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US 2005O112067A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0112067 A1 Kumar et al. (43) Pub. Date: May 26, 2005

(54) METHODS AND COMPOSITIONS FOR (22) Filed: Nov. 26, 2003 DETERRING ABUSE OF OPOD CONTAINING DOSAGE FORMS Publication Classification (76) Inventors: Vijai Kumar, Morris Plains, NJ (US); (51) Int. Cl.' ...... A61 K 49/00; A61K 31/485 David Dixon, Woodside, NY (US); (52) U.S. Cl...... 424/10.1; 514/282 Divya Tewari, Suffern, NY (US); Dilip B. Wadgaonkar, Suffern, NY (US) (57) ABSTRACT Correspondence Address: MORGAN, LEWIS & BOCKIUS LLP 1701 MARKET STREET This invention relates to an abuse deterrent dosage form of PHILADELPHIA, PA 19103-2921 (US) , wherein an analgesically effective amount of opioid is combined with a polymer to form a (21) Appl. No.: 10/723,654 matrix. Patent Application Publication May 26, 2005 Sheet 1 of 9 US 2005/0112067 A1

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METHODS AND COMPOSITIONS FOR parenteral (e.g. intravenous injection), 2) intranasal (e.g., DETERRING ABUSE OF OPOD CONTAINING Snorting), and 3) repeated oral ingestion of excessive quan DOSAGE FORMS tities of orally administered tablets or capsules. One mode of abuse of oral Solid drugs involves the extraction of the FIELD OF INVENTION opioid component from the dosage form by first mixing the dosage form with a Suitable Solvent (e.g., water), and then 0001. This invention pertains to abuse deterrent compo Subsequently extracting the opioid component from the Sitions containing a drug (e.g., an analgesic opioid). Addi mixture for use in a Solution Suitable for intravenous injec tionally, the invention relates to a method of administering tion of the opioid to achieve a “high.” a dose of an analgesic from a dosage form, which is abuse deterrent. 0007 Attempts have been made to diminish abuse of orally administered opioid drugs. These attempts generally centered on the inclusion in the oral dosage form of an BACKGROUND OF THE INVENTION which is not orally active but which will 0002 The class of drugs exhibiting or morphine Substantially block the analgesic effects of the opioid if one like properties are referred to as opioids, or opioid agonists. attempts to dissolve the opioid and administer it parenterally. Certain opioids act as agonists, interacting with Stereo 0008 For example, commercially available Talwing)NX Specific and Saturable binding sites in the brain and other tablets from Sanofi-Winthrop contain a combination of tissues. Endogenous opioid-like peptides are present in areas and . Pentazocine is a of of the central nervous System that are presumed to be related tl receptors and also has affinity for K receptors, whereas, to the perception of pain; to movement, mood and behavior, naloxone is an antagonist of u receptors. Talwin RNX con and to the regulation of neuroendocrinological functions. tains pentazocine hydrochloride equivalent to 50 mg base Three classical types, mu (), delta (Ö), and and naloxone hydrochloride equivalent to 0.5 mg base. kappa (K), have been Studied extensively. Each of these Talwin ENX is indicated for the relief of moderate to severe receptorS has a unique anatomical distribution in the brain, pain. The amount of naloxone present in this combination Spinal cord, and the periphery. Most of the clinically used has no action when taken orally, and will not interfere with opioids are relatively Selective for u receptors, reflecting the pharmacologic action of pentazocine. However, this their similarity to morphine. However, it is important to note amount of naloxone given by injection has profound antago that opioid containing drugs that are relatively Selective at nistic action to opioid analgesics. Thus, the inclusion of standard doses will often interact with additional receptor naloxone is intended to curb a form of misuse of oral Subtypes when given at Sufficiently high doses, leading to pentazocine, which occurs when the dosage form is Solubi possible changes in their pharmacological effect. This is lized and injected. Therefore, this dosage has lower potential especially true as opioid doses are escalated to overcome for parenteral misuse than previous oral pentazocine formu tolerance. lations. 0003. The potential for the development of tolerance, 0009 U.S. Pat. No. 6.559,159 (Carroll et al.) describes physical and/or psychological, dependence (i.e., addiction) the use of kappa receptors antagonist for the treatment of with repeated opioid use is a characteristic feature of most opioid related addictions. One Such compound is , opioid containing drugs. The possibility of developing which is commercially available in the tablet form Revia(E) addiction is one of the major concerns in the use of opioids for the treatment of dependence and for the blockade for the management of pain. Another major concern asso of exogenously administered opioids. (Physicians Desk Ref ciated with the use of opioids is the diversion of these drugs from a patient in legitimate pain to other individuals (non erence 57" ed., Montvale, N.J.) patients) for recreational purposes. 0010 U.S. Pat. No. 6,375,957 (Kaiko et al.) describes in detail the combination of opioid agonist, NSAID, and an 0004 Drug abusers and/or addicts typically may take a orally active opioid antagonist. The purpose of adding the dosage form containing one or more opioid analgesics and opioid antagonist is the same as discussed above. crush, shear, grind, chew, dissolve and/or heat, extract or otherwise damage the product So that a significant amount or 0.011 U.S. Pat. No. 4,457.933 (Gordon et al.) describes in even an entire amount of the drug becomes available for detail a method for decreasing both the oral and parenteral immediate absorption by 1) injection, 2) inhalation, and/or abuse potential of analgesic agents Such as Oxycodone, 3) oral consumption. propoxyphene and pentazocine by combining an analgesic dose of the analgesic agents with naloxone in Specific, 0005 There are three basic patterns of behavior leading relatively narrow ranges. to opioid abuse. The first involves individuals whose opioid drug use begins in the context of medical treatment and who 0012 U.S. Pat. No. 6.228,863 B1 (Palermo et al.) obtain their initial drug Supplies through prescriptions from describes a method for reducing the abuse potential of an physicians. The Second begins with experimental or “recre oral dosage form of an opioid analgesic, whereby an orally ational’ drug use and progresses to more intensive use. A active opioid agonist is combined with an opioid antagonist third pattern of abuse involves users who begin in one or into an oral dosage form requiring at least a two-step another of the preceding ways but later Switch to oral opioids extraction process to be separated from the opioid agonist, Such as , obtained from organized addiction treat the amount of opioid antagonist included being Sufficient to ment programs. counteract opioid effects if extracted together with the opioid agonist and administered parenterally. 0006 There are various routes of administration an abuser may commonly attempt to abuse an opioid containing 0013 The prior art describes several other methods and drug formulation. The most common methods include 1) compositions to minimize the abuse of an opioid containing US 2005/01 12067 A1 May 26, 2005

drug. One such method is discussed in U.S. Pat. No. Such that emesis ensues only if more than a prescribed 6,593,367 (Dewey et al.), describing a method whereby the amount of the analgesic is consumed, and combining the addiction-related behavior of a mammal Suffering from analgesic, gel forming polymer, nasal tissue irritant and addiction could be changed by a combination of drugs. The emetic to form a therapeutic composition. method includes administering to the mammal an effective 0019. The present invention includes a therapeutic phar amount of gamma vinyl GABA (GVG) or a pharmaceuti maceutical composition including an analgesic, a gel form cally acceptable Salt, or an enantiomer or a racemic mixture, ing polymer, a Surfactant present in Sufficient amount to where the effective amount is Sufficient to diminish, inhibit cause mucosal tissue irritation, and an emetic in Sufficient or eliminate behavior associated with craving or use of the amount to cause emesis if greater than a prescribed amount combination of abused drugs. of the analgesic included in the therapeutic composition is 0014 U.S. Pat. Nos. 4,175,119 and 4,459.278 (Porter et ingested. al.) describe compositions and methods useful for the pre vention of accidental and/or intentional oral overdoses of a 0020 Compositions and methods of the present invention drug. can deter abuse of the analgesic by forming a Viscous gel upon contact with a Solvent Such that the gel and analgesic 0.015. In summary, various attempts have been made and cannot be easily drawn into a Syringe and/or by inducing are described in prior art to develop abuse-deterrent dosage nasal irritation if the composition is inhaled, and/or by forms. Clearly there is a need for a delivery system for inducing emesis if more than a prescribed dosage amount of commonly used oral dosage formulations (e.g., immediate the analgesic is consumed. release, Sustained or extended release and delayed release) of drugs, and in particular analgesicS Such as opioid anal BRIEF DESCRIPTION OF THE DRAWINGS gesics, for patients Seeking drug therapy and which deters abuse and minimizes or reduces the potential for physical or 0021. The present invention will be better understood by psychological dependency. examining the following figures which illustrate certain properties of the present invention wherein: SUMMARY OF THE INVENTION 0022 FIG. 1 shows a percentage amount of certain 0016. The present invention includes a therapeutic phar opioid drugs available in Solution for injection after Standard maceutical composition including an analgesic, a gel form dosage forms are crushed and exposed to a Solvent; ing polymer, a surfactant present in sufficient amount to 0023 FIG. 2 shows a percentage amount of certain cause nasal irritation, and an inert excipient in Sufficient opioid drugs available in Solution for injection after dosage amount to cause emesis if greater than a prescribed amount forms of the present invention are crushed and exposed to a of the analgesic included in the therapeutic composition is Solvent; ingested. The present invention also includes a therapeutic pharmaceutical composition including an analgesic, a gel 0024 FIG. 3 shows an amount of drug recoverable from forming polymer, a Surfactant present in Sufficient amount to a solvent contacted with five embodiments of the present cause nasal irritation, and an emetic in Sufficient amount to invention compared to a Standard formulation; cause emesis if greater than a prescribed amount of the 0025 FIG. 4 shows a dissolution profile of six embodi analgesic included in the therapeutic composition is ments of the present invention; ingested. 0026 FIG. 5a shows various methods used to formulate 0.017. In one embodiment, the therapeutic pharmaceutical the dosage forms having one or more abuse deterrent composition can be formed into a unit dose including an properties of the present invention; opioid analgesic, a gel forming polymer, a nasal tissue irritating amount of a Surfactant, and an emetic in Sufficient 0027 FIG. 5b shows a particular dosage form having one amount to cause emesis if greater than a prescribed amount or more abuse deterrent properties of the present invention; of the analgesic included in the therapeutic composition is 0028 FIG. 5c shows a particular dosage form having one ingested. In one embodiment, the polymer includes one or or more abuse deterrent properties of the present invention more of polyethylene oxide (e.g., having average molecular and a disintegrant; weight ranging form about 300,000 to about 5,000,000), polyvinyl alcohol (e.g., having a molecular weight of about 0029 FIG. 6 shows a process flow chart for the manu 20,000 to 200,000), hydroxypropyl methyl cellulose (e.g., facture of a dosage form of the present invention; and having a molecular weight of about 10,000 to 1,500,000), 0030 FIG. 7 shows a dissolution profile of three and a carbomer (e.g., having a molecular weight ranging of extended release formulations of the present invention. about 700,000 to 4,000,000,000), the nasal irritant includes about 1 to 5 percent by weight Sodium lauryl Sulfate, and the 0031. With reference to the Figures, features that are the emetic includes less than about 0.6 to 2.0gm of Zinc Sulfate. Same across the Figures are denoted with the same reference numbers. 0.018. The present invention also provides methods of making a pharmaceutical composition Suitable for deterring DETAILED DESCRIPTION OF THE drug abuse including one or more Steps of providing an INVENTION analgesic, a gel forming polymer having a Suitable Viscosity, a nasal tissue irritant and emetic, controlling the molecular 0032. The present invention includes an abuse deterrent weight or Viscosity of the gel forming polymer, controlling formulation for reducing the potential for one or more of a) the amount of nasal tissue irritant Such that nasal tissue parenteral abuse, b) inhalation (e.g., intranasal abuse), and/ irritation occurs if inhaled, controlling the amount of emetic or c) oral abuse of a drug, typically an opioid analgesic type US 2005/01 12067 A1 May 26, 2005 drug, for Satisfaction of a physical or psychological depen which includes an analgesic, one or more gel forming dence. In one embodiment, the present invention deters agents, one or more mucous membrane irritants and/or nasal parenteral abuse by providing a pharmaceutical composition passageway tissue irritants, and one or more emetics. which includes an analgesic with one or more gel forming agents Such that upon contact with a Solvent (e.g., water), the 0037 Each of the components of the pharmaceutical agents Swell by absorbing the Solvent thereby 1) entrapping composition of the present invention are described in more the drug in a gel matrix and/or 2) reducing or preventing a detail below. Significant amount of the opioid analgesic from being drawn 0038 A. Drugs Suitable for Use With the Present Inven into a Syringe. In one embodiment, the present invention tion deters inhalation abuse by providing a pharmaceutical com position which includes a therapeutically active pharmaceu 0039. Any drug, therapeutically acceptable drug salt, tical (e.g., an analgesic), with one or more mucous mem drug derivative, drug analog, drug homologue, or poly brane, mucosa or mucosal tissue irritants (collectively morph can be used in the present invention. In one embodi referred to as mucous membrane irritants). In one embodi ment, the drug can be orally administered. In certain ment, the mucosal tissue is nasal passageway tissue. embodiments, drugs Susceptible to abuse are used. Drugs commonly Susceptible to abuse include psychoactive drugs 0033. Upon contact with a mucous membrane, the irri and analgesics, including but not limited to opioids and tants induce temporary pain and/or irritation of the mem drugs that can cause psychological and/or physical depen branes and/or tissues to thereby deter abuse. For example, if dence on the drug. inhaled by Snorting, the mucous membrane in the nasal passageway will be irritated and result in pain to the indi 0040. A drug for use in the present invention can be one vidual. In one embodiment, the present invention provides a or more of the following: , amphetamines, pharmaceutical composition which includes an analgesic , , , , , with one or more emetics, Such that after oral consumption diacetylmorphine, , , of more than a typically prescribed amount of the dosage , diprenorphine, , , hydroc form, emesis is induced. odone, , B-hydroxy-3-methylfentanyl, levo O-, , , meperidine, 0034. In one embodiment, two or more of the abuse methadone, methylphenidate, morphine, , deterrents can be combined into one composition according , O-, naloxone, naltrexone, Oxy to the present invention. codone, , pentazocine, , pro poxyphene, , , and tramodol, 0035. The present invention describes formulations Salts, derivatives, analogs, homologues, polymorphs thereof, which have abuse deterrent properties as described herein. Examples of Specific oral Solid dosage forms containing and mixtures of any of the foregoing. morphine, hydrocodone and oxycodone were evaluated 0041. In one embodiment, a pharmaceutical composition using suitable analytical test methods, such as UVNVIS of the present invention includes one or more opioids Such Spectrophotometry. In the evaluation, dosage forms were as hydrocodone, morphine and oxycodone and/or Salts crushed and contacted with a Small amount of water (about thereof, as the therapeutically active ingredient. Typically a teaspoon or tablespoon). After attempting to dissolve the when processed into a Suitable dosage form, as described in dosage form, the resultant material was drawn into a Syringe, more detail below, the drug can be present in Such dosage Volume was measured and opioid content was quantitated. forms in an amount normally prescribed, typically about 0.5 As shown in FIG. 1, almost 100% of the opioid can be to about 25 percent on a dry weight basis, based on the total extracted from Standard formulations. Comparatively, as weight of the formulation. shown in FIG. 2, an abuse deterrent formulation of the present invention for the same opioids, provides a signifi 0042. With respect to analgesics in unit dose form, such cantly lower percentage of extractable opioid. AS shown in an amount can be typically from about 5, 25, 50, 75, 100, FIG. 1, approximately 93%, 103% and 99% of the opioid 125, 150, 175 or 200 mg. More typically, the drug can be analgesic drugs contained in a dosage form were recoverable present in an amount from 5 to 500 mg or even 5 to 200 mg. using the above described techniques. Comparatively, as In other embodiments, a dosage form contains an appropri shown in FIG. 2, using an abuse deterrent polymer of the ate amount of drug to provide a therapeutic effect. present invention, only 9%, 5%, and 6% of the opioid 0043 B. Gel Forming Agents analgesic drugs were recoverable. 0044 As described above, the present invention can 0036). In another embodiment, the present invention is a include one or more gel forming agents. The total amount of pharmaceutical composition that includes an opioid analge gel forming agent is typically about 3 to about 40 percent on Sic, one or more gel forming agents, and one or more a dry weight basis of the composition. mucous membrane irritants or nasal passageway tissue irri tants. In another embodiment, the present invention includes 0045 Suitable gel forming agents include compounds a pharmaceutical composition, which includes an analgesic, that, upon contact with a Solvent (e.g., water), absorb the one or more gel forming agents and one or more emetics as Solvent and Swell, thereby forming a Viscous or Semi described herein. In another embodiment, the present inven Viscous Substance that significantly reduces and/or mini tion includes a pharmaceutical composition, which includes mizes the amount of free Solvent which can contain an an opioid analgesic, one or more mucous membrane irritants amount of Solublized drug, and which can be drawn into a or nasal passageway tissue irritants and one or more emetics Syringe. The gel can also reduce the Overall amount of drug as described herein. In one particular embodiment, the extractable with the Solvent by entrapping the drug in a gel present invention includes a pharmaceutical composition matrix. In one embodiment, typical gel forming agents US 2005/01 12067 A1 May 26, 2005 include pharmaceutically acceptable polymers, typically Specific gravity of the polyvinyl alcohol can range from hydrophilic polymers, Such as hydrogels. about 1.19 to about 1.31 and the viscosity from about 4 to about 65 cps. The polyvinyl alcohol used in the formulation 0046. In some embodiments, the polymers exhibit a high is preferably a water-Soluble Synthetic polymer represented degree of Viscosity upon contact with a Suitable Solvent. The by -(-CHO-), , where n can range from about 500 high Viscosity can enhance the formation of highly viscous to about 5,000. Examples of Suitable, commercially avail gels when attempts are made by an abuser to crush and able polyvinyl alcohol polymers include PVA, USP, avail dissolve the contents of a dosage form in an aqueous vehicle able from Spectrum Chemical Manufacturing Corporation, and inject it intravenously. New Brunswick, N.J. 08901. 0047 More specifically, in certain embodiments the poly meric material in the present invention provides Viscosity to 0056) c) Hydroxypropyl Methyl Cellulose the dosage form when it is tampered. In Such embodiments, 0057. In one embodiment, the gel forming agent includes when an abuser crushes and dissolves the dosage form in a hydroxypropyl methyl cellulose (Hypromellose). The Solvent (e.g., water or Saline), a Viscous or semi-Viscous gel hydroxypropyl methyl cellulose can have a molecular is formed. The increase in the viscosity of the solution weight ranging from about 10,000 to about 1,500,000, and discourages the abuser from injecting the gel intravenously typically from about 5000 to about 10,000, i.e., a low or intramuscularly by preventing the abuser from transfer molecular weight hydroxypropyl methyl cellulose polymer. ring Sufficient amounts of the Solution to a Syringe to cause The Specific gravity of the hydroxypropyl methyl cellulose a desired "high” once injected. can range from about 1.19 to about 1.31, with an average 0.048 Suitable polymers include one or more pharmaceu specific gravity of about 1.26 and a viscosity of about 3600 tically acceptable polymerS Selected from any pharmaceu to 5600. The hydroxypropyl methylcellulose used in the tical polymer that will undergo an increase in Viscosity upon formulation can be a water-Soluble Synthetic polymer. contact with a solvent. Preferred polymers include polyeth 0058 Examples of Suitable, commercially available ylene oxide, polyvinyl alcohol, hydroxypropyl methyl cel hydroxypropyl methylcellulose polymers include Methocel lulose and carbomers. In preferred embodiments, the poly K10OLV and Methocel K4M, available from Dow chemi mers include: cals. 0049 a) Polyethylene Oxide 0059) d) Carbomers 0050. In some embodiments, the polymer includes poly 0060. In one embodiment, the present invention includes ethylene oxide. The polyethylene oxide can have an average carbomers. The carbomers can have a molecular weight molecular weight ranging from about 300,000 to about ranging from 700,000 to about 4,000,000,000. The viscosity 5,000,000, more preferably from about 600,000 to about of the polymer can range from about 4000 to about 39,400 5,000,000, and most preferably at least about 5,000,000. In cpS. Examples of Suitable, commercially available car one embodiment, the polyethylene oxide includes a high bomers include carbopol 934P NF, carbopol 974P NF and molecular weight polyethylene oxide. carbopol 971 PNF, available from Noveon Pharmaceuticals. 0051. In one embodiment, the average particle size of the 0061 Following the teachings set forth herein, other polyethylene oxide ranges from about 840 to about 2,000 Suitable gel forming agents can include one or more of the microns. In another embodiment, the density of the poly following polymers: ethylcellulose, cellulose acetate, cellu ethylene oxide can range from about 1.15 to about 1.26 g/ml. lose acetate propionate, cellulose acetate butyrate, cellulose In another embodiment, the Viscosity can range from about acetate phthalate and cellulose triacetate, cellulose ether, 8,800 to about 17,600 cps. cellulose ester, cellulose ester ether, and cellulose, acrylic 0.052 The polyethylene oxide used in a directly com resins comprising copolymerS Synthesized from acrylic and pressible formulation of the present invention is preferably methacrylic acid esters, the acrylic polymer may be Selected a homopolymer having repeating oxyethylene groups, i.e., from the group consisting of acrylic acid and methacrylic -(-O-CH-CH2-)-, where n can range from about acid copolymers, methyl methacrylate copolymers, ethoxy 2,000 to about 180,000. Preferably, the polyethylene oxide etlryl methacrylates, cyanoetlryl methacrylate, poly(acrylic is a commercially available and pharmaceutically acceptable acid), poly(methaerylic acid), methacrylic acid alkylamide homopolymer having moisture content of no greater than copolymer, poly(methyl methacrylate), polymethacrylate, about 1% by weight. Examples of Suitable, commercially poly(methyl methacrylate) copolymer, polyacrylamide, ami available polyethylene oxide polymers include PolyoxOR), noalkyl methacrylate copolymer, poly(methacrylic acid WSRN-1105 and/or WSR-coagulant, available from Dow anhydride), and glycidyl methacrylate copolymers. chemicals. 0062) Any of the above described polymers can be com 0053. In some embodiments, the polyethylene oxide bined together or combined with other Suitable polymers, powdered polymers can contribute to a consistent particle and Such combinations are within the Scope of the present Size in a directly compressible formulation and eliminate the invention. problems of lack of content uniformity and possible Segre 0063. In one embodiment, the abuse deterrent, gel form gation. ing agent can prevent leSS than or equal to about 95%, 94%, 0054 b) Polyvinyl Alcohol 70%, 60%, 54%, 50%, 45%, 40%, 36%, 32%, 30%, 27%, 20%, 10%, 9%, 6%, 5% or 2% of the total amount of drug 0055. In one embodiment, the gel forming agent includes in a dosage form from being recovered from a Solvent in polyvinyl alcohol. The polyvinyl alcohol can have a molecu contact with a dosage form of the present invention. AS lar weight ranging from about 20,000 to about 200,000. The shown in FIG. 3, formulations A3, B3, C3, D3 and E3 US 2005/01 12067 A1 May 26, 2005

reduce the amount of drug extractable or recoverable from 0071. In one embodiment, the present invention includes a dosage for of the present invention. Specifically, formu one or more mucous membrane irritants to cause irritation of lation A3 provides for recovery of 26.77% of the total mucous membranes located anywhere on or in the body, amount of drug in the dosage form, formulation B3 provides including membranes of the mouth, eyes and intestinal tract. for recovery of 31.8% of the total amount of drug in the Such compositions can deter abuse Via oral, intra-ocular or dosage form, formulation C3 provides for recovery of rectal or vaginal routes. 35.75% of the total amount of drug in the dosage form, formulation D3 provides for recovery of 35.8% of the total 0072 The above-described irritants can be further opti amount of drug in the dosage form, and formulation E3 mized as necessary or desired in terms of concentration, provides for recovery of 42.5% of the total amount of drug irritation Severity, etc. in the dosage form. In FIG. 3, all five formulations A3 through E3 are compared with a Standard dosage form of 0.073 D. Emetics oxycontin, which provided for recovery of 98.6% of the total 0074 As described above, the present invention can amount of drug in the dosage form. include one or more emetics or emesis inducing agents. Preferably, the emetic is a pharmaceutically acceptable inert 0064. The five formulations A3 through E3 are set forth excipient that only induces emesis after a certain threshold in Examples 14 through 18, respectively. amount is ingested. In another embodiment, the emetic can 0065. It should be noted that the above described formu be a pharmaceutically active emetic. lations also have dissolution profiles as determined by the 0075. In one embodiment, the amount of emetic present USP2-paddle method, as shown in FIG. 4. In particular, for in a pharmaceutical composition of the present invention can formulations A3 through E3, about 50% to about 82% of be tied directly to the amount of drug in the pharmaceutical each formulation dissolves after about 15 minutes and about composition. Thus, by controlling the quantity of the emetic 80% to about 95% dissolves after 90 minutes. FIG. 4 further compound in the pharmaceutical composition, emesis can be includes the dissolution profile of Formulation F3. With avoided if normal prescription directions are followed. respect to FIG. 4, the composition of formulation F3 is set However, if an overdosage occurs by ingesting more than a forth in Example 19. prescribed quantity of a drug in a pharmaceutical composi 0.066 The above described gel forming agents can be tion of the present invention, the amount of ingested emetic further optimized as necessary or desired in terms of vis can exceed the threshold amount necessary to induce eme cosity, molecular weight, etc. SS. 0067) C. Mucous Membrane Irritants and/or Nasal Pas 0076. In some embodiments, the threshold amount of Sageway Tissue Irritants emetic for inducing emesis can be reached when the normal prescription directions are inappropriately increased by fac 0068. As described above, the present invention can tors of 2, 3, 4, 5, 6, 7, or 8 times, or more. Thus, in Some include one or more mucous membrane irritants and/or nasal embodiments, the amount of emetic present in a pharma passageway tissue irritants. In one embodiment, Suitable ceutical composition of the present invention is an amount mucous membrane irritants and/or nasal passageway tissue Such that the amount of emetic ingested does not exceed the irritants include compounds that are generally considered threshold amount necessary for inducing emesis until a pharmaceutically inert, yet can induce irritation. Such com Subject ingests 2, 3, 4, 5, 6, 7, or 8 or more times the amount pounds include, but are not limited to Surfactants. In one of drug normally prescribed. In Some embodiments, emesis embodiment, Suitable Surfactants include Sodium lauryl Sul can preclude death or Serious illness in the Subject. fate, poloxamer, Sorbitan monoesters and glyceryl monooleates. Other suitable compounds are believed to be 0077. In one embodiment, the emetic includes zinc sul within the knowledge of a practitioner skilled in the relevant fate. Zinc Sulfate is an excipient, which can induce emesis when more than about 0.6 to 2.0 gm is ingested, typically art, and can be found in the Handbook of Pharmaceutical more than about 0.6 gm, or about 5 to 25 percent by weight Excipients, 4th Ed. (2003), the entire content of which is on a Solid basis, more typically about 5 to 10 percent by hereby incorporated by reference. weight. Accordingly, pharmaceutical compositions of the 0069. In one embodiment of the present invention, the present invention can be easily designed to induce emesis if irritant can be present in amount of from 1 to 10 percent by a prescribed dosage is exceeded and/or if prescription direc weight on a Solid basis, preferably 1 to 5 percent by weight tions are not followed for dosage forms containing a com on a Solid basis. In another embodiment, the amount of position of the present invention. Typically, Suitable embodi irritant can be present in an amount from 1 to 3 percent by ments of the present invention include less than about 0.6 to weight. 2.0 gm of Zinc Sulfate. 0070. In certain embodiments, the irritant can deter abuse 0078 For example, in one embodiment, if a practitioner of a dosage form when a potential abuser tampers with a desires to create a dosage form that will induce emesis only dosage form of the present invention. Specifically, in Such after four or more dosage forms are ingested, the amount of embodiments, when an abuser crushes the dosage form, the Zinc Sulfate in each dosage form should not exceed about irritant is exposed. The irritant discourages inhalation of the 0.19 gm. Thus, if three dosage forms are ingested, the crushed dosage form by inducing pain and/or irritation of the amount of emetic is 0.57 gm, which is less than a typical abuser's mucous membrane and/or nasal passageway tissue. threshold amount of the particular emetic. However, if a In one embodiment, the irritant discourages inhalation (e.g., fourth dosage form having 0.19 gm. of Zinc Sulfate is via Snorting through the nose) by inducing pain and/or ingested, the amount of emetic exceeds the threshold irritation of the abuser's nasal passageway tissue. amount, and emesis is induced. US 2005/01 12067 A1 May 26, 2005

0079 The above-described emetics can be further opti the disintegrant can minimize Segregation and provide an mized as necessary or desired in terms of concentration in immediate release profile to the formulation. In Some the pharmaceutical composition, etc. embodiments, the disintegrant (S) are present in an amount 0080. Other suitable emetics can include one or more of from about 2 to about 25 percent by weight on a solid basis cephaeline, methyl cephaeline, psychotrine, O-methylpsy of the directly compressible formulation. chotrine and emetamine. 0087. In one embodiment, the present invention can 0081 E. Other Ingredients include one or more pharmaceutically acceptable glidants, including but not limited to colloidal Silicon dioxide. In one 0082 The present invention can also optionally include embodiment, colloidal silicon dioxide (Cab-O-Sil(R) having other ingredients to enhance dosage form manufacture from a density of about 0.029 to about 0.040 g/ml can be used to a pharmaceutical composition of the present invention and/ improve the flow characteristics of the formulation. Such or alter the release profile of a dosage forming including a glidants can be provided in an amount of from about 0.1 to pharmaceutical composition of the present invention. about 1 percent by weight of the formulation on a Solid basis. 0.083. Some embodiments of the present invention It will be understood, based on this invention, however, that include one or more pharmaceutically acceptable fillerS/ while colloidal Silicon dioxide is one particular glidant, diluents. In one embodiment, Avicel PH (Microcrystalline other glidants having Similar properties which are known or cellulose) is a filler used in the formulation. The Avicel PH to be developed could be used provided they are compatible can have an average particle size ranging from 20 to about with other excipients and the active ingredient in the for 200 um, preferably about 100 um. The density ranges from mulation and which do not significantly affect the flowabil 1.512-1.668 g/cm. The Avicel PH should have molecular ity, homogeneity and compressibility of the formulation. weight of about 36,000. Avicel PH effectiveness is optimal 0088. In one embodiment, the present invention can when it is present in an amount of from about 10 to 65 include one or more pharmaceutically acceptable lubricants, percent, by weight on a Solid basis, of the formulation. including but not limited to magnesium Stearate. In one Typical fillers can be present in amounts from 10 to 65 embodiment, the magnesium Stearate has a particle size of percent by weight on a dry weight basis. Other ingredients about 450 to about 550 microns and a density of about 1.00 can include Sugars and/or polyols. to about 1.80 g/ml. In one embodiment, magnesium Stearate 0084. Other ingredients can also include dibasic calcium can contribute to reducing friction between a die wall and a phosphate having a particle size of about 75 to about 425 pharmaceutical composition of the present invention during microns and a density of about 0.5 to about 1.5 g/ml, as well compression and can ease the ejection of the tablets, thereby as calcium Sulfate having a particle size of about 1 to about facilitating processing. In Some embodiments, the lubricant 200 microns and a density of about 0.6 to about 1.3 g/ml and resists adhesion to punches and dies and/or aid in the flow mixtures thereof. Further, lactose having a particle size of of the powder in a hopper and/or into a die. In an embodi about 20 to about 400 microns and a density of about 0.3 to ment of the present invention, magnesium Stearate having a about 0.9 g/ml can also be included. particle size of from about 5 to about 50 microns and a density of from about 0.1 to about 1.1 g/ml is used in a 0085. In some embodiments of the invention, the fillers pharmaceutical composition. In certain embodiments, a which can be present at about 10 to 65 percent by weight on lubricant should make up from about 0.1 to about 2 percent a dry weight basis, also function as binders in that they not by weight of the formulation on a solids basis. Suitable only impart cohesive properties to the material within the lubricants are stable and do not polymerize within the formulation, but can also increase the bulk weight of a formulation once combined. Other lubricants known in the directly compressible formulation (as described below) to art or to be developed which exhibit acceptable or compa achieve an acceptable formulation weight for direct com rable properties include Stearic acid, hydrogenated oils, pression. In Some embodiments, additional fillers need not Sodium Stearyl fumarate, polyethylene glycols, and Lubri provide the same level of cohesive properties as the binders tab(E). Selected, but can be capable of contributing to formulation homogeneity and resist Segregation from the formulation 0089. In certain embodiments, the most important criteria once blended. Further, preferred fillers do not have a detri for Selection of the excipients are that the excipients should mental effect on the flowability of the composition or achieve good content uniformity and release the active dissolution profile of the formed tablets. ingredient as desired. The excipients, by having excellent binding properties, and homogeneity, as well as good com 0.086. In one embodiment, the present invention can pressibility, cohesiveness and flowability in blended form, include one or more pharmaceutically acceptable disinte minimize Segregation of powders in the hopper during direct grants. Such disintegrants are known to a skilled artisan. In compression. the present invention, disintegrants can include, but are not limited to, Sodium starch glycolate (Explotab(E) having a 0090. In another embodiment, the present invention can particle Size of about 104 microns and a density of about include an opioid antagonist in addition to the other ingre 0.756 g/ml, starch (e.g., Starch 21) having a particle size of dients, or as a Substitute for one of the other abuse deterrent about 2 to about 32 microns and a density of about 0.462 ingredients of a formulation of the present invention. Suit g/ml, Crospovidone(E) having a particle size of about 400 able antagonists are described above. One particular antago microns and a density of about 1.22 g/ml, and croScarmel nist includes naloxone. AS described above, typically nalox lose sodium (Ac-Di-Sol) having a particle size of about 37 one has no action when taken orally, and will not interfere to about 73.7 microns and a density of about 0.529 g/ml. The with the pharmacologic action of an opioid agonist. How disintegrant Selected should contribute to the compressibil ever, when given by injection naloxone can have profound ity, flowability and homogeneity of the formulation. Further antagonistic action to opioid agonists. An appropriate US 2005/01 12067 A1 May 26, 2005 antagonist can be used in combination with one or more of 0097 Suitable formulations and dosage forms of the gel forming agents, mucous membrane irritants and/or nasal present invention include but are not limited to powders, passageway tissue irritants, or emetics in the present inven caplets, pills, Suppositories, gels, Soft gelatin capsules, cap tion. An appropriate antagonist can also be used as a Sules and compressed tablets manufactured from a pharma Substitute for one or more of gel forming agents, mucous ceutical composition of the present invention. The dosage membrane irritants and/or nasal passageway tissue irritants, forms can be any shape, including regular or irregular shape or emetics in the present invention. Suitable opioid receptor depending upon the needs of the artisan. antagonists can include but are not limited to the antagonists 0098 Compressed tablets including the pharmaceutical described in U.S. Pat. Nos. 6,559,159 and 6,375,957, the compositions of the present invention can be direct com entire content of which are hereby incorporated by refer pression tablets or non-direct compression tablets. In one CCC. embodiment, a dosage form of the present invention can be 0091 F. Dosage Forms of the Present Invention made by Wet granulation, and dry granulation (e.g., slugging 0092 A pharmaceutical composition of the present or roller compaction). The method of preparation and type of invention including one or more drug components, one or excipients are Selected to give the tablet formulation desired more of gel forming agents, mucous membrane irritants physical characteristics that allow for the rapid compression and/or nasal passageway tissue irritants, and emetics, and of the tablets. After compression, the tablets must have a optionally other ingredients, can be Suitably modified and number of additional attributes Such as appearance, hard processed to form a dosage form of the present invention. AS neSS, disintegrating ability, and an acceptable dissolution referred to herein and in FIGS. 5a, 5b, 5c and 6, an “abuse profile. deterrent composition” or “ADC" (labeled “40” in these 0099 Choice of fillers and other excipients typically Figures) includes a composition having one or more gel depend on the chemical and physical properties of the drug, forming agents and/or mucous membrane irritants and/or behavior of the mixture during processing, and the proper nasal passageway tissue irritants, and/or emetics according ties of the final tablets. Adjustment of Such parameters is to the teachings Set for-th herein. In this manner, an abuse understood to be within the general understanding of one deterrent composition can be layered onto, coated onto, skilled in the relevant art. Suitable fillers and excipients are applied to, admixed with, formed into a matrix with, and/or described in more detail above. blended with a drug and optionally other ingredients, thereby providing a therapeutic composition of the present 0100. The manufacture of a dosage form of the present invention. invention can involve direct compression and wet and dry 0093. As shown in FIG. 5a, an abuse deterrent compo granulation methods, including slugging and roller compac Sition can be combined with a drug and/or opioid analgesic tion. However, in the present invention, it is preferred to use (e.g., hydrocodone) in one or more layered dosage forms. direct compression techniques because of the lower proceSS According to the present invention, drug 50 can be a layer ing time and cost advantages. on or near the surface (I) of ADC 40 of the present invention, 0101 Accordingly, and as described further below, a or sandwiched between two or more distinct layers (II and directly compressible pharmaceutical composition of the III) of ADC 40 of the present invention. In other embodi present invention can be designed following the teachings ments, drug 50 can be a coating (IV) on ADC 40. Drug 50 Set forth herein that can deter one or more of a) parenteral can be any of the pharmaceutically active ingredients (e.g., abuse of a drug, b) inhalation abuse of a drug, and c) oral opioids) described herein and can be combined with other abuse of a drug. excipients, e.g. disintegrants including but not limited to 0102) Such compositions and dosage forms are formed Sodium Starch glycolate or Explotab(E). according to the present invention are described. Steps for 0094. As shown in FIG. 5b an abuse deterrent compo making the compositions or dosage forms include the Step of sition 40 of the present invention can be combined with drug providing one or more drugs and/or analgesics described 50, e.g., hydrocodone, in a blended mixture. In such embodi above and an amount of a gel forming polymer having a ments, drug 50 and ADC 40 can be evenly mixed. desired molecular weight or Viscosity as described above, 0.095 As shown in FIG. 5c abuse deterrent composition and/or providing a nasal tissue irritant, and/or providing an 40 of the present invention can be combined with drug 50, emetic in the amounts as described above. e.g., hydrocodone, in a blended mixture with other ingredi 0103). By controlling the molecular weight and/or viscos ents 60, e.g., a disintegrant. ity of the gel forming polymer, and/or by controlling the 0096 FIG. 6 shows one embodiment of the present amount of mucous membrane irritant and/or nasal tissue invention for making a dosage form of the present invention. irritant Such that nasal tissue irritation occurs if the compo Specifically, a first step (step 1) of FIG. 4 shows drug 50 Sition is inhaled (e.g. Snorting), and/or by controlling the combined with abuse deterrent composition 40 of the amount of emetic Such that emesis ensues if more than a present invention. ADC 40 can contain one or more gel prescribed amount of the analgesic is consumed, a thera forming agents and/or mucous membrane irritants and/or peutic composition Suitable for use to deter drug abuse can nasal passageway tissue irritants, and/or emetics according be formed. The compositions according to the present inven to the teachings set forth herein. In a Second step (step 2), the tion can deter abuse of the analgesic by (1) forming a combination of drug 50 and ADC 40 can then be blended Viscous Substance upon contact with a Solvent Such that the with other ingredients 60, e.g. disintegrants and lubricants, Substance and analgesic cannot be easily drawn into a to form a mix 100. Lastly, in a third step (step 3) combina Syringe and/or (2) by inducing mucous membrane irritation tion 100 can then be processed using conventional practices and/or nasal tissue irritation if the composition is inhaled, 110, e.g., compression, into a Suitable unit dosage form 120, and/or (3) by inducing emesis if more than a prescribed e.g. tablets. amount of the analgesic is consumed. US 2005/01 12067 A1 May 26, 2005

0104. The present invention can be used to manufacture 0113 (iv) The volume of the sample removed from immediate release, and controlled drug release formulations. the Spoon is measured and the contents of the Syringe Controlled release formulations can include delayed release are tested for the active, using a Suitable analytical and extended release oral Solid dosage preparations. test method such as UV/VIS spectrophotometry. Examples 25 (formulation A7 of FIG. 7), 26 (formulation B7 of FIG. 7) and 27 (formulation C7 of FIG. 7) provide TABLE 1. embodiments of the invention that can provide controlled release of a drug. The release profiles of the controlled Component Weight (mg)/tablet release dosage forms of the present invention are shown in Hydrocodone bitartrate 5 FIG. 7. The dosage forms in FIG. 7 include hydrocodone Polyvinyl alcohol 160 Avice PH 102 333 bitaritrate (HCBT) as an active. As shown in FIG. 7, about Starch 21 54 80 to 95% of the drug in a controlled release dosage form of Zinc sulfate 3O the present invention is released after about 10 hours, as Explotab 15 compared to an immediate release dosage form (a conven Cab-O-Sil 1.5 tional dosage form) which is at least 75% dissolved after Magnesium stearate 1.5 about 45 minutes. Other opioid formulations having an Total 6OO extended effect, which can be modified to further include one or more of the abuse deterrent compositions of the present invention, are described in U.S. Pat. No. 6,572,885, the entire content of which is hereby incorporated by refer 0114) An in-vitro dissolution criterion of NLT 75% of the CCC. drug dissolved in 45 minutes was met. 0105 Certain aspects of the present invention may be 0115 The drug extracted by the abuse-test method better understood as illustrated by the following examples, detailed above was about 34 percent. which are meant by way of illustration and not limitation. EXAMPLE 2 EXAMPLE 1. 0116 0106 A direct compression formulation, as shown in Table 1, for an immediate release opioid analgesic, e.g. TABLE 2 hydrocodone bitartrate, tablet having 5 mg of hydrocodone Component Weight (mg)/tablet bitartrate was formed by weighing each component Sepa rately and mixing the hydrocodone bitartrate and the poly Hydrocodone bitartrate 5 Polyvinyl alcohol 160 mer in a V-blender for about 5 to 10 minutes at low shear Crospovidone 90 conditions or in a high shear blender by mixing 2 to 5 Avice PH 102 12O minutes. The other formulation excipients were added to the Starch 21 43 above blend excepting the lubricant and mixed at the same Zinc sulfate 3O rate for additional 5 to about 10 minutes. Finally, the Cab-O-Sil 1. lubricant, magnesium Stearate was added to the formulation Magnesium stearate 1. and blended at the same rate for an additional 3 to 5 minutes. Total 450 This polymeric matrix containing the drug and other excipi ents was further compressed on a rotary tablet preSS to form pharmaceutically acceptable tablets. 0117. As shown by Table 2, a direct compression formu lation of hydrocodone bitartrate immediate release formu 0107 The tablets were monitored for weight, hardness, lation including a dosage of 5 mg of hydrocodone bit artrate thickness and friability. The tablets were tested for assay, was prepared and tested using the blending conditions and release characteristics (in-vitro dissolution method) and procedure as Stated in Example 1. abuse deterrent properties. 0108 Samples of the tablets were subjected to dissolution 0118. An in-vitro dissolution criterion of NLT 75% of the testing using USPApparatus 2 (U.S. Pharmacopoeia, XXVI, drug dissolved in 45 minutes was met. 2003), speed 50 rpm at 37 C., in purified water as disso 0119) The drug extracted by the abuse-test method was lution medium for a period of 90 minutes. The acceptable about 31 percent. dissolution criterion is not leSS than 75 percent of the drug dissolved in 45 minutes. EXAMPLE 3 0109 To evaluate abuse deterrent properties of the for 0120 mulation a method has been developed that mimics the Street abuser's method for abuse. TABLE 3 0110 (i) The tablets are crushed and the resulting Component Weight (mg)/tablet powder is placed into table/teaspoon. Hydrocodone bitartrate 5 0111 (ii) Measured amount of water is added to the Polyox 70 Spoon. Contents of the Spoon are heated for about 1 Crospovidone 152 to 2 minutes. Avice PH 102 304 Zinc sulfate 150 0112 (iii) Contents of the spoon are withdrawn Sodium lauryl sulfate 1. using a Syringe equipped with a needle. US 2005/01 12067 A1 May 26, 2005

TABLE 3-continued TABLE 5-continued Component Weight (mg)?tablet Component Weight (mg)/tablet Cab-O-Sil 14 Cab-O-Sil 2 Magnesium stearate 4 Magnesium stearate 1.

Total 700 Total 490

0121. As shown by Table 3, a direct compression formu 0129. As shown by Table 5, a direct compression formu lation of hydrocodone bitartrate immediate release formu lation of hydrocodone bitartrate immediate release formu lation including a dosage of 5 mg of hydrocodone bit artrate lation including a dosage of 5 mg of hydrocodone bit artrate was prepared and tested using the blending conditions and was prepared and tested using the blending conditions and procedure as Stated in Example 1. procedure as Stated in Example 1. 0130. An in-vitro dissolution criterion of NLT 75% of the 0122) An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45 minutes was met. drug dissolved in 45 minutes was met. 0131 The drug extracted by the abuse-test method was 0123 The drug extracted by the abuse-test method was about 17 percent. about 11 percent. EXAMPLE 6 0132) EXAMPLE 4 0124 TABLE 6 Component Weight (mg)?tablet TABLE 4 Oxycodone hydrochloride 5 Component Weight (mg)?tablet Polyox 25 Avice PH 102 3OO Hydrocodone bitartrate 5 Zinc sulfate 50 Polyvinyl alcohol 8O Sodium lauryl sulfate 7 Polyox 15 Crospovidone 1OO Avice PH 102 3OO Cab-O-Sil 2 Zinc sulfate 50 Magnesium stearate 1. Sodium lauryl sulfate 7 Crospovidone 1OO Total 490 Cab-O-Sil 2 Magnesium stearate 1. 0.133 As shown by Table 6, a direct compression formu Total 560 lation of oxycodone hydrochloride immediate release for mulation including a dosage of 5 mg of oxycodone hydro chloride was prepared and tested using the blending 0.125. As shown by Table 4, a direct compression formu conditions and procedure as Stated in Example 1. lation of hydrocodone bitartrate immediate release formu lation including a dosage of 5 mg of hydrocodone bit artrate 0134) An in-vitro dissolution criterion of NLT 70% of the was prepared and tested using the blending conditions and drug dissolved in 45 minutes was met. procedure as Stated in Example 1. 0.135 The drug extracted by the abuse-test method was about 9 percent. 0126 An in-vitro dissolution criterion of NLT 75% of the EXAMPLE 7 drug dissolved in 45 minutes was met. 0136 0127. The drug extracted by the abuse-test method was about 6.5 percent. TABLE 7 Component Weight (mg)/tablet EXAMPLE 5 Morphine sulfate 2O 0128 Polyox 2O Avice PH 102 3OO Zinc sulfate 50 TABLE 5 Sodium lauryl sulfate 7 Crospovidone 1OO Component Weight (mg)?tablet Cab-O-Sil 2 Hydrocodone bitartrate 5 Magnesium stearate 1. Methocel K10O LV 25 Avice PH 102 3OO Total 500 Zinc sulfate 50 Sodium lauryl sulfate 7 Crospovidone 1OO 0.137 As shown by Table 7, a direct compression formu lation of morphine Sulfate immediate release formulation US 2005/01 12067 A1 May 26, 2005

including a dosage of 20 mg of morphine Sulfate was EXAMPLE 10 prepared and tested using the blending conditions and pro cedure as Stated in Example 1. 0148 0138 An in-vitro dissolution criterion of NLT 75% of the TABLE 10 drug dissolved in 45 minutes was met. Component Weight (mg)/tablet 0.139. The drug extracted by the abuse-test method was Morphine sulfate 40 about 16 percent. Polyvinyl alcohol 2OO Avice PH 102 278 EXAMPLE 8 Zinc sulfate 3O Explotab 3O Starch 21 54 0140 Cab-O-Sil 1.5 Magnesium stearate 1.5 TABLE 8 Total 635 Component Weight (mg)?tablet Morphine sulfate 2O Polyvinyl alcohol 160 0149. As shown by Table 10, a direct compression for Avice PH 102 318 mulation of morphine Sulfate immediate release formulation Zinc sulfate 3O including a dosage of 40 mg of morphine Sulfate was Explotab 3O Starch 21 54 prepared and tested using the blending conditions and pro Cab-O-Sil 1.5 cedure as Stated in Example 1. Magnesium stearate 1.5 0150. An in-vitro dissolution criterion of NLT 75% of the Total 615 drug dissolved in 45 minutes was met. 0151. The drug extracted by the abuse-test method was 0.141. As shown by Table 8, a direct compression formu about 6 percent. lation of morphine Sulfate immediate release formulation including a dosage of 20 mg of morphine Sulfate was EXAMPLE 11 prepared and tested using the blending conditions and pro 0152) cedure as Stated in Example 1. TABLE 11 0142. An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45 minutes was met. Component Weight (mg)/tablet 0143. The drug extracted by the abuse-test method was Hydrocodone bitartrate 7.5 Polyox 25 about 12 percent. Avice PH 102 297.5 Crospovidone 1OO EXAMPLE 9 Zinc sulfate 50 Sodium lauryl sulfate 7 0144) Cab-O-Sil 2 Magnesium stearate 1.

TABLE 9 Total 490 Component Weight (mg)?tablet Morphine sulfate 40 0153. As shown by Table 11, a direct compression for Polyox 15 Avice PH 102 3OO mulation of hydrocodone bitartrate immediate release for Zinc sulfate 50 mulation including a dosage of 7.5 mg of hydrocodone Sodium lauryl sulfate 7 bitartrate was prepared and tested using the blending con Crospovidone 1OO ditions and procedure as Stated in Example 1. Cab-O-Sil 2 Magnesium stearate 1. 0154) An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45 minutes was met. Total 515 O155 The drug extracted by the abuse-test method was about 5 percent. 0145 As shown by Table 9, a direct compression formu lation of morphine Sulfate immediate release formulation EXAMPLE 12 including a dosage of 40 mg of morphine Sulfate was 0156) prepared and tested using the blending conditions and pro cedure as Stated in Example 1. TABLE 12 0146). An in-vitro dissolution criterion of NLT 75% of the Component Weight (mg)/tablet drug dissolved in 45 minutes was met. Hydrocodone bitartrate 1O 0147 The drug extracted by the abuse-test method was Polyvinyl alcohol 8O about 15 percent. US 2005/01 12067 A1 May 26, 2005 11

TABLE 12-continued TABLE 14-continued

Component Weight (mg)?tablet Formulation A3 Polyox 15 Component Weight (mg/tablet) Avice PH 102 295 Crospovidone 1OO Starch 21 54 Zinc sulfate 50 Explotab 3O Sodium lauryl sulfate 7 Cab-O-Sil 1.5 Cab-O-Sil 2 Magnesium Stearate 1.5 Magnesium stearate 1. Total 6OO Total 560 0.165. As shown by Table 14, a direct compression for O157 As shown by Table 12, a direct compression for mulation of hydrocodone bitartrate immediate release for mulation of hydrocodone bitartrate immediate release for mulation including a dosage of 5 mg of hydrocodone mulation including a dosage of 10 mg of hydrocodone bitartrate was prepared and tested using the blending con bitartrate was prepared and tested using the blending con ditions and procedure as Stated in Example 1. ditions and procedure as Stated in Example 1. 0166 An in-vitro dissolution showed about 62% of the 0158 An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45 minutes. drug dissolved in 45 minutes was met. 0.167 The drug extracted by the abuse-test method was 0159. The drug extracted by the abuse-test method was about 26.77 percent. about 9.5 percent. EXAMPLE 1.5 EXAMPLE 13 0168) 0160 TABLE 1.5 TABLE 13 Formulation B3 Component Weight (mg)?tablet Component Weight (mg/tablet) Hydrocodone bitartrate 5 Carbopol 971P 1O Hydrocodone Bitartrate 5 Avice PH 102 3OO Polyvinyl Alcohol 160 Crospovidone 1OO Avice PH 102 333 Zinc sulfate 50 Zinc Sulfate 3O Sodium lauryl sulfate 7 Explotab 15 Cab-O-Sil 2 Starch 21 54 Magnesium stearate 1. Cab-O-Sil 1.5 Total 490 Magnesium Stearate 1.5

Total 6OO 0.161. As shown by Table 13, a direct compression for mulation of hydrocodone bitartrate immediate release for 0169. As shown by Table 15, a direct compression for mulation including a dosage of 5 mg of hydrocodone mulation of hydrocodone bitartrate immediate release for bitartrate was prepared and tested using the blending con mulation including a dosage of 5 mg of hydrocodone ditions and procedure as Stated in Example 1. bitartrate was prepared and tested using the blending con 0162 An in-vitro dissolution criterion of NLT 75% of the ditions and procedure as Stated in Example 1. drug dissolved in 45 minutes was met. 0170 An in-vitro dissolution showed about 72% of the 0163 The drug extracted by the abuse-test method was drug dissolved in 45 minutes. about 27 percent. 0171 The drug extracted by the abuse-test method was EXAMPLE 1.4 about 31.8 percent. 0164) EXAMPLE 16 TABLE 1.4 0172

Formulation A3 TABLE 16 Component Weight (mg/tablet) Formulation C3 Hydrocodone Bitartrate 5 Component Weight (mg/tablet) Polyvinyl Alcohol 160 Avice PH 102 318 Hydrocodone Bitartrate 5 Zinc Sulfate 3O Polyvinyl Alcohol 160 US 2005/01 12067 A1 May 26, 2005 12

0179 The drug extracted by the abuse-test method was TABLE 16-continued about 35.8 percent.

Formulation C3 EXAMPLE 1.8 0180 Component Weight (mg/tablet) TABLE 1.8 Avice PH 102 12O Formulation E3 Zinc Sulfate 3O Crospovidone (PVP XL) 40 Component Weight (mg/tablet) Starch 21 43 Hydrocodone Bitartrate 5 Cab-O-Sil 1. Polyvinyl Alcohol 160 Avice PH 102 333 Magnesium Stearate 1. Zinc Sulfate 3O Starch 21 54 Crospovidone (PVP XL) 15 Total 400 Cab-O-Sil 1.5 Magnesium Stearate 1.5

Total 6OO 0173 As shown by Table 16, a direct compression for mulation of hydrocodone bitartrate immediate release for mulation including a dosage of 5 mg of hydrocodone 0181. As shown by Table 18, a direct compression for bitartrate was prepared and tested using the blending con mulation of hydrocodone bitartrate immediate release for ditions and procedure as Stated in Example 1. mulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending con 0.174. An in-vitro dissolution showed about 75% of the ditions and procedure as Stated in Example 1. drug dissolved in 45 minutes. 0182 An in-vitro dissolution showed about 79% of the 0.175. The drug extracted by the abuse-test method was drug dissolved in 45 minutes. about 35.75 percent. 0183 The drug extracted by the abuse-test method was EXAMPLE 1.7 about 42.5 percent.

0176) EXAMPLE 1.9 TABLE 1.7 0184

Formulation D3 TABLE 1.9

Formulation F3 Component Weight (mg/tablet) Component Weight (mg/tablet) Hydrocodone Bitartrate 5 Hydrocodone Bitartrate 5 Polyvinyl Alcohol 160 Polyvinyl Alcohol 160 Avice PH 102 12O Avice PH 102 119 Zinc Sulfate 3O Zinc Sulfate 3O Crospovidone (PVP XL) 1OO Crospovidone (PVP XL) 1OO Starch 21 33 Starch 21 33 Cab-O-Sil 1. Magnesium Stearate 2 Cab-O-Sil 1. Magnesium Stearate 1. Total 450

Total 450 0185. As shown by Table 19, a direct compression for mulation of hydrocodone bitartrate immediate release for 0177 As shown by Table 17, a direct compression for mulation including a dosage of 5 mg of hydrocodone mulation of hydrocodone bitartrate immediate release for bitartrate was prepared and tested using the blending con mulation including a dosage of 5 mg of hydrocodone ditions and procedure as Stated in Example 1. bitartrate was prepared and tested using the blending con 0186. An in-vitro dissolution criterion of NLT 75% of the ditions and procedure as Stated in Example 1. drug dissolved in 45 minutes was met. 0178 An in-vitro dissolution showed about 82% of the 0187. The drug extracted by the abuse-test method was drug dissolved in 45 minutes. about 54 percent. US 2005/01 12067 A1 May 26, 2005 13

EXAMPLE 2.0 0188) TABLE 22-continued Component Weight (mg/tablet) TABLE 2.0 Avice PH 102 192 Component Weight (mg/tablet) Zinc Sulfate 3O Starch 21 140 Hydrocodone Bitartrate 5 Ac-Di-Sol 35 Polyvinyl Alcohol 95 Cab-O-Sil 1. Avice PH 102 192 Magnesium Stearate 2 Zinc Sulfate 3O Starch 21 140 Total 455 Ac-Di-Sol 35 Cab-O-Sil 1. Magnesium Stearate 2 0.197 As shown in Table 22, a direct compression for Total 500 mulation of hydrocodone bitartrate immediate release for mulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending con 0189 As shown in Table 20, a direct compression for ditions and procedure as Stated in Example 1. mulation of hydrocodone bitartrate immediate release for mulation including a dosage of 5 mg of hydrocodone 0198 An in-vitro dissolution criterion of NLT 75% of the bitartrate was prepared and tested using the blending con drug dissolved in 45 minutes was met. ditions and procedure as Stated in Example 1. 0199 The drug extracted by the abuse-test method was 0190. An in-vitro dissolution criterion of NLT 75% of the about 70 percent. drug dissolved in 45 minutes was met. 0191 The drug extracted by the abuse-test method was EXAMPLE 23 about 60 percent. 0200 EXAMPLE 21 TABLE 23 0192) Component Weight (mg/tablet) TABLE 21 Hydrocodone Bitartrate 5 Polyvinyl Alcohol 160 Component Weight (mg/tablet) Avice PH 102 318 Zinc Sulfate 3O Oxycodone Hydrochloride 5 Explotab 3O Avice PH 102 119 Cab-O-Sil 1.5 Zinc Sulfate 3O Magnesium Stearate 1.5 Crospovidone (PVP XL) 1OO Starch 21 33 Total 6OO Cab-O-Sil 1. Magnesium Stearate 2 Total 290 0201 AS shown in Table 23, a direct compression for mulation of hydrocodone bitartrate immediate release for mulation including a dosage of 5 mg of hydrocodone 0193 As shown by Table 21, a direct compression for bitartrate was prepared and tested using the blending con mulation of hydrocodone bitartrate immediate release for ditions and procedure as Stated in Example 1. mulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending con 0202) An in-vitro dissolution criterion of NLT 75% of the ditions and procedure as Stated in Example 1. drug dissolved in 45 minutes was met. 0194 An in-vitro dissolution criterion of NLT 75% of the 0203 The drug extracted by the abuse-test method was drug dissolved in 45 minutes was met. about 33 percent. 0.195 The drug extracted by the abuse-test method was about 94 percent. EXAMPLE 24 0204) EXAMPLE 22 0196) TABLE 24 Component Weight (mg/tablet) TABLE 22 Hydrocodone Bitartrate 1O Component Weight (mg/tablet) Avice PH 102 31.8 Zinc Sulfate 50 Hydrocodone Bitartrate 5 Crospovidone (PVP XL) 1OO Polyvinyl Alcohol 50 Sodium Lauryl Sulfate 7 US 2005/01 12067 A1 May 26, 2005 14

EXAMPLE 27 TABLE 24-continued 0212 Component Weight (mg/tablet) TABLE 27

Formulation C7 Cab-O-Sil 1.5 Magnesium Stearate 1.5 Component Weight (mg/tablet) Hydrocodone Bitartrate 88 Total 488 Polyvinyl Alcohol 6OO Cab-O-Sil 1.5 Magnesium Stearate 2.O

Total 691.5 0205 As shown in Table 24, a direct compression for mulation of hydrocodone bitartrate immediate release for mulation including a dosage of 5 mg of hydrocodone 0213 An in-vitro dissolution showed about 80% disso bitartrate was prepared and tested using the blending con lution after 10 hours. ditions and procedure as Stated in Example 1. 0214. It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made 0206. An in-vitro dissolution criterion of NLT 75% of the to the invention shown in the specific embodiments without drug dissolved in 45 minutes was met. departing form the Spirit and Scope of the invention as broadly described. Further, each and every reference cited 0207. The drug extracted by the abuse-test method was above is hereby incorporated by reference as if fully set forth about 85 percent. herein. EXAMPLE 25 What is claimed is: 1. A therapeutic pharmaceutical composition comprising 0208 (a) an analgesic, TABLE 25 (b) a gel forming polymer;

Formulation A7 (c) a nasal tissue irritant; and (d) an emetic in Sufficient amount to cause emesis if Component Weight (mg/tablet) greater than a prescribed amount of the analgesic of the therapeutic composition is ingested. Hydrocodone Bitartrate 22 2. The therapeutic pharmaceutical composition of claim 1, Polyvinyl Alcohol 250 wherein the pharmaceutical composition is in unit dose Cab-O-Sil 1.38 form. Magnesium Stearate 2.76 3. The therapeutic pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in a Suppository, Total 276.14 capsule, caplet, pill, gel, Soft gelatin capsule, or compressed tablet form. 4. The therapeutic pharmaceutical composition of claim 1, 0209 An in-vitro dissolution showed about 98% disso wherein the analgesic comprises an opioid analgesic present lution after 10 hours. in an amount of about 5 mg to about 200 mg on a Solid weight basis. EXAMPLE 26 5. The therapeutic pharmaceutical composition of claim 1, wherein the analgesic comprises hydrocodone or a thera 0210) peutically acceptable Salt thereof. 6. The therapeutic pharmaceutical composition of claim 1, TABLE 26 wherein the analgesic comprises oxycodone or a therapeu tically acceptable Salt thereof. Formulation B7 7. The therapeutic pharmaceutical composition of claim 1, Component Weight (mg/tablet) wherein the analgesic comprises morphine or a therapeuti cally acceptable Salt thereof. Hydrocodone Bitartrate 44 Polyvinyl Alcohol 450 8. The therapeutic pharmaceutical composition of claim 1, Cab-O-Sil 1.5 wherein the analgesic is Selected from the group consisting Magnesium Stearate 2.O of alfentanil, amphetamines, buprenorphine, butorphanol, carfentanil, codeine, dezocine, diacetylmorphine, dihydro Total 497.5 codeine, dihydromorphine, diphenoxylate, diprenorphine, etorphine, fentanyl, hydrocodone, hydromorphone, B-hy droxy-3-methylfentanyl, levo-O-acetylmethadol, levorpha 0211) An in-vitro dissolution showed about 82% disso nol, lofentanil, meperidine, methadone, methylphenidate, lution after 10 hours. morphine, nalbuphine, nalmefene, O-methylnaltrexone, US 2005/01 12067 A1 May 26, 2005

naloxone, naltrexone, oxycodone, Oxymorphone, pentazo 20. The method of claim 17, wherein the drug comprises cine, pethidine, propoxyphene, remifentanil, Sufentanil, tili an opioid analgesic. dine and tramodol, or therapeutically acceptable Salts 21. The method of claim 17, wherein the drug is selected thereof. from the group consisting of alfentanil, amphetamines, 9. The therapeutic composition of claim 1, wherein the gel buprenorphine, butorphanol, carfentanil, codeine, dezocine, forming polymer comprises one or more of polyethylene diacetylmorphine, dihydrocodeine, dihydromorphine, oxide having average molecular weight ranging form about diphenoxylate, diprenorphine, etorphine, fentanyl, hydroc 300,000 to about 5,000,000, polyvinyl alcohol having a odone, hydromorphone, B-hydroxy-3-methylfentanyl, levo molecular weight of about 20,000 to 200,000, hydroxypro O-acetylmethadol, levorphanol, lofentanil, meperidine, pyl methyl cellulose having a molecular weight of about methadone, methylphenidate, morphine, nalbuphine, 10,000 to 1,500,000, and a carbomer having a molecular nalmefene, O-methylnaltrexone, naloxone, naltrexone, Oxy weight ranging of about 700,000 to 4,000,000,000. codone, Oxymorphone, pentazocine, pethidine, pro 10. The therapeutic composition of claim 1, wherein the poxyphene, remifentanil, Sufentanil, tilidine and tramodol, gel forming polymer comprises one or more of polyethylene or therapeutically acceptable Salts thereof. oxide having a viscosity in the range from about 8,800 to 22. The method of claim 17, wherein the drug comprises about 17,600 cpS., polyvinyl alcohol having a Viscosity in hydrocodone or a therapeutically acceptable Salt thereof. the range from about 4 to about 65 cpS., hydroxypropyl 23. The method of claim 17, wherein the drug comprises methyl cellulose having a Viscosity in the range from about Oxycodone or a therapeutically acceptable Salt thereof. 3600 to about 5600 cps., and a carbomer having a viscosity 24. The method of claim 17, wherein the drug comprises in the range from about 4000 to about 39,400 cps. morphine or a therapeutically acceptable Salt thereof. 11. The therapeutic composition of claim 1, wherein the gel forming polymer comprises polyvinyl alcohol. 25. The method of claim 17, wherein the gel forming 12. The therapeutic composition of claim 1, wherein the polymer comprises one or more of polyethylene oxide gel forming polymer comprises hydroxypropyl methyl cel having average molecular weight ranging form about 300, 000 to about 5,000,000, polyvinyl alcohol having a molecu lulose. lar weight of about 20,000 to 200,000, hydroxypropyl 13. The therapeutic composition of claim 1, wherein the methyl cellulose having a molecular weight of about 10,000 gel forming polymer comprises polyethylene oxide. to 1,500,000, and a carbomer having a molecular weight 14. The therapeutic composition of claim 1, wherein the ranging of about 700,000 to 4,000,000,000. nasal tissue irritating amount of a Surfactant includes 1 to 5 26. The method of claim 17, wherein the gel forming percent by weight of one or more of poloxamer, Sorbitan polymer comprises one or more of polyethylene oxide monoesters, glyceryl monooleates and Sodium lauryl Sulfate. having a viscosity in the range from about 8,800 to about 15. The therapeutic composition of claim 1, wherein the 17,600 cps., polyvinyl alcohol having a viscosity in the nasal tissue irritating amount of a Surfactant includes 1 to 5 range from about 4 to about 65 cpS., hydroxypropyl methyl percent by weight Sodium lauryl Sulfate. cellulose having a viscosity in the range from about 3600 to 16. The therapeutic composition of claim 1, wherein the about 5600 cpS., and a carbomer having a Viscosity in the emetic comprises Zinc Sulfate at about 5 to 25 percent by range from about 4000 to about 39,400 cps. weight on a Solid basis. 27. The method of claim 17, wherein the step of control 17. A method of making a therapeutic composition Suit ling the amount of nasal tissue irritant comprises the Step of able for deterring drug abuse comprising adding 1 to 5 percent by weight of one or more of polox (a) providing an drug, a gel forming polymer having a amer, Sorbitan monoesters, glyceryl monooleates and Viscosity, a nasal tissue irritant and emetic, Sodium lauryl Sulfate. (b) controlling the molecular weight or Viscosity of the gel 28. The method of claim 17, wherein the gel forming forming polymer; polymer comprises polyvinyl alcohol. 29. The method of claim 17, wherein the gel forming (c) controlling the amount of nasal tissue irritant Such that polymer comprises hydroxypropyl methyl cellulose. nasal tissue irritation occurs if inhaled; 30. The method of claim 17, wherein the gel forming (d) controlling the amount of emetic Such that emesis polymer comprises polyethylene oxide. ensueS only if more than a prescribed amount of the 31. The method of claim 17, wherein the step of control drug is consumed; and ling the amount of nasal tissue irritant comprises the Step of adding 1 to 5 percent by weight Sodium lauryl Sulfate. (e) combining the analgesic, gel forming polymer, nasal 32. The therapeutic composition of claim 1, wherein the tissue irritant and emetic to form a therapeutic compo emetic comprises Zinc Sulfate at about 5 to 25 percent by Sition; weight on a Solid basis. wherein the composition deters abuse of the analgesic by 33. Atherapeutic pharmaceutical composition in unit dose forming a Viscous gel upon contact with a Solvent; form comprising inducing nasal irritation if inhaled, and inducing emesis if more than a prescribed amount of the analgesic is (a) an opioid analgesic, consumed. (b) a gel forming polymer comprising one or more of 18. The method of claim 17, further comprising the step polyethylene oxide having average molecular weight of processing the composition into a unit dose form. ranging form about 300,000 to about 5,000,000, poly 19. The method of claim 17, further comprising the step Vinyl alcohol having a molecular weight of about of processing the composition into a Suppository, capsule, 20,000 to 200,000, hydroxypropyl methyl cellulose caplet, pill, or a direct compressed tablet form. having a molecular weight of about 10,000 to 1,500, US 2005/01 12067 A1 May 26, 2005 16

000, and a carbomer having a molecular weight ranging 38. Atherapeutic pharmaceutical composition comprising of about 700,000 to 4,000,000,000; (a) an analgesic, (c) 1 to 5 percent by weight Sodium lauryl Sulfate; and (b) a gel forming polymer; (d) less than about 0.6 to 2.0 gm of zinc sulfate. 34. The therapeutic pharmaceutical composition in unit (c) a mucosal tissue irritant; and dose form of claim 33, wherein the analgesic is Selected from the group consisting of alfentanil, amphetamines, (d) an emetic in Sufficient amount to cause emesis if buprenorphine, butorphanol, carfentanil, codeine, dezocine, greater than a prescribed amount of the analgesic of the diacetylmorphine, dihydrocodeine, dihydromorphine, therapeutic composition is ingested. diphenoxylate, diprenorphine, etorphine, fentanyl, hydroc 39. The therapeutic pharmaceutical composition of claim odone, hydromorphone, B-hydroxy-3-methylfentanyl, levo 38, wherein the analgesic comprises hydrocodone or a O-acetylmethadol, levorphanol, lofentanil, meperidine, therapeutically acceptable Salt thereof. methadone, methylphenidate, morphine, nalbuphine, 40. The therapeutic pharmaceutical composition of claim nalmefene, O-methylnaltrexone, naloxone, naltrexone, Oxy 38, wherein the analgesic comprises oxycodone or a thera codone, Oxymorphone, pentazocine, pethidine, pro peutically acceptable Salt thereof. poxyphene, remifentanil, Sufentanil, tilidine and tramodol, or therapeutically acceptable Salts thereof. 41. The therapeutic pharmaceutical composition of claim 35. The therapeutic pharmaceutical composition of claim 38, wherein the analgesic comprises morphine or a thera 33, wherein the analgesic comprises hydrocodone or a peutically acceptable Salt thereof. therapeutically acceptable Salt thereof. 42. The therapeutic pharmaceutical composition of claim 36. The therapeutic pharmaceutical composition of claim 1, wherein the nasal tissue irritant comprises a Surfactant. 33, wherein the analgesic comprises oxycodone or a thera 43. The therapeutic pharmaceutical composition of claim peutically acceptable Salt thereof. 38, wherein the mucosal tissue irritant comprises a Surfac 37. The therapeutic pharmaceutical composition of claim tant. 33, wherein the analgesic comprises morphine or a thera peutically acceptable Salt thereof.