<<

US 2008.0075770A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0075770 A1 Vaughn et al. (43) Pub. Date: Mar. 27, 2008

(54) HYDROPHILICABUSE DETERRENT filed on Aug. 30, 2006. Provisional application No. DELIVERY SYSTEM 60/871,504, filed on Dec. 22, 2006. Provisional appli cation No. 60/824,057, filed on Aug. 30, 2006. Pro (76) Inventors: Jason M. Vaughn, Round Rock, TX visional application No. 60/903,235, filed on Feb. 22, (US); Michael M. Crowley, Austin, TX 2007. Provisional application No. 60/893,825, filed (US); Feng Zhang, Austin, TX (US); on Mar. 8, 2007. Provisional application No. 60/893, John J. Koleng, Austin, TX (US); 798, filed on Mar. 8, 2007. Justin M. Keen, Round Rock, TX (US); Justin R. Hughey, Austin, TX Publication Classification (US) (51) Int. Cl. Correspondence Address: A6IR 9/56 (2006.01) MEYERTONS, HOOD, KIVLIN, KOWERT & GOETZEL, P.C. A6II 3/34 (2006.01) P.O. BOX 398 A6IP 25/04 (2006.01) AUSTIN, TX 78767-0398 (US) (52) U.S. Cl...... 424/463: 514/468 (21) Appl. No.: 11/781,032 (57) ABSTRACT (22) Filed: Jul. 20, 2007 Related U.S. Application Data Disclosed herein are oral dosage forms of therapeutic agents that are resistant to abuse and methods of their formulation. (60) Provisional application No. 60/820,091, filed on Jul. In particular, oral dosage forms that are resistant to disso 21, 2006. Provisional application No. 60/824,042, lution in aqueous solutions of ethanol are described. US 2008/0075770 A1 Mar. 27, 2008

HYDROPHILICABUSE DETERRENT DELIVERY there are numerous legitimate users of narcotic Substances SYSTEM that need oral dosage forms that release large quantities of narcotic over an extended period of time for the treatment of PRIORITY CLAIM extreme pain. 0001) This application claims the benefit of U.S. Provi 0008 Oral formulations that deter abuse have also been sional Application No. 60/820,091 entitled “Abuse Deter suggested. U.S. Pats. No. 5,747,058 and 5,968,542 and U.S. rent Delivery System,” filed Jul. 21, 2006 and U.S. Provi Patent Application No. 200401611382 disclose an oral drug sional Application No. 60/824,042 entitled “Hydrophobic delivery system based on the use of therapeutic agents Abuse Deterrent Delivery System,” filed Aug. 30, 2006 and Suspended in high Viscosity liquid carrier material. U.S. Provisional Application No. 60/871,504 entitled “Hydrophobic Abuse Deterrent Delivery System,” filed Dec. 0009 U.S. Patent Application No. 2003.0118641 dis 2, 2006 and U.S. Provisional Application No. 60/824,057 closes controlled-release delivery compositions that entitled “Hydrophilic Abuse Deterrent Delivery System” are resistant to extraction with commonly-available sol filed Aug. 30, 2006 and U.S. Provisional Application No. vents. The formulation between 30 and 65% of a matrix 60/903,235 entitled “Hydrophilic Abuse Deterrent Delivery forming polymer and between 5 and 15% of an ionic System” filed Feb. 22, 2007 and U.S. Provisional Applica exchange resin. However the disclosed formulations are tion No. 60/893,825 entitled “Hydrophobic Abuse Deterrent prepared as tablets of compressed powder that can be readily Delivery System For Opioid Agents' filed Mar. 8, 2007 and crushed. This fails to deter methods of drug abuse involving U.S. Provisional Application No. 60/893,798 entitled nasal inhalation. “Hydrophilic Abuse Deterrent Delivery System For Opioid 0010. Other abuse deterrent systems include oral dosage Agents' filed Mar. 8, 2007. forms that include an opioid and an that is released when the dosage form is tampered with. Examples BACKGROUND OF THE INVENTION of this approach can be found at U.S. Pat. Nos. 6,696,088, 6,696,066, 6,627,635, 6,326,027 and 6,228,863. 0002) 1. Field of the Invention 0011 U.S. Patent Application 20040052731 discloses 0003. The invention generally relates to pharmaceutical oral dosage forms of drugs that have been modified to delivery systems and methods of their use, in particular oral increase their lipophilicity entrapped in coated micropar dosage systems for the delivery of drugs that are resistant to ticles wherein the coatings render the microparticles abuse. insoluble or poorly soluble in various solvents. The formu 0004 2. Description of the Relevant Art lations can still be crushed, but the formulations are intended 0005 Drug formulations for the oral delivery of pharma to prevent immediate release of the drug even when crushed. ceuticals have been used for centuries. More recently, 0012 U.S. Patent Application 60/820,091 filed Jul. 21, numerous compositions and methods have been developed 2006 discloses substantially solid oral dosage forms com for the controlled release of pharmaceuticals after oral prising at least 20% of a hydrophobic polymer. The solid delivery. Such extended-release characteristics can be useful dosage forms are extremely hard and therefore resistant to for many reasons. One reason is that extended-release deliv crushing. Hydrophobic polymers are useful in retarding ery systems can limit the number of doses a patient must dissolution of the oral dosage form in aqueous Solutions, take over a period of time thus improving compliance with particularly aqueous ethanol solutions such as bev a dosing regimen. Another reason is that extended release erages. However in Some applications oral dosage forms delivery systems can provide a steady dose of to comprising mainly hydrophilic polymers are preferable to a patient, thereby avoiding Sudden increases and decreases those containing Substantial quantities of hydrophobic poly in the level of medication being delivered to the blood mer. Hydrophilic polymers can often be formed by extru stream. Controlled release of pharmaceuticals is particularly Sion, injection molding and the like at lower temperatures critical with drugs that are habit forming, as the controlled than hydrophobic polymers. A dispersion or Solution of release of the medication can significantly reduce the like therapeutic agent within a matrix of hydrophilic polymers lihood of a patient developing an addiction to the Substance. can also have substantially different chemical properties that result in improved bioavailability and release characteristics 0006 The difficulty in the art is that it is desirable among for the hydrophilic oral dosage forms over the hydrophobic drug abusers to bypass the extended release characteristics of oral dosage forms. By negating the controlled release forms. mechanisms of the dosage form, the abuser is able to 0013 Therefore there remains a significant need in the art produce a quick and intense rush of drug into the brain that for hydrophilic oral dosage forms that are resistant to results in a high. Abusers have found many methods by attempts by potential abusers to bypass the controlled or which the extended release characteristics of certain oral extended release characteristics of conventional oral dosage dosage forms can be bypassed. These include: (i) intrave forms. In particular, hydrophilic oral dosage forms are nous injection of dissolved tablets or capsules, (ii) inhala needed that are resistant to crushing and dissolution in water tion/nasal Snorting of crushed tablets or capsules, (iii) chew or aqueous alcohol solutions such as alcoholic beverages. ing tablets or capsules and (iv) dissolving of tablets or capsules in alcoholic beverages followed by oral adminis SUMMARY OF THE INVENTION tration. 0014. In certain embodiments, the invention relates to 0007. Abuse of narcotic substances is particularly prob oral dosage forms of a therapeutic agent. In one embodi lematic. Such drugs are highly habit forming when misused ment, a monolithic Solidified oral dosage form is described and thus are in high demand by drug abusers. In contrast, which is prepared by a thermal process. The oral dosage US 2008/0075770 A1 Mar. 27, 2008 form comprises a therapeutic agent and a hydrophilic poly therapeutic agent after 5 minutes of shaking at 240 cycles/ mer. The oral dosage form releases at least 80% of the min in a 0.1 NHCl solution followed by 3 hours of shaking therapeutic agent after 2 hours of stirring in a 0.1 NHCl on an orbital shaker at 240 cycles/min in an acidic aqueous solution and 16 hours stirring in a pH 6.8 phosphate buffer Solution of 40% ethanol at 25° C. solution using a United States Pharmacopoeia (USP) Type II paddle apparatus at 75 rpm and 37° C. Additionally, the oral DETAILED DESCRIPTION OF THE dosage form exhibits abuse deterrent properties. For PREFERRED EMBODIMENTS example, the oral dosage form releases less than 40% of the therapeutic agent after 5 minutes of shaking at 240 cycles/ 0022. Embodiments described herein relate to oral dos min in a 0.1 NHCl solution followed by 3 hours of shaking age forms that are designed to deter misuse of controlled on an orbital shaker at 240 cycles/min in an acidic aqueous Substances or other therapeutic agents. Furthermore, the Solution of 40% ethanol at 25° C. embodiments described herein are directed to methods of formulating such oral dosage forms. Additionally, embodi 0015. In preferred embodiments, the therapeutic agent is ments described herein provide methods of deterring sub a Substance that has a significant potential for abuse Such as stance abuse. As used herein, “abuse deterrent’ oral dosage , CNS depressants, , , , forms exhibit the following properties: (i) are resistant to cannabinoids, dissociatives, steroids, hormonal active dissolution in water, thus inhibiting intravenous injection of agents, anabolic steroids, anorexics and . dissolved oral dosage form; (ii) are resistant to breaking thus The oral dosage forms can further comprise one or more inhibiting abuse by inhalation/nasal Snorting of crushed plasticizers, emetics, nasal irritants or functional excipients tablets or capsules or by chewing tablets or capsules and (iii) Such as colorants, lubricants, thermal lubricants, antioxi are resistant to dissolution in aqueous ethanolic solutions or dants, buffering agents, disintegrants, binders, diluents, pure ethanol, thus inhibiting oral administration by dissolv Sweeteners, chelating agents, flavorants, Surfactants, solubi ing in alcoholic beverages. lizers, stabilizers, hydrophilic polymers, hydrophobic poly mers, waxes, lipophilic materials, absorption enhancers, 0023. In one embodiment, oral dosage forms are pro preservative, absorbent, cross-linking agents, bioadhesive vided that are significantly harder than conventional oral polymers, pore formers, osmotic agents, polycarboxylic dosage forms and which are relatively insoluble in water, acids and fragrance, or combinations thereof. aqueous solutions of 40% ethanol, or acidified aqueous 0016. In one embodiment, the oral dosage form includes solutions of 40% ethanol. an opioid therapeutic agent; at least one hydrophilic poly 0024 Hardness of the oral dosage form presents a sig mer, and at least one polycarboxylic acid. The oral dosage nificant deterrent to abuse because the dosage forms cannot form releases at least 80% of the therapeutic agent after 2 be readily crushed for inhalation or dissolution prior to oral hours of stirring in a 0.1 NHCl solution and 16 hours stirring ingestion or intravenous use. They are also resistant to being in a pH 6.8 phosphate buffer solution using a USPType II crushed by chewing. Indeed, in certain embodiments the oral paddle apparatus at 75 rpm and 37° C. Additionally, the oral dosage forms are so hard that tablets made according to the dosage form exhibits abuse deterrent properties. For embodiments described herein may be pounded with a example, the oral dosage form releases less than 40% of the hammer and still incur Surprisingly little damage. Crushing opioid therapeutic agent after 5 minutes of shaking at 240 oral dosage forms described in embodiments disclosed cycles/min in a 0.1 NHCl solution followed by 3 hours of herein would pose a significant challenge to a potential shaking on an orbital shaker at 240 cycles/min in an acidic abuser. aqueous solution of 40% ethanol at 25° C. 0025 The relative insolubility of the oral dosage forms in 0017. The invention further relates to methods of formu water or aqueous solutions of 40% ethanol is a deterrent to lating an oral dosage form that deters abuse. The oral dosage abuse because it is difficult and time-consuming to prepare form may be made by: the dosage form for oral ingestion. In the case of many of the 0018 mixing one or more water-soluble polymers and oral dosage forms disclosed herein, not only is dissolution of a therapeutic agent, wherein the water-soluble poly the oral dosage form for intravenous injection difficult, the mers comprises 20 to 99.9% of the mixture by weight; resulting solution would contain water-insoluble polymers that could cause serious internal damage if injected intra 0019 melting the mixture; and venously in significant quantities. 0020 permitting the mixture to solidify as a substan 0026. In preferred embodiments the oral dosage form is tially solid oral dosage form, wherein the oral dosage monolithic and Substantially solid, that is it is formed as a form weighs at least 40 mg. unitary mass that is molded, cut, ground or otherwise formed 0021. In yet other embodiments, a method of providing a in its final shape, and is not, for example, an aggregate or therapeutic agent to a patient includes providing a mono composite of individual Solid particulates, pellets, beads lithic solidified oral dosage form which is prepared by a microspheres or the like. Preferably, the monolithic substan thermal process. The oral dosage form comprises a thera tially solid oral dosage form is formed by providing a peutic agent and a hydrophilic polymer. The oral dosage mixture including a suitable hydrophobic polymer and a form releases at least 80% of the therapeutic agent after 2 therapeutic agent, melting the mixture and permitting the hours of stirring in a 0.1 NHCl solution and 16 hours stirring mixture to Solidify as a Substantially solid oral dosage form. in a pH 6.8 phosphate buffer solution using a USPType II Embodiments described herein further provide methods of paddle apparatus at 75 rpm and 37° C. Additionally, the oral administering a therapeutic agent to a patient that include dosage form exhibits abuse deterrent properties. For Supplying said Substantially solid oral dosage form to a example, the oral dosage form releases less than 40% of the patient. US 2008/0075770 A1 Mar. 27, 2008

0027. The phrase “oral dosage form as used herein additionally or alternatively (ii) releases less than about refers to pharmaceutical compositions formed as tablets, 60%, less than about 50%, less than about 40% or less than caplets and the like that are swallowed substantially intact about 30% of a therapeutic agent when subjected to shaking when used as intended. Films, wafers and the like which are in aqueous ethanol solution as described above. not intended to be swallowed substantially intact are not 0032 For purposes of the present disclosure a matrix contemplated embodiments of oral dosage forms. material is considered to be hydrophilic or a polymer is 0028. The hardness of an oral dosage form can be deter considered to be water-soluble, or hydrophilic, if it is mined using a standard test known to those of skill in the art. “soluble' or “very soluble” as defined by USP29/NF 24. In That test is called Hardness or Crushing Strength and it other embodiments, the hydrophilic material is soluble or involves the following steps: a dosage form is compressed very soluble in aqueous solution. In other embodiments the between a moving piston and a stationary plate until it hydrophilic material is water swellable or exhibits a high laminates, ruptures or breaks. The force required to lami affinity for water. nate, rupture or break the dosage form is a measure of its 0033. The release characteristics of the oral dosage form hardness or breaking strength. Typical Solid oral dosage can be determined in vitro using simulated gastric or intes forms exhibit hardness values between 4-18 kp. In contrast tinal fluids, but is preferably determined in vivo by moni to conventional oral dosage forms, the oral dosage forms of toring blood levels of the therapeutic agent in Subjects that the described embodiments have a hardness at room tem have ingested the oral dosage form. Methods of determining perature of at least about 20 kp, at least about 30 kp, at least the in vivo and in vitro release of therapeutic agents from about 35 kp, at least about 40 kp, or at least about 50 kp. oral dosage forms are well-known to those skilled in the art. 0029. The solubility of oral dosage forms in aqueous Extended release oral dosage forms will typically result in solutions of 40% ethanol (a standard test widely used in the an therapeutically-acceptable, extended-time release of art) may be determined by placing the oral dosage form in therapeutic agents over a period of at least about 4, 6, 8, 10. a room-temperature aqueous solution of 40% ethanol and 12, 14, 16, 18, 20, 22, 24, 30, 36, 48, 60 or 72 hours. stirring or shaking the solution for a period of time. In one 0034. In some embodiments, the oral dosage form com typical method, the oral dosage form in 60 mL of an aqueous prises one or more pharmaceutically-acceptable hydrophilic solution of 40% ethanol is shaken for 3 hours in an orbital matrix materials which include, but are not limited to shaker at 240 cycles/min. Preferably, the volume of 40% hydrophilic polymers such as polyethylene oxide (PEO), ethanol used is 60 mL, or approximately 2 fluid ounces. In oxide-propylene oxide co-polymers, polyethylene Some instances, acidified aqueous solutions of 40% ethanol polypropylene glycol (e.g. poloxamer), carbomer, polycar are used, particularly when the oral dosage form is disposed bophil, chitosan, polyvinyl pyrrolidone (PVP), polyvinyl in a gelatin-capsule or coated with a gelatin coating, which alcohol (PVA), hydroxyalkyl celluloses such as hydroxypro are otherwise insoluble in 40% ethanol. In one embodiment, pyl cellulose (HPC), hydroxyethyl cellulose, hydroxymethyl the oral dosage form releases less than 40% of the hydro cellulose and hydroxypropyl methylcellulose, Sodium car morphone and/or pharmaceutically acceptable salts of boxymethyl cellulose, methylcellulose, hydroxyethyl meth after 5 minutes of shaking at 240 cycles/min ylcellulose, hydroxypropyl methylcellulose, polyacrylates in a 0.1 NHCl solution, to at least partially dissolve the Such as carbomer, polyacrylamides, polymethacrylamides, capsule material or remove a coating material, followed by polyphosphazines, polyoxazolidines, polyhydroxyalkylcar 3 hours of shaking on an orbital shaker at 240 cycles/min in boxylic acids, alginic acid and its derivatives such as car an acidic aqueous solution of 40% ethanol at 25° C. Dif rageenate alginates, ammonium alginate and sodium algi ferent shaking methods and alternate periods of time can be nate, starch and starch derivatives, polysaccharides, used, if appropriate, and Such variations would be well carboxypolymethylene, polyethylene glycol, natural gums known to those skilled in the art. However for the purposes of this disclosure the typical method described above was Such as gum guar, gum acacia, gum tragacanth, karayagum used to determine the solubility of the oral dosage forms. For and gum Xanthan, povidone, gelatin or the like. the purposes of this disclosure, an oral dosage form is 0035) In preferred embodiments, a single water-soluble insoluble in a 40% solution of aqueous ethanol if three hours polymer or a mixture of water-soluble polymers can be used of shaking according to the protocol described above results to make up the hydrophilic matrix of the oral dosage form. in a release of less than about 40% of the therapeutic agent, When used as the hydrophilic matrix material the water preferably less than about 30% of the therapeutic agent, soluble polymer or polymers make up about 20% to about more preferably less than about 20% of the therapeutic agent 99.9%, at least about 30%, at least about 40%, or at least and most preferably less than about 10% of the therapeutic about 50% of the oral dosage form by weight. agent. 0036) The oral dosage forms of the present invention can Matrix Materials also includes up to less than 20% by weight of one or more pharmaceutically-acceptable hydrophobic matrix materials 0030. In certain embodiments, oral dosage forms com including water-insoluble polymers such as acrylic polymer, prise a hydrophilic matrix material that in which one or more acrylic copolymer, methacrylic polymer or methacrylic therapeutic agents is Suspended. In some embodiments the copolymer, including but not limited to Eudragit(R) L100, matrix material is a fusible, thermoplastic or thermosetting Eudragit R L100-55, Eudragitg L30 D-55, EudragitR) S100, material, typically a resin or polymer. Eudragit R. 4135F, Eudragit(R) RS, acrylic acid and meth 0031. The hydrophilic matrix material must be a phar acrylic acid copolymers, methyl methacrylate, methyl meth maceutically acceptable carrier and preferably is (i) capable acrylate copolymers, ethoxyethyl methacrylates, cyanoethyl of producing an oral dosage form that has a hardness of at methacrylate, aminoalkyl methacrylate copolymer, poly least about 20 kp, 25 kp, 30 kp, 35 kp, 40 kp, or 50 kp and acrylic acid, polymethacrylic acid, methacrylic acid alky US 2008/0075770 A1 Mar. 27, 2008 lamine copolymer, polymethyl methacrylate, poly alfentanil, allylprodine, alphaprodine, anilleridine, apomor methacrylic acid anhydride, polymethacrylate phine, apocodeine, , bezitramide, buprenor polyacrylamide, polymethacrylic acid anhydride and gly phine, , clonitaZene, , codeine methyl cidyl methacrylate copolymers, an alkylcellulose such as , codeine phosphate, codeine Sulfate, cyclazocine, ethylcellulose, methylcellulose, calcium carboxymethyl cel cyclorphen, cyprenorphine, desomorphine, dextromora lulose, certain Substituted cellulose polymers such as mide, dezocine, diampromide, , dihydroco hydroxypropyl methylcellulose phthalate, and hydroxypro deinone enol acetate, dihydromorphine, dimenoxadol, dime pyl methylcellulose acetate Succinate, cellulose acetate pheptanol, dimethylthiambutene, dioxyaphetyl butyrate, butyrate, cellulose acetate phthalate, and cellulose, acetate dipipanone, eptazocine, ethoheptazine, ethylmethylthiam trimaleate, polyvinyl acetate phthalate, polyester, waxes, , , etonitaZene, fentanyl, , hydro shellac, Zein, or the like. codone, bitartrate, hydroxymethylmorphinan, 0037. In alternate embodiments, the hydrophobic poly hydromorphone, hydroxypethidine, , ketobe mers make up less than 15%, less than 10%, or less than 5% midone, , levorphanol, levophenacylmorphan, by weight of the oral dosage form. In further embodiments, lofentanil, meperidine, meptazinol, metazocine, , the oral dosage forms of the present invention are Substan methylmorphine, metopon, , morphine derivatives, tially free of any hydrophobic polymers. myrophine, nalbuphine, narceline, nicomorphine, norlevor phanol, , , normorphine, norpi 0038 For purposes of the present disclosure a matrix panone, ohmefentanyl, , oxycodone, oxymorphone, material is considered to be hydrophobic or a polymer is papaveretum, pentazocine, phenadoxone, phenomorphan, considered to be water-insoluble if it is less than “soluble' phenazocine, phenoperidine, pheoperidine, , according to USP 29/NF 24, for example, it is classified as piminodine, piritramide, propheptazine, promedol, profadol, “sparingly soluble' or “practically insoluble' as defined by properidine, propiram, propoxyphene, remifentanyl, Sufen USP 29/NF 24. tanyl, , tilidine, , , , 0.039 Preferred materials used to produce an oral dosage methylmaltrexone, naloxone methiodide, naloxonazine, form will be pharmaceutically acceptable materials, such as nalide, nalmexone, nalbuphine, nalorphine dinicotinate, nal those indicated to be generally regarded as safe (“GRAS trindole (NTI), naltrindole isothiocyanate, (NTII), naltriben certified') or national formulary certified. (NTB), norbinal torphimine (nor-BNI), funaltrexamine (b-FNA), BNTX., cyprodime, ICI-174,864, LY117413, Therapeutic Agents MR2266, etorphine, DAMGO, CTOP, , nalox 0040 Oral dosage forms also include a therapeutic agent. one benzoylhydraZone, bremazocine, ethylketocyclazocine, In preferred embodiments the therapeutic agent is a drug that U50,488, U69,593, spiradoline, DPDPE, D-Ala2,Glu4del has a potential for abuse. The United States Drug Enforce torphin, DSLET Metenkephalin, Leu-enkephalin, B-endor ment Administration makes determinations about various phin, dynorphin A, dynorphin B. a-neoendorphin, or an therapeutic agents potential for abuse and assigns them to opioid having the same pentacyclic nucleus as nalmefene, various schedules. Schedule I drugs or other Substances are maltrexone, buprenorphine, levorphanol, meptazinol, penta compounds with a high potential for abuse which currently Zocine, dezocine, or the pharmacologically effective esters have no accepted medical uses for treatment in the United or salts of any of the foregoing opioids. States, in some instances due to the extremely high potential for abuse. Schedule II drugs or other substances are com 0043. In other embodiments the therapeutic agent will be pounds with a high potential for abuse and which have a CNS depressant, or Such as Acyclic medically acceptable uses in the United States when used ureides such as , Apronalide, Bomisovalum, under severe restrictions. When abused schedule II drugs Capuride, and Ectylurea; such as Chlo may lead to severe psychological or physical dependence in rhexadol, , Meparfynol, 4-Methyl-5-thiaz a user. Schedule III drugs are drugs that have some potential oleethanol, tert-Pentyl Alcohol and 2.2.2-Trichloroethanol: for abuse and that have a currently accepted medical use in Amides such as Butoctamide, Diethylbromoacetamide, the United States. Abuse of schedule II drugs or substances Ibrotamide, Isovaleryl Diethylamide, , Triceta may lead to moderate to low physical dependence or high mide, Trimetozine, Zolpidemand ; Barbituric acid psychological dependence. Schedule IV and schedule V derivatives such as , , , drugs or Substances have a low potential for abuse and abuse , Brallabarbital, Sodium, , of these compounds leads to more limited or non-existent , Butethal, , , Cyclopen physical or psychological dependence. tobarbital, Enallylpropymal, 5-Ethyl-5-(1-piperidyl)barbitu ric Acid, 5-Furfuryl-5-isopropylbarbituric Acid, Heptabar 0041. The compositions and methods disclosed herein bital, Sodium, , Mephobarbital, will most preferably be used with therapeutic agents that are , , , or have been designated as schedule II or schedule III drugs Sodium, Phenallymal, , Phenobarbital or Substances. The compositions and methods disclosed Sodium, Phenylmethylbarbituric Acid, , Propal herein may also be used to develop medically-acceptable lylonal, Proxibarbal, , Sodium, Thio oral dosage forms of therapeutic agents that are designated pental, , . . , Vin as schedule I drugs or Substances. In other embodiments, it barbital Sodium and ; derivatives may also be desirable to formulate therapeutic agents that Such; as , , , chlordiazep are designated as schedule IV or schedule V drugs or oxide, , , , , Substances according to the compositions and methods dis , , , , closed herein to prevent abuse. , Lorimetazepam, , , 0042. In preferred embodiments, the therapeutic agent and ; such as Ammonium will be a narcotic. The narcotic can be an opioid Such as Bromide, Calcium Bromide, Calcium Bromolactobionate, US 2008/0075770 A1 Mar. 27, 2008

Lithium Bromide, Magnesium Bromide, Potassium Bro tenolone, Methyltestosterone, 17C.-Methyltesteosterone, mide and ; such as Amyl 17C.-Methyltestosterone 3-Cyclopentyl Enol Ether, Nore -Tertiary, , Hexaprpymate, thandrolone, Normethandrone, Oxandrolone, Oxymester Meparfynol Carbamate, Novonal and Tricholorourethan; one, Oxymetholone, Prasterone, Stanlolone, Stanozolol, derivatives such as Carbocloral, , (Acetate, Enanthate, Isobutyrate, Propionate Chloral Formamide, , Chloralantipyrine, and Undecanoate), Testosterone 17-Chloral Hemiacetal, , Pentaerythritol Chloral and : Testosterone 17 B-Cypionate and Tiomesterone. Piperidinediones such as Glutehimide, , Pip eridione, , Taglutimide and Thalidomide: 0048 (E) anabolic steroids such as Androisoxazole, Quinazolone derivatives such as , Androstenediol, Bolandiol, Bolasterone, Clostebol, Ethyl and ; and others such as Acetal, Acetophe estrenol. Formyldienolone, 4-Hydroxy-19-nortestosterone, none, Aldol. Ammonium Valerate, Amphenidone, d-Bornyl Methandriol, Methenolone, Methyltrienolone, Nandrolone, a-Bromoisovalerate, d-Bornyl Isovalerate, Bromoform, Cal Nandrolone Decanoate, Nandrolone p-Hexyloxyphenylpro cium 2-Ethylbutanoate, Carfinate, a-Chlorolose, Clomethia pionate, Nandrolone Phenpropionate, Norbolethone, Zole, Cypripedium, , Etodroxizine, , Oxymesterone, Pizotyline, Quinbolone, Stenbolone and , Homofenazine, Hydrobromic Acid, Meclox Trenbolone; amine, Menthyl Valerate, Opium, , , 0049 (F) anorexics such as , Amphecloral, , , , Sulfonethyl , BenZaphetamine, , methane and . , Cloforex, , Cyclexedrine, Destro amphetamine Sulfate, Diethylpropion, Diphemethoxidine, 0044) In yet other embodiments the therapeutic agent can N-Ethylamphetamine, , , Fenpro be any suitable therapeutic agent, and preferably those porex. Furfurylmethylamphetamine, Levophacetoperate, subject to abuse, including but not limited to the following: , , Metamfeproamone, Methamphet (A) stimulants, for example amphetamine (including dex amine, Norpseudoephedrine, , Phendime troamphetamine and ), , trazine Tartrate, , , Phenylpro (Ritalin R), phenmetrazine, modatinil, panolamine Hydrochloride and : advafinil, , and ampakimes such as CX516, CX546, CX614, and CX717. 0050 (G) anticonvulsants such as Acetylpheneturide, Albutoin, Aloxidone, Aminoglutethimide, 4-Amino-3-hy 0.045 (B) cannabinoids such as tetrahydro-cannabinol, droxybutyric Acid, Atrolactamide, Beclamide, Buramate, nabilone, hashish and hashish oil and 1-piperidinocyclohex Calcium Bromide, , Cinromide, Clomethia anecarbonitrile; Zole, Clonazepam, Decimemide, Diethadione, Dimethadi one, Doxenitoin, , Ethadione, Ethosuximide, Etho 0046) (C) dissociatives such as (PCP), toin, Fluoresone, Garbapentin, 5-Hydroxytryptophan, ketamine, tiletamine, , , dixo Lamotrigine, Lomactil, Magnesium Bromide, Magnesium cilpine and riluzole; Sulfate, Mephenyloin, Mephobarbital, , Meth 0047 (D) steroid or hormonal active agent (including etoin, MethSuximide, 5-Methyl-5-(3-phenanthryl)hydan both natural, semi-synthetic and synthetic compounds and toin, 3-Methyl-5-phenylhydantoin, Narcobarbital, their derivatives having steroidal or hormonal activity) , Nitrazepam, Paramethadione, Phenacemide, including, for example, (a) estrogens such as Colpormon, Phenetharbital, Pheneturide, Phenobarbital, Phenobarbital Conjugated Estrogens, Estradiol (173- and Cl-) and its Esters Sodium, Phensuximide, Phenylmethylbarbituric Acid, Phe (e.g., Acetate, Benzoate, Cypionate, Dipropionate Diacetate, nyloin, Phethenylate Sodium, , Pregaba Enanthate, Estradiol-16,17-Hemisuccinate, Undececenoate, tin, , Progabide, Sodium Bromide, Sodium Val Undecylate and Valerate), Estriol, Estrone, Ethinyl Estra proate, Solanum, Strontium Bromide, Suclofenide, diol, Equilenin, Equilin, Mestranol, Methyl Estradiol, Mox Sulthiame, Tetrantoin, Tiagabine, Trimethadione, Valproic estrol, Mytatrienediol, Quinestradiol, Quinestrol, Dienes Acid, Valpromide, Vigabatrin and ; and trol, Clomifen, Chlorotrianisen, and Cyclofenil; (b) progestagenically effective hormones Such as Allylestrenol, 0051 (H) others including , derivatives, Anagestone, Chlormadinone Acetate, Delmadinone Acetate, lysergic acid and lysergic acid amide. Demegestone, Desogestrel, 3-Keto Desogestrel, Dimethis 0052 The compositions and methods disclosed herein terone, Dydrogesterone, Ethinylestrenol, Ethisterone, are not limited to therapeutic agents that are subject to abuse Ethynodiol (and Diacetate), Fluorogestone Acetate, or that are precursors to abused Substances and can include Gestodene, Gestonorone Caproate, Haloprogesterone, (17 any type of therapeutic agent. Further types of therapeutic Hydroxy- and 17-Acetate-) 16-Methylene-, agents that can be used in the methods and compositions of 17C-Hydroxyprogesterone (Acetate and Caproate), the present invention include, but are not limited to, C.-adr Levonorgestrel, Lynestrenol, Medrogestone, MedroX energic agonists, B-adrenergic agonists, C.-adrenergic block yprogesterone (and Acetate), Megestrol Acetate, ers, B-adrenergic blockers, alcohol deterrents, aldose reduc Melengestrol, Norethindrone (Acetate and Enanthate), tase inhibitors, non-narcotic analgesics, anesthetics, Norethisterone, Norethynodrel, Norgesterone, Norgesti anthelmintics, antiacne drugs, antiallergenics, antiamebics, mate, Norgestrel, Norgestrienone, 19-Norprogesterone, antiandrogens, antianginals, antiarrhythmics, anticoagu Norvinisterone, Pentagestrone, Progesterone, Promege lants, anti-erectile dysfunction agents, anti-infectives, anti stone, Quingestrone and Trengestone; and (c) androgeni oxidants, antiarteriosclerotics, antiarthritic/antirheumatics, cally effective hormones such as Aldosterone, , antibacterial (antibiotic) drugs, antibacterial drugs (syn Boldenone, Cloxotestosterone, Dehydroepiandrosterone, thetic), anticholinergics, anticonvulsants, , Fluoxymesterone, Mestanolone, Mesterolone, Methandros antidiabetics, antidiarrheal drugs, antidiuretics, antiestro US 2008/0075770 A1 Mar. 27, 2008 gens, antifungal drugs (antibiotics), antifungal drugs (syn col and glycerin. Such plasticizers can also include ethylene thetic), antiglaucoma drugs, antigonadotropins, antigout glycol, 1.2-butylene glycol, 2,3-butylene glycol, Styrene drugs, , antihyperlipoproteinemics, antihyper glycol, diethylene glycol, triethylene glycol, tetraethylene tensive drugs, antihyperthyroids, antihypotensive drugs, glycol and other poly(ethylene glycol) compounds, mono antihypothyroid drugs, anti-Inflammatory (non-steroidal) propylene glycol monoisopropyl ether, propylene glycol drugs, antimalarial drugs, antimigraine drugs, antinauseant monoethyl ether, ethylene glycol monoethyl ether, diethyl drugs, antineoplastic drugs, antineoplastic (hormonal) ene glycol monoethyl ether, Sorbitol lactate, ethyl lactate, drugs, antineoplastic adjuncts, antiparkinsonian drugs, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyltribu antipheochromocytoma drugs, antipneumocystis drugs, tylcitrate, triethyl citrate, acetyl triethyl citrate, tributyl cit antiprostatic hypertrophy drugs, antiprotozoal drugs, anti rate and allyl glycolate. puritics, antipsoriatic drugs, drugs, antipyret ics, antirickettsial drugs, antiseborrheic drugs, antiseptics, 0054) Excipients antispasmodic drugs, antithrombotic drugs, antitussive 0055. In addition to a hydrophilic matrix material and a drugs, antiulcerative drugs, antiurolithic drugs, antivenin therapeutic agent, compositions may also include one or drugs, antiviral drugs, anxiolytic drugs, benzodiazepine more excipients such as lubricants, thermal lubricants, anti antagonists, bronchodilators, calcium channel blockers, cal oxidants, buffering agents, alkalinizing agents, disintegrants, cium regulators, cardiotonics, chelating agents, cholecysto binders, diluents, Sweeteners, chelating agents, colorants, kinin antagonists, cholelitholytic agents, choleretics, cholin flavorants, Surfactants, solubilizers, wetting agents, stabiliz ergic agents, inhibitors, cholinesterase ers, hydrophilic polymers, hydrophobic polymers, waxes, reactivators, central nervous system stimulants and agents, lipophilic materials, absorption enhancers, preservatives, decongestants, dental agents, depigmentors, diuretics, absorbents, cross-linking agents, bioadhesive polymers, receptor agonists, ectoparasiticides, enzymes, retardants, pore formers, osmotic agents and fragrance. enzyme inducers (hepatic), estrogens (non-steroidal), gastric secretion inhibitors, glucocorticoids, gonad-stimulating 0056 Lubricants or thermal lubricants useful as an principles, gonadotropic hormones, growth hormone inhibi excipient include, but are not limited to fatty esters, glyceryl tors, growth hormone releasing factors, growth stimulants, monooleate, glyceryl monostearate, wax, carnauba wax, hemolytic agents, antagonists, hepatoprotectants, beeswax, Vitamin E Succinate, and a combination thereof. immunomodulators, immunosuppressants, ion exchange 0057. As used herein, the term “antioxidant’ is intended resins, lactation stimulating hormone, LH-RHagonists, lipo to mean an agent that inhibits oxidation and thus is used to tropic agents, lupus erythematosus Suppressants, mineral prevent the deterioration of preparations by oxidation due to corticoids, miotic drugs, monoamine oxidase inhibitors, the presence of oxygen free radicals or free metals in the mucolytic agents, muscle relaxants (skeletal), narcotic composition. Such compounds include, by way of example antagonists, neuroprotective agents, nootropic agents, oph and without limitation, ascorbic acid (Vitamin C), ascorbyl thalmic agents, ovarian hormone, oxytocic drugs, pepsin palmitate, butylated hydroxyanisole (BHA), butylated inhibitors, peristaltic stimulants, prolactin inhibitors, pros taglandins and prostaglandin analogs, protease inhibitors, hydroxytoluene (BHT), hypophophorous acid, mono respiratory stimulants, Sclerosing agents, thrombolytic thioglycerol, Sodium ascorbate, Sodium formaldehyde Sul agents, thyrotropic hormones, uricoSurics, vasodilators foxylate, sodium metabisulfite, sodium bisulfite, vitamin E (cerebral), vasodilators (coronary), Vasodilators (periph and its derivatives, propyl gallate and others known to those eral), chemotherapeutic agents, retinoids, antibiotics, desen of ordinary skill in the art. sitizing agents, vaccines, antiproliferatives, antiphotoaging 0058 Binders are ingredients added to mixtures to pro agents, melanotropic peptides, radiation absorbers, para vide adhesive qualities during and after formation of an oral sympatholytics, sympatholytics, androgenic steroids, dosage. Examples of binders include, but are not limited to: progestational agents, humoral agents, cardioactive agents, waxes such as beeswax, carnauba wax, microcrystalline wax nutritional agents, and natural and synthetic bioactive pep and paraffin wax, cetyl palmitate; behenate; glyc tides and proteins. eryl palmitostearate; glyceryl Stearate; hydrogenated castor Plasticizers oil; stearic acid; stearic alcohol; stearate 6000 WL1644; gelucire 50/13; polyethylene glycols (PEG) such as PEG 0053. In preferred embodiments, a plasticizer is also 2000, PEG 3000, PEG 6000, PEG 8000, PEG 10000, PEG included in the oral dosage form. Plasticizers interact with 20000; polyethylene oxide; polypropylene oxide; polyvi the hydrophobic matrix material resulting in a lower vis nylpyrrolidone; polyvinylpyrrolidone-co-vinylacetate; acry cosity of the mixture during extrusion or molding. The result late-methacrylate copolymers; polyethylene; polycaprolac is that extrusion or injection molding of the oral dosage form tone; alkylcelluloses such as methylcellulose; can occur at lower temperatures, thereby reducing the pos hydroxyalkylcelluloses such as hydroxymethylcellulose, sibility of thermally degrading the therapeutic agent. The hydroxyethylcellulose, hydroxypropylcellulose, and most suitable plasticizers are those that lower the glass hydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as transition temperature (Tg) of the hydrophobic matrix mate hydroxyethyl methylcellulose and hydroxypropyl methyl rial. Plasticizers suitable for use with the compositions and cellulose; starches, pectins; polylactic acid (PLA); polygly methods disclosed herein include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, colic acid (PLGA), polyesters (e.g., shellac); and polysac Small organic molecules, low molecular weight polyols charides such as cellulose, tragacanth, gum arabic, guar having aliphatic hydroxyls, ester-type plasticizers, glycol gum, and Xanthan gum. ethers, poly(propylene glycol), multi-block polymers, single 0059 A buffering agent is used to resist change in pH block polymers, low molecular weight poly(ethylene gly upon dilution or addition of acid or alkali. Such compounds col), citrate ester-type plasticizers, triacetin, propylene gly include, by way of example and without limitation, potas US 2008/0075770 A1 Mar. 27, 2008

sium metaphosphate, potassium phosphate, monobasic amount as desired by those of ordinary skill in the art. Sodium acetate and sodium citrate anhydrous and dihydrate, Particular flavors are the grape and cherry flavors and citrus salts of inorganic or organic acids, salts of inorganic or flavors such as orange. organic bases, and others known to those of ordinary skill in 0065 Surfactants include soaps, synthetic detergents, and the art. wetting agents. Suitable Surfactants include cationic Surfac 0060. As used herein, the term "alkalizing agent” is tants, anionic Surfactants, non-ionic Surfactants, and ampho intended to mean a compound used to provide alkaline teric surfactants. Examples of surfactants include Polysor medium for product stability. Such compounds include, by bate 80; sorbitan monooleate; sodium lauryl sulfate (sodium way of example and without limitation, ammonium carbon dodecylsulfate); Soaps such as fatty acid alkali metal salts, ate, diethanolamine, monoethanolamine, potassium hydrox ammonium salts, and triethanolamine salts; cationic deter ide, sodium borate, Sodium carbonate, sodium bicarbonate, gents such as dimethyl dialkyl ammonium halides, alkyl Sodium hydroxide, triethanolamine and others known to pyridinium halides, and alkylamine acetates; anionic deter those of ordinary skill in the art. gents such as alkyl, aryl and olefin Sulfonates, alkyl, olefin, ether and monoglyceride Sulfates, and SulfoSuccinates; non 0061 As used herein, the term "disintegrant' is intended ionic detergents such as fatty amine oxides, fatty acid to mean a compound used in Solid dosage forms to promote alkanolamides, and poly(oxyethylene)-block-poly(oxypro the disruption of a solid mass (layer) into Smaller particles pylene) copolymers; and amphoteric detergents, for that are more readily dispersed or dissolved. Exemplary example, alkyl B-aminopropionates and 2-alkylimidazoline disintegrants include, by way of example and without limi quaternary ammonium salts; wetting agents such as, glyc tation, starches Such as corn starch, potato starch, pre erin, proteins, and peptides; water miscible solvents such as gelatinized and modified starches thereof, Sweeteners, clays, glycols; and mixtures thereof. bentonite, microcrystalline cellulose (e.g., AviceITM), car boxymethylcellulose calcium, croScarmellose sodium, alg 0066 Solubilizers include cyclodextrins, povidone, com inic acid, Sodium alginate, cellulose polyacrilin potassium binations thereof, and others known to those of ordinary skill (e.g., AmberliteTM), alginates, Sodium starch glycolate, in the art. gums, agar, guar, locust bean, karaya, pectin, tragacanth, 0067 Exemplary absorption enhancers include dimethyl crospovidone and other materials known to one of ordinary sulfoxide, Vitamin E PGS, sodium cholate and others known skill in the art. A Superdisintegrant is a rapidly acting to one of ordinary skill in the art. disintegrant. Exemplary Superdisintegrants include 0068 Exemplary waxes include carnauba wax, beeswax, crospovidone and low substituted HPC. microcrystalline wax and others known to one of ordinary 0062) Exemplary chelating agents include EDTA, skill in the art. polyamines, derivatives thereof, and others known to those 0069 Preservatives include compounds used to prevent of ordinary skill in the art. the growth of microorganisms. Suitable preservatives 0063 As used herein, the term “colorant' is intended to include, by way of example and without limitation, benza mean a compound used to impart color to Solid (e.g., tablets) lkonium chloride, benzethonium chloride, benzyl alcohol, pharmaceutical preparations. Such compounds include, by cetylpyridinium chloride, , , phenyl way of example and without limitation, FD&C Red No. 3, ethyl alcohol, phenylmercuric nitrate and thimerosal and FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. others known to those of ordinary skill in the art. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, 0070) Examples of absorbents include sodium starch gly caramel, and ferric oxide, red, other FD&C dyes and natural colate (ExplotabtM, PrimojelTM); croscarmellose sodium coloring agents such as grape skin extract, beet red powder, (Ac-Di-SolR); polyvinylpyrrolidone (PVP) (e.g., Polyplas beta carotene, annato, carmine, turmeric, paprika, and other doneTM XL 10); Veegum; clays; alginates; alginic acid; materials known to one of ordinary skill in the art. The carboxymethylcellulose calcium; microcrystalline cellulose amount of coloring agent used will vary as desired. (e.g., AviceITM); polacrillin potassium (e.g., AmberliteTM); Sodium alginate; corn starch; potato starch; pregelatinized 0064. As used herein, the term “flavorant' is intended to mean a compound used to impart a pleasant flavor and often starch; modified Starch; cellulosic agents; montmorrilonite odor to a pharmaceutical preparation. Exemplary flavoring clays (e.g., bentonite); gums, agar locust bean gum, gum agents or flavorants include synthetic flavor oils and flavor karaya; pectin; tragacanth; and other absorbents known in to ing aromatics and/or natural oils, extracts from plants, those of ordinary skill in the art. leaves, flowers, fruits and so forth and combinations thereof. 0071. In an embodiment, the oral dosage form may These may also include cinnamon oil, oil of wintergreen, include one or more polycarboxylic acids. Polycarboxylic peppermint oils, clove oil, bay oil, anise oil, eucalyptus, acids include organic compounds that have two or more thyme oil, cedar leave oil, oil of nutmeg, oil of Sage, oil of carboxyl ( COOH) groups and from 2 to 9 carbon atoms in bitter almonds and cassia oil. Other useful flavors include a chain or ring to which the carboxyl groups are attached. Vanilla, citrus oil, including lemon, orange, grape, lime and The carboxyl groups are not included when determining the grapefruit, and fruit essences, including apple, pear, peach, number of carbon atoms in the chain or ring (e.g., 1.2.3 Strawberry, raspberry, cherry, plum, pineapple, apricot and tricarboxylic acid would be considered to be a C so forth. Flavors that have been found to be particularly polycarboxylic acid containing three carboxyl groups and useful include commercially available orange, grape, cherry 1,2,3,4 butanetetracarboxylic acid would be considered to be and bubblegum flavors and mixtures thereof. The amount of a C polycarboxylic acid containing four carboxyl groups). flavoring may depend on a number of factors, including the C-C polycarboxylic acids include, but are not limited to organoleptic effect desired. Flavors will be present in any aliphatic, aromatic, and alicyclic acids, either saturated or US 2008/0075770 A1 Mar. 27, 2008 olefinically unsaturated, with at least two carboxyl groups a preparation. Such compounds include, by way of example per molecule. In some embodiments, aliphatic polycarboxy and without limitation, aspartame, dextrose, glycerin, man lic acids may include a hydroxyl group attached to a carbon nitol, Saccharin Sodium, Sorbitol. Sucrose, fructose and other atom alpha to a carboxyl group (an o-hydroxy polycarboxy such materials known to those of ordinary skill in the art. lic acid). C.-hydroxy polycarboxylic acids include citric acid (also known as 2-hydroxy-1.2.3 propane tricarboxylic acid) 0078. It should be understood that compounds used as and tartaric acid. excipients or that are used to modify the oral dosage form, may serve a variety of functions or purposes. Thus, whether 0072 Examples of specific polycarboxylic acids include, a compound named herein is assigned to one or more but are not limited to, Oxalic acid, malonic acid, Succinic classifications or functions, its purpose or function should acid, glutaric acid, adipic acid, maleic acid, fumaric acid, not be considered as being limited to the named purpose or malic acid, pimelic acid, nonanedioic acid, dodecanedioic function. acid, octanedioic acid, phthalic acid, isophthalic acid, terephthalic acid, citraconic (methylmaleic acid), citric acid, Emetics and Nasal Irritants tartaric acid, itaconic acid (methylenesuccinic acid), 1.2.3 propane tricarboxylic acid, transaconitic acid (trans-1-pro 0079. In certain embodiments the oral dosage form also pene-1,2,3-tricarboxylic acid), 1,2,3,4-butanetetracarboxy includes an emetic. While the use of emetics to deter abuse is not required for the oral dosage forms described herein, lic acid, all-cis-1,2,3,4-cyclopentanetetracarboxylic acid, they can provide an additional deterrent to abuse when used mellitic acid (benzenehexacarboxylic acid), oxydisuccinic in combination with the other components of the oral dosage acid (2,2'-oxybis(butanedioic acid), C.-bromoglutaric acid, forms. In principle, the amount of emetic Supplied must be 3.3-dimethylpentanedioic acid, and 2,4-dicholoropen low enough to produce no ill effects on a Subject or patient tanedioic acid. when the oral dosage form containing the emetic is used 0.073 Bioadhesive polymers include polyethylene oxide, properly, that is, swallowed whole. However when the KLUCEL (hydroxypropylcellulose), CARBOPOL, polycar dosage form is crushed or dissolved, the result will be to bophil, GANTREZ, and combinations thereof, and others release an amount of emetic that will produce known to one of ordinary skill in the art. when the crushed or dissolved oral dosage form is ingested. 0074 Retardants are agents that are insoluble or slightly Suitable emetics include but are not limited to denatonium soluble polymers with a Tg above 45° C., or above 50° C. benzoate, syrup of ipecac, potassium tartrate, copper Sulfate, before being plasticized by other agents in the formulation Zinc sulfate, cephaeline, methyl cephaeline, psychotrine, including other polymers and other excipients needed for O-methylpsychotrine and emetamine and others known to processing. The excipients include waxes, acrylics, cellulo one of ordinary skill in the art. sics, lipids, proteins, glycols, and the like. 0080 Similarly, in some embodiments, the oral dosage 0075 Exemplary pore formers include water soluble form can also include a nasal irritant. Similar to emetics, use polymers such as polyethylene glycol, propylene glycol, and of nasal irritants to deter abuse is not required for the oral povidone; binders such as lactose, calcium sulfate, calcium dosage forms described herein. Furthermore, the type and phosphate and the like; salts such as Sodium chloride, amount of nasal irritant present in the oral dosage form must magnesium chloride and the like, poloxamers and combi be such that substantially no ill side effects on a subject or nations thereof and other similar or equivalent materials patient occur when the oral dosage form is ingested. How which are widely known in the art. Examples of poloxamers ever, when the dosage form is crushed and inhaled, the include, but are not limited to: PluronicR) F-68 (Poloxamer presence of the nasal irritant will result in Sneezing or 188), Pluronic(R). F87 (Poloxamer 237), Pluronic(R) F108 discomfort in the user that deters further abuse. Suitable (Poloxamer 338), Pluronic(R) F127 (Poloxamer 407, Lutrol nasal irritants for use include but are not limited to sodium F127) and the like. Pluronic R is a registered tradename for lauryl Sulfate, pepper, capsaicin, ethylene glycol, poloxamer, BASF Corporation for block copolymers of ethylene oxide Sorbitan monoesters and glyceryl monooleates and others and propylene oxide represented by the chemical structure known to one of ordinary skill in the art. HO(CHO) (CHO) (CHO), H wherein for: (a) Plu Methods of Formulation ronic(R) F-68, a is 80 and b is 27; (b) Pluronic(R) F87, a is 64 and b is 37; (c) Pluronic R. F108, a is 141 and b is 44; and 0081 Further provided are methods of formulating oral Pluronic RF127, a is 101 and b is 56. The average molecular dosage forms. Oral dosage forms that deter abuse may be weights of these block copolymers are 8,400, 7,700, 14,600 formulated by: and 12,600 for Pluronic RF-68, Pluronic(R) F-87, Pluronic(R) F108 and Pluronic(R) F127, respectively. 0082 a. mixing one or more hydrophilic matrix materials and a therapeutic agent, wherein the hydrophilic matrix 0.076 Exemplary osmagents or osmotic agents include materials comprises 20 to 99.9% of the mixture by weight, organic and inorganic compounds such as salts, acids, bases, and wherein the mixture comprises less than 20% by weight chelating agents, sodium chloride, lithium chloride, magne of one or more hydrophobic matrix materials; sium chloride, magnesium sulfate, lithium Sulfate, potas sium chloride, Sodium sulfite, calcium bicarbonate, sodium 0083) b. melting the mixture: Sulfate, calcium sulfate, calcium lactate, d-, urea, tartaric acid, raffinose, Sucrose, alpha-d-lactose monohy 0084 c. permitting the mixture to solidify as a substan drate, glucose, combinations thereof and other similar or tially solid mass or as a Substantially solid oral dosage form, equivalent materials which are widely known in the art. wherein the mass or oral dosage form weighs at least 40 mg: 0.077 As used herein, the term “sweetening agent' is 0085 d. and optionally, shaping the mass into an oral intended to mean a compound used to impart Sweetness to dosage form. US 2008/0075770 A1 Mar. 27, 2008

0.086 For purposes of the present disclosure a mixture is 0094) Hot-melt extrusion typically involves the use of an "melted by applying thermal or mechanical energy Sufi extruder device. Such devices are well-known in the art. cient to render the mixture partially or Substantially com Such systems include mechanisms for heating the mixture to pletely molten. For instance, in a mixture that includes a an appropriate temperature and forcing the melted feed matrix material, "melting the mixture may include Substan material under pressure through a die to produce a rod, sheet tially melting the matrix material without substantially melt or other desired shape of constant cross-section. Subsequent ing one or more other materials present in the mixture (e.g., to or simultaneous with being forced through the die the the therapeutic agent and one or more excipients). Generally, extrudate can be cut into Smaller sizes appropriate for use as a mixture is sufficiently molten, for example, when it can be an oral dosage form. Any suitable cutting device known to extruded as a continuous rod, or when it can be subjected to those skilled in the art can be used, and the mixture can be injection molding. cut into appropriate sizes either while still at least somewhat soft or after the extrudate has solidified. The extrudate may 0087. In preferred embodiments the hydrophilic matrix be cut, ground or otherwise shaped to a shape and size material is a water-soluble polymer. appropriate to the desired oral dosage form prior to Solidi 0088. The mixture of the hydrophilic matrix material, fication, or may be cut, ground or otherwise shaped after therapeutic agent, optional plasticizer, optional functional solidification. excipients and optional emetic or nasal irritant can be 0095 Under certain conditions, extrusion of composi accomplished by any suitable means. Well-known mixing tions of the present invention may result in “die-swelling.” means known to those skilled in the art include dry mixing, a phenomenon in which the extrudate swells diametrically dry granulation, wet granulation, melt granulation, high after exiting the die. In certain embodiments die-Swelling shear mixing, and low shear mixing. can be desirable, producing an extrudate having greater 0089 Granulation generally is the process wherein par porosity and thus accelerated release characteristics. In other ticles of powder are made to adhere to one another to form embodiments, it can be desirable to avoid die swelling, granules, typically in the size range of 0.2 to 4.0 mm. thereby producing a more solid composition that has slower Granulation is desirable in pharmaceutical formulations therapeutic release and/or is slower to dissolve in a solvent because it produces relatively homogeneous mixing of dif Such as aqueous ethanol Solutions and/or is harder. In some embodiments, an oral dosage form may be made as a ferent sized particles. non-compressed hot-melt extrudate. In other embodiments, 0090 Dry granulation involves aggregating powders an oral dosage form is not in the form of a compressed tablet. under high pressure. Wet granulation involves forming gran 0096. Injection molding typically involves the use of an ules using a granulating fluid or wetting agent that is injection-molding device. Such devices are well-known in Subsequently removed by drying. Melt granulation is a the art. Injection molding systems force a melted mixture process in which powders are transformed into Solid aggre into a mold of an appropriate size and shape. The mixture gates or agglomerates while being heated. It is similar to wet solidifies as least partially within the mold and then is granulation except that a binder acts as a wetting agent only released. after it has melted. All of these and other methods of mixing pharmaceutical formulations are well-known in the art. 0097 Compression molding typically involves the use of an compression-molding device. Such devices are well 0.091 Subsequent or simultaneous with mixing, the mix known in the art. Compression molding is a method in which ture of hydrophobic matrix material, therapeutic agent, the mixture is optionally preheated and then placed into a optional plasticizer, optional functional excipients and heated mold cavity. The mold is closed and pressure is optional emetic or nasal irritant is melted to produce a mass applied. Heat and pressure are typically applied until the sufficiently fluid to permit shaping of the mixture and/or to molding material is cured. The molded oral dosage form is produce melding of the components of the mixture. The then released from the mold. melted mixture is then permitted to solidify as a substan tially solid oral dosage form. The mixture can optionally be 0098. The oral dosage forms may be of any size suitable shaped or cut into Suitable sizes during the melting step or for oral administration. In some embodiments, oral dosage during the solidifying step. In one embodiment, oral dosage forms are roughly cylindrical in shape. In a plane perpen forms are single Substantially solid masses of at least 40 dicular to the long axis of the cylinder the roughly cylin mgs, at least 60 mgs, at least 80 mgs, at least 100 mgs, at drical preferred oral dosage form has a diameter of 5 mm or least 150 mgs, at least 200 mgs, at least 250 mgs, at least 300 greater, 6 mm or greater, 7 mm or greater, 8 mm or greater, mgs, at least 400 mgs or at least 500 mgs. As used herein, 9 mm or greater, or 10 mm or greater. Along the long axis a Substantially solid oral dosage form is a dosage form that of the cylinder the preferred oral dosage form has a length cannot be readily crushed or divided by hand into smaller of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 mm or parts and that preferably has a hardness of at least 20 kp, at greater. Such dosage forms could be formed, for example, by least 25 kp, at least 30 kp, at least 35 kp, at least 40 kp, at extruding the oral dosage form through a die that is at least least 45 kp, or at least 50 kp. 0.5 mm in diameter, 0.6 mm in diameter, 0.7 mm, etc., in diameter and then cutting the extrudate to a length of 1, 2, 0092. In preferred embodiments, the mixture becomes a 3, 4, 5 mm, etc., in length. homogeneous mixture either prior to or during the melting step. 0099] It has been found, for some embodiments, that the release characteristics of the therapeutic agent from the oral 0093 Methods of melting the mixture include, but are not dosage form may be dependent on the ratio of the Surface limited to, hot-melt extrusion, injection molding and com area of the oral dosage form to the Volume of the oral dosage pression molding. form. In some embodiments, the Surface area/volume ratio US 2008/0075770 A1 Mar. 27, 2008

of the oral dosage form should be held constant to allow 0110. The mixing and melting steps are carried out as constant Swelling and release of the therapeutic agent as the described above. The mixture may be divided into particu size of the oral dosage form is altered. In some embodi lates either before or after solidification of the solid mass or ments, it is preferred that the surface are/volume ratio of the oral dosage form and can be carried out by any Suitable oral dosage form be maintained between about 0.5 to about means known to those skilled in the art. Particulates are less 10, or between about 1 to about 5. than 40 mg in weight, preferably less than 30 mg or less than 20 mg, and most preferably less than 10 mg or less than 5 0100. An oral dosage form produced by a thermal process mg. The particulates can be shaped by any suitable means may exhibit low moisture content. Reduced moisture con including cutting, grinding, molding and the like. Further, tent of the oral dosage form may improve the stability of the the particulates can take any suitable geometric shape and oral dosage form, thus extending the shelf life of the oral size. Such as a particle size ranging from about 0.1 mm to 30 dosage form. In one embodiment, the oral dosage form has mm in diameter. a moisture content of less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%. 0111. In preferred embodiments, the particulates are 0101 The final step in the process of making oral dosage melted using an extrusion process that does not permit forms is permitting the oral dosage form as a Substantially die-Swelling or by a molding process that also does not Solid oral dosage form, wherein the oral dosage form weighs permit swelling of the melted mixture prior to solidification. at least 40 mg. The oral dosage form may optionally be 0.112. The particulates can be formed as an oral dosage shaped either prior to solidification or after solidification of form using any Suitable means known in the art, including the dosage form. Solidification will generally occur either as pressing the particulates into tablet form using standard a result of cooling of the melted mixture or as a result of tablet-forming techniques known in the art, or containing the curing of the mixture however any suitable method for particulates within a hard or soft gelatin capsule, also using producing a solid dosage form may be used. techniques known in the art. While oral dosage forms made according to the present embodiment are more Susceptible to 0102) In certain embodiments, prior to administration the crushing or dissolution in aqueous ethanol than other Substantially solid oral dosage form may be cut, ground or embodiments of the present invention, they nevertheless otherwise shaped into its final form, or may be allowed to have improved characteristics over prior art formulations in remain in its final molded configuration. Optionally the these regards, and can potentially produce oral dosage forms Substantially solid oral dosage form can further include one with faster drug release characteristics than the substantially or more coatings, including polymeric coatings and the like. Solid dosage forms. 0103) In preferred embodiments, the oral dosage form comprises a therapeutic agent as a Substantially uniform 0113 Release Characteristics Solution or dispersion within a matrix of hydrophilic poly 0114 Previous uses in the art of hot-melt extrudates and mer. However in alternative embodiments the distribution of other polymeric Solids containing agents have involved therapeutic agent within the hydrophilic polymer can be providing a unit dosage form including the Solid in the form Substantially non-uniform. One method of producing a non of particulates, pellets, granules, or the like. This is because uniform distribution of therapeutic agent is through the use the use of particulates Substantially increases the Surface of one or more coatings of water-soluble or water-soluble area of the unit dosage form. It was widely believed that polymer. Another method is by providing two or more Such increased Surface area was required to achieve Sufi mixtures of polymer or polymer and therapeutic agent to cient drug release upon ingestion to make the dosage form different Zones of a compression or injection mold. A further Suitable for pharmaceutical use. Oral dosage forms consist method is by providing the therapeutic agent in form of ing essentially of a Substantially-solid mass were not dis particulates embedded in a matrix of 20-100% water-soluble closed as oral dosage forms because the Surface area of Such polymer by weight. These methods are provided by way of dosage forms was considered to be inadequate for Sufi example and are not exclusive. Other methods of producing ciently rapid release of the embedded therapeutic agent. a non-uniform distribution of therapeutic agent within the 0115 Surprisingly, compositions described herein are abuse-deterring oral dosage forms of the present invention suitable for immediate release, controlled release and will be apparent to those skilled in the art. extended release applications, or combinations thereof, 0104. In an embodiment, a method of formulating oral depending on the types of hydrophobic matrix materials, dosage forms includes: therapeutic agent, plasticizers and excipients used and their proportions. Methods for adjusting these characteristics will 0105 a. mixing one or more hydrophilic matrix materials be apparent to those skilled in the art or can be determined and a therapeutic agent, wherein the hydrophilic matrix without undue experimentation. For example, immediate materials comprises 20 to 99.9% of the mixture by weight, release characteristics of the oral dosage forms may be and wherein the mixture comprises less than 20% by weight enhanced by the inclusion of hydrophilic therapeutic agents, of one or more hydrophobic matrix materials; plasticizers and/or excipients to enhance the formation of 0106 b. melting the mixture; pores in the oral dosage form, particularly those that begin forming when the oral dosage form is subjected to gastric 01.07 c. permitting the mixture to Solidify: conditions. Alternatively, immediate release characteristics 0108 d.dividing the mixture into particulates of less than may be suppressed, for example, by coating the oral dosage form with a suitable enteric coating that does not contain the 40 mg: therapeutic agent. By adjusting variables such as these, a 0109 e. preparing an oral dosage form comprising two or range of release characteristics can be obtained from the oral more of the particulates. dosage forms. US 2008/0075770 A1 Mar. 27, 2008

0116. In one embodiment, the oral dosage form releases 0120 Methods of Deterring Drug Abuse at least 80% of the therapeutic agent after 2 hours of stirring 0121 The present invention further provides methods of in a 0.1 NHCl solution and 16 hours stirring in a pH 6.8 preventing drug abuse comprising the steps of phosphate buffer solution using a USP Type II paddle apparatus at 75 rpm and 37° C. The oral dosage form, in 0.122 a. identifying a therapeutic agent that is subject some embodiments, releases between about 10% and about to abuse; 50% of the therapeutic agent after 2 hours of stirring in a 0.1 N HCl solution and 1 hour stirring in a pH 6.8 phosphate 0123 b. formulating an oral dosage form that has a hardness of at least about 20 kp or greater and which buffer solution using a USPType II paddle apparatus at 75 releases less than about 40% of the therapeutic agent rpm and 37°C. The oral dosage form, in some embodiments, after 3 hours of shaking on an orbital shaker at 240 releases between about 40% and about 70% of the thera cycles/min in an aqueous solution of 40% ethanol at peutic agent after 2 hours of stirring in a 0.1 NHCl solution room temperature; and and 10 hours stirring in a pH 6.8 phosphate buffer solution using a USPType II paddle apparatus at 75 rpm and 37° C. 0.124 c. providing the oral dosage form to a patient. The oral dosage form, in Some embodiments, releases between about 70% and about 100% of the therapeutic agent 0.125. In an embodiment, an oral dosage form is formu lated to have a hardness of at least about 20kp, at least about after 2 hours of stirring in a 0.1 NHCl solution and 16 hours 25 kp, at least about 30 kp, at least about 35 kp, at least about stirring in a pH 6.8 phosphate buffer solution using a USP 40 kp, at least about 45 kp, or at least about 50 kp. In an Type II paddle apparatus at 75 rpm and 37° C. embodiment, an oral dosage form is formulated to have a 0117. In some embodiments, it has been found that the release of less than about 40%, less than about 30%, less release characteristics and the abuse deterrent properties of than about 20% or less than about 10% of the therapeutic a monolithic oral dosage form may be accomplished without agent after 3 hours of shaking on an orbital shaker at 240 the use of digestible Cs-Cso Substituted and unsubstituted cycles/min in an aqueous solution of 40% ethanol at room hydrocarbons. Thus oral dosage formulation may be used temperature. that are substantially free of digestible Cs-Cso substituted 0.126 The resulting oral dosage forms are highly resistant and unsubstituted hydrocarbons such as Cs-Cso fatty acids, to crushing and to dissolution in an ethanol solution Such as Cs-Cso fatty alcohols, glyceryl esters of Cs-Cso fatty acids, a typical alcoholic beverage. As a resultan abuser is deterred mineral oils, vegetable oils and waxes. from bypassing the extended-release characteristics of the formulation Such that they receive a single concentrated 0118. In some embodiments, the oral dosage form may be dose of the therapeutic agent. disposed in a capsule. Examples of materials that may be used to encapsulate the oral dosage form include, but are not 0127. In further embodiments, methods of deterring drug limited to, gelatin capsules, hydroxypropylmethyl cellulose abuse by the present invention include: (“HPMC) capsules, or polysaccharide capsules (e.g., pull 0.128 a. mixing one or more hydrophilic matrix materials lulan capsules). In other embodiments, the oral dosage form and a therapeutic agent that is Subject to abuse, wherein the may be coated. Examples of coating materials include hydrophilic matrix materials comprises 20 to 99.9% of the gelatins, aesthetic polymers, proteins or polysaccharides mixture by weight, and wherein the mixture comprises less (e.g., Sucrose). than 20% by weight of one or more hydrophobic matrix materials; 0119). In embodiments of the oral dosage form, it will be desirable to formulate compositions that they have specific 0.129 b. melting the mixture: release characteristics for treatment of a human or animal. 0.130 c. permitting the mixture to solidify as a substan Formulations of the oral dosage form, by their nature, lend tially solid mass or as a Substantially solid oral dosage form, themselves to immediate and extended-release applications. wherein the mass or oral dosage form weighs at least 40 mg: Not to be limited by theory, it is believed that the release 0131 d. optionally, shaping the mass into a substantially characteristics of the oral dosage forms are a function of the Solid oral dosage form; solubility of the drug and the matrix in the gastric and intestinal milieu. It is anticipated that in Some embodiments, 0.132 e. and administering the substantially solid oral drug release in the gastric milieu will be limited to diffusion dosage form to a patient. of drug particles on the Surface of the matrix, and that drug 0.133 Alternatively, methods of deterring abuse drug release from the matrix in the intestinal milieu will occur abuse provided by the present invention also includes: slowly by erosion and diffusion. For example, the release characteristics can be adjusted by one of ordinary skill in the 0.134) a. mixing one or more hydrophilic matrix materials art by use of pore formers, hydrophilic polymers, osmotic and a therapeutic agent that is Subject to abuse, wherein the agents, plasticizers and other functional excipients. The hydrophilic matrix materials comprises 20 to 99.9% of the chemical and physical properties, including the release char mixture by weight, and wherein the mixture comprises less acteristics, of the dosage form can also be adjusted by the than 20% by weight of one or more hydrophobic matrix process, processing parameters (temperature, shear rate) and materials; equipment design (melt pump or rotating screw). Methods of adapting the oral dosage form to different therapeutic 0135) b. melting the mixture: agents and different release profiles are routine in the art and 0.136 c. permitting the mixture to solidify, preferably in can be accomplished without undue experimentation. a manner that prevents Swelling of the mixture; US 2008/0075770 A1 Mar. 27, 2008

0137 d. dividing the mixture into particulates of less than Eudragit RL100-55, Eudragit R. L30 D-55, EudragitR) S100, 40 mg: Eudragit R. 4135F, Eudragit(R) RS, acrylic acid and meth acrylic acid copolymers, methyl methacrylate, methyl meth 0138 e. preparing an oral dosage form comprising two or acrylate copolymers, ethoxyethyl methacrylates, cyanoethyl more of the particulates; methacrylate, aminoalkyl methacrylate copolymer, poly 0139 f. and administering the oral dosage form to a acrylic acid, polymethacrylic acid, methacrylic acid alky patient. lamine copolymer, polymethyl methacrylate, poly methacrylic acid anhydride, polymethacrylate, 0140. In certain embodiments, oral dosage forms that are polyacrylamide, polymethacrylic acid anhydride and gly resistant to ethanol extraction or dose-dumping in ethanol cidyl methacrylate copolymers, an alkylcellulose such as are disclosed. The disclosed formulations are also resistant ethylcellulose, methylcellulose, carboxymethyl cellulose, to opioid abuse by including a therapeutic amount of an hydroxyalkylcellulose, hydroxypropyl methylcelluloses opioid agent and an effective amount of an opioid antago Such as hydroxypropyl methylcellulose phthalate, and nist. The opioid antagonist is sequestered from the opioid hydroxypropyl methylcellulose acetate Succinate, cellulose agent Such that the antagonist has no significant effect on the acetate butyrate, cellulose acetate phthalate, and cellulose activity of the opioid when the dosage form is taken orally acetate trimaleate, polyvinyl acetate phthalate, polyester, as prescribed. Tampering with the dosage form, or crushing waxes, shellac, Zein, or the like. The coating of the opioid the dosage form however, releases the antagonist in an antagonist particles can also include hydrophilic materials amount effect to reduce the abuse potential of the opioid Such as a pharmaceutically-acceptable, water-soluble poly agent. mer such as polyethylene oxide (PEO), ethylene oxide 0141 An antagonist is a drug or medication that prevents propylene oxide co-polymers, polyethylene-polypropylene molecules of other drugs/ from binding to a glycol (e.g. poloxamer), carbomer, polycarbophil, chitosan, receptor (e.g., an opioid receptor). Antagonists can also polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), displace other opioids and can precipitate withdrawal, or hydroxyalkyl celluloses such as hydroxypropyl cellulose block the effects of other opioids. Opioid antagonists suit (HPC), hydroxyethyl cellulose, hydroxymethyl cellulose able for the present formulations include any opioid antago and hydroxypropyl methylcellulose, carboxymethyl cellu nist known in the art, mixed agonist/antagonists and partial lose, Sodium carboxymethyl cellulose, methylcellulose, antagonists. Such agents include but are not limited to hydroxyethyl methylcellulose, hydroxypropyl methylcellu naloxone, cyclazocine, naltrexone, nalmephene, alvimopan, lose, polyacrylates such as carbomer, polyacrylamides, nalide, nalmexone, nalorphine, nalorphine dinicotinate, and polymethacrylamides, polyphosphazines, polyoxazolidines, levallorphan, or the pharmacologically effective esters or polyhydroxyalkylcarboxylic acids, alginic acid and its salts of any of the foregoing antagonists. derivatives such as carrageenate alginates, ammonium algi nate and Sodium alginate, starch and starch derivatives, 0142 Further provided are methods of formulating the polysaccharides, carboxypolymethylene, polyethylene gly oral dosage forms. Oral dosage forms that deter abuse are formulated by: mixing one or more hydrophilic matrix col, natural gums such as gum guar, gum acacia, gum materials, an opioid agent, and a coated opioid antagonist, tragacanth, karayagum and gum Xanthan, poVidone, gelatin wherein the hydrophilic matrix materials comprises 20 to or the like. 99.9% of the mixture by weight; melting the mixture: 0145 Oral dosage forms may be produced by mixing the permitting the mixture to solidify as a Solid mass or oral hydrophilic matrix material, opioid agent, opioid antagonist, dosage form, wherein the mass or oral dosage form weighs optional plasticizer, optional functional excipients and at least 40 mg. optionally, shaping the mass into a monolithic optional emetic or nasal irritant by any Suitable means. oral dosage form, and optionally, over-encapsulating or Well-known mixing means known to those skilled in the art coating the mass or oral dosage form in a shell. include dry mixing, dry granulation, wet granulation, melt 0143. The coated particles or microparticles of opioid granulation, high shear mixing, and low shear mixing. antagonist can be prepared by various methods known in the 0146) Subsequent or simultaneous with mixing, the mix art, including but not limited to hot melt procedures Such as ture of hydrophilic matrix material, opioid agent, opioid extrusion, compression molding or injection molding as antagonist, optional plasticizer, optional functional excipi described herein for production of the monolithic dosage ents and optional emetic or nasal irritant is melted to produce forms. Other types of coatings for the opioid antagonists can a mass Sufficiently fluid to permit shaping of the mixture include coatings that are pH dependent or pH independent, and/or to produce melding of the components of the mixture. Such as acrylic polymers, cellulose derivate polymers, The melted mixture is then permitted to solidify as a waxes, or curable polymers, for example. Any coatings solidified oral dosage form. The mixture can optionally be known in the art can be used, so long as the opioid antagonist shaped or cut into Suitable sizes during the melting step or is not released simultaneously with the opioid agent when during the solidifying step. Oral dosage forms may be a placed in simulated gastric juice, but is released when the single Solidified mass of at least 40 mgs, at least 60 mgs, at dosage form is crushed. least 80 mgs, at least 100 mgs, at least 150 mgs, at least 200 014.4 pH dependent coatings can include any of shellac, mgs, at least 250 mgs, at least 300 mgs, at least 400 mgs or cellulose acetate phthalate (CAP), polyvinyl acetate phtha at least 500 mgs. late (PVAP), hydroxypropylmethylcellulose phthalate, and 0.147. Further embodiments, include methods of prevent methacrylic acid ester copolymers, or Zein, for example. ing drug abuse including: formulating a monolithic oral Hydrophobic polymeric coatings include acrylic polymer, dosage form comprising an opioid agent and an opioid acrylic copolymer, methacrylic polymer or methacrylic antagonist, wherein the dosage form has a weight of at least copolymer, including but not limited to Eudragitg L 100, 40 mg; and wherein the dosage form releases less than about US 2008/0075770 A1 Mar. 27, 2008

40% of the opioid agent after 3 hours of shaking on an orbital shaker in an aqueous solution of 40% ethanol at room TABLE II temperature and further wherein the opioid antagonist is sequestered from the opioid agent Such that the antagonist Extruder Zones Temperature has no significant effect on the activity of the opioid when Zone 1 80° C. Zone 2 135° C. the dosage form is taken orally as prescribed, but wherein Zone 3 140° C. the antagonist is released in an amount effect to reduce the Die 140° C. abuse potential of the opioid agent contained in the dosage form when the dosage form is crushed; and optionally providing the oral dosage form to a patient. 0153. After solidification, the tablets were analyzed for their alcohol extractability in 40% ethanol with an orbital 0148. In further embodiments, methods of deterring shaker at 240 cycles/min for 3 hours. After solidification the abuse include: mixing one or more hydrophilic matrix tablets were analyzed for their alcohol extractability in 40% materials, an opioid agent and a coated opioid antagonist, ethanol with an orbital shaker at 240 cycles/min for 3 hours. The tablets were placed into 4 ounce containers with 36 mL wherein the hydrophilic matrix materials comprises 20 to 0.1N HCl and shaken using an orbital shaker for 5 minutes 99.9% of the mixture by weight; melting the mixture: at room temperature. Twenty four mL of Ethanol (100%) permitting the mixture to Solidify as a solidified mass or as was added to the HCl solution to adjust the final alcohol a solidified oral dosage form, wherein the mass or oral concentration to 40% and shaking was continued for 3 dosage form weighs at least 40 mg. optionally, shaping the hours. Less than 40% of the oxycodone was released after 3 mass into a monolithic oral dosage form; and optionally hours. administering or providing the oral dosage form to a patient. Example 2 0149 Further embodiments relate to methods of treating a number of conditions and diseases, particularly the treat 0154 Water-soluble polymer was used to prepare an oral ment of pain. The methods include preparing oral dosage dosage form also comprising water-insoluble polymer (ethyl forms comprising at least 20% by weight of one or more cellulose). hydrophilic materials, one or more opioid agents, and one or more coated opioid antagonists. Certain methods further TABLE III comprise providing said oral dosage forms to a patient in Ingredient % Wiw need of treatment for the disease or condition. Oxycodone 5 Hydroxypropyl Cellulose (Klucel HF) 66 0150. The following examples are included to demon Dibutyl Sebacate 6 strate preferred embodiments of the invention. It should be Ethyl Cellulose 17 appreciated by those of skill in the art that the techniques Poloxamer 407 6 disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of O155 The ingredients of Table III were blended and the invention, and thus can be considered to constitute introduced to an extruder. Dibutyl sebacate is a plasticizer. preferred modes for its practice. However, those of skill in Rods were extruded with a screw speed of 25 rpm and the the art should, in light of the present disclosure, appreciate extruder Zones were heated to the temperatures listed in that many changes can be made in the specific embodiments Table IV. The resultant rods were cut into 400 mg tablets. which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. TABLE IV Extruder Zones Temperature Example 1 Zone 1 110° C. Zone 2 110° C. 0151 Water-soluble polymer was used to prepare an oral Zone 3 115° C. dosage form. Die 115° C.

TABLE I 0156 After solidification the tablets were analyzed for Ingredient % Wiw their alcohol extractability in 40% ethanol with an orbital Oxycodone 5 shaker at 240 cycles/min for 3 hours. The tablets were placed Hydroxypropyl Cellulose (Klucel HF) 85 into 4 ounce containers with 36 mL 0.1N HCl and shaken Poloxamer 407 10 using an orbital shaker for 5 minutes at room temperature. Twenty four mL of Ethanol (100%) was added to the HCl solution to adjust the final alcohol concentration to 40% and 0152 The ingredients of Table 1 were blended and intro shaking was continued for 3 hours. Less than 40% of the duced to an extruder. Rods were extruded with a screw speed oxycodone was released in 3 hours. of 25 rpm and the extruder Zones were heated to the 0157. Further modifications and alternative embodiments temperatures listed in Table II. The resultant rods were cut of various aspects of the invention will be apparent to those into 400 mg tablets. skilled in the art in view of this description. Accordingly, this US 2008/0075770 A1 Mar. 27, 2008

description is to be construed as illustrative only and is for 20. The oral dosage form of claim 1, further comprising the purpose of teaching those skilled in the art the general one or more polycarboxylic acids. manner of carrying out the invention. It is to be understood 21. The oral dosage form of claim 1, further comprising that the forms of the invention shown and described herein one or more O.-hydroxy polycarboxylic acids. are to be taken as examples of embodiments. Elements and 22. (canceled) materials may be substituted for those illustrated and 23. The oral dosage form of claim 1, further comprising described herein, parts and processes may be reversed, and one or more pore formers. certain features of the invention may be utilized indepen 24. (canceled) dently, all as would be apparent to one skilled in the art after 25. (canceled) having the benefit of this description of the invention. 26. (canceled) Changes may be made in the elements described herein 27. (canceled) without departing from the spirit and scope of the invention 28. The oral dosage form of claim 1, wherein the oral as described in the following claims. dosage form has a hardness of at least about 50 kp. 29. The oral dosage form of claim 1, wherein the oral 1. A monolithic solidified oral dosage form prepared by a dosage form has a diameter of greater than about 5 mm. thermal process comprising a therapeutic agent and a hydro 30. (canceled) philic polymer wherein the oral dosage form releases at least 31. (canceled) 80% of the therapeutic agent after 2 hours of stirring in a 0.1 32. The oral dosage form of claim 1, wherein the oral N HCl solution and 16 hours stirring in a pH 6.8 phosphate dosage form has a moisture content of less than about 5%. buffer solution using a USPType II paddle apparatus at 75 33. The oral dosage form of claim 1, wherein the oral rpm and 37°C., and wherein the oral dosage form releases dosage form is disposed in a capsule. less than 40% of the therapeutic agent after 5 minutes of 34. The oral dosage form of claim 1, wherein the oral shaking at 240 cycles/min in a 0.1 NHCl solution followed dosage form is coated. by 3 hours of shaking on an orbital shaker at 240 cycles/min 35. (canceled) in an acidic aqueous solution of 40% ethanol at 25°C. 36. The oral dosage form of claim 1, wherein the oral 2. The oral dosage form of claim 1, wherein the oral dosage form is not in the form of an aggregate or composite dosage form releases between about 10% and about 50% of of individual solid particulates. the opioid after 2 hours of stirring in a 0.1 NHCl solution 37. The oral dosage form of claim 1, wherein the oral and 1 hour stirring in a pH 6.8 phosphate buffer solution dosage form is not in the form of a compressed tablet. using a USPType II paddle apparatus at 75 rpm and 37° C. 38. The oral dosage form of claim 1, wherein the oral 3. The oral dosage form of claim 1, wherein the oral dosage form is abuse deterrent. dosage form releases between about 40% and about 70% of 39. The oral dosage form of claim 1, wherein the oral the opioid after 2 hours of stirring in a 0.1 NHCl solution dosage form is Substantially free of digestible Cs-Cso Sub and 10 hours stirring in a pH 6.8 phosphate buffer solution stituted and unsubstituted hydrocarbons. using a USPType II paddle apparatus at 75 rpm and 37° C. 40. The oral dosage form of claim 1, wherein the oral 4. (canceled) dosage form is Substantially free of Cs-Cso fatty acids, 5. (canceled) C-Cso fatty alcohols, glyceryl esters of Cs-Cso fatty acids, 6. (canceled) mineral oils, vegetable oils and waxes. 7. The oral dosage form of claim 1, wherein the thera 41. The oral dosage form of claim 1, wherein the thera peutic agent is an opioid. peutic agent is Substantially uniformly dispersed within the 8. The oral dosage form of claim 1, wherein the thera oral dosage form. peutic agent is a . 42. An oral dosage form comprising: 9. The oral dosage form of claim 1, wherein the thera peutic agent is a hypnotic. an opioid therapeutic agent; and 10. The oral dosage form of claim 1, wherein the thera at least one hydrophilic polymer; peutic agent is a sedative. wherein the oral dosage form releases at least 80% of the 11. (canceled) opioid therapeutic agent after 2 hours of stirring in a 0.1 12. (canceled) N HCl solution and 16 hours stirring in a pH 6.8 13. The oral dosage form of claim 1, wherein the hydro phosphate buffer solution using a USPType II paddle philic polymer comprises at least 20% by weight of the oral apparatus at 75 rpm and 37° C., and wherein the oral dosage form. dosage form releases less than 40% of the opioid 14. The oral dosage form of claim 1, wherein the hydro therapeutic agent after 5 minutes of shaking at 240 philic polymer comprises one or more hydroxyalkyl cellu cycles/min in a 0.1 NHCl solution followed by 3 hours loses. of shaking on an orbital shaker at 240 cycles/min in an 15. The oral dosage form of claim 1, further comprising acidic aqueous solution of 40% ethanol at 25°C. one or more hydrophobic polymers. 43-72. (canceled) 16. The oral dosage form of claim 1, further comprising 73. A method of providing a therapeutic agent to a patient one or more acrylic acid based polymers, one or more comprising providing the patient with a monolithic Solidi methacrylic acid based polymers, or mixtures thereof. fied oral dosage form prepared by a thermal process, the oral 17. The oral dosage form of claim 1, further comprising dosage form comprising the therapeutic agent and a hydro one or more alkyl celluloses. philic polymer, wherein the oral dosage form releases at 18. The oral dosage form of claim 1, further comprising least 80% of the therapeutic agent after 2 hours of stirring in one or more plasticizers. a 0.1 N HCl solution and 16 hours stirring in a pH 6.8 19. (canceled) phosphate buffer solution using a USP Type II paddle US 2008/0075770 A1 Mar. 27, 2008 15 apparatus at 75 rpm and 37°C., and wherein the oral dosage permitting the mixture to solidify, releases at least 80% of form releases less than 40% of the therapeutic agent after 5 the therapeutic agent after 2 hours of stirring in a 0.1 minutes of shaking at 240 cycles/min in a 0.1 NHCl solution HCl solution and 16 hours stirring in a pH 6.8 phos followed by 3 hours of shaking on an orbital shaker at 240 phate buffer solution using a USP Type II paddle cycles/min in an acidic aqueous solution of 40% ethanol at apparatus at 75 rpm and 37° C., and wherein the oral 250 C. dosage form releases less than 40% of the therapeutic 74-112. (canceled) agent after 5 minutes of shaking at 240 cycles/min in a 113. A method of formulating a monolithic solidified oral 0.1 NHCl solution followed by 3 hours of shaking on dosage form, comprising: an orbital shaker at 240 cycles/min in an acidic aqueous Solution of 40% ethanol at 25° C. forming a mixture of hydrophilic polymer with a thera- 114-155. (canceled) peutic agent; melting the mixture; k . . . .