AU2013206525B2 - Methods and compositions for deterring abuse of opioid containing dosage forms - Google Patents

Abstract

This invention rates to an abuse deterrent dosage form of opioid analgesics, wherein an analgesically effective amount t of opioid analgesic iS combined with a poymer to form a matrix

Description

AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Invention Tile" Methods and compositions for deterring abuse of oploid containing dosage forms The following statement is a full description of this invention, including the best method of performing it known to us; Title METHODS AND COMPOSITIONS FOR DETERRING ABUSE OF OPIOD) CONTAMING DOSAGE FORMS Field of Invention This invention pertains to abuse deterrent compositions containing a drug (e.ananalgesic opioid), Additionally, the invention relates to a method of administering a dose of an analgesic from a dosage form, which is abuse deterrent Batcgrond of the Invention The class of drugs exhibiting opium or morphine-ikeproperties are 10 referred toas opioids, or opiold agonists. Certain opioids act as agonists, nteracting with stereo specific and satutable binding sites in the brain and other tissues. Endogenous opioid-like peptides are present in areas of the central nervous system that are presumed to b related to the perception of pain; to movement mood and behavior, and to the regulation of neuroendoerinoiogical functions. Three classical opioid receptor types, am 15 (E), delta (8)7 and kappa ) have been studied extensively, Each of these receptors has a unique anatomical distribution in the brain, spinal cord, and the periphery Most of the clinically used opinids are relatively seleidve for p receptors,reflecing their similarity to morphine. Howeverit is important to note that opieid containing drugs that are relatively selective at standard doses will often interact with additional receptor subtypes when 20 given at sufficiently high dosesleading to possible changes in their pharmacological effect. This is especially tme as opioid doses are escalated to overcome tolerance. The potential fr the development of tolerance, physical and/or psyhologica dependence (ioe addiction) with repeated opinid use is a characteristic feature of most opioid containing drugs. The possibility of developing addiction is one of 25 the maor concerns in the use of opioids for the management of pain Another major concern associated with the use of opioids is the diverDon of these drugs fm a patient in legitimate pain to other individuals (non-paients) for recreational paposes. Drug abusers an/or addicts typically may take a dosage form containing one or moe opioid analgesics and crush, shear grind, chew, dissolve and! or heat, extact 30 or 1 otherwise damage the product so that a significant amount or even an entire amount of the drag becomes available for immediate absoption by 1 Injection 2) inhalation, and/or3) oral consumption. There are three basic patters of behavior leading to opioid abuse. The .5 first involves individuals whose opioid drug use begins in the context of medical treatment and who obtain their initial drug supplies through prescriptions from physicians. The second begins with experimental or "recreational" drug use and progresses to 'more intensive use. A third patter of abuse involves users who begin in one or another of the preceding ways but later switch to oral opioids such as methadone, 10 obtained from organized addiction treatment programs. There are various routes of administration an abuser may commonly attempt to abuse an opioid containing drug formulation. The most common methods include 1) parenteral (e.g. intravenous injection), 2) intranasal (e.g, snorting), and 3) repeated oral ingestion of excessive quantities of orally administered tablets or capsules. 151 One mode of abuse of oral solid drugs involves the extraction of the opioid component from the dosage form by first mixing the dosage form with a suitable solvent (e.g, water), and then subsequently extracting the opioid component from the mixture for use in a solution suitable for intravenous injection of the opioid to achieve a "high " Attemtpts have been made to diminish abuse of orally administered opioid 20 drugs. These attempts generally centered on the inclusion in the oral dosage form of an opioid antagonist which is not orally active but which will substantially block the analgesic effects of' the oploid if one attempts to dissolve the opioid ardadminister it parenterallt. For example, commercially available Talwin*Nx tablets from Sanofi 25 Winthrop contain a combination of pentazocine and naloxone, Pentazocine is a partial agonist of pv receptors and also has affinity for K receptors, whereas, naloxone is an antagonist of p receptors. Talwin*Nx contains pentazocine hydrochloride equivalent to 50 mg base and naloxone hydrochloride equivalent to 0.5 mghbase. Talwin*Nx is indicated for the relief of moderate to severe pain, The amount of naloxone present in 30 this combination has no actIon when taken orally, and will not interfere with the pharmacologic action of pentazocine. However, this amount of naloxone given by injection has profound antagonistic action to opioid analgesics. Thus, the inclusion of naloxone is intended to curb a form of misuse of oral pentazocine, which occurs when the 2 dosage form is solubilized and injected. Therefore, this dosage has lower potential for parenteral misuse than previous oral pentazocine formulations, U.S. Patent No. 6,559,159 (Carroll et at) describes the use of kappa receptors antagonist for the treatment of opioid related addictions. One such compound is 5 naltrexone, which is commercially available in the tablet form Revia* for the treatment of alcohol dependence and. for the blockade of exogenously administered opioids. (Physicians Desk Reference 57" ed., Montvale, NJ) US. Patent No. 6,375,957 (Kaiko et al) describes in detail the combination of opioid agonist, NSAID, and an orally active opioid antagonist. The 10 purpose of adding the opioid antagonist is the same as discussed above. U.S. Patent No, 4,457,933 (Gordon et al) describes in detail a method for decreasing both the oral and parenteral abuse potential of amagesic agents such as oxycodone, propoxyphene and pentazocine by combining an analgesic dose of the analgesic agents with naloxone in specific, relatively narrow ranges. 15 US. Patent No. 6,228,863 31 (Palermo et at) describes a method for reducing the abuse potential of an oral dosage form of an opioid analgesic, whereby an orally active opioid agonistiss combined with an opiold antagonist into an oral dosage form requiring at least a two-step extraction process to be separated from the opioid agonist; the amount of opoid antagonist included being sufficient to counteract opioid 20 effects if extracted together with the opioid agonist and administered parenterally, The prior t describes several other methods and compositions to minimize the abuse of an opioid containing drug, One such method i§ discussed in U.S. Patent No. 6,593,367 (Dewey et a,), describing a method whereby the addiction-related behavior of a mammoal suffering from addiction could be changed by a combination of 25 drugs. The method includes administering to the mammal an effective amount of gamma vinyl GABA (GVG) or a pharmaceutically acceptable salt, or an enantiomer or a racemic mixture, where the effective amount is sufficient to diminish, inhibit or eliminate behavior associated with craving or use of the combination of abused drugs. U.S, Patent Nos. 4,175,119 and 4,459,273 (Porter et at) describe 30 compositions and methods usefui.l for the prevention of accidental and/or intentional oral overdoses of a drag. 3 In summary, various attempts have been made and are described in prior art to develop abuse- deterrent dosage forms. Clearly there is a need for a delivery system for commonly used oral dosage formulations (e.g, innediate release, sustained or extended release and delayed release) of drugs, and in particular analgesics such as 5 opioid analgesics, for patients seeking drug therapy and which deters abuse and minimizes or reduces the potential for physical or psychological dependency, SSummary of the Invention The present invention includes a therapeutic pharmaceutical composition including an analgesic, a gel forming polymer, a surfactant present in sufficient amount to 10 cause nasal ir station, and -a inert excipIent in sufficient amount to cause emesis if greater than a prescribed amount of the analgesic included in the therapeutic composition is ingested. The present invention also includes a therapeutic pharmaceutical composition including an analgesic, a gel forming polymer, a surfactant present in sufficient amount to cause nasal irritation, and an emetic in sufficient amount to cause emesis if greater than a i5 prescribed amount of the analgesic included in the therapeutic composition is ingested, In one embodiment, the therapeutic pharmaceutical composition can be formed into a unit dose including an opiaid analgesic, a gel forming polymer, a nasal tissue irrtating amount of a surfactant, and an emetic in sufficient amount to cause nemesis if greater than a prescribed amount of the analgesic included in the therapeutic 20 composition is ingested. In one embodiment, the polymer includes one or more of polyethylene oxide (e.g, having average molecular weight ranging form about 300,000 to about 5,000,000), polyvinyl alcohol (e~g, having a molecular weight of about 20,000 to 200,000) hydroxypropyl methyl cellulose (e.g, having a molecular weight of about 10,000 to 1,500,00), and a carbomer (e.g., having a molecular weight ranging of about 2.5 700,000 to 4,000,000,000), the nasal irritant includes about I to $ percent by weight sodium lauryl sulfate, and the emetic includes less than about 0. to 20 gm of zinc .sufate. The present invention also provides methods of making a pharmaceutical composition suitable for deterring drug abuse including one or more steps of providing an 30 analgesic, a gel forming polymer having a suitable viscosity, a nasal tissue irritant and emetic, controlling the molecular weight or viscosity of the gel forming polymer, controlling the amount of nasal tissue irritant such that nasal tissue irritation occurs if inhaled, controlling the amount of emetic such that nemesis ensues only if more than a 4 prescribed amount of the anagesie is consumed, and combining the analgesic, gel forming polymer, nasal tissue irritant and emetic to form a therapeutic composition. The present invention includes a therapeutic pharmaceutical composition including an analgesic , a gel fomin Polymer, a surfactant present in sufficient amount to 5 cause mucosal tissue irritation, and an emetic in sufficient amount to cause emesis if greater than a prescribed amount of the analgesic included in the therapeutic composition is ingested. Compositions and methods of thepresent invention can deter abuse of the analgesic by forming a viscous gel upon contact with a solvent such that the gel and t, analgesic cannot be easily drawn into a syrige and/or byinducing nasal irritation the composition is inhaled, and/or by inducing emesis if more than a prescribed dosage amount of the analgesic is consumed. Brief Description of the Drawings The present inventions will be heferunderstood by examining the 15 following figures which ilustate ertain properties of theyresent invention wherein: Fig shows a percentage amountof certain opioid dags available in solution for injection after standard dosage formnae acushed and exposed to a solvent; Fg 2 shows a percentage amount of certain opiod drugs available in solution for injection afer dosage fons of the present invention are crashed and exposed to a solvent; 20 Fig3 shows an amo-unt ofdrug recoverable from a solvent contacted with Five embodiments of the present invention compared to a standard formulation; Fig, shows a dissolution profile of six embodiments of thepresent. invent ion. i Sashows various methods used to fomulate the dosageforms havng one or more abuse deterrent properties ofthe present invention; 25 Fig, 5b shows a particular dosage form having on or more abuse deterrent properties of the present invention g.sc shows a particular dosage form having o or more abuse deterrent properties of the present invention cd a disintegrant; Fig 6bows a processflow chart for the ranutre of a dosage forni of the present 30 invention; and Fig. 7 shows a dissolution profile of three extended release formulations of the present invention. With reference to the Figures, features that are the same across the Figures are denoted with the sa ference numbers Detailed Description of the lpvention The present invention includes an abuse deterrent formulation for reducing the potential for one or more of a) parentern abuse, b) inhalation (e.g, intranasal abuse), and/or c) oral abuse of a drug, typically an opioid analgesic type drug, for satisfaction of a physical or psychological dependence. In one embodiment the present invention deters 1 parenteral abuse by providing a phanaceutical composition which includes an analgesic wit one or more gel nfoing agents such that upon contact with a solvent (e,g., water), the agents swell by absorbing the solvent thereby 1) entrapping the drug in a gel matrix and/or 2) reducing or preventing a significant amount of the opioid analgesic from being drawn into a syringe. In one embodiment, the present invention deters inhalation abuse 1$ by providing a pharmaceutical compostion which includes a therapeutically active pharmaceutical (e.g, an analgesic), with one or more mcous membrane, mucosa or Mucosal tissue irritants (collectively referred to as mucous membrane irritants). In one emubodinenit, the muOsal tissue is nasal passageway tissue, Upon contact with a mucous membrane, the irritants induce temporary 20 pain and/or irritation of the membranes and/or tissues to thereby deter abuse. For example, inhaled by snorting the mucous membane in the nasal passageway will be irritated and result in pain to the individual. In on embodiment, the Present invention provide pharmaceutical composition whhic includes an analgesic with one ornmore rneics, such thatafter an consumptn ofmore tha a typically prescribed amount of 25 the dosage form,esi isinduced. In one embodiment, two or more of the abuse deterrents can be combined into one composition according to the present invention The present invention describes formulations which have abuse deterrent propertes as described herein. Examples of specific oral solid dosage forms containing 30 morphine, hydrocodone and oxycodone were evaluated using suitable analytical test methods, such as UV/VS spectrophotomey. In the evaluation, dosage forms were crushed and contacted with a small amount of water (about a teaspoon or tablespoon). 6 After attempting to dissolve tie dosage form, the resultant material was drawn into a syringe, olume was measured and opioid content was quantiated. As shown in FigiL almost 100 % of the opioid can be extracted from standard formulations Comparatively as shown inFig 2, an abuse deterrent formulation of the present invention for te same 5 oploids, provides a significantly lower percentage of extractable opioid. As shown in Fig. I, approximately 93%, 103% and99% ofthe opioid analgesic drugs contained in a dosage formwere recoverale using the above described techniques, Compartively as shown in Pig.2 using an abyse deterrent polymer of the present invention only 9%. %, and 6% of the opioid analgesic dgs were recoverable. 10In another embodiment the present invention is a pharmaceutical composition that includes an pioid analgesic one or mte gel fonning ageut, and one or more mucous mentraned rritants or nasal passageway tissue irritants. Another embodiment, the present invention includes a pharmaceutical compositiov, Which includes an analgesic, one or more gel fonning agentl and one or more einetics as 15 described herein. In another embodiment, the present invention includes a pharmaceutical composition, which includesan opioid analgesic, one or more mucous merane irritants or nasal passageway tissue irritants and one or more emetiecs as described herein. In one paRteular embodiment, the present invention includes a pharmaceutical compositon which includes an analgesic, one or more gel fonning agents 20 one or more aucous membrane irritants and/or nasal passageway tssue irritants, and one or more ees, Each of the componen f the pharmaceutical composition of the present invention are described in nore detail below, A. DrugsSuitabe for Use With the Present Invenon 25Anydg, therapeutically acceptable drug salt, drug derivative, dng analog, drug homologue, o mpolymorqh can be used in the present invention In one embodiment, the drg can be oray administered, In certain embodiments, drugs susceptible to abuse are used Drugs commonly susceptibleto abuse nclude pychoedive drugs and analgesics, finding but not limited to opioids and drugs that can 30 cause psychological and/or physical dependence on the drug, A di-ug for use in thepesent invention can be one or more of the f wing: alfentanil,ampheannnsbuprenoune, butorphano cardentancodeine geoie diacetylnorphinle; dihydrocodeine, dihydroinurphine, diphenoxylate, diprenorphineC, etorphine, fentanyl, hydrocodon; hydromorphonehydroxy methylfentanl, levo aacetyhethadolevorphanol, lofentanil mepeidie, methadone, methylphenidte morphine, nalbuphine nalmefeneo-methyhnaltrexonenaloxone, naitreone oxycodone, oxymorphone, pentazocinepethidinepropoxyphene, S remifentanlhl saufentanii, tilidine and tranrodol, salt derivatives, aniogshomologues, polymorpha thereof, and mixtures of any of the foregoing, none embodiment, a pharmaceutical composition of the present invention includes, one or more oploids such as hydrocodone morphine and oxycodone and/cr salts thereof, as the therapeutically active ingredient Typically when processed into a stable 10 dosage fom, as described in nore detail below, the drug can be present in such dosage forms in an amount normally prescribed, typically about 0. Sto about 25 percent on a dry weight basis, based on the total weight ofthe formulation With respect to analgesics in unit dose form, such an amount can be typically from about 5, 25, 50, 75, 100, 125, 150, 175 or 200 mg. More typically, the 15 drug can be present i an amount from 5 to 500 g or even 5 to 200tug in other embodimnwits, a dosage ibrm contains an appropriate amount of dug to provide a therapeutic effect, B. (Gel Forming Agents As described above the present invention can include one or more gel 20 forming agents. The total amount of gel forming agent is typically about 3 to about 40 percent on a dry weight basis of the composition, Suitable gel fuming agents include compounds that> on contact wvith a solvent (eg, water, absorb the solvent and swel thereby forming a viscous or semi~ viscous substance that significantly redues andior minimizes the amount of free solventt which cancontain an amount of allied drug, and which canbe drawn into a syrnge. The gel can &Iso reduce the overall amount of drug extractable with the soavent by entrapping the drug in a gelntrix In one embodimentdtypical gel forming agents includepharmaceutically acceptable polymers typically hydrophulie polymers, such as hydrogels. In some embodiments, the polymers exhibit a high degree of viscosity upon contactavith a suitable aolvet The high viscosty can enhance the formation of upol colu" Cf ""TIUI a lit 8 highly viscous gels when attempts are made by an abuser to crush and dissolve the contents of a dosage form in an aqueous vehicle and injcti it intravenously, More specifically, in certain embodiments the polymeric material in the present invention provides viscosity to The dosage fonn when it is tampered. In such S embodimentS, when a abuser crushes and dissolves the dosage form in a solvent (e.g., water or saln a viscous Or emi-viscous gel is formed, The increase in the viscosity of the solution discourages the abuser from injecting the gel intravenously or intramuscularly by preventing the abuser fron transferring sufficient amounts of the solution to a syringe to cause a desired "high" once injected. Suitable polymers include one or more pharmaceutically acceptable polymers selected from any pharmaceutical polymer that will undergo an increase in viscosity upon contact with a solvent. Preferred polymers include polyethylene oxide, polyvinyl alcohol, hydroxypropyl methyl cellulose and carbomers. In preferred enbodinents, the polymers icdude: a) Polyethylene Oxide In some enbodiments, the polymer includes polyethylene oxide. The polyethylene oxide can have an average molecular weight ranging frm aboutD00000 to about 5,000,000, more preferably from about 600,000 to about 51000,000g and most preferably at least 20 about 5,000,000. I one abodiment, the polyethylene oxide includes igh mbolecular weight polyethylene oxide. i one embodiment, the average particle size of the polyethylene oxide ranges from about 840 to about 2,000 microns, In another embodiment, the density of the polyethylene oxide can range from 25about 1.15 to about 1,26 g/ml In another embodiment, the viscosity can range from about 8,800 to about 17,600 cps. The polyethylene oxide used in a directly compressible formulation of the present invention is preferably a homopolymer having repeating oxyethylenc groups, i,e, -(--CHiCTH2 -) a - where n can 30 range from about 2,000 to about 180,000. Preferably, the polyethylene oxide is a commercially available and pharmaceutically acceptable homopolymer having moisture content of no greater than 9 about P1 by weight Examples of suitable, commercially available polyethylene oxide polymers include Polyox * WSRN- 105and/or WSRcoagulant, available fim Dow chemicals. In some embodiments, the polyethylene oxide powdered polymers can contribute to a consistent particle size in a directly compressible fonnulation and eliminate the problems of lack of content uniformity and possible segregation, b) Polyvinyl Alcohol In one embodiment, the gel forming agent includes polyvinyl alcohol. The polyvinyl alcohol can have a molecular weight hanging from about 20000 to about 20,000. The specific gravity of the polyvinyl alcohol can range from about 1.19 to about 1.31 and the viscosity from about 4 to about65 eps, The polyvinyl alcohol used in the formulation is preferably awater-sluble synthetic polymer represented by -(-QH1 4 0- ) where n can range fiom about 500 to about 5,000; Examples of suitable, commercially available polyvinyl alcohol polymers includeWA, LUSP, available from Spectum Chemical Manufacturing Corporation, New Branswick/New jersey 08901. 20 c) Hydroxypropyl Methyl Cellulose In one embodiment, the gel forming agent includes hydroxypropyl methyl cellulose (Hlypromelose). The hydroxypropyl methyl cellulose can have a molecular weight ranging from about 10,000 to about 1,500,00 and typically from about 5000 to about 10,000, i.e, 25a low molecular weight hydroxypropyl methyl cellulose polymer, The specific gravity of the hydroxypropyl methyl cellulose can range from about 1.19 to about 1 31, with an average specific gravity of about 1.26 and a viscosity of about 3600 to 5600. The hydroxypropyl methyl cellulose used in the formulation can be a 30 watersoluble synthetic polymer, Examples of suitable, commercially available hydroxypropyl methylelose polymers include Methocel K100 LV and Methocei K4M, available from Dow chemicals 10 d) Carbomers! In one embodiment, the present invention includes carboners. The carbomers can have a molecular weight ranging from 700000 to about 4,000,000,000. The viscosity of the polymer can range from about 4000 to about 39,400 ep, Examples of suitable, commercially available carbomers include carbopol 934P NF, carbopol 9741 NF and carbopol 971P NF, available from Noveon Pharmaceuticals. Following the teachings set forth herein, other suitable gel forming agents can include one or more of the following polymers: ethyl celhuose, cellulose acetate, 10 celhuose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate and cellulose triacetate, cellulose ether, cellulose ester, cellulose ester ether, and cellulose 5 acrylic resins comprising copolymers symhesized from acrylic and methacrylic acid esters, the acrylic polymer may be selected from the group consisting of acrylic acid and methacrylic acid copolymers, methyl methacrylate copolyners, ethoxyctiryl 15 methacrylates, cyanoetryl methacrylate, poly(acryic, acid), poly(methaerylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylie acid anhydride), and glycidyl methacrylate copolymers. Any of the above described polymers can be combined together or 20 combined with other suitable polyme-rs, and such combinations are within the scope of the present invention. In one embodiment, the abuse deterren 5 gel formg agent can prevent less than or equal to about 95%, 94%, 70%, 60%, 54%, 50%, 45%, 40%, 36%, 32%, 30%, 27%, 20%, 10%, 9%, 6%, 5%or 2% of the total amount of drug in a dosage fonn from 25 being recovered from a solvent in contact with a dosage form of the present invention. As shown in Fig. 3, forulations A3, $3, C3, D3 and 13 reduce the amount of drug extractable or recoverable from a dosage for of the present invention. Specifically, formulation A3 provides for recovery of 26.77% of the total amount of drug in the dosage form, formulation B3 provides for recovery of 31.8% of the total amount of drug in the 30 dosage form, formulation C3 provides for recovery of 35.75% of the total amount of drug in the dosage form, formulationD3 provides for recovery of 35,8% of the total amount of drug in the dosage hom, and formulation E3 provides for recovery of 42,5% of the total amount of drug in the dosage form. In Fig, 3, all five formulations A3 throughE3 are I i compared with a standard dosage form of oxyconin which provided for recovery of 9.6% of the total amount of drug in the dosage form The five formulations A3 through E3 are set forth in Exampls 14 through 18, respectively. 5 It should be noted that the above described formulations also have dissolution profiles as determined by the USP 2-paddle method, as shown in Fig. 4, In particular, for formulations A3 through 3, about 50% to about 82% of each formulation dissolves after about 15 minutes and about 80% to about 95% dissolves after 90 minutes. Fig. 4 further includes the dissolution profile of Formulation F3. With respect to Fig. 4, the composition of formulation F3 is set forth in Example 19 The above described gel forming agents can be further optimized as pecessai or desired in terms of viscosity, molecular weight, etc, C> Mucous Membrane Irritants and/r Nasal Passageway Tisse Iritants As described above,the present invention can include one or more mucous membrane irritants and/ornasal passageway tissue iritants, In one embodiment suitable mucous membrane iritants andor nasal passageway tissue irritants include compounds that are generally considered pharmaceutically inet, yet can induce irritation. Such compoundS include, but are not limited to surfactants In one embodiment suitable srfactants include sodiun lauryl sulfate, poloxamer, sorbitan monoesters and glyceryl 20 mon ooleates. Other suitable compounds are believed to be within the knowledge of a practitioner skilled in the relevant art, and can be found in the Handbook of Pharmaceutical Excipients, 4th Ed. (2003) the entire c ntent of which ishereby incorporated by reference. in one embodiment of the present invention, the irritant can be present in 25 amount of fom 1 to 20 percent by weight on a solid basis, preferably i to 10 percent by weight on a solid basis. In another embodiment, the amount of irritant can be present in arn amount of 5 to 15 percent by weight. In another embodiment, the irritant can be present in an amount of at least 5 percent by weight. In yet another embodiment, the irritant can be present in an amount from 1 to 5 percent by weight, In another 30 embodiment the amount of irritant can be present in an amount from 1 to 3 percent by weight. 12 In certain embodiments, the irritant can deter abuse of a dosage formn when a potential abuser tampers with a dosage form of the present invention, Specifically, in such eibodiments, when an abuser crushes the dosage tbrm, the irritant is exposed. The irritant discourages inhalation of the crushed dosage fbrm by inducing pain and/or 5 irritation of the abuse's mucous membrane and/or nasal passageway tissue. in one embodiment, the irritant discourages inhalation (e.g. via snorting through the nose) by inducing pain and/or irritation of the abuser's nasal passageway tissue. in one embodiment, the present invention includes one or more mucous membrane irritants to cause irritation of mucous membranes located anywhere on or in 10 the body, including membranes of the mouth, eyes and intestinal tract. Such compositions can deter abuse via ora intra-ocular or rectal or vaginal routes. The above-described irritants can be further optimized as necessary or desired in terms of concentration, irritation severity, etc. D. Enietics As described above, the present invention can include one or more emetics oiremesis inducing agents Preferably, the emetic is a pharmaceutically acceptable inert excipient that only induces emesis after a certain threshold amount is ingested. 1In another einbodinient, the emetic can be a pharmaceutically active emetic. n one embodiment the amount of emetic present in a pharmaceutical composition of the present inention can be tied directly to the amount of drug in the pharmaceutical composition. Thus, by controlling the quantity of the emetic compound in the phamaceutial canmposition, emcsis can be avoided tfnormal prescrpton direcions areolowed Howeveriftoverdosage occurs by ingesting more than a prescried Iuantity of a drugi a phamaceuticalcomposition of the present invention 25 theamount of ingestedemeti can exceed the threshold amount necessary to induce emesis. In some embodiments, the threshold amount of emetic for inducing nemesis can be reached when the normal prescription directions are inappropriately increased by factors of 2, 3, 4, 5, 6, 7, or 8 times, or more. Thus, in some embodiments, the amount of 30 emetic present in a pharmaceutical composition of the present invention is an amount such that the amount of emetic ingested does not exceed the threshold amount necessary for inducing nemesis until a subject ingests 2, 3, 4, 5, 6, 7, or or more times the amount 13 of drug normally prescribed in some embodiments, nemesis can preclude death or serious illness in the subject in one embodiment, the emetic includes zine sulfate. Zinc sulfate is an excipient, which can induce emesis when more than about 0,6 to 2.0 gn is ingested, 5 typically more than about 0.6 gu. In one embodiment, a phannaceutically acceptable inert excipient which can induce emesis (e.g, zine sulfate) can be present at about 5 to 60 percent by weight on a solid basis, or about 5 to 40 percent by weight on a solid basis or about 5 to 25 percent by weight on a solid basis more typically about 5 to 10 percent by weight on a solid basis, 10 Accordingly, pharmaceutical compositions of the present invention can be easily designed to induce emesis if a prescribed dosage is exceeded and/or if prescription directions are not followed for dosage fons containing a composition of the present invention. In some embodiments of the present invention, a dosage form can include about 0,01, 0,05,0.1, 0,15, 0.2, 025, 0.3, 0.35, 0.4, 0,45, 0,5, 0,55, 0.6, 0.65, 0.7, 0.5, 15 0.8, 0.85, 0.90, 0.95, 1.0 grams of a pharmaceutically acceptable inert excipient which can induce emnesis (e.g,. zinc sulfate) or pharmaceutically active emetic. 1 another embodiment the present invention includes arn inert excipient which can induce nemesis (e.g., zinc sulfate) or pharmaceutically active emetic in an amount that is a summation of two or more of the above described amounts. 20 hi another embodiment, the present invention can include 1, 2, 3, 4. or 5 times or more of the above described amounts of pharmaceutically acceptable inert excipient which can induce enmesis (eg., in sulfate) r a phanmaceutically active emetic. Typically, suitable embodiments f the presentnvention include from about 0.1 m toabout m2.0 gI of uc sulfate in other embodiments the present invention can include 25 about. otees than aout 2.0 gm of zinc sultae For exunplein. one embodiment if a pacioner desires to create a dosage fom that willinduce emesis only after four or more dosage forms are ingested, the amount ofzinc sulfate in each dosage form should not exceed about 0.9 gn Tuf three dosage fomsare ingestedthe amount of emeticis 0.57 gin, which is less than a so tpical threshold amount of the particular emoe. However, if a fourth dosage form having 0.9 gi of znc sulfate is ingestedthe amount of emetic exceeds the threshold amount, nd tiesis is induced, 14 The above-described emetics can be further optimized as necessary or desired In terms of concentration in the pharmaceutical composition, etc. Other suitable emetics can include one or more of cephaeline, methl cephaeline, psychotrine, O-mcthylpsychotrinie, ammonium chloride, potassium chloride, magnesium sulfate, ferrous gluconate, ferrous sulfate, atoi, and emetine. F. Other ingredients The present invention can also optionally include other ingredients to enhance dosage form manufacture from a pharmaceutical composition of the present invention and/or alter the release profile of a dosage forming including a pharmaceutical io composition of the prsentivention. Some embodiments ofthe present inveation include one or more pbarmaceutically acceptable fillers / diluents. In one embodimentAvicel PI (Microcrystalline cellulose) is a flerused in the formulation The Avicel PET an have an average parties size rang from 20 to about 200 pm, preferably about 100 pun. The 1 density niges from 1,512-1.668 g/ cur The AVicel PH should have molecular weight of about 36,000. A i PH effectiveness is optima when it is present if an amount of from about 10 to 65 percent by weight on a solid basis, of the formulaon. Typical fillers can be present in amounts from 10 to 65 percent byweight on a dry weight basis Other ingredients can indude sugars and/or polyols. 20 Other ingredients can also include dibasic calcium phosphate having a particle size ofafbout 75 to about 425 microns and a density of about 0.5 to about 13 ga, as, a e a calcium sulfate having a particle size of about I to about 200microns and a density ofabout 06 to about 1.3 gmI and mixtures thereof, Further, lactose having a parteSize of about20 to about 400 irons and a density of about 0.3 to about 0.9 g/ml 25 can also be incdaded la some embodiments of the invention, the fillers which can be present at about 10 to 65 percent by weight on a dry weight bais, also function as binders in that teynot only impart cohesive properties to te materid wihinthe fonmlatin but can alsoicrease the bulk weight of a directly compressed formulation describedd below) 30 to achienn accepted e a e tt n tO emnboditnenits, additional filers need not provide the same level of cohesive properties as the binders seeted,but can be capable of contributing to formation homogneity and 15 resist segregation frnm the formulation once blended. Further, preferred fillers do not have a detrimental effect on the flowability of the composition or dissoluti on profile of the formed tablets. In one embodiment, the present invention can include one or more 5 pharmaeutiCaIIy acceptable disintegrates. Such disintegrates are known to a skilled artisan. In the present invention disintegranits can include, but are not limited to, sodium starch glycolate (Explotab@-)) having a particle size of about 104 microns and a density of about 0.756 g/ ni, starch (e.g, Starch 21) having a particle size of about 2 to about 32 microns and a density of about 0.462 g/ ml, Crospovidone@ having a particle size of 10 about 400 microns and a density of about 1.22 g/ nil, and croscarmellose sodium (Ac-Di Sol) having a particle size of about 37 to about 73.7 microns and a density of about 0.529 g/ mL The disintegrant selected should contribute to the compressibility, flowabilty and homogeneity of the formulation, Farther the disintegrant can minimize segregation and provide an immediate release profile to the formulation. In some embodiments, the U disitegrant (a) are present in an amount from about 2 to about 25 percent by weight on a solid basis of the directly compressible formulation. In one embodiment, the present invention can include one or more pharmaceutically acceptable glidants, including but not limited to colloidal silicon dioxide. In one embodimet coloidal silion dioxide (Cab-O-Sil@) having a density of 20 about 0,029 to about 0.040 g/ ml can be used to improve the flow characteristics of the formulaion Such glidants can be provided in an amount of from about 0A to about I percent by weight of the formulation on a solid basis, It will be understood, based on this invention, however that while colloidal silicon dioxide is one particular glidant, other glidants hang inilaproperties whichare known or to be developed could be used 25 pmided theyae compatible with oter cxcipients and the active ingredient in the formation and which do not significantly af fect the flowability honogenetyand ompressibility of the fornulation. in one embodiment, the present invention can include one or more pharmaceuticallY acceptable lubricants, including but not limited to magnesium stearate. 9 j one embodiment, the magesiumi stearate has a particle size of about 450 to about 550 microns and a density of about 1.00 to about 1.80 g/ml. In one embodiment, magnesium stearate can contribute to reducing fiction between a die wall and a pharmaceutical composition of the present invention during compression and can ease the ejection of the 16 tablets,.thereby facilitating processing. In some embodiments, the lubricant resists adhesion to punches and dies and/or aid in the flow of the powder in a hopper and/or into a die. In an embodiment of the present invention, magnesium stearate having a particle size of from about 5 to about 50 microns and a density of from about 0,1 to about 1. I 5 g/nl is used in a pharnnceutical composition. In certain embodiments, a lubricant should make up from about 0,1 to about 2 percent by weight of the formulation on a solids basis. Suitable lubricants are stable and do not polymerize within the formulat ion once combined, Other lubricants known in the art or to be developed which exhibit acceptable or comparable properties include stearic acid, hydrogenated oils, sodium stearyl fumarate, i1) polyethylene glycol, and Lubritab*. In certain embodiments, the most important criteria for selection of the excipients are that the recipients should achieve good content unifornity and release the active ingredient as desired. The excipients, by having excellent binding properties, and homogeneity, as well as good compressibility, cohesiveness and flowability in blended 15 form, minimize segregation of powders in the hopper during direct compression. In another embodiment, the present invention can include an opioid antagonist in addition to the other ingredients, or as a substitute for one of the other abuse deterrent ingredients of a formulation of the present invention. Suitable antagonists are described above, One particular antagonist includes naloxone. As described above, 20 typically naloxone has no action when taken orally, and will not interfere with the pharmacologic action of an opioid agonist. However, when given by injection naioxonet can have profound antagonistic action to opiold agonists. An appropriate antagonist can be used in combination with one or more of gel forming agents, mucous membrane irritants and/or nasal passageway tissue irritants, or emetics in the present invention. An 25 appropriate antagonist can also be used as a substitute for one or more of gel forming agents, mucous membrane irritants and/or nasal passageway tissue irritants, or emetics in the present invention, Suitable opioid receptor antagonists can include but are not limited to the atagonists described in U.S. Patent Nos. 6,559,159 and 6,3'5,957, the entire content of which are hereby incorporated by reference. 3Q rDosage Forms of the Present Invention A pharmaceutical composition of the present invention including one or more drug components, one or more of gel forming agentsnmcous membrane irritants and/or nasal passageway tissue irritants, and metics and optionally other ingredients, 17 oan be suiably modified and processed to form a dosage fmiut of the present invention. As referred to herein and in Figs. 5a, 5b, 5c and 6, an "abuse deterrent composition" or ADO" (labeledi"40" in these Figures) includes a composition having one or more gel forming agents and/or nmcous membrane irritants and/or nasal passageway tissue z, irritants and/or emetis according to the teachings set forth herein. In this manner, an abuse deterrent composition can be layered onto, coated onto, applied to, admixed with, formed into a mantra with, and/or blended with a drug and optionally other ingredients, thereby providing a therapeutic composiion of the present invention. As shown in Fig a, an abuse deterrent composition can be corbinedwith 10 a drug and/or opioid analgesic .g hydrocodone) in one or more layered dosage forms. According to the present invention, drug 50 can be a layer on or near the surface (I) of ADC 40 of the present invention, or sandwiched between two or more distinct layers (H and II) of AD 40 of the present invention. In other embodiments, drug 50 can be a coating IV) on ADC 4O, Drug 50 can be any of the pharmaceutically active ingredients 15 (e g.. opinids) described herein and can be combined with other exipients.e disintegrants includingbut not limited to sodium starch glycolate or Explotab@. As shown in Fig. 5b an abuse deterrent composition 40 of the present inventioni can be combined with drug 50, 4g, hyrhocodone in a blended mixture. In such embodinuts, drug 50 and ADO 40 can be evenly mixed. 20 As shown in Fig. 5c abuse deterrent composition 40 of the present invention ca be combined with drug 50 eg hydrocdone in a blended mixture with other ingredients 60, eg, a disintegrant Fig, 6 shows one embodiment of the present invention For making a dosage foR1m of the present invention. Specifically, a first step (step 1) of Fig, 4 shows 25 drug 50 combined with abuse deterrent composition 40 of the present invention. ADC 40 can contain one or more gel forming agents and/or mucous membrane irritants and/or nasal passageway tissue irritants, and/or emetics according to the teachings set forth heroin, In a second step (step 2). the combination of drug 50 and ADO 40 can then be blended with other ingredients 60, e.g. disintegrates and lubricants, to form a mix 100. 30 Lastly, in a third step (step 3) combination 100 can then be processed using conventional practices 110, e.g, compression, into a suitable unit dosage form 120, e.g. tablets. Suitable formulations and dosage forms of the present invention include but are not limited to powders, caplets, pills suppositories, gels, soft gelatin capsules, 118 capsules and compressed tablets manufactured from a pharmaceutical composiion ofthe pres inventn. The dosage forms can be any shapincluding regular or irregular shape depending upon the needs of the arisan. Compressed tablets including the pharmaceutical compositions of the 5 present invention can be direct compression tablets or non-direct compression tablets. In one embodiment, a dosage form of the present invention can be made by wet granulation, and dry granulation (e~g, slugging or roller compaction) The method of preparation and type of recipients are selected to give the tablet formulation desired physical characteristics that allow for the rapid compression of the tablets. Adler compression, the 10 tablets must have a number of additional attributes such as appearance, hardness, disintegrating ability, and an acceptable dissolution profile. Choice of fillers and other recipients typically depend on the chemical and physical properties of the drug, behavior of the mixture during processing, and the properties of the Inal tablets. Adjustment of such parameters is understood to be within 15 the general understanding of one skilled in the relevant art, Suitable tillers and recipients are described in more detail above. The manufacture of a dosage form of the present invention can involve direct compression and wet and dry granulation methods, including slugging and roller compaction. However, in the present invention, it is preferred to use direct compression 20 techniques because of the lower processing time and cost advantages. Accordingly, and as described father below, a directly compressible pharmaceuticalcomposton of the present invention can be designed following the teachtingset forth herein that can deter one or more of a) parenteral abuse of a drug, b) inhalation abuse of a drug, and c) oral abuse of a drug. 25 Such compositions and dosage forms are fonned according to the present invention are descrbed. Steps fibr makingthe compositons or dosage fons include the step of providing one or more drugs and/or analgesics desnibed above and an amount of a el forn-ing polymer having a desired niolecula weight or viscosity as described abov and/or providing a nasal tissue irritantand/or providing an emetic in the amounts as l0 described above. By conttolling the molecular weight and/orviscosity of the gel forming by counting the amount of mucous membrne irritant and/or nasal 19 tissue irritant such that nasal tissue irritation occurs if the composition is inhaled (e.g. snorting), and/or by controlling the amount of emetic such that nemesis ensues if more than a prescribed amount of the analgesic is consumed, a therapeutic composition suitable for use to deter dng abuse can be fbmied, The compositions according to the present S invention can deter abuse of the analgesic by fIforming a viscous substance upon contact with a solvent such that the sustance and analgesic cannot be easily drawn into a syringe and/or (2)by inducing mucous membrane irritation and/r asal tissue irritation if the composition is inhakd, and/or (3) by inducing emesis if more than a prescribed amount of the analgesic is consured i) The present invention can he used to manufacture immediate release, and controlled drug release fonmulations. Controlled release fonmulations can include delayed release and extended release oral solid dosage preparations. Examples 25 (formulation A7 of Fig, 7), 26 (formilation B7 of Fig. 7) and 27 (formulation C7 of Fig, 7) provide enbodinents of the invention that can provide controlled release of a drug. 15 The release profiles of the controlled release dosage forms of the present invention are shown in Fig, 7, The dosage forms in Fig, 7 include hydrocodone bitautrate (HC3T) as an active. As shown in Fig. 7, about 80 to 95% of the drug in a controlled release dosage form of the present invention is released after about 10 hours, as compared to an imnediate release dosage form (a conventional dosage form) which is at least 75% 20 dissolved after about 45 minutes, Other opioid fonnulations having an extended effect. which can be modified to further include one or more of the abuse detertent compositions of the present invention, are described in U.S Paten No. 6,572,885, the entire content of which is hereby incorporated by reference, Certain aspects of the present invention may be better understood as 25 ilhistrated by the following examples, which are meant by way of illustration and not limitatiori. Example I A direct compression formulation as shown inTable 1, for a immediate release opioid analgesic e g hydrocodone bitarate tablet having g5 gof hydrocodoe 30 hitartrate was formed by weighing each component separately and mixing the hyocodone bitartrate nd the polymer in a V-blender for about 5 to 0 minutes atlow shear conditions or in a high shearhlener by fixing 2 to 5 Mnutes. The other formulatiOn excipientS were added to the above biend excepting the libricant and mixed 20 at t same rate for additional 5 to about 10 minutes. Finally, the lubricant, magnesium stearate was added to the formulation and blended at the same rate for an additional to 5 minutes This polymeric matrix containing the drg and other recipients was further compressed on a rotary tablet press to form pharmaceuticals acceptable tablets. 5 The tablets were monitored for weight, hardness thickness and liability The tablets were tested for assay, release characteristics (in-vitro dissolution method) and abuse deterrent properties. Samples of the tablets were subjected to dissolution testig using USP Apparatus 2 (U.S. Pharmacopoeia, XXVL 2003), speed 50 rpm at 37"C, in purified water 10 as dissolution medium for a period of 90 minutes. The acceptable dissolution criteion is not less than 75 percent of the dreg dissolved in 45 minutes, To evaluate abuse deterrent properties of the formulation a method has been developed that maiics the street abuser's method for abuse. Wi) The tablets are crushed and the resulting powder is placed into table/teaspoon, 15 (ii Measured amount of water is added to the spoon. Contents of the spoon are heated for about I to 2 minutes Contents of the spoon are withdrawn using a syringe equipped with a needle. (iV) The voalune of the sample removed from the spoon is measured and the contents of the syringe are tested for the active sing a suitable analytical test 20 method such as UWM '/1S spectrophotometry. Table 1 - CWeight (mg)i tablet H-ydrocodone bitartrate5 Polyvinyl alcohol 6 Avicel PH 102 3"3 Starch 21 54 Zinc sulfate 30 Explotab 1 Cab~O-Sil 1.5 Total 600 A intro dissolution criterion of NLT 75 % of the drug dissolved in 45 25 minutes was metb The drug extracted by the abuse-test method detailed above was about 34 percent. 21 Example 2 able 2 Pant We htfa tablet Hlydrocodone bitartrate5 ~Poyvinyl alc ohol 6 Crospovidone 90 Avicel PH 102 120 Starch 21 43 Zinc sulfate 30 Cab-O--Sil Magnium stearate .. Tota---- - -- As hown by Tab'e 2, a direct eompressidn formulation of hydrocodone S bitartrate imm ediate release forrmdiatOenjneluding a dosage of 5 mug of hydrocodone itratewsprepared and tested using the blending conditions and procedure as stated in Examnple l An i-vitro dissolution criterion ofNLT 75 % of the drag dissolved in 45 inutes was net. 10 The drug extracted by the abuse-est method was about 31 percent Example N Table 3 - pne ____ Wei bt gy tablet Hydrocodonie bitartrate poyox 70 Cospovidone 152 Avicel PH 102 304 Ziac sulfide15 Sodiumlauryl sufate Cab -051i1 Magnesu seagtat 4 Total 1.11___ 06 . .....-... -. a......... 15 As shown by Table 3, a direct compression formlationof hydrocodoue bitarate immediate release formulation including a dosage of 5 gof hydrocodone bitarrate was prepared and steed uing the blending conditions and procedure as stated in Example i An in-vitro dissolhtion criterion of NLT 75 % of the drug dissoled in 45 20 minuteasintet. Tie drug extracted by the abuse-test method was about .11 percent. 21.

Example 4 Table 4 potent - eih mgtablet iHydrotodonle bitartrate Polyvinyl alcohol 8 Polyox 15 Avicel PH 102 300 Zinc sulfate 50 Sodium lauryl sulfate 7 Crospovidone 100 Cab-Oi-Sil Magn'esrimC3steaat Total 560 As shown by Table 4 a direct compression formulation of hydrocodone 5 bitartrate immediate release fornulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in Example 1 An initro dissolhtion criteron of NLT 75 % of the drug dissolved in 45 minutes was met. 10 The drug extracted by the abstestmethod was about 65 percent Example 5 Table 5 Com -nlt Weight( tablet Hydrocodonie bitartrate Mlethocel K100 LV 25 Avicel PH 102 300 Zinc sulate 50 Sodium lauryl sulfate 7 Crospovidone 0 Cab-0--Sit Magneswiumsearate Total40 15 As shown y Tabl 5, a direct compression formulatinof ydrocodone bitartrat immediate release Lom.lation induding a dosage of 5 g of ydrocodone bitrtrate mas prpared and tested using the blending conditions and procedure as atted in Example 1. An jn-vitro dissolution cterion of NT 75 % of the drug disalved in 45 20 minutes was met 23 The drug extracted by the abuse-test method was about percent Example 6 Table 6 Coponent __ __ Weight m~g)/tabbt Oxycodone hydrochloride 5 Polyox 25 Avicel PH 102 300 Zinc sulfate 0 Sodium lauryl suite 7 Crospovidone10 Cab-O-Sil Magnesiwn stearale Total 490 As shown by Table 6, a directtmpression formulation of oxycodone hydrochloide immediate release fonulation including a dosage of 5 f of oxycodone hydrochloride was prepared and tested using the blending conditions and procedure as stated in Example 1 to An in-vitro dissolution criterion of NLT 70 % of the drug dissolved in 45 minutes was met. The drug extracted by the abuse-test method was about 9 percent 24 Table 7 Component Weig htq )tablet Morphine sulfate 20 Polyox 20 Avicel PH 102 300 Zinc sulfate 50 Sodium lauryl sulfate 7 Crospovdone 100 Cab-O-Sil M-agnesi stearate _____ Total _00 As shown by Table 7,a direct compression fom ulaion ofmorphine 5 ulfate immediate release formlation including a dosage of 20 rg of morphine sulfate was preared and tested using the blending conditions and procedure as stated in Example An invitto dissolution criterion of NLT75 % of the drug dissoled in 45 minutes was met 10 The drug extrated by the abuse-test method was about 16percent Example 8 Table 8 SComponeght ( h et Morphine sulfate 20 Polyvinyl acohol 160 Avieci PH 102 318 Zinc sulfate 30 Explotab 30 Starch 21 54 Gab-CY~l15 Total 615 xvsprepared and tested using the blending conditions and procedhure as stated in lixampie 1 20 An in-itro di , Stion criterion of NT 75 %of the drug dissolved in 45 minutes was met 1-/2i24 .

The drug extracted by the abuse-test method was about percent Example 9 Table 9 Onlp Oflt (m_ IegtQnfalt Morphine sulfate 40 Polyox is Avicel PH 102 300 Zinc sulfate 50 Sodium lauryl sulfate 7 Crospovido100 Cab-O-Sil 2 a-esiun stearate Total 515 As shown by Table9 diect compassion formulation of morpine sulfate immediate release formulation including a dosageof 40 mng ofmorphine sulfate was prepared and tested using the blending conditions and poedure as stated in Example 10 An in-vitro dissolution crtenon ofNLT 75 % of th drug dissolved in 45 minutes was metp The drug extracted by the abuse-test method was about 15 percent Example 10 NN__ Table 0l - ---- - - ------- 6COnen~Mt __ __ Weight (mg)Iaiet Morphine sulfate 4 Polyvinyl alcohol 200 AviceLPH 102 2 7 Zinc sulfate Expiotab 30 Starch 21 54 Cab-OSil L5 ~ 1.5 Total 635 As shown by Table 10, a diret compression fominlation of morphine sulfate immediate release formulation including a dosage of 40 rng of morphine.sulfate was prepared and tested using the blending conditions and prcedur as stated in Example 20 1. An in-vito dissolution criterion of NST 75 % of the dirg dissolved in 45 minutes was met2 Thedarug extracted by the abuse-test method was about 6 percent Example 11 TableIll Cmponeat ___ _____ We i4mg)/ablet Hlydrocodone bitartrate 75 Polyox 25 Avicel H 10295 Crospovidone 100 Zinc sulfate 50 Sodium lauxyl sulfate 7 Cab-O-SiI 2 Tota 490 As shown by Table 11, a direct compression formultion of hydrocodonwe bitartrate immediate release formulation including a dosage of75 rug of hydrocodone bitarate was prepared and tested using the blending condins asnd procedure as stated in Example I. 10 An in-vitro dissohuin criterion fNLT 75 % of the drg disolved in 45 Minutes was met. The dg extracted by the abuse-test method was about 5 percent Example 12 15 Table 12 S-------- .Weight ( tabet Hyvdrocodone bitar~ate 10 Polyvinyl alcohol SO Polyox 1 Avicei PH 102 295 Crospovidone10 Zine suflate 50 Sodiumt auryl sulfate 7 Cab-O-Sil 2 Magnesitut stearate I _______ Total 560 As shown by Table 2 a direct compression fomultion of hydroc-done bitartrate immedate eleaseomnulation including a dosage of 10 mg of hydrocodone 20 bitartrate was prepared and tested usg the. blending conditions and procedure as stated i Exiaple i. 27 inmates was met, erhe drag extracted by the abuSietest method was about 9.5 percent. SExample 13 Table 13 H-ydrocodone bitartrateo Carbopol 971P 10 Avicel PH 102 300 Crospovidone 100 Zinc sulfate 5 Sodium lauryl sulfate 7 aab-O-Sil 2 Magnesium steaate ____ _____ otal 490 As shown by Table 13, a direct compreson fomulation of hydrocodone bitartrale immediate release formulation including a osage of5 mtg of hydrocod one 10 bhitartrste was prepared and tested using the blending conditions and procedure as stated in Example L An ir-vtro dissoItion- criterion of N; 75 % of the drug dissolved in 45 minutes was niet. The drugextracted by he abuse4est method was about 27 percent. 15 Example 14 Table 14: Formn ation A3 Componlent___ Weightk tablet) Hydrocodone Blhtartrate 5 Polyvinyl Alcohol 160 Avicel PH 102 318 Zinc Sulfate 30 Starch 21 54 Explotab 30 Cab-O-Sil1.s Total 600 As shown by Table 14 a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone 20 bitartrate was prepared and tested using the blending conditions and procedure as stated ntExamuple I.

An in-viro dissolution showed about 62% of the drug dissolved in 45 minutes The drug extracted by the abuse-est method vas about 277 percent Example IS Table Formulaton 113 nponent Weiht (mg tabet) Hydrocodonle Bitartrate Polyvinyl Alcohol 160 Avicel PH 102 333 Zinc Sulfate 30 Explotab 15 Starch 21 54 Cab-O-Sil 5s Magnesium Stearate ____ _ 13 5-___ Total 600 As shown by Table 15, a direct compression frmulation of hylocodone bitattrate immediate release formulation including a dosage of5 mg of hydrocodone bitaitrate was prepared and tested using the blending conditions and procedure as sated 10 in Example L An in-vitro dissolution showed about 72% of the dng dissolved in 45 minutes. The drug extracted by the abuse-test method was about 31 8 percent Example 16 15 Table 16 Formulation C3 CoXenteit (mg/talet Hvdrocodone Bitartrate5 Polyvinyl Alcohol 160 Avicei PH 102 120 ZinC Sulf ae 30 Crospovidone (PVP XL) 40 Starch 21 43 Cab-O-Sil MAgnes I um Steaat Total 400 As shown by Table 16, a direct compression formulatinn o hydrocodone bitartrate immediate release formulation including a dosage of 5 mug of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated 20 in Example 1 29 An in-vitro dissolution showed about 75% of the drug dissolved in45 muinutes& 'The dvag extracted by the abuse-test method was about 3575 percent. Example 17 5 Table 17: Fonnulation D3 ZIZI Z oE ponent _ ___ eigmg teby Hlydrocodone~ Bita rtratec Polyvinyl Alcobol 160 Zinc Sulfate 30 Crospovidone (PVP XL) 100 Starch 21 33 Cab-O-Sil Manesium Stearate 'otal .. - -- 450 As shown by Table 17, a direct compression ormulation of hydrocodone bitaitrate immediate release formulation including a dosage of5 mirg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in Ernmpe I1 10An in-vitro dissolution showed about% ofthe drg dissolved i 45 nmutes The dug extracted by the abusetest method was about 35.8 percent. Example 18 Table 18: Forn-mlation £3 CompnentWiht ae Hlydrocodone Bitartrate Polyvinyl Alcohol 160 Avicci P4 102 333 Zinc Sulfate 30 Starch 21 54 Crospovidone (PVP 3 XL) 15 Cab-0-Sil1. Total 600 15 As shown by Table 18, a direct compression formulation of hydrocodone bitartrate immediate release formlation including a dosage of 5 mg of bydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in Example 1. An in-vto dissolution howed about79% ohe drug dissolved in 45 minutes. 30 The drug etracted by the abuse-test method was about 425 percent. Example 19 Table 19: Fonmilation F3 Component ____ Weight (mg/ tablet) Hlydrocodonte Bitartrate5 Polyvirnyl Alcohol 160 Avicel PH 102 119 Zinc Sulfate 30 Crospovidone (PVP XL) 100 Starch 21 33 Cab-O-Sil agreiumSteaate_ ___ _____ 2 __ Total __ _ _450 -sshowvn by Table 19, a direct compression formulation of hydrocodone 5 bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitattrate was prepared and tested using the blending conditions and procedure as stated in Example 1. Ain-vitro dissolution criterion of NLT 75 % of the drug dissolved in 45 minutes was met. to The drag extracted by the abuse-test method was about 54 percent. Iample 20 Table 20 Component Wei hfi(/tablet)__ Hydrocodone itatrate Polyvinyl Alcohol 95 Avicel P11 102 192 Zinc Sulfate 30 starch 21 140 A\c-D)i-Sol Cab-O-Sil Total 500 As shown in Table 20, a direct compression fornulation of hydrocodone 15 btra tenimediate release formulation including a dosage of 5,g ofhydmecdone bitariratewas prepared and teste using the blending conditions and procedure as stated nExamiple L An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45 Minutes vbas met 20 ~ The drug extracted by the abuse-test method was about 60 percent. 31 Example 21 Table 21 Com~poent ____WIghtQ! tablet OxycodonleHydrochloride Avicel PH 102 119 Zinc Sulite 30 Crospovidone (PVP XL) ~100 Starch 21 33 Cab-0i-Si 1 Magnesium Stearate ____ -2___ Total _290 As shon by Table 21 a direct compression formulatironof hydrocodone 5 bitaarate immediate release formulation including a dosage of 5 rg ofhydrcodone bitartrate was prepared and tested usingthe blending conditions and pocedur as stated in Example An in-vit dissolution criterion of NUT 75 % of the drug dissolved in 45 minutes was met. 10 The drg extracted by the abuse-test method was About 94 percent. Example 22 Table 22 Component Weht (mg/ tablet) Hydrocodone B itartrate Polyvinyl Alcohol 50 Avicel PH 102 192 Zinc Sulfate 30 Starch 21 140 Ac-Di-So 35 Cab-0-Sil Total _455 - - ~~ -------------- 5 As shown in Table 22, a direct compression forrmulation of hydrocodonc 1 bitarrate inmmediaterelease fommlation including a dosago of 5 mg of hydrocodone bitanratewas prepared and tested using thebending conditionsIand procedure as stated inExample 1. Ar in-vitro dissolution criterion of NLT 75 % of the drug dissolved in 45 mnuteSs 'as mnet. 20 The dbytacted by the abuse-est method was about70 percent 32 Example 23 Table 23 Componen Weight§ (mg/ tablett_ Hy'drocodone Bitarirate Polyvinyl Alcohol 6 Avicel PH 102 318 Zinc Sulfate 30 Explotab 30 Cab-C-Sit 1.5 s Stearate ._....1,5 -_--- Total ......... 600 As shown in Table 23, a direct compression fomrnuation ofhydrocodone 5 bitartate immediate release formulation including a dosage of 5mg of hydrocodone bitartratwas prepared and tested using the blending conditions and procedure as stated in Example An il itro dissolution criterion of NLT 7- % ofthe drug dissolved in 45 anutes w as met. The drug extracted by the abuse-test method was about 33 percent. Example 24 Table 24 - omo _n Weight (mg/ tablet) Hydi ucodo e Bitattrate 10 Aicel PH 102 318 Zinc Suhate 50 C rospo\ idone (PV XL) 100 Sodium L auryl Sulfate 7 Cab -Sil .5 Stearate 1.5 Ttal488 As shown Table 24,a direc otmprssion form ulationof hydrocodone 5 bitattrate immediate release fonn iaon including a dosage of 5 ug of hydrocodone bitartiate was preared and tested -using the blending conditions and procedure as stated in Example 1. An in-vito dissolution criterion of NLT75 % of the drag d.issoived in45 minutes was met. The drug extracted by the abuse-test method vas about 85 percent, Example 25 Table 25 Formulation A7 Component Weight(mg/tablet) Ilydrocodone Bitrtte 22 Polyvinyl Alcohol 25 0 Cab-O--Si 1 1.38 Magesimtste2.76 276.14 An in-vitro dissolution showed about 98% dissolution after 0 hours. 5 Example 26 Table 26 Formulation B7 - Veght(mg tablet) - do--l--n-t44 Polyvinyl Alcohol 450 Cab-C-8i 1.5 agn_ umtpara ___ __.0 T t

-

-- - - - -_497.5 __ An in-vitro dissolution shiowed about 82% disSolution afher 10 ho urs 10 Example 27 Table 27 Fonymmation 07 -________ __ Weight (mg/ tablet) fydt one Bitartrate 88 Polyvinyl Alcohol 600 Cab-C-Si 1.5 - - 691-5--- An in-vitro dissolution showed about% diss-olution after 10 hours. 153 34 Example 28 Table 28

--

Weiht onentable Oxycodone hydrochloride pol x25 Avicel PH 102 250 ZInc sulfateIO Sodium laury sulfate 7 CrospovidoneC10 Cab-0-Sil 2 Maes7im stearate Total 4) As shown by Table 28, a direct compression formulation cf oxycodone 5 hydrochloride immediate release foru ion incdigdosageo o c hydrochloride was prepared us ng the blending condition and procedure as stated in Example 1 Example 29 Table 29 - Comp-nent tablet Oxycodone hydochioride 5 Polyox25 Avicel PH 102 200 Zinc sulfat150 Sdim laurl sulfate Csgidone*l00 Cab-O-Sii Maqgyntigstearate __ 1_______ T-- 490 As howni by Table29, a direct compression formulation of oxycodeone hydrochiOride immediate release formulation iacuding a dosage of 5 mug of oxycodone hydrochiflride was prepared using the blerdingconditions and procedure asstated nl 15 Example I. It will be appreciated by: persons skilled in the art that numerous variations and/or modifcations may be made to the invention shown'x in the specific embodiments without departing~ form the spirit and scope of the invention as broadly described. Further, each and every reference cited above is hereby inco rporated by reference as if 20 fuly set forth heren. .)A .m

Claims (11)

1. A therapeutic pharmaceutical composition comprising: a mixture including (a) water soluble drug susceptible to abuse; 5 (b) a gel-forming polymer in an amount of about 3 to about 40 wt %; (c) a disintegrant; and (d) a surfactant; wherein the disintegrant is present in an amount sufficient to cause the pharmaceutical composition to exhibit an immediate release profile. 10

2. The therapeutic pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in unit dose form.

3. The therapeutic pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition is in suppository, capsule, caplet, pill, gel, soft gelatin capsule, or compressed tablet form. 15

4. The therapeutic pharmaceutical composition of any one of claims 1 to 3, wherein the water soluble drug susceptible to abuse is present in an amount of 0.5 to about 25 wt % of the composition.

5. The therapeutic pharmaceutical composition of any one of claims 1 to 4, wherein the disintegrant is present in an amount of about 2 to about 25 wt % of the composition. 20

6. The therapeutic pharmaceutical composition of any one of claims 1 to 5, wherein the surfactant is present in an amount of about 1 to about 10 wt % of the composition.

7. The therapeutic pharmaceutical composition of any one of claims 1 to 6, wherein the gel forming polymer is present in an amount of about 3 to about 40 wt % of the composition.

8. The therapeutic pharmaceutical composition of any one of claims 1 to 7, wherein the 25 disintegrant is selected from the group consisting of sodium starch glycolate, crospovidone, and croscarmellose sodium. 36

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the water soluble drug susceptible to abuse comprises an opioid selected from the group consisting of alfentanil, buprenorphine, butorphanol, carfentanil, codeine, dezocine, diacetylmorphine, dihydrocodeine, dihydromorphine, diprenorphine, etorphine, fentanyl, hydrocodone, 5 hydromorphone, p-hydroxy-3-methylfentanyl, levo-a-acetylmethadol, levorphanol, lofentanil, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, pethidine, prepoxyphene, remifentanil, sufentanil, tilidine, tramadol, and pharmaceutically acceptable salts thereof.

10. The therapeutic pharmaceutical composition of claim 1, wherein the water soluble drug 10 susceptible to abuse comprises oxycodone hydrochloride.

11. The therapeutic pharmaceutical composition of claim 1, wherein the water soluble drug susceptible to abuse comprises pseudoephedrine. 37