Purdue Pharma et. al. v. Impax Laboratories

7/30/2019 Purdue Pharma et. al. v. Impax Laboratories

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13 CIVIN THE UNITED STATES DISTRICT COURT

FOR THE SOUTHERN DISTRICT OF NEW YORK

PURDUE PHARMA L.P.,THE P.F. LABORATORIES, INC., andPURDUE PHARMACEUTICALS L.P.,

Plaintiffs,v.

IMPAX LABORATORIES, INC.,Defendant.

))))))))))))_______________________________)

COMPLAINTPlaintiffs Purdue Pharma L.P., The P.F. Laboratories, Inc., and Purdue

Pharmaceuticals L.P. for their Complaint herein, aver as follows:NATURE OF THE ACTION

1. This is an action for patent infringement arising under the patent laws ofthe United States, Title 35, United States Code.

THE PARTIES: PLAINTIFFS2. Plaintiff Purdue,Pharma L.P. ("Purdue Pharma") is a limited partnership

organized and existing under the laws of the State of Delaware, having a place of business at OneStamford Forum, 201 Tresser Boulevard, Stamford, CT 06901-34 31. Purdue Pharma is anowner of United States Patent No. 8,33 7,888 identified in paragraph 10 below. Purdue Pharmais also the holder of New Drug Application ("NDA'') No. 022272 for the controlled-releaseoxycodone pain-relief medication OxyContin' and is involved in the sales of OxyContin in theUnited States.

Case 1:13-cv-03188-UA Document 1 Filed 05/10/13 Page 1 of 32


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3. Plaintiff The P.F. Laboratories, Inc. ("P.F. Labs") is a corporationorganized and existing under the laws of the State of New Jersey, having a place of business at700 Union Boulevard, Totowa, NJ 07512. P.F. Labs is an owner of United States Patent No.8,337,888 identified in paragraph 10 below, and is involved in the manufacture of controlled-release oxycodone pain-relief medication under the brand name OxyContin.

4. Plaintiff Purdue Pharmaceuticals L.P. ("Purdue Pharmaceuticals") 1s alimited partnership organized and existing under the laws of the State of Delaware, having aplace of business at 4701 Purdue Drive, Wilson, NC 27893. Purdue Pharmaceuticals is an ownerof United States Patent No. 8,337,888 identified in paragraph 10 below, and is involved in themanufacture of controlled-release oxycodone pain-relief medication under the brand nameOxyContin.

THE PARTIES: DEFENDANT5. Upon information and belief, Defendant Impax Laboratories, Inc.

'("Impax") is a corporation organized and existing under the laws of the State of Delaware,having a principal place of business at 30831 Huntwood Avenue, Hayward, CA 94544.

6. Upon information and belief, Impax is registered as a PharmacyEstablishment in the State ofNew York by the New York State Department ofEducation, Officeof the Professions. (Registration No. 025847). The Registration has an active status.

JURISDICTION AND VENUE

7. This Court has jurisdiction over the subject matter of this action pursuantto 28 U.S.C. 1331, 1338(a), 2201 and 2202.

8. This Court has personal jurisdiction over Impax because, inter alia, Impaxhas purposefully availed itself of the rights and benefits of the laws of this State and this Judicial

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District. Upon information and belief, Impax does business in this State and this JudicialDistrict, has engaged in continuous and systematic contact with this State and this JudicialDistrict, and derives substantial revenue from things used or consumed in this State and thisJudicial District. Upon information and belief, Impax engages in the manufacture and sale of arange of pharmaceutical products within and directed to the United States, this State, and thisJudicial District specifically. Impax did not contest personal jurisdiction in this Judicial Districtin patent litigations concerning United States Patent Nos. 6,488,963, 7,674,799, 7,674,800,7,683,072, 7,776,314, 8,114,383, and 8,309,060, which suits were based on the sameAbbreviated New Drug Application ("ANDA'') described in paragraph 11 below that Impaxsubmitted to the FDA based on Purdue Pharma's OxyContin NDA No. 022272. See PurduePharma L.P. et al. v. Impax Laboratories, Inc., No. 11-civ-2400 (SHS) (S.D.N.Y. Apr. 7, 2011)and Purdue Pharma L.P. et al. v. Impax Laboratories, Inc., No. 13-civ-0763 (SHS) (S.D.N.Y.Feb. 1, 2013). Further, this Court has personal jurisdiction over Impax because, uponinformation and belief, Impax has an active registration status as a Pharmacy Establishment inthe State of New York by the New York State Department of Education, Office of theProfessions. In addition, upon information and belief, Impax is actively preparing to make theproposed generic copies of OxyContin that are the subject of ANDA No. 202483, and to use,sell and offer for sale such generic copies in this State and this Judicial District.

9.(c) and 1400(b).

Venue is proper in this Judicial District under 28 U.S.C. 1391(b) and

THE PATENT IN SUIT

10. Plaintiffs Purdue Pharma, P.F. Labs, and Purdue Pharmaceuticals are thelawful owners of all right, title and interest in United States Patent No. 8,337,888 entitled

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"PHARMACEUTICAL FORMULATION CONTAINING GELLING AGENT" ("the '888patent"), including the right to sue and to recover for past infringement thereof. The '888 patentis listed in the FDA's Orange Book as covering the drug OxyContin, 10 mg, 15 mg, 20 mg, 30mg, 40 mg, 60 mg, and 80 mg, which is the subject of approved NDA No. 022272. A copy ofthe '888 patent is attached hereto as Exhibit A, which was duly and legally issued on December25, 2012, naming Curtis Wright, Benjamin Oshlack, and Christopher Breder as the inventors.

DEFENDANT'S ANDA11. Upon information and belief, Impax submitted ANDA No. 202483 to the

FDA, under 505G) of the Federal Food, Drug and Cosmetic Act (21 U.S.C. 355G)), seekingapproval to engage in the commercial manufacture, use, sale, offer for sale or importation ofgeneric oxycodone hydrochloride extended release tablets ("Impax' s proposed generic copies ofOxyContin"), 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg, based on the ReferenceListed Drug ("RLD") OxyContin, which is the subject of approved NDA No. 022272, beforethe expiration ofthe '888 patent.

12. Upon information and belief, Impax's ANDA No. 202483 contains a"Paragraph IV" certification under 21 U.S.C. 355(j)(2)(A)(vii)(IV) alleging that the '888patent, listed in the FDA's Orange Book as covering the drug OxyContin, which is the subjectof approved NDA No. 022272, is "invalid, unenforceable, or not infringed" by the commercialmanufacture, use or sale oflmpax's proposed generic copies ofOxyContin.

13. In a letter dated March 28, 2013 addressed to Plaintiffs and received byPlaintiff Purdue Pharma on March 29, 2013, Impax provided "Notice" with respect to itsproposed generic copies of OxyContin, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80mg, and the '888 patent under 21 U.S.C. 355(j)(2)(B), and thereby demonstrated an actual and

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justiciable controversy.CLAIM FOR RELIEF

14. Impax's submission of its ANDA was an act of infringement of the '888patent under the United States Patent Law, 35 U.S.C. 271(e)(2)(A), with respect to Impax'sproposed generic copies of OxyContin.

15. Upon information and belief, Impax's proposed generic copies ofOxyContin, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg, are covered by one ormore claims ofthe '888 patent.

16. Upon information and belief, Impax's commercial manufacture, use, sale,and/or offer for sale of the proposed generic copies of OxyContin, 10 mg, 15 mg, 20 mg,30 mg, 40 mg, 60 mg, and 80 mg, would infringe, contribute to the infringement of, and/orinduce the infringement of one or more claims of the '888 patent.

17. Upon information and belief, Impax has been aware ofthe existence ofthe'888 patent, and has no reasonable basis for believing that its proposed generic copies ofOxyContin, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg, will not infringe the '888patent, thus rendering the case "exceptional," as that term is used in 35 U.S.C. 285 .

.18. The acts of infringement by Impax set forth above will cause Plaintiffsirreparable harm for which they have no adequate remedy at law, and will continue unlessenjoined by this Court.

WHEREFORE, Plaintiffs pray for judgment:A. Adjudging that Impax has infringed the '888 patent, and that the

commercial sale, offer for sale, use, and/or manufacture of the proposed generic copies ofOxyContin, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg, described in ANDA No.202483 would infringe, induce infringement of, and/or contribute to the infringement of the '888

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patent;B. Adjudging, pursuant to 35 U.S.C. 271(e)(4)(A), the effective date of any

approval of ANDA No. 202483 under 5050) ofthe Federal Food, Drug and Cosmetic Act (21U.S.C. 355(j)), to be a date not earlier than the date of expiration of the '888 patent plus anyadditional periods of exclusivity;

C. Preliminarily and permanently enjoining, pursuant to 35 U.S.C. 271(e)(4)(B) and 283 and Rule 65, Fed. R. Civ. P., Impax, its officers, partners, agents,servants, employees, parents, subsidiaries, divisions, affiliate corporations, other related businessentities and all other persons acting in concert, participation, or in privity with them, and theirsuccessors and assigns, from any commercial manufacture, use, offer to sell, or sale within theUnited States, or importation into the United States, of any drug product that infringes the '888patent;

D. Declaring this an fXCeptional case and awarding Plaintiffs their attorneys'fees, as provided by 35 U.S.C. 271(e)(4) and 285; and

E. A warding Plaintiffs such other and further relief as this Court may deemjust and proper.Dated: May 10,2013

1211 A venue of the AmericasNew York, NY 10036(212) [email protected]@ropesgray.com

Robert J. Goldman1900 University A venue, 6th Floor

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East Palo Alto, CA 94303(650) [email protected] for Plaintiffs

Purdue Pharma L.P.,

7

The P.F. Laboratories, Inc., andPurdue Pharmaceuticals, L.P.



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EXHIBIT A



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c12) United States PatentWright et al.

(54) PHARMACEUTICAL FORMULATIONCONTAINING GELLING AGENT

(75) Inventors: Curtis Wdght, Norwalk, CT (US);Benjamin Oshlack, New York, NY(US); Christopher Breder, Greenwich,CT (US)(73) Assignee: Purdue Pharma L.P., Stamford, CT(US)( *) Notice: Subject to any disclaimer, the term of thispatent is extended or adjusted under 35U.S.C. 154(b) by 0 days.

This patent is subject to a tenninal disclaimer.(21) Appl. No.: 13/349,449(22) Filed:(65)

Jan.12,2012Prior Publication Data

US 2012/0 I 08622 Al May 3, 2012Related U.S. Application Data

(63) Continuation of application No. 12/653,115, filed onDec. 8, 2009, now abandoned, which is a continuationof application No. 10/214,412, filed on Aug. 6, 2002,now abandoned.

( 60) Provisional application No. 60/310,534, filed on Aug.6, 2001.(51) Int. Cl.

A61K 9120 (2006.01)(52) U.S. Cl. . ...................................... 424/464; 424/465(58) Field of Classification Search ........................ None

(56)See application file for complete search history.

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(Continued)Primary Examiner- Robert A WaxAssistant Examiner- Olga V Tcherkasskaya(74) Attorney, Agent, or Firm- Lowenstein Sandler PC(57) ABSTRACTDisclosed in certain embodiments is a controlled release oraldosage form comprising a therapeutically effective amount ofa drug susceptible to abuse together with one or more pharmaceutically acceptable excipients; the dosage form furtherincluding a gelling agent in an effective amount to impart aviscosity unsuitable for administration selected from thegroup consisting of parenteral and nasal administration to asolubilized mixture formed when the dosage form is crushedand mixed with from about 0.5 to about 10 ml of an aqueousliquid; the dosage form providing a therapeutic effect for atleast about 12 hours when orally administered to a humanpatient.

24 Claims, No Drawings



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US 8,337,888 B2Page 2

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us 8,337,888 821

PHARMACEUTICAL FORMULATIONCONTAINING GELLING AGENT

RELATED APPLICATIONS

2U.S. Pat. No. 3,980,766 to Shaw et al., is related to drugswhich are suitable for therapy in the treatment of narcotic

drug addiction by oral use, e.g., methadone, fonnulated toprevent injection abuse through concentration of the activeTI1is application is a continuation of U.S. patent applica

tion Ser. No. 12/653,115, filed Dec. 8, 2009, which is acontinuation of U.S. patent application Ser. No. 10/214,412,filed Aug. 6, 2002, which claims the benefit of U.S. Provisional Application No. 60/310,534, filed Aug. 6, 2001. Thecontents of these applications are hereby incorporated byreference in their entirety.

5 component in aqueous solution by incorporating in a soliddosage or tablet torr of such drug an ingestible solid havingthickening properties which canse rapid increase in viscosityupon concentration of an aqueous solution thereof.However, there still exists a need for a safe and effective10 treatment of pain with opioid analgesic dosage forms whichare less subject to abuse than current therapies.

BACKGROUND OF THE INVENTION 15Opioid analgesics are sometimes the subject of abuse.Typically, a particular dose of an opioid analgesic is morepotent when administered parenterally as compared to thesame dose administered orally. Therefore, one popular mode 20of abuse of oral opioid formulations involves the extraction of

the opioid from the dosage fonn, and the subsequent injectionof the opioid (using any "suitable" vehicle for injection) inorder to achieve a "high." Also, some formulations can betampered with in order to provide the opioid agonist con- 25tained therein better available for illicit use. For example, acontrolled release opioid agonist formulation can be crushedin order to provide the opioid contained therein available forinunediate release upon oral or nasal administration. Anopioid formulation can also be abusable by achninistration of 30more than the prescribed dose of the drug.Opioid antagonists have been combined with certainopioid agonists in order to deter the parenteral abuse of opioidagonists. In the prior art, the combination of immediaterelease pentazocine and naloxone has been utilized in tablets 35available in the United States, commercially available asTalwinNx from Sanofi-Winthrop. TalwinNx containsimmediate release pentazocine hydrochloride equivalent to

All document


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us 8,337,888 823

pered dosage form. Preferably, the gelling agent is releasedwhen the dosage fonn is tampered with and provides a gellike quality to the tampered dosage form which slows theabsorption of the opio id analgesic such that an abuser is lesslikely to obtain a rapid "high". In certain preferred embodiments, when the dosage fonn is tampered with and exposed to

4effect) even if all of he aversive agent is immediately releasedupon oral administration of an intact dosage fonn as directed.The aversive agent(s) can also be in the dosage form inreleasable form and non-releasable form in any combination.For example, a dosage form can have a bittering agent, irritant, gel or combination thereof in releasable form and nonreleasable form as disclosed in U.S. Application entitled"Phannaceutical Formulations Containing Opioid Agonist,Releasable Antagonist, and Sequestered Antagonist" filed

10 Aug. 6, 2002, the disclosure of which is hereby incorporatedby reference in its entirety.

a small amount (e.g., less than about 10 ml) of an aqueousliquid (e.g., water), the dosage form will be unsuitable forinjection and/or inhalation. Upon the addition of the aqueousliquid, the tampered dosage fonn preferably becomes thickand viscous, rendering it unsuitable for injection. 1bc term"unsuitable for injection" is defined for purposes of thepresent invention to mean that one would have substantialdifficulty injecting the dosage fom1 (e.g., due to pain upon 15administration or difficulty pushing the dosage form through

The tenn "aversive agent" is defined for purposes of thepresent invention to mean a bittering agent, an irr-itant, agelling agent, or combinations thereof.TI1e term "tampered dosage form" is defined for purposes

of he present invention to mean that the dosage form has beenmanipulated by mechanical, thermal, and/or chemical meanswhich changes the physical properties of the dosage form,e.g., to liberate the opioid agonist for ill1!l1ediate release if t isa syringe) due to the viscosity imparted on the dosage form,thereby reduc ing the potential for abuseof the opioid analge-sic in the dosage form. In certain embodiments, the gellingagent is present in such an anwunt in the dosage fonn thatattempts at evaporation (by the application of heat) to anaqueous mixture of the dosage form in an effort to produce ahigher concentration of the therapeutic agent, produces ahighly viscous substance unsuitable for injection.When nasally inhaling the tampered dosage form, the gelling agent c an become gel like upon administration to thenasal passages due to the moistureof he mucous membranes.1bis also makes such formulations aversive to nasal administration, as the gel will stick to the nasal passage and minimize absorption of he abusable substance. In certain embodiments of the present invention, the dosage form comprises acombination of any or all of the aforementioned aversiveagents (e.g., a bittering agent, an irritant, and/or a gellingagent) to discourage an abuser from tampering with the dosage form and thereafter inhaling, injecting, and/or swallowing the tampered dosage form.Embodiments specifically contemplated include bitteringagent; gelling agent; irritant; bittering agent and gellingagent; bittering agent and irritant; gelling agent and irritant;and bittering agent and gelling agent and irritant.In certain preferred embodiments, the dosage forms arecontrolled release oral dosage forms comprising a therapeutically effective an10unt of an opioid analgesic with one ormore of the aversive agents described above such that thedosage form provides effective pain relieffor at least about 12hours, or at least about 24 hours when orally administered toa human patient.In certain embodiments of the present invention the aversive agent present in the dosage form is present in a substantially non-releasable form (i.e., "sequestered") when the dosage form is administered intact as directed. Preferably,because the aversive agent is present in the dosage form in asubstantially non-releasable form, it is not substantiallyreleased in the gastrointestinal tract when the dosage fonn isorally administered intact.In other embodiments, the aversive agent may not be"sequestered" as disclosed above wherein the aversive agentis not released or minimally released from an intact dosageform, but ma y have a modified or sustained release so as not

20 in sustained release form, or to make the opioid agonist available for inappropriate use such as administration by an alternate route, e.g., parenterally. The tampering can be, e.g., bymeans of crushing, shearing, grinding, chewing, dissolutionin a solvent, heating, (e.g., greater than about 45 C.), or any

25 combination thereof.TI1e term "substantially non-releasable form" for purposes

of the present invention refers to an aversive agent that is notreleased or substantially not released at one hour after theintact dosage form containing an opioid agonist and at least30 one aversive agent is orally administered (i.e., without havingbeen tampered with). The aversive agent in a substantiallynon-releasable form may be prepared in accordance with theteachings of U.S. application Ser. No. 09/781,081, entitled"Tamper Resistant Oral Opioid Agonist Formulations" filed35 Feb. 8, 2001, the disclosure of which is hereby incorporatedby reference in its entirety, which describes a dosage formcomprisingan opioidantagonist in a substantially non-releasable form. For purposes of he present invention, the amountreleased after oral administration of the intact dosage form40 may be measured in-vitro via the dissolution at 1hour of thedosage form in 900 ml of Simulated Gastric Fluid using aUSP Type II (paddle) apparatus at 75 rpm at 37 C. Such adosage form is also referred to as comprising a "sequesteredaversive agent" depending on the agent or agents which are45 not released or substantially not released. In certain preferredembodiments of the invention, the substantially non-releasable form of the aversive agent is resistant to laxatives (e.g.,mineral oil) used to manage delayed colonic transit and resistant to achlorhydric states. Preferably, the aversive agent is50 not released or not substantially released 4, 8, 12 and/or 24hours after oral administration.The phrase "analgesic effectiveness" is defined for purposes of he present invention as a satisfactory reduction in orelimination of pain, along with a tolerable level of side55 effects, as determined by the human patient.The term "sustained release" is defined for purposes of hepresent invention as the release of the opioid analgesic fromthe oral dosage form at such a rate that blood (e.g., plasma)concentrations (levels) are maintained within the tl1erapeutic60 range but below toxic levels over an extended period oftime ,e.g., from about 12 to about 24 hours as compared to an

ill1!l1ediate release product. Preferably the sustained release issufficient to provide a twice-a-day or a once-a-day formulation.

to dump the aversive agent in a particular section of thegastrointestinal tract, e.g. the stomach, where it may cause anunwanted effect such as excessive irritation. The aversiveagent can be combined with an enteric carrier to delay itsrelease or combined with a carr-ier to provide a sustainedrelease of the aversive agent. However, it is contemplated in 65the present invention that the aversive agent will preferablynot have any significant side effect (e.g., gastrointestinal side

The term "particles" of aversive agent, as used herein,refers to granules, spheroids, beads or pellets comprising theaversive agent. In certain preferred embodiments, the aver-



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sive agent particles are about 0.2 to about 2 mm in diameter,more preferably about 0.5 to about 2 mm in diameter.The tenn "parenterally" as used herein includes subcutaneous injections, intravenous injections, intramuscular i ~ e c -

tions, intrasternal injections, infusion techniques, or othermethods of injection known in the art.The term "inhaled" as used herein includes trans-mucosal,trans-bronchial, and trans-nasal abuse.The tenn "biltering agent" as used herein includes a compotmd used to impart a bitter taste, bitter flavor, etc., to an 10abuser administering a tampered dosage fonn of the presentinvention.

6embodiments spoils or hinders the pleasure of obtaining ahigh from the tampered dosage form, and preferably preventsthe abuse of the dosage fom1.A bittering agent may be added to the fonnulation in anamount ofless than about 50% by weight preferably less thanabout 10% by weight, most preferably less than about 5% byweight of he dosage form, and most preferably in an amountranging from about 0.1 to 1.0 percent by weight of the dosageform, depending on the particular bittering agent(s) used. Adosage form including a bittering agent preferably discourages improper usage of he tampered dosage form by impart-ing a disagreeable taste or flavor to the tampered dosage form.In certain embodiments of the present invention whereinthe dosage form includes an aversive agent comprising anhe term "irritant" as used herein includes a compoundused to impart an irritating or burning sensation to an abuseradministering a tampered dosage fonn of the present invention.The term "gelling agent" as used herein includes a compound or composition used to impart gel-like or thickeningquality to a tampered dosage form upon the addition ofmoisture or liquid.

15 irritant, various irritants can be employed including, forexample and without limitation capsaicin, a capsaicin analogwith similar type properties as capsaicin, and the like. Somecapsaicin analogues or derivatives include for example andwithout limitation, resiniferatoxin, tinyatoxin, heptanoyl-

DETAILED DESCRIPTION OF THE INVENTION

20 isobutylamide, heptanoyl guaiacylamide, other isobutylamides or guaiacylamides, dihydrocapsaicin, homovanillyloctylester, nonanoyl vanillylamide, or other compounds ofthe class known as vaniiloids. Resiniferatoxin is described,for example, in U.S. Pat. No. 5,290,816 (Blumberg), issuedThe aversive agents of he present invention are preferablyfor use in connection with oral dosage forms including opioidanalgesics, which provide valuable analgesia but which maybe abused. Tills is particularly true for controlled releaseopioid analgesic products which have a large dose of opioidanalgesic intended to be released over a periodof ime in eachdosage unit. Drug abusers typically may take a controlledrelease product and crush, shear, grind, chew, dissolve and/orheat, extract or otherwise damage the product so that the fullcontents of the dosage form become available for immediateabsorption by injection, inhalation, and/or oral consumption.

25 Mar. 1, 1994. U.S. Pat. No. 4,812,446 (Brand), issued Mar.14, 1989, describes capsaicin analogs and methods for theirpreparation. Further, U.S. Pat. No. 4,424,205 (LaHannet a!.),issued Jan. 3, 1984, cite Newman, "Natural and SyntheticPepper-Flavored Substances" published in 1954 as listing30 ptmgencyof capsaicin-like analogs. Tonet a!., British JournalofPharmacology, 10, pp. 175-182 (1955) discuss pharmacological actions of capsaicin and its analogs.With the inclusion of an irritant (e.g., capsaicin) in thedosage form, when the dosage form is tampered with, the

In certain embodiments, the present invention comprises amethod for preventing or deterring the abuse of opioid analgesics by the inclusion of at least one aversive agent in thedosage form with the opioid analgesic.

35 capsaicin imparts a burning or discomforting quality to theabuser to preferably discourage the inhalation, injection, ororal administration of the tampered dosage form, and preferably to prevent the abuse of the dosage form. Suitable capsaicin compositions include capsaicin (trans 8-methyl-N-va-

40 niiiyl-6-noneamide or analogues thereof in a concentrationbetween about 0.00125% and 50";(, by weight, preferablybetween about 1 and about 7.5% by weight, and most preferably, between about 1 and about 5% by weight of he dosageIn certain alternative embodiments, the present invention

comprises a method for preventing or deterring the abuse ofdrugs other than opioid analgesics which may also be thesubject of abuse, by including at least one of the aversiveagents described herein in a dosage fonn comprising the drug 45other than an opioid analgesic which is the subject of abuse.In certain embodiments of the present invention whereinthe dosage form includes an aversive agent comprising abittering agent, various bittering agents can be employedincluding, for example and without limitation, natural, artifi- 50cia! and synthetic flavor oils and flavoring aromatics and/oroils, oleoresins and extracts derived from plants, leaves, flowers, fruits, and so forth, and combinations thereof. Nonlimiting representative flavor oils include spearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, aUspice, mace, oil of 55bitter almonds, menthol and the like. Useful bittering agentscan be artificial, natural and synthetic fruit flavors such ascitrus oils including lemon, orange, lime, grapefruit, and fruitessences and so forth. Additional bittering agents includesucrose derivatives (e.g., sucrose octaacetate , chlorosucrose 60derivatives, quinine sulphate, and the like. The preferred bittering agent for use in the present invention is DenatoniumBenzoate NF-Anhydrous, sold under the name Bitrex(Macfarlan Smith Limited, Edinburgh, UK).With the inclusion of a bittering agent in the formulation, 65the intake of the tampered dosage form produces a bitter tasteupon inhalation or oral administration which in certain

form.In certain embodiments of the present invention whereinthe dosage form includes an aversive agent comprising agelling agent, various gelling agents can be employed including, for exan1ple and without limitation, sugars or sugarderived alcohols, such as mannitol, sorbitol, and the like,starch and starch derivatives, cellulose derivatives, such asmicrocrystalline cellulose, sodium cahoxymethyl cellulose,methylcellulose, ethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, and hydroxypropyl methylcellulose, attapulgites, bentonites, dextrins, alginates, carrageenan, gum tragacanth, gum acacia, guar gum, xanthan gum,pectin, gelatin, kaolin, lecithin, magnesium aluminum sili-cate, the carbomers and carbopols, polyvinylpyrrolidone,polyethylene glycol, polyethylene oxide, polyvinyl alcohol,silicon dioxide, surfactants, mixed surfactant/wetting agentsystems, emulsifiers, other polymeric materials, and mixturesthereof, etc. certain preferred embodiments, the gelJing agentis xanthan gum. In other preferred embodiments, the geliingagent of the present invention is pectin. The pectin or pecticsubstances useful for this invention include not only purifiedor isolated pectates but also crude natural pectin sources, suchas apple, citrus or sugar beet residues which have been sub-jected, when necessary, to esterification or de-esterification,



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e.g., by alkali or enzymes. Preferably, the pectins used in tllisinvention are derived from citrus fruits such as lime, lemon,grapefruit, and orange.With the inclusion of a gelling agent in the dosage form,when the dosage form is tampered with, the gelling agentpreferably imparts a gel-like quality to the tampered dosageform wllich preferably spoils or hinders the pleasure ofobtaining a rapid lligh from the tampered dosage form due tothe gel like consistency in contact with the mucous membrane, and in certain embodiments, prevents the abuse of thedosage fom1 by minimizing absorption, e.g. in the nasal passages. A gelling agent may be added to the formulation in aratio of gelling agent to opioid agonist of from about 1:40 toabout 40: I by weight, preferably from about 1: 1 to about 30: 1by weight, and more preferably from about 2:1 to about 10:1by weight of he opioid agonist. In certain alternative embodiments, the gelling agent may be present in a ratio to the opioidagonist of from about 1:15 to about 15:1, preferably in a ratioof from about 1:8 to about 8:1, and more preferably fromabout 1:3 to about 3:1 by weight of the opioid agonist.In certain other embodiments, the dosage form forms aviscous gel after the dosage form is tampered with, dissolvedin an aqueous liquid (from about 0.5 to about 10 ml andpreferably from 1 to about 5 ml), causing the resulting mixture to have a viscosity of at least about 10 cP. Most preferably, the resulting mixture will have a viscosity of at leastabout 60 cP.In certain other embodiments, the dosage form forms aviscous gel after the dosage form is tampered with, dissolvedin an aqueous liquid (from about 0.5 to about 10 ml andpreferably from 1 to about 5 ml) and then heated (e.g., greaterthan about 45 C.), causing the resulting mixture to have aviscosityof at least about 10 cP. Most preferably, the resultingmixture will have a viscosity of at least about 60 cP.In certain embodiments, the dosage form may include one

or more of the aforementioned aversive agents. For safetyreasons, the amount of the bittering agent, irritant, or gellingagent in a formulation of the present invention should not betoxic to humans.In certain embodiments, the aversive agent included in thedosage fom1 may be in a substantially non-releasable form.Where the aversive agent is in a substantially non-releasableform, the substantially non-releasable fonn of the aversiveagent comprises an aversive agent that is formulated with oneor more phannaceutically acceptable hydrophobic materials,such that the aversive agent is not released or substantially notreleased during its transit through the gastrointestinal tractwhen administered orally as intended, without having beentampered with.In certain embodiments of the present invention, the substantially non-releasable form of he aversive agent is vulnerable to mechanical, thermal and/or chemical tampering, e.g.,tampering by means of crushing, shearing, grinding, chewingand/or dissolution in a solvent in combination with heating(e.g., greater, than about 45 C.) of the oral dosage form.When the dosage form is tampered with, the integrity of thesubstantially non-releasable fonn of the aversive agent willbe compromised, and the aversive agent will be made available to be released. In certain embodiments, when the dosageform is chewed, crushed or dissolved and heated in a solvent,the releaseof he aversive agent hinders, deters or prevents theadministration of the tampered dosage form orally, intranasally, parenterally and/or sub lingually.The opioid agonists useful in the present invention include,but are not limited to, alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, buprenorplline,butorphanol, clonitazene, codeine, desomorphine, dextro-

8moramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyland derivatives, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myro-

1o phine, narceine, nicomorphine, norlevorphanol,nonnethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum,pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine,1s promedol, properidine, propoxyphene, sufenta1lil, tilidine,tramadol, mixtures of anyof he foregoing, salts of any of heforegoing, and the like. In certain embodiments, the amount

of the opioid agonist in the claimed opioid composition maybe about 75 ng to about 750 mg.20 In certain preferred embodiments, the opioid agonist isselected from the group consisting of hydrocodone, morplline, hydromorphone, oxycodone, codeine, levorphanol,meperidine, methadone, oxymorphone, buprenorphine, fentanyl and derivatives thereof, dipipanone, heroin, tramadol,25 etorphine, dihydroetorphine, butorphanol, levorphanol, orsalts thereof or mixtures thereof. In certain preferred embodiments, the opioid agonist is oxycodone or hydrocodone.In embodiments in which the opioid analgesic compriseshydrocodone, dosage forms may include analgesic doses30 from about 2 mg to about 50 mg ofhydrocodone bitartrate. Inembodiments in which the opioid analgesic comprises hydromorphone the dosage form may include from about 2 mg toabout 64 mg hydromorphone hydrochloride. In embodimentsin which the opioid analgesic comprises morphine, the dos-35 age form may include from about 2.5 mg to about 800 mgmorphine sulfate, by weight. In embodiments in which theopioid analgesic comprises oxycodone, the dosage form mayinclude from about 2.5 mgto about 320 mg oxycodonehydrochloride. The dosage form may contain more than one opioid40 analgesic to provide a therapeutic effect. Alternatively, thedosage form may contain molar equivalent amounts of othersalts of the opioids useful in the present invention.Hydrocodone is a senlisynthetic narcotic analgesic andantitussive with multiple central nervous system and gas-45 trointestinal actions. Chemically, hydrocodone is 4,5-epoxy-3-methoxy-17 -methylmorphinan-6-one, and is also known asdihydrocodeinone. Like other opioids, hydrocodone may behabit forming and may produce drug dependence of he morphine type. In excess doses hydrocodone, like other opiumso derivatives, will depress respiration.Oral hydrocodone is also available in Europe (Belgium,Germany, Greece, Italy, Luxembourg, Norway and Switzerland) as an antitussive agent. A parenteral formulation is alsoavailable in Germany as an antitussive agent. For use as an55 analgesic, hydrocodone bitartrate is commercially availablein the United States only as a fixed combination with nonopiate drugs (i.e., ibuprofen, acetaminophen, aspirin, etc.) forreliefof moderate or moderately severe pain.A common dosage form ofhydrocodone is in combination60 with acetaminophen, and is commercially available, e.g., asLortab in the U.S. from UCB Pharma. Inc. as 2.5/500 mg,5/500 mg, 7.5/500 mg and 10/500 mg hydrocodone/acetanlinophen tablets. Tablets are also available in the ratio of7.5 mghydrocodone bitartrate and 650 mg acetaminophen; and 7.565 mg hydrocodone bitartrate and 750 mg acetaminophen.Hydrocodone in combination with aspirin is given in an oraldosage form to adults generally in 1-2 tablets every 4-6 hours



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the form of an alcoholic solution. In certain other embodiments, the hydrophobic material comprises polylactic acid,polyglycolic acid ora co-polymer ofthepolylact ic and polyglycolic acid.

as needed to alleviate pain. The tablet form is 5 mg hydrocodone bitartrate and 224 mg aspirin with 32 mg caHeine; or 5mg hydrocodone bitartrate and 500 mg aspirin. A relativelynew formulation comprises hydrocodone bitartrate and ibuprofen. Vicoprofen, commercially available in the U.S.from Knoll Laboratories, is a tablet containing 7.5mg hydrocodone bitartrate and 200 mg ibuprofen. 'll1e present invention is contemplated to encompass all such formulations, withthe inclusion of one or more aversive agents as describedherein.Oxycodone, chemically known as 4,5-expoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one, is an opioidagonist whose principal therapeutic action is analgesia. Othertherapeutic effects ofoxycodone include anxiolysis, euphoriaand feelings of elaxation. The precise mechanism of ts anal- 15gesic action is not known, but specific CNS opioid receptorsfor endogenous compounds with opioid-like activity havebeen identified throughout the brain and spinal cord and play

In certain embodiments, the hydrophobic material maycomprise a cellulose polymer selected from the group consistingof cellulose ether, cellulose ester, cellulose ester ether,and cellulose. The cellulosic polymers have a degree of substitution, D.S., on the anhydroglucose unit, from greater than10 zero and up to 3 inclusive. By degree of substitution is meantthe average number ofhydroxyl groups present on the anhydroglucose unit comprising the cellulose polymer that arereplaced by a substituting group. Representative materials

a role in the analgesic effects of this drug.Oxycodone is commercially available in the United States, 20e.g., as Oxycontin from Purdue Phanna L.P. as controlledrelease tablets for oral administration containing I 0 mg, 20mg, 40 mg or 80 mg oxycodone hydrochloride, and asOxyiR, also from Purdue Pharma L.P., as immediate-release capsules containing 5 mg oxycodone hydrochloride. 25The present invention is contemplated to encompass all suchformulations, with the inclusion of one or more aversiveagents as described herein.Additionally, agents other than opioid analgesics which aresubject to abuse may be used in accordance with the present 30invention in place of he opioid analgesics in the dosage form.Certain agents include, for example and without limitation,tranquilizers, CNS depressants, CNS stimulants, sedativehypnot ics and the like. More specifically, barbiturates such asphenobarbital, secobarbital, pentobarbital, butabarbital, talb- 35uta!, aprobarbital, mephobarbital, butalbital, pharmaceutically acceptable salts thereof, and the like; benzodiazepinessuch as diazepam, chlordiazepoxide, alprazolam, triazolam,estazolam, clonazepam, flunitrazepam, pharmaceuticallyacceptable salts thereof, and the like; stimulants such as 40gma-hydroxybutyrate, dextroamphetamine, methylphenidate, sibutramine, methylenedioxymethamphetamine, pharmaceutically acceptable salts thereof, and the like; and otheragents such as marino!, meprobamate, carisoprodol, phannaceutically acceptable salts thereof and the like. 45

Preparation of Aversive Agent in a SubstantiallyNon-Releasable Form

include a polymer selected from the group consisting of cellulose acyl ate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono,di, and tricellulose alkanylates, mono, di, and tricellulosearoylates, and mono, di, and tricellulose alkenylates. Exem-plary polymers include cellulose acetate having a D.S. and anacetyl content up to 21 %; cellulose acetate having an acetylcontent up to 32 to 39.8%; cellulose acetate having a D.S. of1 to 2 and an acetyl content of 21 to 35%; cellulose acetatehaving a D.S. of 2 to 3 and an acetyl content of35 to 44.8%.More specific cellulosic polymers include cellulose propionate having a D.S. of 1.8 and a propyl content of39.2 to 45and a hydroxyl content of 2.8 to 5.4%; cellulose acetatebutyrate having a D.S. of 1.8, an acetyl content of 13 to 15%and a butyryl content of34 to 39%; cellulose acetate butyratehaving an acetyl content of 2 to 29%, a butyryl content of 17to 53% and a hydroxyl content of 0.5 to 4.7%; cellulosetriacylate having a D.S. of2.9 to 3 such as cellulose triacetate,cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate, and cellulose trioctanoate; cellulose diacylates having a D.S. of 2.2 to 2.6 such as cellulosedisuccinate, cellulose dipalmitate, cellulose dioctanoate, cel-lulose dipentanoate, and coesters of cellulose such as cellulose acetate butyrate, cellulose acetate octanoate butyrate andcellulose acetate propionate. Additional cellulose polymers useful for preparing an aversive agent in a substantially non-releasable form includeacetaldehyde dimethy I cellulose acetate, cellulose acetateethylcarbamate, cellulose acetate methylcarbamate, and cellulose acetate dimethylaminocellulose acetate.Acrylic polymers useful for preparation of the aversiveagent in a substantially non-releasable form include, but arenot limited to, acrylic resins comprising copolymers synthesized from acrylic and methacrylic acid esters (e.g., thecopolymer of acrylic acid lower alkyl ester and methacrylicIn certain embodiments of the present invention, an aversive agent in a substantially non-releasable form may beprepared by combining the aversive agent with one or more of

a pharmaceutically acceptable hydrophobic material. Forexample, aversive agent particles may be coated with coatingthat substantially prevents the release of the aversive agent,the coating comprising the hydrophobic materials(s).Another example would be an aversive agent that is dispersedin a matrix that renders the aversive agent substantially nonreleasable, the matrix comprising the hydrophobicmaterials(s). In certain embodiments, the pham1aceuticallyacceptable hydrophobic material comprises a cellulose polymer selected from the group consisting of ethylcellulose,cellulose acetate, cellulose propionate (lower, medium orhigher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate and cellulose triacetate. An exampleof ethyl cellulose is one that has ancthoxy content of 44 to 55%. Ethylcellulose may be used in

50 acid lower alkyl ester) containing about 0.02 to 0.03 mole ofa tri (lower alkyl) monium group per mole of the acrylicand methacrylic monomers used. An example of a suitableacrylic resin is a polymer manufactured by Rohm PharmaGmbH and sold under the Eudragit RS trademark. Eudragit

55 RS30]) is preferred. Eudragit RS is a water insolublecopolymerofethyl acrylate (EA), methyl methacrylate (MM)and trimethylanunoniumethyl methacrylate chloride (TAM)in which the molar ratio ofTAM to the remaining components(EA and MM) is 1 40. Acrylic resins such as Eudragit RS60 may be used in the form of an aqueous suspension.In certain embodiments of the invention, the acrylic polymer may be selected from the group consisting of acrylic acidand methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cyanoethyl meth-65 acrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)



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copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, poly(methacrylic acid anhydride), and glycidylmethacrylate co-polymers.When the aversive agent in a substantially non-releasableform comprises aversive agent particles coated with a coatingthat renders the aversive agent substantially non-releasable,and when a cellulose polymer or an acrylic polymer is usedfor preparation ofthe coating composition, suitable plasticizers, e.g., acetyl triethyl citrate and/or acetyl tributyl citratemay also be admixed with the polymer. The coating may also 10contain additives such as coloring agents, talc and/or magnesium stearate, which are well known in the coating art.

12In certain preferred embodiments of the invention, the oraldosage form is a capsule or a tablet. When being formulated

as a tablet, the aversive agent and opioid agonist may becombined with one or more inert, non-toxic phannaceuticalexcipients which are suitable for the manufacture of tablets.Such excipients include, for example, an inert diluent such aslactose; granulating and disintegrating agents such as comstarch; binding agents such as starch; and lubricating agentssuch as magnesium stearate.The oral dosage form of the present invention may beformulated to provide inuncdiate releaseof he opioid agonistcontained therein. In other embodiments of the invention,however, the oral dosage form provides sustained-release ofthe opioid agonist.In certain embodiments, the oral dosage forms providingsustained release of the opioid agonist may be prepared byadmixing the aversive agent in a substantially non-releasableform with the opioid agonist and desirable pharmaceuticalexcipients to provide a tablet, and then coating the tablet with

'Ibe coating composition may be applied onto the aversiveagent particles by spraying it onto the particles using any 15suitable spray equipment known in the art. For example, aWuster fluidized-bed system may be used in which an air jet,injected from underneath, fluidizes the coated material andeffects drying while the insoluble polymer coating is sprayedon. The thickness of the coating will depend on the characteristics of the particular coating composition being used.However, it is well within the ability of one skilled in the art

20 a sustained-release tablet coating.In certain embodiments of he invention, sustained releaseopioid agonist tablets may be prepared by admixing the substantially non-releasable form of an aversive agent with anaversive agent in a matrix that provides the tablets with sus-to determine by routine experimentation the optimum thickness of a particular coating required for a particular dosageform of the present invention. 25 tained-releasing properties.TI1e pharmaceutically acceptable hydrophobic materialuseful for preparing an aversive agent in a substantially nonreleasable form includes a biodegradable polymer comprising a poly(lactic/glycolic acid) ("PLGA"), a polylactide, apolyglycolide, a polyanhydride, a polyorthoester, polycapro- JOlactones, polyphosphazenes, polysaccharides, proteinaceouspolymers, polyesthers, polydioxanone, polygluconate, polylaetic-acid-polyethy ene oxide copolymers,po ly(hydroxybutyrate), polyphosphoesther or mixtures or blends of any ofthese.

Dosage FormsThe opioid analgesic formulation in combination with one

or more aversive agents can be formulated as an immediaterelease formulation or controlled release oral formulation inany suitable tablet, coated tablet or multiparticulate formulation known to those skilled in the art. The controlled releasedosage form may include a controlled release material which35 is incorporated into a matrix along with the opioid analgesic.In certain embodiments, biodegradable polymer comprisesa poly(lactic/glycolic acid), a copolymer of lactic and glycolic acid, having molecular weight of about 2,000 to about500,000 daltons. The ratio of lactic acid to glycolic acid isfrom about 100:0 to about 25:75, with the ratio oflac tic ac id 40to glycolic acid of 65:35 being preferred.Poly(lactic/glycolic acid) may be prepared by the procedure set forth in U.S. Pat. No. 4,293,539 (Ludwig et al.), thedisclosure ofwhich is hereby incorporated by reference in itsentirety. In brief, Ludwig prepares the copolymer by conden- 45sation of lactic acid and glycolic acid in the presence of areadily removable polymerization catalyst (e.g., a strong acidion-exchange resin such as Dow ex HCR- W2-H). The amount

ofcatalyst is not critical to the polymerization, but typically isfrom about 0.01 to about 20 parts by weight relative to the 50total weight of combined lactic acid and glycolic acid. Thepolymerization reaction may be conducted without solventsat a temperature from about 100 C. to about 250 C. for about48 to about 96 hours, preferably under a reduced pressure tofacilitate removal of water and by-products. Poly(lactic/gly- 55colic acid) is then recovered by filtering the molten reactionmixture in an organic solvent such as dichloromethane oracetone and then filtering to remove the catalyst.Once the aversive agent in a substantially non-releasableform is prepared, it may b e combined with an opioid agonist, 60along with conventional excipients known in the art, to prepare the oral dosage form of the present invention. It is contemplated that a bittering agent or capsaicin would be themost likely aversive agent to be included in a sequesteredformulation. The polymers and other ingredients above may 65also be utilized to formulate the aversive agents to slowrelease or delay release as disclosed above.

In addition, the aversive agent may be separate from thematrix, or incorporated into the matrix.The controlled release dosage form may optionally comprise particles containing or comprising the opioid analgesic,wherein the particles have diameter from about 0.1 mm toabout 2.5 mm, preferably from about 0.5 mm to about 2 mm.Additionally, the aversive agent may be incorporated intothese particles, or may be incorporated into a tablet or capsulecontaining these particles. Preferably, the particles are filmcoated with a material that permits release of the opioidanalgesic at a controlled rate in an environment of use. Thefilm coat is chosen so as to achieve, in combination with theother stated properties, a desired in-vitro release rate. Thecontrolled release coating formulations of he present invention should be capable ofproducing a strong, continuous filmthat is smooth and elegant, capable of supporting pigmentsand other coating additives, non-toxic, inert, and tack-free.In certain embodiments, the dosage forms of the presentinvention comprise normal release matrixes containing theopioid analgesic and the aversive agent.Coated Beads

In certain embodiments of the present invention a hydrophobic material is used to coat inert pharmaceutical beadssuch as nu panel18/20 beads comprising an opioid analgesic,and a plurality of the resultant solid controlled release beadsmay thereafter be placed in a gelatin capsule in an amountsufficient to provide an effective controlled release dose wheningested and contacted by an environmental fluid, e.g., gastricfluid or dissolution media. The one or more aversive agentsmay also be coated onto the beads comprising the opioid



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analgesic, may be prepared as separate beads and then combined in a dosage fonn including the controlled release beadscomprising an opioid analgesic, or the one or more aversiveagents may be mixed in the dosage form with the controlledrelease beads comprising the opioid analgesic. In preferredembodiments where the opioid analgesic and the aversiveagent are mixed in a capsule as different beads, the beads have

14film-fom1er, such as Opadry, is optionally applied to thebeads. This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads.The release of the opioid analgesic from the controlledrelease fommlation of the present invention can be furtherinfluenced, i.e., adjusted to a desired rate, by the addition ofone or more release-modifying agents, or by providing one ormore passageways through the coating. T11e ratio of hydrophobic material to water soluble material is determined by,

an exact or similar appearance in order to deter an abuser frommanually separating the beads prior to abuse in order to avoidthe aversive substance. In tablet dosage forms, the aversiveagent is preferably not included as a distinct layer which canbe easier to separate from the active agent, although thepresent invention docs encompass these embodiments.

10 among other factors, the release rate required and the solubility characteristics of the materials selected.

T11e controlled release bead formulations of the presentinvention slowly release the opioid analgesic, e.g., wheningested and exposed to gastric fluids, and then to intestinalfluids. The controlled release profile of the formulations ofthe invention can be altered, for example, by varying theamount ofovercoating with the hydrophobic material, altering the manner in which a plasticizer is added to the hydrophobic material, by varying the amount of plasticizer relativeto hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture,etc. The dissolution profile of the ultimate product may alsobe modified, for example, by increasing or decreasing thethickness of the retardant coating.

The release-modifying agents which function as poreformers may be organic or inorganic, and include materialsthat can be dissolved, extracted or leached from the coating in15 the environment ofuse. The pore-formers may comprise oneor more hydrophilic materials such as hydroxypropylmethylcellulose.The controlled release coatings of he present invention canalso include erosion-promoting agents such as starch and20 gmns.The contra lied release coatings of he present invention canalso include materials useful for making microporous lanlinain the environment of use, such as polycarbonates comprised

of linear polyesters of carbonic acid in which carbonate25 groups reoccur in the polymer chain.The release-modifying agent may also comprise a senlipermeable polymer.pheroids or beads coated with an opioid analgesic areprepared, e.g., by dissolving the opio id analgesic in water andthen spraying the solution onto a substrate, for example, nupariel 18/20 beads, using a Wuster insert. Thereafter, the one

or more aversive agent is optionally added to the beads priorto coating. Optionally, additional ingredients are also addedprior to coating the beads in order to assist the binding of theopioid to the beads. For example, a product which includeshydroxypropylmethylcellulose, etc. (e.g., Opadry, commercially available from Colorcon, Inc.) may be added to thesolution and the solution mixed (e.g., for about 1 hour) prior

In certain preferred embodiments, the release-modifyingagent is selected from hydroxypropylmethylcellulose, lac-30 tose, metal stearates, and mixtures of any of the foregoing.The controlled release coatings of the present inventionmay also include an exit means compdsing at least one passageway, orifice, or the like. The passageway may be formedby such methods as those disclosed in U.S. Pat. Nos. 3,845,35 770; 3,916,889; 4,063,064; and 4,088,864. The passagewaycan have any shape such as round, triangular, square, elliptical, irregular, etc.to applicationofthe same onto the beads. T11e resultant coatedsubstrate, in this example beads, may then be optionally overcoated with a barrier agent, to separate the opioid analgesic 40from the hydrophobic controlled release coating. An example

Matrix FormulationsIn certain embodiments of the present invention, the sustained release formulation is achieved via a matrix optionallyhaving a controlled release coating as set forth herein. Thepresent invention may also utilize a sustained release matrix

of a suitable barrier agent is one which comprises hydroxypropyhnethylcellulose. However, any film-fom1er known inthe art may be used. It is preferred that the barrier agent doesnot affect the dissolution rate of the final product. 45 that affords in-vitro dissolution rates of the opioid analgesicwithin desired ranges and releases the opioid analgesic in apH-dependent or pH-independent mallller.The beads may then be overcoated with an aqueous dispersion of the hydrophobic material. The aqueous dispersion ofhydrophobic material preferably further includes an effectiveamount of plasticizer, e.g. triethyl citrate. Pre-formulatedaqueous dispersions of ethylcellulose, such as Aquacoat or 50Surelease, may be used. If Surelease is used, it is notnecessary to separately add a plasticizer. Alternatively, preformulated aqueous dispersions of acrylic polymers such asEudragit can be used.Plasticized hydrophobic material may be applied onto the 55substrate comprising the opioid analgesic by spraying usingany suitable spray equipment known in the art. In a preferredmethod, a Wurster fluidized-bed system is used in which anair jet, injected from underneath, fluidizes the core materialand effects drying while the acrylic polymer coating is 60sprayed on. A sufficient amount of the hydrophobic materialto obtain a predetennined controlled release of said opioidanalgesic when the coated substrate is exposed to aqueoussolutions, e.g. gastric fluid, is preferably applied, taking intoaccount the physical characteristics of the opioid analgesic, 65the manner of incorporationof the plasticizer, etc. After coat-ing with the hydrophobic material, a further overcoat of a

A non-limiting list of suitable sustained-release materialswhich r-ay be included in a sustained-release matrix according to the invention includes hydrophilic and/or hydrophobicmaterials, such as gums, cellulose ethers, acrylic resins, pro-tein derived materials, waxes, shellac, and oils such as hydrogenated castor oil and hydrogenated vegetable oil. However,any pharmaceutically acceptable hydrophobic or hydrophilicsustained-release material which is capable of imparting sustained-release of the opioid analgesic may be used in accor-dance with the present invention. Preferred sustained-releasepolymers include alkylcelluloses such as ethylcellulose,acrylic and methacrylic acid polymers and copolymers; andcellulose ethers, especially hydroxyalkylcelluloses (especially hydroxypropyhnethylcellulose) and carboxyalkylcel-luloses. Preferred acrylic and methacrylic acid polymers andcopolymers include methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, ethyl acrylate,trimethylmonioethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copoly-



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mer, poly(methylmethacrylate), poly(methacrylicacid) (anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylatecopolymers. Certain preferred embodiments utilize mixturesof any of the foregoing sustained-release materials in thematrix of the invention.

16In one preferred embodiment, the ratio of, e.g., the at least

one hydroxyalkyl cellulose or acrylic resin to the at least onealiphatic alcohol/polyalkylene glycol determines, to a considerable extent, the release rate of he opioid analgesic fromthe formulation. In certain embodiments, a ratio of thehydroxyalkyl cellulose to the aliphatic alcohollpolyalkyleneglycol of between I: 1 and 1 4 is preferred, with a ratio ofbetween 1 2 and 1:3 being particularly preferred.

The matrix also may include a binder. In such embodiments, the binder preferably contributes to the sustainedrelease of the opioid analgesic or pharmaceutically acceptable salt thereof from the sustained-release matrix.If an additional hydrophobic bind er material is included, itis preferably selected from natural and synthetic waxes, fattyacids, fatty alcohols, and mixtures of the same. Examplesinclude beeswax, carnauba wax, stearic acid and stearyl alcohol. This list is not meant to be exclusive. In certain preferred 15embodiments, a combination of two or more hydrophobicbinder materials are included in the matrix formulations.

In certain embodiments, the polyalkylene glycol may be,10 for example, polypropylene glycol, or polyethylene glycolwhich is preferred. The average molecular weight of the atleastonepolyalkylene glycol is preferably between 1,000 and15,000, especially between 1,500 and 12,000.Another suitable sustained-release matrix comprises analkylcellulose (especially ethylcellulose), a cl2 to c35 aliphatic alcohol and, optionally, a polyalkylene glycol.

Preferred hydrophobic binder materials which may be usedin accordance with the present invention include digestible,long chain (C8-C50 , especially C 12-C4 0), substituted orunsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters offatty acids, mineral and vegetable oils,natural and synthetic waxes and polyalkylene glycols. Hydrocarbons having a melting point ofbetween 25 and 90 C. arepreferred. Of the long-chain hydrocarbon binder materials,fatty (aliphatic) alcohols are preferred in certain embodiments. The oral dosage fonn may contain up to 80% (byweight) of at least one digestible, long chain hydrocarbon.

In addition to the above ingredients, a sustained-releasematrix may also contain suitable quantities of other materials,

20 e.g., diluents, lubricants, binders, granulating aids, andglidants that are conventional in the pharmaceutical art.In order to facilitate the preparation of a solid, sustainedrelease oral dosage form according to this invention there isprovided, in a further aspect of the present invention,a ro-

25 cess for the preparation of a solid, sustained-release oraldosage form according to the present invention comprisingincorporating an opioid analgesic in a sustained-releasematrix. Incorporation in the matrix may be effected, forexample, by:(a) forming granules comprising atleast one hydrophobicand/or hydrophilic material as set forth above (e.g., a watersoluble hydroxyalkyl cellulose) together with the opioidanalgesic, and at least one aversive agent;(b) mixing the at least one hydrophobic and/or hydrophilic35 material containing granules with at least one C 12 -C36 aliphatic alcohol, and

In certain embodiments, the hydrophobic bind er materialmay comprise natural or synthetic waxes, fatty alcohols (such 30as Iaury!, myristyl, stearyl, cetyl or preferably cetostearylalcohol), fatty acids, including but not limited to fatty acidesters, fatty acid glycerides (mono-, di-, and tri-glycerides),hydrogenated fats, hydrocarbons, normal waxes, stearic acid,stearyl alcohol and hydrophobic and hydrophilic materialshaving hydrocarbon backbones. Suitable waxes include, forexample, beeswax, glycowax, castor wax and camaub a wax.For purposes of the present invention, a wax-like substance isdefined as any material which is normally solid at roomtemperature and has a melting point offrom about 30 to about100 C. In certain preferred embodiments, the dosage formcomprises a sustained release matrix comprising an opioidanalgesic; one or more aversive agents; and at least one watersoluble hydroxyalkyl cellulose, at least one C 12 -C36 , preferably C14-C22 , aliphatic alcohol and, optionally, at least onepolyalkylene glycol. The hydroxyalkyl cellulose is preferablya hydroxy (C1 to C 6 ) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, especially,hydroxyethyl cellulose. The amount of the at least onehydroxyalkyl cellulose in the present oral dosage form maybe determined, inter alia, by the precise rate of opioid analgesic release required. TI1e aliphatic alcohol may be, forexample, Iaury! alcohol, myristyl alcohol or stearyl alcohol.

(c) optionally, compressing and shaping the granules.The granules may be formed by any of the procedureswell-known to those skilled in the art of pharmaceutical for-

40 mulation. For example, in one preferred method, the granulesmay be formed by wet granulating the hydroxyalkyl cellulose, opioid analgesic, and one or more aversive agents withwater. In a particularly preferred embodiment of his process,the amount of water added during the wet granulation step is45 preferably between 1.5 and 5 times, especially between 1.75

and 3.5 times, the dry weight of he opioid analgesic. Optionally, the opioid analgesic and/or the one or more aversiveagents are add ed extragranularly.A sustained-release matrix can also be prepared by, e.g.,50 melt-granulation or melt-extrusion techniques. Generally,melt-granulation teclmiques involve melting a normally solidhydrophobic binder material, e.g., a wax, and incorporating apowdered drug therein. To obtain a sustained release dosageform, it may be necessary to incorporate a hydrophobic sus-n particularly preferred embodiments of the present oraldosage form, however, the at least one aliphatic alcohol iscetyl 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 opioid analgesicrelease required. It may also depend on whether at least onepolyalkylene glycol is present in or absent from the oral 60dosage form. In the absence of at least one polyalkyleneglycol, the oral dosage form preferably contains betweenabout 20% and about 50% (by wt) of tlie aliphatic alcohol.

When a polyalkylene glycol is present in the oral dosageform, then the combined weight of the aliphatic alcohol andthe polyalkylene glycol preferably constitutes between about20% and about 50% (by wt) of the total dosage form.

55 tained-release material, e.g. ethylcellulose or a water-insoluble acrylic polymer, into the molten wax hydrophobicbinder material. Examples of sustained-release formulationsprepared via melt-granulation teclmiques are found, e.g., inU.S. Pat. No. 4,861,598.The additional hydrophobic binder material may compriseone or more water-insoluble wax-like thermoplastic substances possibly mixed with one or more wax-like thermoplastic substances being less hydrophobic than said one ormore water-insoluble wax-like substances. In order to

65 achieve sustained release, the individual wax-like substancesin the formulation should be substantially non-degradableand insoluble in gastrointestinal fluids during the initial



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release phases. Useful water-insoluble wax-like binder substances may be those with a water-solubility that is lower thanabout 1:5,000 (w/w).

18plurality of the melt-extmded matrix multi particulates maybe placed in a gelatin capsule in an amount sufficient toprovide an effective sustained release dose when ingested andcontacted by gastrointestinal fluid.In another embodiment, a suitable amount of the multiparticulate extmdate is compressed into an oral tablet usingconventional tableting equipment using standard techniques.Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and

10 pills are also described in Remington's Pharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980).

TI1e preparation of a suitable melt -extmded matrix according to the present invention may, for example, include thesteps of blending the opioid analgesic and at least one aversive agent, together with a sustained release material andpreferably 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 toextmde the same. The resulting homogeneous mixture is thenextmded, e.g., using a twin-screw extmder, to form strands.TI1e extmdate is preferably cooled and cut into multiparticulates by any means known in the art. The matrix multiparticulates are then divided into unit doses. The extmdate prefer- !5ably has a diameter of from about 0.1 to about 5 mm andprovides sustained release of he opioid analgesic or pharmaceutically acceptable salt thereof for a time period of at leastabout 12 hours.An optional process for preparing the melt extmded for-mulations of he present invention includes directly meteringinto an extruder a hydrophobic sustained release material, theopioid analgesic, one or more aversive agents, and an optionalbinder material; heating the homogenous mixture; extmdingthe homogenous mixture to thereby form strands; cooling thestrands containing the homogeneous mixture; cutting thestrands into matrix multiparticulates having a size from about0.1 mm to about 12 mm; and dividing said particles into unitdoses. In this aspect of the invention, a relatively continuousmanufacturing procedure is realized..Optionally, the one or more aversive agents may be addedto a dosage form including multiparticulates comprisingopioid analgesic (without the one or more aversive agents).Plasticizers, such as those described above, may beincluded in melt-extmded matrices. The plasticizer is preferably included as fromaboutO.l to about 30% by weightof hematrix. Other pharmaceutical excipients, e.g., talc, mono orpoly saccharides, lubricants and the like may be included inthe sustained release matrices of the present invention asdesired. The amounts included will depend upon the desiredcharacteristic to be achieved.The diameter of the extmder aperture or exit port can beadjusted to vary the thickness of the extruded strands. Furthermore, the exit partof he extruder need not be round; it canbe oblong, rectangular, etc. The exiting strands can bereduced to particles using a hot wire cutter, guillotine, etc.A melt extruded matrix multi particulate system can be, forexample, in the form ofgranules, spheroids or pellets depending upon the extruder exit orifice. For purposes of he present

In yet another preferred embodiment, the extmdate can beshaped into tablets as set forth in U.S. Pat. No. 4,957,681(Klimesch, ct. a!.).Optionally, the sustained-release matrix multiparticulatesystems, tablets, or capsules can be coated with a sustainedrelease coating such as the sustained release coatingsdescribed herein. Such coatings preferably include a sufficient amount of hydrophobic and/or hydrophilic sustained-20 release material to obtain a weight gain level from about 2 toabout 25 percent, although the overcoat may be greaterdepending upon, e.g., the desired release rate. The coating canoptionally contain one or more of he aversive agents. In suchembodiments, an optional second overcoat can be applied as25 to minimize the perception of the aversive agent when adosage form of the present invention is administered intact.The dosage forms of the present 'invention may furtherinclude combinations of melt-extruded matrix multi particulates containing an opioid analgesic; one or more aversive30 agents; or mixtures thereof. Furthermore, the dosage formscan also include an amount of an immediate release opioidanalgesic for prompt therapeutic effect. The immediaterelease opioid analgesic may be incorporated, e.g., as separate multiparticulates within a gelatin capsule, or may be35 coated on the surface of, e.g., melt extruded matrix multi particulates.The sustained-release profile of the melt-extruded formulations of the invention can be altered, for example, by varying the amount of sustained-release material, by varying the40 amount of plasticizer relative to other matrix constituents, byvarying the amount ofhydrophobic material, by the inclusion

ofadditional ingredients or excipients, by altering the methodof manufacture, etc.In other embodiments of he invention, melt-extmded for-

45 mulations are prepared without the inclusion of the opioidanalgesic; one or more aversive agents; or mixtures thereof;which is added thereafter to the extmdate. Such formulationstypically will have the opioid analgesic; one ormore aversiveinvention, the tenns "melt-extmded matrix 50 agents; or mixtures thereof blended together with theextruded matrix material, and then the mixture would betableted in order to provide a slow release formulation. Suchultiparticulate(s)" and "melt-extruded matrix multi particulate system(s)" and "melt-extruded matrix particles" shallrefer to a plurality of units, preferably within a range ofsimilar size and/or shape and containing one or more activeagents and one or more excipients, preferably including a 55hydrophobic sustained release material as described herein.Preferably the melt-extruded matrix multi particulates will beofarangeoffromabout0.1 to about 12mminlengthandhavea diameter of from about 0.1 to about 5 mm. In addition, it isto be understood that the melt-extruded matrix multiparticu- 60lates can be any geometrical shape within this size range. Incertain embodiments, the extmdate may simply be cut intodesired lengths and divided into unit doses of the therapeutically active agent without the need of a spheronization step.In one preferred embodiment, oral dosage fom1s are pre- 65pared that include an effective amount of melt-extmdedmatrix multiparticulates within a capsule. For example, a

formulations may be advantageous, for example, when theopioid analgesic; one or more aversive agents; or mixturesthereof included in the formulation is sensitive to temperatures needed for softening the hydrophobic material and/orthe retardant material.Typical melt-extrusion production systems suitable for usein accordance with the present invention include a suitableextruder drive motor having variable speed and constanttorque control, start-stop controls, and a meter. In addition,the production system will include a temperature controlconsole which includes temperature sensors, cooling meansand temperature indicators throughout the length of theextmder. In addition, the production system will include anextmder such as a twin-screw extruder which consists of wocounter-rotating intenneshing screws enclosed within acyl-inder or barrel having an aperture or die at the exit thereof.



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The feed materials enter through a feed hopper and are movedthrough the barrel by the screws and arc forced through the dieinto strands which are thereafter conveyed such as by a continuous movable belt to allow for cooling and being directedto a pelletizer or other suitable device to render the extrudedropes into the matrix multiparticulate system. The pelletizercan consist ofrollcrs, fixed knife; rotating cutter and the like.Suitable instruments and systems are available from distributors such as C.W. Brabender Instruments, Inc. ofSouth Hackensack, N.J. Other suitable apparatus will be apparent to thoseof ordinary skill in the art.A further aspect of the invention is related to the preparation of melt-extruded matrix multiparticulates as set forthabove in a manner which controls the amount of air includedin the extruded product. By controlling the amount of airincluded in the cxtrudate, the release rate of the opioid analgesic, one or more aversive agents, or mixtures thereof maybe altered.Thus, in a further aspect of he invention, the melt-extrudedproduct is prepared in a marmer which substantially excludesair during the extrusion phase of the process. This may beaccomplished, for example, by using a Leistritz extruder having a vacuum attachment. The extruded matrix multi particulates prepared according to the invention using the Leistritzextruder under vacuum provides a melt-extruded producthaving different physical characteristics. In particular, theextrudate is substantially non-porous when magnified, e.g.,using a scanning electron microscope which provides anSEM (scanning electron micrograph). Such substantiallynon-porous formulations may provide a faster release of thetherapeutically active agent, relative to the same formulationprepared without vacuum. SEMs of the matrix multi particulates prepared using an extruder under vacuum appear verysmooth, and the multi particulates tend to be more robust thanthose multi particulates prepared without vacuum. It has beenobserved that in at least certain formulations, the use of extrusion under vacuum provides an extruded matrix multiparticulate product which is more pH-dependent than its counterpartformulation prepared without vacuum.Alternatively, the melt-extruded product is prepared usinga Werner-Pfleiderer twin screw extruder.In certain embodiments, a spheronizing agent is added to agranulate or matrix multiparticulate and then spheronized toproduce sustained release spheroids. The spheroids are thenoptionally overcoated with a sustained release coating bymethods such as those described above.

20multiparticulates. In such embodiments, the sustained-release coating may include a water insoluble material such as(a) a wax, either alone or in admixture with a fatty alcohol; or(b) shellac or zein. The coating is preferably derived from anaqueous dispersion of the hydrophobic

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