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US 20150.064251A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0064251A1 Ghebre-Sellassie (43) Pub. Date: Mar. 5, 2015

(54) TAMPER RESISTANT DOSAGE FORM Publication Classification COMPOSITION AND PROCESS OF MAKING THE SAME (51) Int. Cl. A619/20 (2006.01) (71) Applicant: Isaac Ghebre-Sellassie, Morris Plains, A613 L/485 (2006.01) NJ (US) A63/37 (2006.01) (52) U.S. C. CPC ...... A61K9/2054 (2013.01); A61 K3I/I37 (72) Inventor: Isaac Ghebre-Sellassie, Morris Plains, (2013.01); A61 K9/2077 (2013.01); A61 K NJ (US) 31/485 (2013.01); A6IK9/2095 (2013.01); A61 K9/2027 (2013.01) USPC ... 424/470; 514/652: 514/289; 521/32: 264/6 (21) Appl. No.: 14/323,412 (57) ABSTRACT A tamper-resistant dosage form including a therapeutic agent-substrate complex embedded in a thermo-formable (22) Filed: Jul. 3, 2014 matrix; Such that the complex includes at least one therapeutic agent bound to at least one Substrate to form the therapeutic agent-substrate complex. The at least one Substrate is being Related U.S. Application Data selected from the group consisting of a polyelectrolyte, an (63) Continuation of application No. 14/157.658, filed on organic counter-ion, a pharmacologically inert organic com Jan. 17, 2014. ponent of a prodrug, an inclusion compound and an inorganic adsorbent; and the thermo-formable matrix includes one or (60) Provisional application No. 61/959,830, filed on Sep. more thermoplastic polymers and optionally at least one 3, 2013. pharmaceutical additive. Patent Application Publication Mar. 5, 2015 Sheet 1 of 5 US 2015/006.4251A1

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TAMPER RESISTANT DOSAGE FORM 0007 While drug abuse has been common with all dosage COMPOSITION AND PROCESS OF MAKING forms, modified release products have been particularly THE SAME attractive to drug abusers due to the high drug content in the dosage forms. When these dosage forms are tampered with or CROSS REFERENCE TO RELATED altered, they may lead to more rapid release of the therapeutic APPLICATION agent, which in turn may provide the drug abusers with greater euphoria that they desperately desire. 0001. This application is based on, and claims the benefit 0008 To address the drug abuse epidemic, pharmaceutical of U.S. Provisional Patent Application No. 61/959,830, filed companies have started to develop abuse deterrent formula Sep. 3, 2013, and U.S. Ser. No. 14/157,658 which are incor tions, and the FDA has also issued a guideline to encourage porated herein by reference in their entirety. development of more effective tamper-resistant formulations. Abuse deterrent formulations are designed to thwart deliber FIELD OF THE INVENTION ate attempts by drug-abusers to extract the active ingredientor 0002 The present invention relates to an improved phar blunt the euphoric effects from unapproved methods of maceutical dosage form. More particularly, the invention administration. relates to a tamper-resistant dosage form including a thera 0009 Common methods of drug abuse include: (1) oral peutic agent-substrate complex and a thermo-formable ingestion, where the dosage form is chewed, to destroy the matrix comprising at least one thermoplastic polymerandone release controlling matrix and deliver high doses of therapeu or more pharmaceutical additives, and the method of making tic agent into the gastrointestinal tract, and Swallowed, with or SaC. without co-ingestion of ; (2) intravenous injection, which involves extraction of the therapeutic agent from the BACKGROUND OF INVENTION dosage form using an appropriate solvent, followed by injec tion of the therapeutic agent directly into the blood stream; (3) 0003 Product tampering occurs when a dosage form is nasal Snorting, where the dosage form is crushed, milled, or manipulated to achieve an objective in ways that is not ground into a fine powder and administered intra-nasally to intended per dosing instructions. It may involve drug abusers facilitate rapid drug absorption through the lining of the nasal who tamper with the dosage form to obtain euphoria, or passages; and (4) Smoking, where the therapeutic agent is non-abusers such as patients and caregivers who innocently vaporized for inhalation by Subjecting the dosage form to tamper with the dosage form to address legitimate concerns. heat. For example, an elderly patient may break a dosage form to 0010. In addition, dosage forms, particularly modified facilitate Swallowing or a caregiver may break a dosage form release dosage forms, are relatively large in size and may pose to reduce the therapeutic dose. a dosing challenge to many people including the elderly and 0004 Prescription medications are being abused at an young. Often, patients and caregivers may break the dosage alarming rate. The most commonly abused classes of pre form to reduce the size. By doing so, they inadvertently Scription drug products are (narcotics), / compromise the release controlling mechanism of the dosage , stimulants, and tranquilizers. The most commonly formand potentially lead to dose dumping, often with adverse abused over-the-counter drugs are decongestants, antihista consequences. mines and cough medicines. An estimated 52 million people 0011 To circumvent dosage form tampering, many have used prescription drugs for nonmedical reasons at least tamper resistant formulations have been described. once in their lifetimes. (0012 U.S. Pat. No. 7,510,726 describes a therapeutic 0005 Particularly, abuse of prescription painkillers is a pharmaceutical composition comprising a mixture consisting growing, public health problem that has been steadily wors of at least one analgesic, gel forming polyethylene ening as reflected in increased treatment admissions, emer oxide, and at least one disintegrant. Due to the physical prop gency room visits, and overdose deaths. About 164 million erties of the gel forming polymer, the extended release prop patients/year visit the doctor office for pain of which 20% erties of the disclosed dosage form is expected to be compro receive opiate prescriptions for pain treatment. Number of mised upon mastication and not prevent abuse by chewing opiate prescriptions has been steadily increasing since 1991. and Swallowing. In 2013 alone, 230 million opioid prescriptions were dis 0013 U.S. Pat. No. 7,771,707 describes a solid abuse pensed. The pain management market generated S7.3 billion deterrent pharmaceutical composition of a pharmaceutically in US sales in 2012. The market is predicted to increase to active agent prone to abuse, and one or more fatty acids or $9.8 billion by 2018 and to S11.3 billion by 2023. fatty amines present in molar excess relative to the pharma 0006. In 2010, more than 40% of all drug poisoning deaths ceutically active agent. As taught, the fatty acids andfatty acid involved opioid analgesics, and the number of overdose amines which impart lipophilicity on the drug Substance may deaths involving opioid analgesics has more than tripled since be susceptible to physical instability. 1999. The CDC's latest figures show that 16,500 people died (0014 U.S. Pat. No. 7,776,314 describes parenteral abuse from overdoses tied to common narcotic pain relievers in proofed solid dosage form for oral administration, compris 2010. Over dosage of opiates occurs due to intentional or ing one or more active ingredients with potential for abuse, unintentional tampering of opiate drug products. Abusers and at least one viscosity-increasing agent. Invention deters tamper with dosage form to obtain euphoria, while patients/ only abuse by injection. caregivers manipulate dosage forms to facilitate dosing. Pain 0015 U.S. Pat. No. 8,075,872 describes an abuse resistant relievers, such as OxyContin R) and Vicodin(R); anti-depres dosage form thermoformed by extrusion and having a break sants, such as Xanax(R) and Valium(R), and stimulants, such as ing strength of at least 500N, which contains a mixture of one Concerta R, Adderall(R), are the most commonly abused pre or more active ingredients with abuse potential, polyalkylene Scription drugs. oxides, physiologically acceptable auxiliary Substances, and US 2015/OO64251 A1 Mar. 5, 2015

optionally wax and cellulosic derivatives. The disclosed dos The invention relates to an erodible dosage form that has a dry age form contains low t hydrophilic polymers that may not core which hydrates on the Surface upon exposure to extrac withstand mastication when exposed to saliva due to plasti tion fluid to form a thin gel layer that limits water penetration cization. into the core. The dosage form also has a synchronized barrier 0016 U.S. Pat. No. 8,409,616 describes a therapeutic system that provides it with plasticity and hardness which pharmaceutical composition comprising a water-soluble drug renders the dosage form resistant to chewing, crashing and Susceptible to abuse, a gel forming polymer and a disinte grinding, and Volatilization. grant. As taught, the gel forming polymers based on polyeth ylene oxide are Susceptible to chewing and mastication upon SUMMARY OF THE INVENTION contact with saliva. 0017 U.S. Pat. No. 8,449,909 describes a therapeutically 0024. According to one embodiment, the present inven effective pharmaceutical composition comprising Solid tion is related to a tamper-resistant dosage form comprising of microparticles, wherein the microparticles comprise an active a therapeutic agent-substrate complex embedded in an erod agent, one or more fatty acids, and one or more carrier mate ible thermo-formable matrix, wherein the therapeutic agent rials selected from waxes or wax-like substances. The fatty Substrate complex is prepared by an extrusion process, and acids and fatty acid amines as taught, impart lipophilicity on the therapeutic agent-substrate complex is embedded in an the drug Substance but may not ensure physical stability upon erodible thermo-formable matrix by a granulation process. storage. U.S. Patent Application Publication 2008/0075770 The ratio of the therapeutic agent to the substrate in the describes a monolithic solidified oral dosage form prepared complex is from 1:20 to 20:1 by weight, while the ratio by a thermal process comprising a therapeutic agent and a between the therapeutic agent-substrate complex to the erod hydrophilic polymer. The disclosed drug molecules incorpo ible thermo-formable matrix is from 1:10 to 10:1 also by rated in a hydrophilic polymeric matrix have a tendency to weight. Optionally, a free therapeutic agent or a Substrate is diffuse when mobility of the polymer is increased due to embedded in the erodible thermo-formable matrix along with solvent or temperature effect, thereby increasing extractabil the therapeutic agent-substrate complex. ity. 0025. Alternatively, a prodrug, which is comprised of a 0018 U.S. Pat. No. 8,486,448 describes a controlled covalently bonded drug with an organic moiety, is embedded release formulation comprising a core comprising a Superab in the erodible thermo-formable matrix in place of the thera sorbent material, a controlled release coat Surrounding the peutic agent-substrate complex. core; and a plurality of controlled release microparticles con 0026. The erodible thermo-formable matrix comprises at taining a pharmaceutically active agent. This abuse deterrent least one cellulosic thermoplastic polymer and optionally at relies on a hard coating that may be susceptible to extraction least one non-cellulosic thermoplastic polymer and at least by both aqueous and organic solvents. one pharmaceutical additive, wherein the amount of the phar 00.19 U.S. Pat. No. 8,202,542 describes an abuse resistant opioid drug-ion exchange resin complexes having hybrid maceutical additive in the matrix is less than 20% by weight. coatings containing a cured polyvinylacetate polymer and a 0027. The tamper-resistant dosage form is comprised of pH-dependent enteric coating layer mixed therein. As taught, tablets and multiparticulates whereintampering is reduced or these polymer coatings are soluble in aqueous or organic eliminated through a synchronized barrier mechanism; solvents which would make the dosage form susceptible wherein the detrimental effects of overdosing is minimized or abuse by extraction. eliminated through the interaction between the dosage form 0020 U.S. Patent Application Publication 2011/0020451 and the contents of the gastrointestinal fluid which limits drug describes a tamper-resistant thermoformed pharmaceutical availability for absorption; wherein the dosage forms com dosage form having a breaking strength of at least 300 N and prise template formulations where one therapeutic agent is comprising an opioid, a physiologically acceptable acid and a Substituted for another in a given formulation without altering polyalkylene oxide. The disclosed dosage form is expected to the dissolution profiles or tamper-resistant properties of the be susceptible to abuse by chewing and Swallowing. dosage form; wherein the chemical and physical stability of 0021 U.S. Patent Application Publication 2012/0148672 the therapeutic agent and the physical stability of the dosage describes a coated modified release opioid-ion exchange form is assured resin complex comprising a pharmaceutically effective amount of an opioid bound to a pharmaceutically acceptable BRIEF DESCRIPTION OF THE DRAWINGS ion exchange resin complex; and a pH-independent, high tensile strength, water permeable, water insoluble, diffusion 0028 FIG. 1 shows a schematic drug release mechanism barrier coating. As disclosed, the coating is expected to dis of tamper resistant dosage forms. Solve in organic solvents and high aqueous pH, which would (0029 FIG. 2a shows extraction of Coffee grinder milled make the dosage form reduce extraction by the complexing tablets after 15 minutes. ion exchange resin only. 0030 FIG. 2b shows extraction of Coffee grinder milled 0022. As a result, in spite of the various tamper-resistant tablets after 60 minutes. formulation approaches mentioned above, there is still a need 0031 FIG.3 shows dissolution profiles of tamper resistant for improved abuse deterrent formulations that better prevent tablets. common methods of dosage form tampering and associated drug abuse administration routes with or without the incor 0032 FIG. 4 shows dissolution profiles of three different poration of aversive agents and agonist/antagonists in the therapeutic agents in the same template tamper resistant tab dosage form. let formulation. 0023. In contrast, the present invention eliminates or 0033 FIG. 5 shows dissolution profiles of tamper resistant reduces all forms of tampering, and hence all modes of abuse. multiparticulates compressed in tablets. US 2015/OO64251 A1 Mar. 5, 2015

DETAILED DESCRIPTION OF THE INVENTION a controlled rate to generate a heavy Suspension. The Suspen sion is collected, dried in a drying oven and stored for further 0034. An embodiment of the invention is an erodible processing. tamper-resistant dosage form that is resistant to various tam 0039. The ratio of the therapeutic agent to the substrate in pering modes. The tamper-resistant dosage form comprises a the complex is from 1:50 to 50:1 by weight, preferably 1:20 to therapeutic agent-substrate complex embedded in a thermo 20:1 and more preferably, from 1:10 to 10:1. The average formable matrix. It has been discovered that a therapeutic particle size distribution of the substrate is less than 500 u agent-substrate complex embedded into a thermo-formable (micron), preferably less than 250 u and more preferably, less matrix is effective againstall forms of product tampering and than 75 u. drug abuse without the use of aversion agents and antagonists. 0040 Alternatively, the complex may be prepared by a A complex of the therapeutic agent and a Substrate is formed variety of processes known in the art. first prior to incorporation into the thermo-formable matrix in 0041 Embedding Therapeutic Agent-Substrate Complex order for the formulation to provide tamper-resistance. While within Thermo Formable Matrix: pre-formation of the complex is preferred for optimal perfor 0042. The therapeutic agent-substrate complex is blended mance, in Some cases, particularly with inorganic additives, with at least one cellulosic thermoplastic polymerand option the drug-Substrate association could occur in situ during pro ally at least one non-cellulosic thermoplastic polymer, or at cessing. Alternatively, a prodrug, which is comprised of a least one pharmaceutical additive, or both, and the blend melt covalently bonded drug with an organic moiety, is embedded granulated at processing temperatures of less than 175° C. in the erodible thermo-formable matrix in place of the thera and preferably less than 150° C. using a twin-screw extruder. peutic agent-substrate complex. Alternatively, a blend of the thermoplastic polymers and 0035. According to the disclosure, a “therapeutic agent' optionally at least one pharmaceutical additive is fed into the means a Substance that elicits a pharmacologic response extruder through the first powder feed port and allowed to when administered by a patient or drug abuser. “Therapeutic melt before the therapeutic agent-substrate complex is intro agent” and “drug are used interchangeably. “Substrate' duced through a second powder feed port downstream from means a Substance that interacts with the therapeutic agent to the first feed port and mixed with the molten mass in the form a complex. "Complex’ means a chemical association of extruder. In both procedures, the melt granulated material or a drug Substance with a Substrate through ionic bonds, polar extrudate is shaped downstream to provide tamper-resistant covalent bonds, covalent bonds, and hydrogen bonds. A "pro tablets or multiparticulates that are filled into capsules or drug is substance that converts into an active form through compressed into tablets. The ratio of the therapeutic agent enzymatic cleavage when ingested, and considered a com substrate complex to the thermo-formable matrix varies, by plex according to the disclosure. A "pharmaceutical additive' weight, from 1:20 to 20:1, and preferably from 1:10 to 10:1, is a Substance that is added to formulations to improve func and more preferably from 1:5: to 5:1. tionality and processability of the dosage forms. A “thermo 0043. The tamper-resistant dosage form of the present plastic' polymer is a polymer that is solid at room tempera invention can be prepared according to the steps of: ture, and becomes pliable and moldable at elevated 0044 (1) Blending at least one therapeutic agent and at temperatures. “Tampering means an intentional or an unin least one substrate in a drug-to-substrate ratio from between tentional manipulation of dosage forms in a manner that is not 1:20 to 20:1 by weight; intended for by dosing instructions, such as by chewing, 0045 (2) Reacting the at least one therapeutic agent and crushing, grinding, extraction and Volatilization. the at least one substrate to formatherapeutic agent-substrate 0036 Preparation of the Therapeutic Agent-Substrate complex using a reactive extrusion process; Complex: 0046 (3) Forming a thermo-formable matrix blend with at least one cellulosic thermoplastic polymer and optionally at 0037. The therapeutic agent-substrate complex is pre least one non-cellulosic thermoplastic polymer, and at least pared using a novel reactive extrusion process. The process is one pharmaceutical additive; fast and continuous and more efficient compared to other 0047 (4) Mixing the therapeutic agent-substrate complex commonly used processes. It allows the complexation pro and the thermo-formable matrix blendinaratio from between cess to proceed at a faster rate by providing flexibility in 1:10 to 10:1; processing temperatures and online incorporation of pH 0048 (5) Granulating the therapeutic agent-substrate modifiers and other additives that promote complex forma complex and the thermo-formable matrix blend to form the tion. As a result, the process has greater than 95% efficiency tamper-resistant dosage form in which the therapeutic agent in the degree of complexation, a factor that is critical when substrate complex is embedded in the thermo-formable considering the high cost of therapeutic agents. The extruder, matrix; and which behaves as a reactor, is preferably a twin screw 0049 (6) Shaping the tamper-resistant dosage form into extruder. It comprises uniquely assembled conveying and one of tablet form and multiparticulate form. mixing elements, and temperature controlled modular barrels 0050. The granulating step of (5) can be carried out by a that constitute a continuous reaction vessel. Along the hot melt extrusion process, or optionally by a wet granulation extruder length, one or more liquid injection and powder feed process or a dry granulation process. ports are inserted in the barrels, wherein the number and 0051. The thermo-formable matrix imparts plasticity and location of the ports are dictated by the complexation process hardness to the dosage form. Embedding the drug-substrate requirements. complex in the thermo-formable matrix produces a synergis 0038. During the complexation process, the drug and sub tic effect that renders the dosage form more resistant to tam strate are pre-blended and the blend introduced into the pering while releasing the therapeutic agent in a controlled extruder through a powder feed port. At a second port down manner. If only the therapeutic agent-substrate is used with stream from the first feed port, an aqueous liquid is added at out the thermo-formable matrix during the preparation of US 2015/OO64251 A1 Mar. 5, 2015

extended release dosage forms, or if the therapeutic agent is dihomo-Y-linoleic acid, docesenoic acid, docosatetraenoic dispersed in the thermo-formable matrix without a substrate, acid, docosohexaconic acid, docosopentanoic acid, eicosap or if only a blend of the therapeutic agent and the substrate but entanoic acid, gondoic acid, lauric acid, linoleic acid, C-li not a complex is dispersed in the thermo-formable matrix the noleic acid, 6-linoleic acid, myristic acid, nervonic acid, oleic formulations do not exhibit both tamper-resistant and acid, oleoStearic acid, palmitic acid, palmitoleic acid, Stearic extended release properties. acid, and vaccenic acid and mixtures thereof. 0052 According to the disclosure, cellulosic thermoplas 0061. In another embodiment, the thermo-formable tic polymers comprise, but not limited to, hydroxylpropyl matrix comprises prodrugs consisting of for example, from cellulose, hydroxylpropyl methylcellulose, hydroxyethyl the group but not limited to amides and esters of therapeutic cellulose, and methylcellulose cellulose; and non-cellulosic agents. thermoplastic polymers comprise, but not limited to, polyvi 0062. In another embodiment, the thermo-formable nyl pyrrolidone, polyvinyl acetate polyvinyl alcohol, butyl/ matrix comprises pharmaceutical additives consisting of methyl methacrylate-dimethylaminoethylmethacrylate plasticizers, waxes, Surfactants, inorganic fillers, anti-adher copolymer, polyethylene glycol, polyethylene oxide, ents, erosion enhancers, and optionally, stabilizers. polypropylene glycol and polyvinyl caprolactam-polyvinyl 0063 Examples of plasticizers include, but not limited to, acetate-polyethylene glycol. dibutyl sebacate, glycerol, polyethylene glycol, propylene 0053. In one embodiment, the thermo-formable matrix glycol, triacetin, tributyl citrate, and triethylcitrate and mix comprises at least hydroxypropyl cellulose wherein the tures thereof. molecular weight is from 80,000 g/mol to 1,150,000 g/mol. 0064. Examples of waxes include, but not limited to, bees 0054. In another embodiment, the thermo-formable wax, candilila wax, carnuba wax, and paraffin wax and mix matrix comprises at least polyvinyl caprolactam-polyvinyl tures thereof. acetate-polyethylene glycol copolymer, wherein the molecu 0065. Examples of surfactants include, but not limited to, lar weight is 118,000 g/mol. alkyl sulfones, alkyl sulfates, ether carboxylates, 0055. The yet another embodiment, the thermo-formable glycerol/propylene glycol fatty acid esters, hexadecyl triam matrix comprises one or more Substrates, including polyelec monium , hydroxylated lecithin, lauryl carnitine, trolytes, inorganic adsorbents, inclusion compounds and fatty lower alcohol-fatty acid esters, mono-fai-glycerides, acids. Ovothin R, polyethylene glycol alkyl ethers, polyethylene 0056. In one aspect, substrates comprising polyelectro glycol-fatty acid monoesters, polyethylene glycol-fatty acid lytes are selected, for example, from the group consisting of diesters, polyethylene glycol-glycerol esters, polyethylene nucleic acids, poly (L-lysine), poly (L-glutamic acid), carra glycol , polyethylene glycol-sorbitan fatty acid esters, geenan, alginates, and hyaluronic acid, pectin, chitosan polyglyceride fatty acids, polyoxyethylene-polyoxypropy (deacetylation of chitin), cellulose-based, starch-based and lene block copolymers, propylene glycol-fatty acid esters, dextran-based polymers poly(vinylbenzyl trialkyl ammo Sodium cholate, Sodium lauryl Sulfate, Sodium palmitate, nium), poly(4-vinyl-N-alkyl-pyridimiun), poly(acryloyl Sodium taurocholate, Sorbitan-fatty acid esters, sterol and oxyalkyl-trialkyl ammonium), poly(acryamido-alkyl-trialkyl sterol derivatives, Sugar esters, transesterification products of ammonium), poly(dially dimethyl-ammonium), poly(acrylic oils and and mixtures thereof. or methacrylic acid), and poly(itaconic acid) and maleic acid/ 0.066 Examples of inorganic fillers include, but not lim diallyamine copolymer, crosslinked copolymers such as car ited to silicon dioxide, aluminum silicate, attapulgite, bento bopols, crosscarmellose, ion exchange resins and mixtures nite, calcium silicate, calcium carbonate, dicalcium phos thereof. phate, kaolin, lithium magnesium aluminum silicate, lithium 0057 Examples of ion exchange resins include sulfonated magnesium silicate, lithium magnesium Sodium silicate, copolymer of styrene and divinylbenzene, a carboxylate magnesium silicate, magnesium trisilicate, montmorillonite, copolymer of styrene and divinylbenzene, a copolymer of pyrophyllite, Sodium magnesium silicate, talc, titanium diox styrene and divinylbenzene containing quaternary ammo ide, Zeolite, and Zirconium silicate, and mixtures thereof. nium groups such as Amberlite(R) IR-120, Amberlite(R) 0067 Examples of anti-adherents include, but not limited XE-69, Amberlite RIRP-64/69, DoweX(R) 50WX2, DoweX(R) to, calcium carbonate, dicalcium phosphate, kaolin, talc, and 5OWX4, DoweX(R)5OWX8, fDuolite RAP 143, Indion(R) 204, titanium dioxide, and mixtures thereof. Indion(R) 214, Indion(R) 234, Indion(R) 264, Tulsion(R) 335, 0068 Examples of erosion enhancers include, but not lim Tulsion(R) 339, and Tulsion R 343 and mixtures thereof. ited to, hydroxyethyl cellulose, hydroxypropyl methyl cellu 0.058. In another aspect, Substrates comprising inorganic lose, polyvinyl pyrrolidone; mannitol, malitol, Sorbitol, Xyly adsorbents are selected, for example, from the group consist tol, sodium lauryl sulfate, Chremophor and Polysorbate 80, ing of but not limited to aluminum silicate, attapulgite, ben and mixtures thereof. tonite, calcium silicate, kaolin, lithium magnesium aluminum 0069. Examples of stabilizers include, but not limited to, silicate, lithium magnesium silicate, lithium magnesium butylhydroxytoulene, butylhydroxyanisole, propyl gallate, Sodium silicate, magnesium silicate, magnesium trisilicate, ascorbic acid, vitamin E-TPGS, phosphates, citrates, montmorillonite, pyrophyllite, sodium magnesium silicate, acetates, oxides and carbonates, and mixtures thereof. Zeolite, and Zirconium silicate and mixtures thereof. 0070. In another embodiment, the tamper-resistant dosage 0059. In yet another aspect, substrates comprising inclu form comprises therapeutic agents that are susceptible to sion compounds are selected, for example, from the group abuse, i.e. “abuse-prone, and those that are not. consisting of but not limited to C-cyclodextrins, B-cyclodex 0071. In one aspect, abuse-prone therapeutic agents com trins and Y-cyclodextrins. prise, but not limited to, alfenatil, allylprodine, alphaprodine, 0060. In yet another aspect, substrates comprising fatty anileridine, apomorphine, apocodeine, benzylmorphine, ben acids are selected from the group, for example, consisting of Zitramide, buprenorphine, butorphanol, clonitraZene, but not limited to arachidonic acid, capric acid, caprylic acid, codeine, codeine methylbromide, codeine phosphate, US 2015/OO64251 A1 Mar. 5, 2015

codeine Sulfate, cyclazocine, cyclorphen, cyprenorphine, anabolic steroids such as androisoxazole, androstenediol. desmorphine, dextromethorphan, dextromoramide, dezo bolandiol, clostebol, ethylesternol, formyldienolone, 4-hy cine, diamromide, dihydrocodeine, dihydrocodeinone, dihy droxy-19-nortestosterone, methandriol, methenolone, meth dromorphine, dimenoxadol, dimepheptanol, dimethylthiam yltrienolone, nandrolone, nandrolone deconate, nandrolone , dioxyaphetyl butyrate, diplpanone, eptazocine, p-hexyloxyphenylpropionate, nandrolone phenpropionate, ethoheptazine, ethylmethylthiambutene, ethylmorphine, eto norbolethone, oxymestrone, pizotyline, quinbolone, Sten nitaZene, fentanyl, hydrocodone, hydrocodone , bolone and trenbolone; anorexics such as aminorex, amphe hydroxymethylmorphinan, hydromorphone, hydroxypethi cloral, benzaphetamine, chlorphentermine, clobenzorex, clo forex, clortermine, cyclexedrine, diethylpropion, dine, isomethadone, ketobemidone, levallorphan, levorpha diphemethoxidine, n-ethylamphetamine, fenbutrazate, fen nol, levophenacylmorphan, lofentanil, meperidine, meptazi fluramine, fenproporex, furfurylmethylamphetamine, nol, metazocine, methadone, methylmorphine, metopon, levophacetoperate, mazindol, mefenorex, metamfeproa , morphine derivatives, myrophine, nalbuphine, mone, norpseudoephedrine, phendimetrazine, phendimetra narceline, nicomorphine, norlevorphanol, normethadone, Zine trtrate, phentermine, phenylpropanolamine hydrochlo nalorphine, normorphine, norpipanol, ohmefentanyl, opium, ride, picilorex, pseudoephedrine, ephedrine, levo oxycodone, oxymorphone, papaverum, pentazocine, phen methamphetamine, phenylpropanolamine, propylhexedrine adoxone, phenomorphan, phenazocine, phenoperidine, pheo peridine, pholcodine, piminodine, piritramide, prophep and Synephrine. tazine, promedol, profadol, properidine, propiram, 0072. In another aspect, therapeutic agents that are not propoxyphene, remifentanyl, Sufentanyl, tramadol, tilidine, Susceptible to abuse comprise, but not limited to, atenolol. maltrexone, naloxone, nalmefene, methylmaltrexone, nalox albendazole, alendronate, alprostadil, allopurinol, amlex one methiodide, naloxonazine, trindole, naltrindole isothio anoX, anagrelide, aminophylline, alitretinoin, amodiaquine, cyanate, naltriben, norbinaltorphimine, funaltrexmine, and astemizole, atovaquone, aztreonam, atorvastatin, azlocillin, salts or esters of any of the opioids, acecabromal, bomisov , benazepril, benzonatate, bitolterol mesylate, bro alum, capruide, cabromal, ectylurea, chlorhexadol, eth mpheniramine, cabergoline, , celecoxib, cefpira cholorvynol, meparfynol, 4-methyl-5-thiazolethanol, tetrap mide, chlorothiazide, , cimetidine, cetirizine, entylalcohol, butoctamide, diethylbromoacetamide, cefotaxime, ciprofloxacin, cephalexin, chloroquine, clo ibrotamide, isovarleryl diethylamide, , triaceta mocycline, cyclobenzaprine, , cyprohepta mide, trimetozine, , ; barbituric acid dine, cefimenoxime, cyclophosphamide, ciclopiroX, cladrib derivatives such as , , , ine, chlorpheniramine, chlorZoxazone, clemastine, , brallabarbital, sodium, butabarbital, clofarabine, cytarabine, dacarbazine, dantrolene, daunorubi , buthetal, , , cyclopento cin, dexamethasone, diclofenac, diethylcarbamazine, barbital, enallylpropymal, 5-ethyl-5-(1-piperidyl)barbituric diphenhydramine, diphenylpyraline, disopyramide, dilt acid, 5-furfuryl-5-isopropylbarbituric acid, heptabarbital, iazem, dopamine, dolfetilide, doxazosin, enoxacin, epirubi sodium, , mephobarbital, , cin, eplerenone, erlotinib, ertapenem, etoposide, exemestane, , , sodium, phenallyl eZetimibe, fexofenadine, flucloxacillin, fulvestrant, fenofi mal, , phenobarbital sodium, phenylmethylbar brate, fenoprofen, fenoldopam, fluocinonide, flunisolide, bituric acid, , , proxibarbal, , fluorouracil, gefitinib, gemcitabine, grepafloxacin, guaifen sodium, thiopental, , , esin, halofantrine, ibuprofen, ibandronate, ipratropium, irino , , sodium, and , tecan, isosorbide mononitrate, ipratropium, , keto derivatives such as , , conazole, ketoprofen, ketorolac, levamisole, letrozole, , , , , dox levosimendan, levofloxacin, lovastatin, loratadine, lymecy efazepam, , , , halox cline, loracarbef, lisuride, meclofenamate, mefloquine, aZolam, , , , , meloxicam, , methylbromide, metolaZone, , , and ; Such as methyldopa, methdilazine, meduitazine, mitotane, mivacu amylcarbamate, , hexaprypymate, meparfynol rium, moxifloxacin, mometasone, midodrine, milrinone, , novonal and trichlorourethan; derivatives nabumetone, naproxen, nifedipine, nilutamide, nedocromil. Such as carbocloral, , chloral formamide, chlo omeprazole, olmesartan, oxaliplatin, oxamniquine; ral hydrate, chloralantipyrine, , pentaer orphenadrine, pantoprazole, pefloxacin, pentamidine, peni ithriol chloral and triclofilos; piperidinediones such as cillamine, pemetrexed, perhexiline, phenylbutaZone, pipo gluthemide, methylprylon, , taglutimide, thalido broman, piroXicam, propranolol, phentermine, phentola mide; quinazolone derivatives such as , mecloqua mine, piperacillin, piperazine, primaquine, piroxicam, none, and ; and others such as acetal, acetophe pivoxil, praziquantel, probenecid, porfimer, propafenone, none, aldol, ammonium Valerate, amphenidone, d-bornyl-a- prednisolone, proguanil, pyrimethamine, quinine, quinidine, bromoisovalerate, d-bornylisovalerate, calcium ranolazine, remikiren, rofecoxib, Salmeterol, Sulfanilamide, 2-ethylbutanoate, carfinate, C.-chlorolose, , Sulfadiazine, Suprofen, Sulfinpyrazone, tenoxicam, triam cypripedium, , etodroxizine, , fenadia terene, tolmetin, toremifene, tolaZoline, tamoxifen, tenipo Zole, homofenazine, hydrobromic acid, mecloxamine, side, theophylline, terbutaline, terfenadine, thioguanine, tol methyl Valerate, opium, , , propiom metin, trimetrexate, triprolidine, trovafloxacin, Verapamil, azine, rimaZafone, , Sulfomethylmethane, Valsartan, vinorelbine, valrubicin, Vincristine, Valdecoxib and , amphethamine, dextroamphethamine, levo mixtures thereof. amphetamine, methamphetamine, methylphenidate, phen 0073 Tamper-Resistant Dosage Form Properties: metrazine, modatinil, avafinil, armodafinil, and ampalimes; 0074 Tamper-resistance is achieved through a synchro cannabinoids such as tetrahydro-cannabinol, nabilone, ket nized barrier mechanism composed of mechanical, physical amine, tiletamine, dextromethorphan, ibogaine, dixocilpine; and chemical components. According to the disclosure, hard US 2015/OO64251 A1 Mar. 5, 2015 ness and plasticity is imparted onto the dosage form through lodged from the tablet and get Suspended in the dissolution a combination of thermal processing and the incorporation of medium or gastrointestinal fluid. Under Step 3, free drug (D) uniquely blended water-soluble and water-insoluble poly is released from the drug-substrate (DS) complexes into the mers and other pharmaceutical additives in the formulation. dissolution medium or gastrointestinal fluid through ionic As a result, the dosage form does not easily get plasticized displacement, enzymatic cleavage or pH effect. during chewing and mastication. It instead hydrates, forms a 0080 According to the invention, drug release from the thin gel layer and slowly erodes from the Surface upon chew tamper-resistant dosage form is controlled by (a) hardness of ing or mastication while keeping the core dry and hard with the dosage from which controls the rate of fluid penetration limited liquid penetration. Similarly, the dosage form resists into the core, (b) composition of the dosage form which crushing, breaking and grinding using commonly used tools controls the strength, hydration rate and dissolution of the gel and hence does not generate fine powders suitable for Snort layer, and (c) the decomplexation process in the dissolution ing. Even grinding using a coffee grinder only produces medium orgastrointestinal fluid. Such control as described in coarse particles that are not suitable for Snorting. Moreover, the present invention ensures that the dosage form would not even if the powders were suitable for snorting, which is not be susceptible to dose dumping or food effect as is frequently the case; the drug would not be available for absorption observed with dosage forms that rely exclusively on matrix through the lining of the nasal cavity due to the complex and control for release. the rigid matrix in the particles. I0081. In one embodiment, the tamper-resistant dosage 0075 Drug extraction from the dosage form is eliminated form according to the invention is resistant to abuse by chew or minimized through a synchronized barrier mechanism. ing. The dosage form cannot be chewed irrespective of the During the extraction process, the thermo-formable matrix bite force. It only erodes over time. The eroded material still generates a thin viscous gel layer on the Surface over the hard contains the drug-substrate complex “coated by the thermo and dry core of the dosage form, the thickness of which is formable matrix components which would in turn make the dictated by the type of extraction solvent employed. In all drug less available for absorption upon ingestion. Examples cases, however, the drug-substrate complex present at the of prescription drugs abused by Swallowing include: barbitu Solvated gel layer cannot diffuse out into the extraction rates such as phenobarbital and secobarbital; opioids such as medium due to its poor mobility within the gel layer. Even if morphine, codeine, fentanyl, methadone, oxycodone HCl, the thingel layer were to erode and releases the drug-substrate hydrocodone bitartrate, hydromorphone, oxymorphone, complex into the extraction medium, the drug which, is meperidine, propoxyphene and dextromethorphan; benzodi tightly bound to the complex, and in turn "coated” by the azepines such as diazepam and clonazepam, sleep medica thermoplastic polymer from the matrix, does not readily tions such as Zolpidem and ; and stimulants such as become available for extraction. This synchronized barrier amphetamine and methylphenidate. mechanism comprising physical, mechanical and chemical I0082 In another embodiment, the dosage form according components is a feature that differentiates the invention from to the invention is resistant to abuse by Snorting. Since the prior art. dosage form does not get reduced into fine powder, it does not 0076 Abusers often heat the dosage forms to vaporize the allow the abuser to administer the therapeutic agent intra drug for Smoking purposes. According to the invention, nasally to facilitate drug absorption through the lining of the vaporization of a drug from the dosage form is prevented nasal passages by Snorting. Even if the dosage from were through density and hardness of the dosage form, immobili Susceptible to produce fine powders upon pulverization, Zation of the drug within the drug-Substrate complex, and which is not the case, the therapeutic agent would still be immobilization of the drug-substrate complex within the tightly bound to the substrate and “coated by the thermo thermo-formable matrix. The drug-substrate complex has plastic polymer, and not become available for intra-nasal much lower vapor pressure than that of the free drug, and, as absorption. Examples of prescription drugs abused by Snort a result, requires much higher heat energy to liberate the free ing include: opioids Such as morphine, codeine, fentanyl. drug from the complex and the matrix, if the dosage form methadone, oxycodone HCl, hydrocodone bitartrate, hydro were thermally stable when exposed to elevated tempera morphone, oxymorphone, meperidine and propoxyphene; tures. However, it was discovered that excessive heating of sleep medications such as Zolpidem and Zaleplon; stimulants the dosage form leads to decomposition and charring of for Such as amphetamine and methylphenidate. mulation components which potentially liberate obnoxious I0083. In yet another embodiment, the dosage form accord fumes that the abuser may not tolerate. ing to the invention prevents abuse by injection. Extraction of 0077 Mechanism of Drug Release: the therapeutic agent using commonly used organic and 0078. Without limiting the scope of this invention, the household solvents with continuous agitation of the dosage mechanism of how a drug is released from the tamper-resis form for at least 8 hours in 30 mL or 200 mL extraction tant dosage form can be illustrated by FIG.1. According to the Volume leads to insignificant drug release. Similar results invention, the tamper-resistant dosage form and the mecha were obtained when the dosage form was milled in a coffee nism of release are applicable to either the tablet or the mul grinder and similarly tested for 15 minutes (as shown in FIG. tiparticulate forms of the drug. As shown in FIG. 1, a tablet 2A) and 60 minutes (as shown in FIG. 2B). Examples of may be represented by a plurality of drug-substrate (DS) prescription drugs abused by injection include: , complexes, including prodrugs, imbedded in a matrix. Such as phenobarbital and secobarbital; opioids such as mor 0079 Under Step 1, the tablet surface undergoes a hydra phine, codeine, fentanyl, methadone, oxycodone HCl, hydro tion process that leads to the formation of a gel layer when a codone bitartrate, hydromorphone, Oxymorphone, meperi tablet is immersed in a dissolution medium orgastrointestinal dine and propoxyphene; stimulants such as amphetamine and fluid. Under Step 2, erosion of the gel layer takes place, methylphenidate. leading to the release of the drug-substrate (DS) complexes. I0084. In yet another embodiment, the present invention At this stage, the drug-Substrate (DS) complexes are dis relates to a dosage form that prevents drug abuse by Smoking US 2015/OO64251 A1 Mar. 5, 2015

where the therapeutic agent needs to vaporize for inhalation 0090. In yet another embodiment, the invention relates a after exposure of the dosage form to heat. For example, the tamper-resistant dosage form comprising multi-particulates dosage form is placed on top of a spoon, and heated from that are compressed into tablets and release the therapeutic underneath using a cigarette lighter or high temperature agent from less than an hour up to 24 hours (FIG. 5). Multi acetylene torch to vaporize the therapeutic agent. Excessive particulates are blended with other tableting excipients and heating of the dosage form leads to decomposition and char compressed prior to dissolution testing. During dissolution, ring of formulation components. Examples of prescription the compressed tablets disintegrate in less than a minute to drugs abused by Smoking include: fentanyl and its analogs, regenerate the original multiparticulates which control the amphetamines, and morphine. release rate. 0085. In yet another embodiment, the present invention relates to a dosage form that prevents drug abuse by ingestion EXAMPLES of multiple tablets. The amount of drug released from mul tiple tablets in simulated gastrointestinal fluid relative to a 0091. The following examples are included to demon single unit is greatly reduced and is not dose proportional. It strate certain embodiments of the present invention and not is expected that the spike desired by abusers would not occur intended to be limiting. They are for illustrative purposes only when more units than required by dosing instructions are and it is to be noted that changes and variations can be made ingested by the abusers. without departing from the spirit and scope of the invention. I0086. In yet another embodiment, the present invention relates to formulations that provide multiple modified release Example 1 profiles. The profiles, which range from over 90% in 4 hours to greater than 90% in 24 hours (FIG. 3), demonstrate the Preparation of Drug-Substrate Complex flexibility of the formulations and the opportunity they pro vide during the development of dosage forms that satisfy the 0092. In this example, a general process for the prepara diverse pharmacokinetic requirements of therapeutic agents. tion of a drug-substrate complex is illustrated using an ion 0087. In yet another embodiment, the present invention exchange resin as a model Substrate. For example, a drug-ion relates to a dosage form that generates release rates that are exchange resin complex is prepared from a blend of the drug independent of therapeutic agents. That is, different therapeu and Amberlite IRP 69 (Sodium polystyrene sulfonate, manu tic agents incorporated in a given formulation provide the factured by Rohm Haas, Philadelphia, Pa., USA and supplied same release profiles. Such a Surprising discovery makes it by Dow Chemical Company, Midland, Mich., USA) using a possible to establish base formulations (templates) that would novel reactive extrusion process. A 16 mm twin-screw form the basis for the development of different products, extruder is used as a reactor, although larger size extruders thereby shortening development time (FIG. 4). could be used if the desired batch size is high. The drug and Amberlite IRP 69 are pre-blended and the blend introduced 0088. In yet another embodiment, the present invention into the extruder through a powder feed port. At a second port relates to a dosage form that increases the shelf life of prod downstream from the first feed port, deionized water is added ucts by eliminating or at least minimizing oxidative or hydro at a controlled rate to generate a heavy Suspension. The extru lytic decomposition of therapeutic agents. Many therapeutic sion process is carried out at a screw speed of 300 rpm and agents, including opioids, undergo oxidative or hydrolytic processing temperatures of 25° C. The Suspension is col degradation when exposed to acidic or alkaline aqueous envi lected, dried in a drying oven and stored for further process ronments or thermal stresses, or both. Moreover, some phar 1ng. maceutical additives. Such as polyethylene oxide, contain trace amounts of peroxides and promote oxidation of the 0093. Alternatively, the suspension is washed using deion therapeutic agent upon storage or during thermal processing, ized water to remove any free uncomplexed drug as is done and, as a result, anti-oxidants and buffering agents are rou with other methods known in the art. The supernatant is tinely added to formulations to prevent potential degradation decanted and discarded. The residue comprising a drug-ion of therapeutic agents through the shelf-life of the dosage exchange resin complex is then dried in a drying oven. forms. In the present invention, the formation and incorpora tion of the drug-substrate complex within the thermo-form Example 2 able matrix generally obviates the need for incorporating anti-oxidants and buffering agents in the dosage form, Propranolol Ion-Exchange Resin Complex Particles although incorporation of these agents is also possible in special cases. 0094. A formulation composed of a complex of a thera 0089. In yet another embodiment, the invention relates to peutic agent (propranolol), and a substrate (ion-exchange a tamper-resistant dosage form that ensures dissolution sta resin) only, without the incorporation ofathermoplastic poly bility and consequently the shelf-life of products. The disso mer, and hence a thermoformable matrix, was prepared. The lution stability of matrix-based dosage forms is dictated by propranolol ion exchange resin complex was prepared using the rate of migration of the drug molecules within the matrix the procedure described in Example 1. which in turn depends on the physical stability of the matrix and the properties of the drug Substance. Changes in the Dissolution Studies: physical stability of the matrix retards or accelerates the migration of the drug molecules, which in turn affect release 0095 Dissolution studies were conducted in 900 mL of rate. In contrast, according to the current invention, mobility pH 6.8 Phosphate buffer (0.05M) consisting of 0.2% sodium of the drug-substrate complex is restricted within the matrix, chloride using USP Apparatus II (Paddle) at 75 rpm. The thereby enhancing dissolution stability of the dosage form. dissolution data is given below: US 2015/OO64251 A1 Mar. 5, 2015

Dissolution Studies: Time % (h) Released (0099 Dissolution studies were conducted in pH 6.8 Phos O.25 78 phate buffer (0.05M) consisting of 0.2% sodium chloride O.S 89 using USP Apparatus II (Paddle) at 75 rpm. The tablets dis 1 96 integrated within 1 minute in the dissolution medium. The 2 98 dissolution data is given below:

Extraction Studies Time % (h) Released 0.096 Extraction studies were conducted in different sol O.25 41 vents using a wrist action shaker at a speed of 416 rpm and 18 O.S 69 angle. Samples were withdrawn at 15 minutes and 60 minutes 1 100 and the drug release was determined using a spectrophotom eter. The results are given below: Extraction Studies Released 0.100 Extraction studies were conducted in different sol Extraction 15 60 vents using a wrist action shaker at a speed of 416 rpm and 18° Solvent min min angle. Samples were withdrawn at 15 minutes and 60 minutes O.9% NaCl 3.4 3.6 and drug release determined using a spectrophotometer. The Solution results are given below: 0.4 O.S Water O.S 0.4 O.1NHCI 1.4 1.4 Ethanol 40% 0.4 0.4 O.1NNaOH 2.7 2.5 Released Ethanol 96% O.2 O.2 Isopropanol O.6 O.8 Extraction 15 60 Ethylacetate O.2 O.2 Solvent min min O.9% NaCl 62.6 94.2 solution Methanol 94.7 99.3 Example 3 Water 77.4 94.2 O.1NHCI 68.7 90.8 Ethanol 40% 42.4 85.9 Propranolol HCl Multiparticulates O.1NNaOH 4.3 S.O Ethanol.96% 42.8 80.7 0097. A formulation composed of a therapeutic agent Isopropanol 22.5 44.1 (propranolol), thermoplastic polymers (hydroxypropylcellu Ethylacetate 23.4 25.4 lose I and II) and a pharmaceutical additive (silicon dioxide) was prepared. Neither a substrate, nor a therapeutic agent Substrate complex was included in the formulation. 0098 Propranolol HCl (free drug), hydroxypropylcellu Example 4 lose (I), hydroxypropylcellulose(II) and silicon dioxide were blended, fed into a 16 mm twin screw extruder and extruded. Propranolol HCl and Ion-Exchange Resin The extrusion process was carried out at a processing tem Blend-Based Multiparticulates perature of 140° C. and a screw speed of 200 rpm. The extrudates were shaped into multiparticulates downstream. A 0101. A formulation composed of a therapeutic agent portion of the multiparticulates were mixed with external (propranolol), a substrate (Amberlite IRP 69), thermoplastic excipients and compressed into tablets. The tablets and the polymers (hydroxypropylcellulose I and II) and a pharmaceu remaining portion of multiparticulates were collected and tical additive (silicon dioxide) was prepared. The therapeutic stored in high density polyethylene (HDPE) bottles. agent and the Substrate were incorporated in the formulation independently and not as a pre-formed complex.

% 0102 Propranolol HCl (free drug), Amberlite IRP 69 (un Ingredient ww complexed resin), hydroxypropylcellulose (I), hydroxypro Propranolol HCl 25 pylcellulose (II) and silicon dioxide were blended, fed into a Hydroxypropyl cellulose (I) 35.5 16 mm twin screw extruder and extruded. The extrusion pro (M.W. 370,000) cess was carried out at processing temperatures of 140° C. Hydroxypropyl cellulose (II) 35.5 and a screw speed of 200 rpm. The extrudates were shaped (M.W. 80,000) into multiparticulates downstream. A portion of the multipar Silicon dioxide 4 ticulates were mixed with external excipients and compressed Total 100 into tablets. The tablets and the remaining portion of the multiparticulates were collected and stored in high density polyethylene (HDPE) bottles. US 2015/OO64251 A1 Mar. 5, 2015

0106 Propranolol ion exchange complex, hydroxypropy % lcellulose (I), hydroxypropylcellulose(II) and silicon dioxide Ingredient ww were blended, fed into a 16 mm twin screw extruder and Propranolol HCl 25 extruded. The extrusion process was carried out at a process Amberlite IRP 69 (Ion-exchange 25 ing temperature of 140°C. and a screw speed of 200 rpm. The resin) extrudates were shaped into multiparticulates downstream. A Hydroxypropyl cellulose (I) 23 (M.W. 370,000) portion of the multiparticulates were mixed with external Hydroxypropyl cellulose (II) 23 excipients and compressed into tablets. The tablets and the (M.W. 80,000) remaining portion of multiparticulates were collected and Silicon dioxide 4 stored in high density polyethylene (HDPE) bottles. Total 1OO % Ingredient ww Dissolution Studies: Propranolol Ion Exchange 50 Resin Complex 0103 Dissolution studies were conducted in pH 6.8 Phos Hydroxypropyl cellulose (I) 23 phate buffer (0.05M) consisting of 0.2% sodium chloride (M.W. 370,000) Hydroxypropyl cellulose (II) 23 using USP Apparatus II (Paddle) at 75 rpm. The tablets dis (M.W. 80,000) integrated within 1 minute in the dissolution medium. The Silicon dioxide 4 dissolution data is given below: Total 100

Time % (h) Released Dissolution Studies: O.25 43 O.S 63 1 93 0107 Dissolution studies were conducted in pH 6.8 Phos 2 100 phate buffer (0.05M) consisting of 0.2% sodium chloride using USP Apparatus II (Paddle) at 75 rpm. The tablets dis integrated within 1 minute in the dissolution medium. The Extraction Studies dissolution data is given below: 0104 Extraction studies were conducted on the multipar ticulates in different solvents using a wrist action shaker at a Time % speed of 416 rpm and 18° angle. Samples were withdrawn at (h) Released 15 minutes and 60 minutes and the drug release was deter mined using a spectrophotometer. The results are given below: 1 13 2 35 3 62 4 77

Released

Extraction 15 60 Solvent min min Extraction Studies

O.9% NaCl 45.6 58.3 Solution 0.108 Extraction studies were conducted in different sol Methanol 75.4 77.6 vents using a wrist action shaker at a speed of 416 rpm and 18° Water 54.5 57.2 angle. Samples were withdrawn at 15 minutes and 60 minutes O.1NHCI 41.2 40.6 and the drug release was determined using a spectrophotom Ethanol 40% 44.6 45.1 O.1NNaOH 5.7 5.4 eter. The results are given below: Ethanol 96% 64.8 69.5 Isopropanol 36.4 55.2 Ethylacetate 9.3 12.3 Released

Extraction 15 60 Example 5 Solvent min min O.9% NaCl 3.1 4.5 Propranolol Ion-Exchange Resin Complex-Based solution Multiparticulates Methanol 2.3 2.6 Water O.9 3.4 O.1NHCI 1.5 2.1 0105. A formulation composed of a therapeutic agent Ethanol 40% 1.O 1.1 substrate complex (Propranolol-Amberlite IRP 69 complex), O.1NNaOH 5.5 5.7 thermoplastic polymers (hydroxypropylcellulose I and II) Ethanol.96% 1.9 S.O and a pharmaceutical additive (silicon dioxide) was prepared. US 2015/OO64251 A1 Mar. 5, 2015

-continued Intact Tablets % Released % Released Extraction 15 60 Solvent min min Extraction 15 60 Solvent min min Isopropanol 1.O 2.5 Ethylacetate 0.7 1.2 Methanol 1.2 2.3 Water O.2 O.3 O.1NHCI 1.7 2.7 Ethanola.0% O.S 0.7 O.1NNaOH 6.9 6.2 Example 6 Ethanol.96% 0.7 1.5 Isopropanol O.3 O6 Dextromethorphan-Ion Exchange Resin Ethylacetate O.3 0.7 Complex-Based Tablets 0109. A mixture of Dextromethorphanion exchange resin Example 7 complex, hydroxypropylcellulose (I), hydroxypropylcellu lose (II) and polyethylene glycol were blended and fed into a 16 mm twin screw extruder and extruded at extrusion tem Propranolol Tablet Formulations Manufactured by peratures of 100° C. and a screw speed of 200 rpm. The Dry Granulation extrudate was shaped into tablets downstream. The tablets 0112 A mixture of Propranolol ion exchange resin com were collected and stored in high density polyethylene plex, hydroxypropyl methyl cellulose K10OM CR (I), Lac (HDPE) bottles. tose, PVP K30 and stearic acid were blended, dry granulated, milled and compressed. Tablets were collected and stored in high density polyethylene (HDPE) bottles. % Ingredient ww Dextromethorphan Ion Exchange Resin 50 % Complex Ingredient ww Hydroxypropyl cellulose (I) (M.W. 26.25 370,000) Propranolol Ion Exchange Resin 50 Hydroxypropylcellulose (II) (M.W. 8.75 Complex 80,000) Hydroxypropylmethyl cellulose 30 Polyethylene glycol (M.W. 400) 15 K1 OOM CR Lactose 10 Total 1OO PVPK30 9.5 Stearic acid O.S

Total Dissolution Studies:

0110 Dissolution studies were conducted in pH 6.8 Phos Dissolution Studies: phate buffer (0.05M) consisting of 0.2% sodium chloride using USP Apparatus I (basket) at 100 rpm. The dissolution 0113 Dissolution studies were conducted using USP data is given below: Apparatus II (Paddle) at 100 rpm in pH 6.8 Phosphate buffer (0.05M) consisting of 0.2% sodium chloride. The dissolution data is given below Time % (h) Released 1 7 Time % 2 15 (h) Released 3 21 O O 4 28 1 11 5 34 2 2O 6 40 3 27 7 45 4 33 8 49 5 38 6 45 7 51 8 56 Extraction Studies 0111 Extraction studies were conducted in different sol 0114 Extraction studies were conducted in different sol vents using a wrist action shaker at a speed of 416 rpm and 18 vents using a wrist action shaker at a speed of 416 rpm and 18° angle. Samples were withdrawn at 15 minutes and 60 min angle. Samples were withdrawn at 15 minutes and 60 minutes utes, and the drug release was determined using a UV-spec and the drug release was determined using a spectrophotom trophotometer. The results are given below: eter. The results are given below: US 2015/OO64251 A1 Mar. 5, 2015 11

% % Released Released Extraction 15 60 Extraction 15 60 Solvent min min Solvent min min Methanol 8.2 9.5 Methanol 3.0 3.2 O.1NHCI 3.5 4.4 O.1NNaOH 7.9 15.4 O.1NHCI 2.9 3.1 Ethylacetate 2.2 3.2 O.1NNaOH 6.7 8.0 Ethylacetate 1.1 1.8 0118. Examples 2-4 demonstrate that a pre-formed thera peutic agent-Substrate complex embedded into the hard, erod ible, thermo-formable matrix is critical to generate a dosage Example 8 form that is tamper-resistant and provides programmed extended release profiles. Examples 5 and 6 show that target dissolution profiles and tamper-resistance can be achieved Propranolol Tablet Formulations Manufactured by whether the dosage form comprises tablets or multiparticu Wet Granulation lates, very Surprising results not taught in the prior art. Examples 7 and 8 demonstrate that a variety of dissolution 0115. A mixture of Propranolol ion exchange resin com profiles with excellent tamper-resistance can be obtained plex, hydroxypropylmethyl cellulose LVCR CR (I), and consistently by a dry granulation process or a wet granulation Polyethylen oxide, PVP K30 were blended and wet granu process as long as the therapeutic agent-Substrate complex is lated. The granulation was dried in forced air oven at 40°C. embedded within the thermo-formable matrix. overnight and delumped by passing through a screen. The What is claimed is: milled granulation was then compressed in to appropriate 1. A tamper resistant dosage form composition, compris tablet size. Tablets were collected and stored in high density ing: a therapeutic agent-substrate complex prepared by an polyethylene (HDPE) bottles. extrusion process. 2. The dosage form of claim 1, wherein the weight ratio of the therapeutic agent to substrate of the therapeutic agent % substrate complex is from between 1:20 and 20:1. Ingredient ww 3. A tamper resistant dosage form composition, comprising Propranolol Ion Exchange Resin 50 a therapeutic agent-substrate complex; said therapeutic Complex agent-substrate complex is embedded in an erodible thermo Hydroxypropylmethyl cellulose LV CR 40 formable matrix prepared by a granulation process. Polyethylenoxide (M.W. 200,000) 10 4. The dosage form of claim3, wherein the weight ratio of Total 1OO the therapeutic agent-substrate complex to the erodible thermo-formable matrix is from between 1:10 to 10:1. 5. The dosage form of claim 3, wherein the therapeutic agent-substrate and a free substrate is embedded in the erod Dissolution Studies: ible thermo-formable by the granulation process. 6. The tamper resistant dosage form composition, compris 0116 Dissolution studies were conducted using USP ing an erodible thermo-formable matrix comprising at least Apparatus II (Paddle) at 100 rpm in pH 6.8 Phosphate buffer one cellulosic thermoplastic polymer and optionally at least (0.05M) consisting of 0.2% sodium chloride. The dissolution one non-cellulosic thermoplastic polymer and at least one data is given below: pharmaceutical additive. 7. The tamper resistant dosage form of claim 6, wherein the amount of the pharmaceutical additives in the thermo-form Time % able matrix is less than 20% by weight. (h) Released 8. The tamper resistant dosage form composition, compris O O ing: monolithic tablets and multiparticulates comprising a 1 6 therapeutic agent-substrate complex embedded in an erodible 2 14 thermo-formable matrix, wherein the dosage form is resistant 3 22 to tampering through a synchronized barrier mechanism. 4 31 5 44 9. The tamper resistant dosage form composition, compris 6 55 ing: monolithic tablets and multiparticulates comprising a 7 71 therapeutic agent-substrate complex embedded in an erodible 8 82 thermo-formable matrix, wherein the release mechanism eliminates or reduces the effect of intentional or unintentional dosing of multiple tablets. 0117 Extraction studies were conducted in different sol 10. The tamper resistant dosage form composition, com vents using a wrist action shaker at a speed of 416 rpm and 18 prising: monolithic tablets and multiparticulates comprising angle. Samples were withdrawn at 15 minutes and 60 minutes a therapeutic agent-substrate embedded in an erodible and the drug release was determined using a spectrophotom thermo-formable matrix, wherein said dosage forms com eter. The results are given below: prise drug independent template formulations. US 2015/OO64251 A1 Mar. 5, 2015

11. The tamper resistant dosage form composition, com codone, pentazocine, naloxone, noltrexone, alprazolam, prising: monolithic tablets and multiparticulates comprising Zopiclone, amphetamine, methylphenidate, dextromethor a therapeutic agent-substrate complex embedded in an erod phan, ephedrine, pseudoephedrine, chlorpheniramine, pro ible thermo-formable matrix wherein the formulations impart pranolol, Verapamil, , albuterol and acceptable salts physical and chemical stability on to dosage form. thereof. 12. The tamper resistant dosage form composition, com 28. The dosage form in claim 1 wherein the substrate is prising: monolithic tablets and multiparticulates comprising selected from the group consisting of a polyelectrolyte, a fatty a therapeutic agent-substrate complex embedded in an erod acid, an inorganic adsorbent and an inclusion compound. ible thermo-formable matrix wherein the release profiles 29. The dosage form in claim 1 wherein reactive extrusion extend from one hour to 24 hours. is carried out in a twin screw extruder under controlled con 13. The dosage form in claim 1 wherein the extrusion ditions of temperature, pressure and pH. process comprises a reactive extrusion process wherein the 30. The dosage form in claim 3, wherein the melt granula therapeutic agent and the Substrate interact to form the com tion is carried out in a twin screw extruder at processing plex. temperatures below 150° C. 14. The dosage form in claim 13 wherein the substrate has 31. The dosage form in claim 28 wherein the polyelectro an average particle size distribution is from 5 u up to 250 u. lyte is selected from the group consisting of nucleic acids, 15. The dosage form in claim 3 wherein the granulation poly (L-lysine), poly (L-glutamic acid), carrageenan, algi process comprises melt granulation, wet granulation and dry nates, hyaluronic acid, pectin, chitosan (deacetylation of granulation. chitin), cellulose-based, starch-based, dextran-based poly 16. The dosage form in claim 6 wherein the cellulosic mers, poly (vinylbenzyl trialkyl ammonium), poly (4-vinyl thermoplastic polymer comprises hydroxylpropyl cellulose, N-alkyl-pyridimiun), poly (acryloyl-oxyalkyl-trialkyl hydroxylpropyl methylcellulose, hydroxyethyl cellulose, and ammonium), poly (acryamidoalkyl-trialkyl ammonium), methylcellulose. poly (dially dimethyl-ammonium), poly (acrylic or meth 17. The dosage form in claim 6 wherein the non-cellulosic acrylic acid), and poly (itaconic acid) and maleic acid/dial thermoplastic polymer comprises polyvinyl pyrrolidone, lyamine copolymer, carbopols, crosscarmellose, and ion polyvinyl acetate polyvinyl alcohol, butyl/methyl methacry exchange resin. late-dimethylaminoethylmethacrylate copolymer, polyethyl 32. The dosage form in claim 30 wherein the ion exchange ene glycol, polyethylene oxide, polypropylene glycol and resin is selected from the group consisting of a Sulfonated polyvinyl caprolactam-polyvinyl acetate-polyethylene gly copolymer of styrene and divinylbenzene, a carboxylate col. copolymer of styrene and divinylbenzene, a copolymer of 18. The dosage form in claim 6 wherein the at least one styrene and divinylbenzene containing quaternary ammo pharmaceutical additives are selected from the group consist nium groups. ing of a plasticizer, a wax, a Surfactant, inorganic filler, an 33. The dosage form in claim 28 wherein the fatty acid is anti-adherent, an erosion enhancer, a stabilizer, and mixtures selected from the group consisting of arachidonic acid, capric thereof. acid, caprylic acid, dihomo-y-linoleic acid, docesenoic acid, 19. The dosage form in claim 1 further comprising a syn docosatetraenoic acid, docosohexaconic acid, docosopen chronized barrier mechanism comprising physical, mechani tanoic acid, eicosapentanoic acid, gondoic acid, lauric acid, cal and chemical components. linoleic acid, C.-linoleic acid, 6-linoleic acid, myristic acid, 20. The dosage form in claim 20 wherein the synchronized nervonic acid, oleic acid, oleoStearic acid, palmitic acid, barrier provides resistance to chewing, crushing, milling, palmitoleic acid, Stearic acid, vaccenic acid and mixtures extraction or vaporization. thereof. 21. The dosage form in claim 19 wherein the synchronized 34. The dosage form in claim 28 wherein the inorganic barrier prevents drug abuse by Swallowing, Snorting, injec adsorbent is selected from the group consisting of silicon tion or Smoking. dioxide, aluminum silicate, attapulgite, bentonite, calcium 22. The dosage form in claim 1 wherein a release mecha silicate, kaolin, lithium magnesium aluminum silicate, nism reduces or eliminates the undesirable effects of Swal lithium magnesium silicate, lithium magnesium Sodium sili lowing multiple dosage forms in a manner not intended by the cate, magnesium silicate, magnesium trisilicate, montmoril dosing instructions. lonite, pyrophyllite, sodium magnesium silicate, Zeolite, and 23. The dosage form in claim 1 wherein a drug independent Zirconium silicate and mixtures thereof. template formulations comprise formulations that permit 35. The dosage form in claim 28 wherein the inclusion substitution of one therapeutic agent for another without compound is selected from the group consisting of C-cyclo altering dissolution profiles and tampering properties. dextrin, B-cyclodextrin and Y-cyclodextrin. 24. The dosage form in claim 3, wherein physical and 36. The dosage form in claim 18, wherein the plasticizer is chemical stability of the therapeutic agent and physical sta selected from the group consisting of dibutyl sebacate, glyc bility of the matrix is achieved by a combination of the thera erol, polyethylene glycol, propylene glycol, triacetin, tributyl peutic agent-substrate complex and the rigid, erodible citrate, and triethyl citrate and mixtures thereof. thermo-formable matrix. 37. The dosage form in claim 18, wherein the wax is 25. The dosage form in claim 1, wherein the tablets release selected from the group consisting of bee’s wax, candilila the therapeutic agent in 4 to 24 hours. wax, carnuba wax, and paraffin wax and mixtures thereof. 26. The dosage form in claim 1, wherein the multiparticu 38. The dosage form in claim 18, wherein the surfactant is lates release the therapeutic agent in 1 to 24 hours. selected from the group consisting of alkylbenzene Sulfones, 27. The dosage form in claim 1 wherein the therapeutic alkyl Sulfates, ether carboxylates, glycerol/propylene glycol agent is selected from the group consisting of morphine, fatty acid esters, hexadecyl triammonium bromide, hydroxy hydromorphone, oxymorphone, codeine, hydrocodone oxy latedlecithin, lauryl carnitine, lower alcohol-fatty acid esters, US 2015/OO64251 A1 Mar. 5, 2015

mono-fcdi-glycerides, Ovothin R, polyethylene glycol alkyl 42. The dosage form in claim 18, wherein the stabilizer is ethers, polyethylene glycol-fatty acid monoesters, polyethyl selected from the group consisting of butylhydroxytoulene, ene glycol-glycerol esters, polyethylene glycol phenols, butylhydroxyanisole, propyl gallate, ascorbic acid, Vitamin polyethylene glycol-sorbitan fatty acid esters, polyglyceride E-TPGS, phosphates, citrates, acetates, oxides, carbonates fatty acids, polyoxyethylene-polyoxypropylene block and mixtures thereof. copolymers, propylene glycol-fatty acid esters, sodium cho 43. A process for making a tamper resistant dosage form; late, Sodium lauryl Sulfate, Sodium palmitate, Sodium tauro the process comprising: cholate, Sorbitan-fatty acid esters, sterol and sterol deriva (1) blending at least one therapeutic agent and at least one tives, Sugar esters, and mixtures thereof. Substrate in a therapeutic agent-to-substrate ratio 39. The dosage form in claim 18, wherein the inorganic between 1:20 to 20:1 by weight; fillers is selected from the group consisting of aluminum (2) reacting the at least one therapeutic agent and the at silicate, attapulgite, bentonite, calcium silicate, kaolin, least one Substrate to form a therapeutic agent-substrate lithium magnesium aluminum silicate, lithium magnesium complex; silicate, lithium magnesium sodium silicate, magnesium sili (3) forming a thermo-formable matrix blend with at least cate, magnesium trisilicate, montmorillonite, pyrophyllite, one thermoplastic polymer and optionally at least one Sodium magnesium silicate, Zeolite, and Zirconium silicate pharmaceutical additive; and mixtures thereof. (4) mixing the therapeutic agent-substrate complex and the 40. The dosage form in claim 18, wherein the anti-adherent thermo-formable matrix blend in a ratio between 1:10 to is selected from the group consisting of calcium carbonate, 10:1 by weight; dicalcium phosphate, kaolin, talc, and titanium dioxide, and (5) granulating the therapeutic agent-Substrate complex mixtures thereof. and the thermo-formable matrix blend to form the 41. The dosage form in claim 18, wherein the erosion tamper-resistant dosage form in which the therapeutic enhancer is selected from the group consisting of hydrox agent-substrate complex is embedded in the thermo ypropyl cellulose, hydroxypropylmethyl cellulose, polyeth formable matrix; and ylene oxide, polyvinyl pyrollidone, mannitol, malitol, Sorbi (6) shaping the tamper-resistant dosage form into a tablet tol, xylitol, lactose, sodium laurylsulfate, Polysorbate 80, and and multiparticulates. chremophor and mixtures thereof. k k k k k