesically effective amount of oxycodone or a
`pharmaceutically acceptable salt thereof and a sustained
`release material, the dosage form providing an analgesic
`effect for at least about 24 hours after oral administration at
`steady state to human patients; and the dosage form provid-
`ing a mean C24/Cmax oxycodone ratio of 0.6 to 1.0 after oral
`administration at steady state to the patients.
`In certain embodiments of the invention, the dos-
`[0007]
`age form after administration to patients provides a mean
`T of oxycodone in-vivo which occurs at about 2 to about
`17hours (e.g., about 2 to about 8 hours) after administration
`at steady state of the dosage form.
`In certain embodiments of the invention, the mean
`[0008]
`Tmax of oxycodone in-vivo occurs at about 6.5 hours to
`about 17 hours, at about 8 to about 16 hours, at about 10 to
`about 16 hours, or at about 12 to about 16 hours after
`administration at steady state of the dosage form.
`In certain embodiments of the invention, the dos-
`[0009]
`age form provides an analgesic effect for at least about 24
`hours after administration of the dosage form to human
`patients at steady state; and provides a mean C24/Cmax
`oxycodone ratio of 0.60 to 1.0 after administration at steady
`state to patients.
`In certain embodiments of the invention, the dos-
`[0010]
`age form provides an analgesic effect for at least about 24
`hours after administration at steady state to human patients;
`and provides a mean C24/Cmax oxycodone ratio of 0.60 to
`1.0 or 0. 7 to 1.0 after administration at steady state to
`
`patients. In certain embodiments of the invention, the dosage
`form provides an in-vitro release rate, of oxycodone or a
`pharmaceutically acceptable salt thereof, when measured by
`the USP Basket Method at 100 rpm in 900 ml aqueous buffer
`at a pH of between 1.6 and 7.2 at 37° C. of from 0% to about
`40% at 1 hour, from about 8% to about 70% at 4 hours, from
`about 20% to about 80% at 8 hours, from about 30% to about
`95% at 12 hours, from about 35% to about 95% at 18 hours,
`and greater than about 50% at 24 hours.
`In certain preferred embodiments the sustained
`[0011]
`release oral dosage form of the present invention provides
`oxycodone plasma levels which are effective for 24 hourly
`dosing, characterized by a W 50 for the oxycodone of
`between 4 and 24 hours after administration at steady state.
`In certain embodiments, the W50 is at least 4 hours, prefer-
`ably at least 12 hours, and more preferably at least 18 hours,
`after administration at steady state.
`In certain embodiments the sustained release oral
`[0012]
`dosage form of the present invention comprises a matrix
`which includes a sustained release material and oxycodone
`or a pharmaceutically acceptable salt thereof. In certain
`embodiments, the matrix is compressed into a tablet and
`may be optionally overcoated with a coating that in addition
`to the sustained release material of the matrix may control
`the release of the oxycodone or pharmaceutically acceptable
`salt thereof from the formulation, such that blood levels of
`active ingredient are maintained within the therapeutic range
`over an extended period of time. In certain alternate embodi-
`ments, the matrix is encapsulated.
`In certain embodiments, the sustained release oral
`[0013]
`dosage form of the present invention comprises a plurality of
`pharmaceutically acceptable sustained release matrices
`comprising oxycodone or a pharmaceutically acceptable salt
`thereof, the dosage form maintaining the blood plasma
`levels of oxycodone within the therapeutic range over an
`extended period of time when administered to patients.
`[0014] Preferably, the formulations prepared in accor-
`dance with the present invention can be presented in tablet,
`capsule, or in any other suitable unit dosage form.
`In certain embodiments the sustained release oral
`[0015]
`dosage form of the present invention is an osmotic dosage
`form which comprises a single layer or bilayer core com-
`prising oxycodone or a pharmaceutically acceptable salt
`thereof; an expandable polymer; a semipermeable mem-
`brane surrounding the core; and a passageway disposed in
`the semipermeable membrane for sustained release of the
`oxycodone or pharmaceutically acceptable salt thereof, such
`that blood levels of active ingredient are maintained within
`the therapeutic range over an extended period of time when
`administered to patients.
`In certain embodiments the sustained release oral
`[0016]
`dosage form of the present invention comprises a substan-
`tially homogenous core comprising oxycodone or a phar-
`maceutically acceptable salt thereof and an expandable
`polymer; a semipermeable membrane surrounding the core;
`and a passageway disposed in the semipermeable membrane
`for sustained release of the oxycodone or pharmaceutically
`acceptable salt thereof, such that blood levels of active
`ingredient are maintained within the therapeutic range over
`an extended period of time when administered to a patients.
`In certain embodiments of the present invention,
`[0017]
`there is provided a method of treating pain associated
`
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`conditions in patients requmng such treatment which
`method includes administering to a patient an effective
`amount of oxycodone or a pharmaceutically acceptable salt
`thereof in a sustained release dosage form as described
`herein.
`In certain embodiments, the invention is directed to
`[0018]
`the use of a sustained release dosage form comprising a
`pharmaceutically acceptable matrix comprising oxycodone
`or a pharmaceutically acceptable salt thereof and a sustained
`release material in the production of an analgesic prepara-
`tion for oral administration to human patients on a once a
`day basis, to provide an analgesic effect for at least about 24
`hours and a mean C24/Cmax oxycodone ratio of 0.6 to 1.0
`after administration at steady state to said patients.
`In certain embodiments, the invention is directed to
`[0019]
`the use of a sustained release oral dosage form comprising
`a bilayer core comprising a drug layer comprising an anal-
`gesically effective amount of oxycodone or a pharmaceuti-
`cally acceptable salt thereof; and a displacement layer
`comprising an osmopolymer; and a semipermeable wall
`surrounding the bilayer core having a passageway disposed
`therein for the release of said oxycodone or pharmaceuti-
`cally acceptable salt thereof; in the production of an anal-
`gesic preparation for oral administration to human patients
`to provide an analgesic effect at least about 24 hours after
`oral administration at steady state to human patients; and to
`provide a mean C24/Cmax oxycodone ratio of 0.6 to 1.0 after
`administration at steady state to said patients.
`In certain embodiments, the invention is directed to
`[0020]
`the use of a sustained release dosage form comprising a
`plurality of sustained release matrices comprising oxyc-
`odone or a pharmaceutically acceptable salt thereof and a
`sustained release material, in the production of an analgesic
`preparation for oral administration to a patient on a once-
`a -day basis, to provide an analgesic effect for at least 24
`hours after oral administration at steady state to human
`patients; and to provide a mean C24/Cmax oxycodone ration
`of 0.6 to 1.0 after oral administration at steady state to said
`patients.
`[0021] The term "Cmax" as it is used herein is the highest
`plasma concentration of the drug attained within the dosing
`interval.
`[0022] The term "C24" as it is used herein is the plasma
`concentration of the drug at 24 hours after administration.
`[0023] The term "Tmax" as it is used herein is the time
`period which elapses after administration of the dosage form
`until the plasma concentration of the drug attains the highest
`plasma concentration within the dosing interval.
`[0024] The term "W 50" for purposes of the present inven-
`tion is the duration over which the plasma concentrations are
`equal to or greater than 50% of the peak concentration. The
`parameter is determined by linear interpolation of the
`observed data and represents the difference in time between
`the first (or only) upslope crossing and the last (or only)
`downslope crossing in the plasma profile.
`[0025] The term "C24/Cmax ratio" is defined for purposes
`of the present invention as the ratio of the plasma concen-
`tration of the drug at 24 hours after administration to the
`highest plasma concentration of the drug attained within the
`dosing interval.
`
`[0026] The term "USP Basket Method" is the Basket
`Method described in U.S. Pharmacopoeia XXII (1990),
`herein incorporated by reference.
`[0027] The term "steady state" means that the amount of
`the drug reaching the system is approximately the same as
`the amount of the drug leaving the system. Thus, at "steady-
`state", the patient's body eliminates the drug at appro xi-
`mately the same rate that the drug becomes available to the
`patient's system through absorption into the blood stream.
`[0028] The term "semipermeable wall" for purposes of the
`present invention means that the wall is permeable to the
`passage of an exterior fluid, such as aqueous or biological
`fluid, in the environment of use, including the gastrointes-
`tinal tract, but impermeable to drug.
`[0029] The term "expandable polymer" for purposes of the
`present invention means a polymer which upon exposure to
`an aqueous or biological fluid, absorbs the fluid resulting in
`a greater mass.
`[0030] The term "mean" for purposes of the present inven-
`tion, when used to define a pharmacokinetic value (e.g.,
`T max) represents the arithmetic mean value measured across
`a patient population.
`[0031] The phrase "pharmaceutically acceptable salt"
`includes, but is not limited to, metal salts such as sodium
`salt, potassium salt, cesium salt and the like; alkaline earth
`metals such as calcium salt, magnesium salt and the like;
`organic amine salts such as triethylamine salt, pyridine salt,
`picoline salt, ethanolamine salt, triethanolamine salt, dicy-
`clohexylamine salt, N,N'-dibenzylethylenediamine salt and
`the like; inorganic acid salts such as hydrochloride, hydro-
`bromide, sulfate, phosphate and the like; organic acid salts
`such as formate, acetate, trifluoroacetate, maleate, fumarate,
`tartrate and the like; sulfonates such as methanesulfonate,
`benzenesulfonate, p-toluenesulfonate, and the like; amino
`acid salts such as arginate, asparginate, glutamate and the
`like.
`
`DESCRIPTION OF THE INVENTION
`
`In certain embodiments of the present invention,
`[0032]
`the sustained release dosage form provides an in-vitro
`release rate of oxycodone or a pharmaceutically acceptable
`salt thereof, when measured by the USP Basket Method at
`100 rpm in 900 ml aqueous buffer at a pH of between 1.6 and
`7.2 at 37° C. of from 0% to about 40% at 1 hour, from about
`8% to about 70% at 4 hours, from about 20% to about 80%
`at 8 hours, from about 30% to about 95% at 12 hours, from
`about 35% to about 95% at 18 hrs, and greater than about
`50% at 24 hours.
`In certain embodiments of the present invention the
`[0033]
`time period during which oxycodone blood levels (after
`administration at steady state) are greater than or equal to
`75% of the maximum blood level (T "'o.?scmaJ may be 4
`hours or greater, preferably 6 hours or greater.
`In certain embodiments, the time at which oxyc-
`[0034]
`odone blood levels reach their maximum concentration
`(T maJ is about 2 to about 17 hours, preferably about 6.5
`hours to about 17 hours, more preferably about 8 to about 16
`hours, and even more preferably about 10 to about 16 or
`about 12 to about 16 hours after administration at steady
`state of the dosage form.
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`In certain embodiments of the present invention,
`[0035]
`the dosage form provides a C24/Cmax ratio after administra-
`tion at steady state of 0.6 to 1.0, a ratio 0.7 to 0.99 or a ratio
`of 0.8 to 0.95. In other embodiments of the present inven-
`tion, the dosage form provides a C24/Cmax ratio after admin-
`istration at steady state of 0.7 to 1.0, a ratio 0.72 to 0.99 or
`a ratio of 0.74 to 0.95.
`In certain embodiments of the present invention,
`[0036]
`the dosage form provides a C24/Cmax ratio after administra-
`tion at steady state of 0.6 to 1.0, a ratio 0.7 to 0.99 or a ratio
`of 0.8 to 0.95 and a (Tmax) of about 6.5 hours to about 17
`hours, about 8 to about 16 hours, about 10 to about 16 hours
`or about 12 hours to about 16 hours. In other embodiments
`of the present invention, the dosage form provides a C I
`cmax ratio after administration at steady state of 0.7 to 1.0,
`a ratio 0.72 to 0.99 or a ratio of 0.74 to 0.95 and a (Tmax) in
`about 2 to about 17 hours.
`In certain embodiments of the present invention,
`[0037]
`the co-administration of food will not significantly increase
`or decrease the extent of oxycodone absorption.
`[0038] The sustained release oral dosage form of the
`present invention includes from about 1 to about 640 mg of
`oxycodone or a pharmaceutically acceptable salt thereof
`(e.g., oxycodone hydrochloride). Preferably the sustained
`release oral dosage form of the present invention includes
`from about 5 to about 500 mg oxycodone or a pharmaceu-
`tically acceptable salt thereof, more preferably from about
`10 to about 320 mg oxycodone or a pharmaceutically
`acceptable salt thereof and even more preferably from about
`10 to about 160 mg oxycodone or a pharmaceutically
`acceptable salt thereof.
`In other preferred embodiments, the sustained
`[0039]
`release dosage form of the present invention comprises from
`about 10 to about 160 mg oxycodone hydrochloride or an
`equivalent amount of oxycodone or a pharmaceutically
`acceptable salt thereof other than the hydrochloride salt.
`[0040] The present invention includes a method for
`administering from about 1 to about 640 mg of oxycodone
`or a pharmaceutically acceptable salt thereof on a once-a-
`day basis to a patient in need of relief of pain, in accordance
`with the pharmacokinetic parameters disclosed herein. Pref-
`erably, the method includes administering from about 5 to
`about 500 mg oxycodone or a pharmaceutically acceptable
`salt thereof.
`[0041] The method of administration according to the
`present invention is particularly applicable to the treatment
`of acute and chronic pain, particularly pain associated with
`terminal disease such as cancer; chronic backpain; and
`post-operative pain.
`
`Dosage Forms
`In certain embodiments the oral dosage form
`[0042]
`includes a sustained-release material which is incorporated
`into a matrix along with the oxycodone or pharmaceutically
`acceptable salt thereof to provide for the sustained release of
`the oxycodone. The sustained-release material may be
`hydrophobic or hydrophilic as desired. The oral dosage form
`of the present invention may be prepared as granules,
`spheroids, matrix multiparticulates, etc. which comprise
`oxycodone or a pharmaceutically acceptable salt thereof in
`a sustained release matrix, which may be compressed into a
`
`tablet or encapsulated. The oral dosage form of the present
`invention may optionally include other pharmaceutically
`acceptable ingredients (e.g., diluents, binders, colorants,
`lubricants, etc.).
`In certain embodiments, the oral dosage form of
`[0043]
`the present invention may be an osmotic dosage form having
`a push or displacement composition as one of the layers of
`a bilayer core for pushing oxycodone or a pharmaceutically
`acceptable salt thereof from the dosage form, and a semi-
`permeable wall composition surrounding the core, wherein
`the wall has at least one exit means or passageway for
`delivering the oxycodone from the dosage form. Alterna-
`tively, the core of the osmotic dosage form may comprise a
`single layer core including a controlled release polymer and
`oxycodone or a pharmaceutically acceptable salt thereof.
`[0044] Preferably the dosage forms of the present inven-
`tion provide an analgesic effect for at least about 24 hours
`after administration.
`
`Sustained-Release Matrix Formulations
`
`In one preferred embodiment of the present inven-
`[0045]
`tion, the sustained release carrier may be incorporated into
`a matrix with the oxycodone or pharmaceutically acceptable
`salt thereof which matrix provides for the sustained release
`of the oxycodone.
`[0046] A non-limiting list of suitable sustained-release
`materials which may be included in a sustained-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 and hydrogenated
`vegetable oil. However, any pharmaceutically acceptable
`hydrophobic or hydrophilic sustained-release material
`which is capable of imparting sustained-release of the oxy-
`codone or pharmaceutically acceptable salt thereof may be
`used in accordance with the present invention. Preferred
`sustained-release polymers include alkylcelluloses such as
`ethylcellulose, acrylic and methacrylic acid polymers and
`copolymers; and cellulose ethers, especially hydroxyalkyl-
`celluloses (especially hydroxypropylmethylcellulose) and
`carboxyalkylcelluloses. Preferred acrylic and methacrylic
`acid polymers and copolymers include methyl methacrylate,
`methyl methacrylate copolymers, ethoxyethyl methacry-
`lates, ethyl acrylate, trimethyl ammonioethyl methacrylate,
`cyanoethyl methacrylate, aminoalkyl methacrylate copoly-
`mer, poly( acrylic acid), poly(methacrylic acid), methacrylic
`acid alkylamine copolymer, poly( methyl methacrylate),
`poly(methacrylic acid)( anhydride), polymethacrylate, poly-
`acrylamide, poly(methacrylic acid anhydride), and glycidyl
`methacrylate copolymers. Certain preferred embodiments
`utilize mixtures of any of the foregoing sustained-release
`materials in the matrix of the invention.
`[0047] The matrix also may include a binder. In such
`embodiments, the binder preferably contributes to the sus-
`tained-release of the oxycodone or pharmaceutically accept-
`able salt thereof from the sustained-release matrix.
`If an additional hydrophobic binder material is
`[0048]
`included, it is preferably selected from natural and synthetic
`waxes, fatty acids, fatty alcohols, and mixtures of the same.
`Examples include beeswax, carnauba wax, stearic acid and
`stearyl alcohol. This list is not meant to be exclusive. In
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`certain preferred embodiments, a combination of two or
`more hydrophobic binder materials are included in the
`matrix formulations.
`
`[0049] Preferred hydrophobic binder materials which may
`be used in accordance with the present invention include
`digestible, long chain (C8 -C50, especially C12-C40), substi-
`tuted 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 embodiments, the hydrophobic binder
`[0050]
`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 acid, stearyl alcohol and hydrophobic and
`hydrophilic materials having hydrocarbon backbones. Suit-
`able waxes include, for example, beeswax, glycowax, castor
`wax and carnauba wax. For purposes of the present inven-
`tion, a wax-like substance is defined as any material which
`is normally solid at room temperature and has a melting
`point of from about 30 to about 100° C. In certain preferred
`embodiments, the dosage form comprises a sustained release
`matrix comprising oxycodone or a pharmaceutically accept-
`able salt thereof and at least one water soluble hydroxyalkyl
`cellulose, at least one C12-C36, preferably C14-C22, aliphatic
`alcohol and, optionally, at least one polyalkylene glycol. The
`hydroxyalkyl cellulose is preferably a hydroxy (C1 to C6)
`alkyl cellulose, such as hydroxypropylcellulose, hydrox-
`ypropylmethylcellulose and, especially, hydroxyethyl cellu-
`lose. The amount of the at least one hydroxyalkyl cellulose
`in the present oral dosage form may be determined, inter
`alia, by the precise rate of oxycodone or oxycodone salt
`release required. The aliphatic alcohol may be, for example,
`lauryl alcohol, myristyl alcohol or stearyl alcohol. In par-
`ticularly 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 may be determined,
`as above, by the precise rate of oxycodone or oxycodone salt
`release required. It may 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
`about 20% and about 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
`about 20% and about 50% (by wt) of the total dosage form.
`
`In one preferred embodiment, the ratio of, e.g., the
`[0051]
`at least one hydroxyalkyl cellulose or acrylic resin to the at
`least one aliphatic alcoholpolyalkylene glycol determines, to
`a considerable extent, the release rate of the oxycodone or
`oxycodone salt from the formulation. In certain embodi-
`ments, a ratio of the hydroxyalkyl cellulose to the aliphatic
`
`alcohol/polyalkylene glycol of between 1:1 and 1:4 is pre-
`ferred, with a ratio of between 1:2 and 1:3 being particularly
`preferred.
`In certain embodiments, the polyalkylene glycol
`[0052]
`may be, for example, polypropylene glycol, or polyethylene
`glycol which is preferred. The average molecular weight of
`the at least one polyalkylene glycol is preferably between
`1,000 and 15,000, especially between 1,500 and 12,000.
`[0053] Another suitable sustained-release matrix com-
`prises an alkylcellulose (especially ethylcellulose ), a C12 to
`C36 aliphatic alcohol and, optionally, a polyalkylene glycol.
`In addition to the above ingredients, a sustained-
`[0054]
`release matrix may also contain suitable quantities of other
`materials, e.g., diluents, lubricants, binders, granulating
`aids, colorants, fiavorants and glidants that are conventional
`in the pharmaceutical art.
`In order to facilitate the preparation of a solid,
`[0055]
`sustained-release oral dosage form according to this inven-
`tion there is provided, in a further aspect of the present
`invention, a process for the preparation of a solid, sustained-
`release oral dosage form according to the present invention
`comprising incorporating oxycodone or a salt thereof in a
`sustained-release matrix. Incorporation in the matrix may be
`effected, for example, by:
`(a) forming granules comprising at least one hydro-
`[0056]
`phobic and/or hydrophilic material as set forth above (e.g.,
`a water soluble hydroxy alkyl cellulose) together with the
`oxycodone or pharmaceutically acceptable salt thereof;
`(b) mixing the at least one hydrophobic and/or
`[0057]
`hydrophilic material-containing granules with at least one
`C1
`, -C36 aliphatic alcohol, and
`(c) optionally, compressing and shaping the gran-
`[0058]
`ules.
`[0059] The granules may be formed by any of the proce-
`dures well-known to those skilled in the art of pharmaceu-
`tical formulation. For example, in one preferred method, the
`granules may be formed by wet granulating hydroxyalkyl
`cellulose/oxycodone or oxycodone salt 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 oxycodone or oxyc-
`odone salt.
`[0060] A sustained-release matrix can also be prepared by,
`e.g., melt-granulation or melt-extrusion techniques. Gener-
`ally, melt-granulation techniques involve melting a normally
`solid hydrophobic binder material, e.g., a wax, and incor-
`porating a powdered drug therein. To obtain a sustained
`release dosage form, it may be necessary to incorporate a
`hydrophobic sustained-release material, e.g. ethylcellulose
`or a water-insoluble acrylic polymer, into the molten wax
`hydrophobic binder material. Examples of sustained-release
`formulations prepared via melt-granulation techniques are
`found, e.g., in U.S. Pat. No. 4,861,598.
`[0061] The additional hydrophobic binder material may
`comprise one or more water-insoluble wax-like thermoplas-
`tic 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 order to
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`KASHIV1026
`IPR of Patent No. 9,492,392
`
`

`

`US 2004/0170680 Al
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`5
`
`Sep.2,2004
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`achieve sustained release, the individual wax-like sub-
`stances 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).
`[0062] The preparation of a suitable melt-extruded matrix
`according to the present invention may, for example, include
`the steps of blending the oxycodone or pharmaceutically
`acceptable salt thereof, together with a sustained release
`material and preferably a binder material to obtain a homo-
`geneous 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
`matrix multiparticulates are then divided into unit doses. The
`extrudate preferably has a diameter of from about 0.1 to
`about 5 mm and provides sustained release of the oxycodone
`or pharmaceutically acceptable salt thereof for a time period
`of at least about 24 hours.
`[0063] An optional process for preparing
`the melt
`extruded formulations of the present invention includes
`directly metering into an extruder a hydrophobic sustained
`release material, the oxycodone or salt thereof, 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 matrix multiparticulates 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.
`[0064] Plasticizers, such as those described above, may be
`included in melt-extruded matrices. The plasticizer is pref-
`erably included as from about 0.1 to about 30% by weight
`of the matrix. Other pharmaceutical excipients, e.g., talc,
`mono or poly saccharides, colorants, flavorants, lubricants
`and the like may be included in the sustained release
`matrices of the present invention as desired. The amounts
`included will depend upon the desired characteristic to be
`achieved.
`[0065] 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.
`[0066] A melt extruded matrix 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 matrix multi-
`particulate(s)" and "melt-extruded matrix multiparticulate
`system(s)" and "melt-extruded matrix 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 hydro-
`phobic sustained release material as described herein. Pref-
`erably the melt-extruded matrix 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 matrix multipar-
`ticulates can be any geometrical shape within this size range.
`
`In certain embodiments, the extrudate may simply be cut
`into desired lengths and divided into unit doses of the
`therapeutically active agent without the need of a spheroni-
`zation step.
`In one preferred embodiment, oral dosage forms
`[0067]
`are prepared that include an effective amount of melt-
`extruded matrix multiparticulates within a capsule. For
`example, a plurality of the melt-extruded matrix multipar-
`ticulates may be placed in a gelatin capsule in an amount
`sufficient to provide an effective sustained release dose when
`ingested and contacted by gastrointestinal fluid.
`In another embodiment a suitable amount of the
`[0068]
`multiparticulate extrudate is compressed into an oral tablet
`using conventional tableting equipment using standard tech-
`niques. Techniques and compositions for malting tablets
`(compressed and molded), capsules (hard and soft gelatin)
`and pills are also