US 2014O105987A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0105987 A1 RARY et al. (43) Pub. Date: Apr. 17, 2014

(54) ABUSE-DETERRENT PHARMACEUTICAL 2002, provisional application No. 60/393,876, filed on COMPOSITIONS OF OPODS AND OTHER Jul. 5, 2002, provisional application No. 60/463,518, DRUGS filed on Apr. 15, 2003, provisional application No. 60/463,514, filed on Apr. 15, 2003, provisional appli (71) Applicant: COLLEGIUM PHARMACEUTICAL, cation No. 60/443,226, filed on Jan. 28, 2003, provi INC., CANTON, MA (US) sional application No. 60/436,523, filed on Dec. 23, 2002, provisional application No. 60/393,876, filed on (72) Inventors: Roman V. RARY, Allston, MA (US); Jul. 5, 2002. Alison B. FLEMING, North Attleboro, MA (US); Jane HIRSH, Wellesley, MA Publication Classification (US); Alexander M. KLIBANOV, Boston, MA (US) (51) Int. Cl. A647/46 (2006.01) (73) Assignee: COLLEGIUM PHARMACEUTICAL, A613 L/485 (2006.01) INC., CANTON, MA (US) A6II 45/06 (2006.01) A647/12 (2006.01) (21) Appl. No.: 14/054,513 (52) U.S. Cl. CPC ...... A61K 47/46 (2013.01); A61K 47/12 (22) Filed: Oct. 15, 2013 (2013.01); A61 K3I/485 (2013.01); A61 K 45/06 (2013.01) Related U.S. Application Data USPC ...... 424/490; 514/783; 424/400: 514/282 (60) Division of application No. 12/473,073, filed on May 27, 2009, now Pat. No. 8,557,291, which is a continu (57) ABSTRACT ation-in-part of application No. 1 1/149.867, filed on An abuse-deterrent pharmaceutical composition has been Jun. 10, 2005, now Pat. No. 7,771,707, said application developed to reduce the likelihood of improper administra No. 12/473,073 is a continuation-in-part of application tion of drugs, especially drugs such as opioids. In a preferred No. 12/112,993, filed on Apr. 30, 2008, now aban embodiment, a drug is modified to increase its lipophilicity. In doned, which is a division of application No. 10/614, some embodiments the modified drug is homogeneously dis 866, filed on Jul. 7, 2003, now Pat. No. 7,399,488, said persed within spherical microparticles composed of a mate application No. 12/473,073 is a continuation-in-part of rial that is either slowly soluble or not soluble in water. In application No. 12/112.937, filed on Apr. 30, 2008, Some embodiments the drug containing microparticles or which is a continuation-in-part of application No. drug particles are coated with one or more coating layers, 10/614.866, filed on Jul. 7, 2003, now Pat. No. 7,399, where at least one coating is water insoluble and/or organic 488. solvent insoluble. The abuse-deterrent composition retards (60) Provisional application No. 60/579,191, filed on Jun. the release of drug, even if the physical integrity of the for 12, 2004, provisional application No. 60/463,518, mulation is compromised (for example, by chopping with a filed on Apr. 15, 2003, provisional application No. blade or crushing) and the resulting material is placed in 60/463,514, filed on Apr. 15, 2003, provisional appli water, snorted, or Swallowed. However, when administered as cation No. 60/443,226, filed on Jan. 28, 2003, provi directed, the drug is slowly released from the composition as sional application No. 60/436,523, filed on Dec. 23, the composition is passes through the GI tract. US 2014/O 105987 A1 Apr. 17, 2014

ABUSE-DETERRENT PHARMACEUTICAL such formulations into an abusable form, they provide virtu COMPOSITIONS OF OPODS AND OTHER ally no deterrent to a potential abuser. DRUGS 0005 For example, the FDA recently strengthened the warnings and precautions sections in the labeling of OxyCon CROSS REFERENCE TO RELATED tin R (oxycodone HC1 controlled release) tablets, a narcotic APPLICATIONS drug approved for the treatment of moderate to severe pain, because of continuing reports of abuse and diversion. Oxy 0001. This application is a continuation-in-part of U.S. ContinR contains oxycodone HCl (available in 10, 20, 40 and Ser. No. 12/112,993, filed Apr. 30, 2008, which is a divisional 80 mg strengths), an opioid agonist with an addiction poten of U.S. Ser. No. 10/614,866 filed Jul. 7, 2003, which claims tial similar to that of morphine. Opioid agonists are Sub priority to U.S. Ser. No. 60/393,876 filed Jul. 5, 2002 entitled stances that act by attaching to specific proteins called opioid “Abuse-Resistant Formulations of Oxycontin and Other receptors, which are found in the brain, spinal cord, and Drugs” by Alexander M. Klibanov, Stephen L. Buchwald, gastrointestinal tract. When these drugs attach to certain Timothy M. Swager, and Whe-Yong Lo: U.S. Ser. No. opioid receptors in the brain and spinal cord they can effec 60/436,523 filed Dec. 23, 2002 by Alison B. Fleming, Roman tively block the transmission of pain messages to the brain. V. Rariy, Alexander M. Klibanov, Whe-Yong Lo, and Jane 0006. OxyContin R) is supplied in a controlled-release dos Hirsh; U.S. Ser. No. 60/443,226 filed Jan. 28, 2003 by Jane age form and is intended to provide up to 12 hours of relief Hirsh, Alison B. Fleming, Alexander M. Klibanov, and Whe from moderate to severe pain. The warning specifically states Yong Lo: U.S. Ser. No. 60/463,514 filed Apr. 15, 2003 by Jane that the tablet must be taken whole and only by mouth. When C. Hirsh, Alison B. Fleming, Roman V. Rariy, Stephen L. the tablet is chewed or crushed and its contents are swal Buchwald, and Timothy M. Swager; and U.S. Ser. No. lowed, Snorted into the nostrils or dissolved and Subsequently 60/463,518 filed Apr. 15, 2003 by Jane C. Hirsh, Alison B. injected intravenously, the controlled release mechanism is Fleming and Roman V. Rariy. destroyed and a potentially lethal dose of oxycodone 0002 This application also is a continuation-in-part of becomes bioavailable. Ser. No. 12/112.937, filed Apr. 30, 2008, which is a continu 0007. In recent years, there have been numerous reports of ation-in-part of U.S. Ser. No. 10/614.866, filed Jul. 7, 2003, Oxycodone diversion and abuse in several states. For which claims priority to U.S. Ser. No. 60/393,876 filed Jul. 5, example, the DEA's Office of Diversion Control reported 700 2002; U.S. Ser. No. 60/436,523 filed Dec. 23, 2002; U.S. Ser. OxyContin R thefts in the United States between January No. 60/443,226 filed Jan. 28, 2003: U.S. Ser. No. 60/463,514 2000 and June 2001. Some of these reported cases have been filed Apr. 15, 2003; and U.S. Ser. No. 60/463,518 filed Apr. associated with serious consequences including death. 15, 2003 and a continuation-in-part of U.S. Ser. No. 1 1/149. According to a report from the Abuse and Mental Health 867, filed Jun. 10, 2005, which claims priority to U.S. Ser. No. Services Administration, Results from the 2004 National Sur 60/579,191, filed Jun. 12, 2004. vey on Drug Use and Health: National Findings (Rockville, Md. US Dept. of Health and Human Services, Office of FIELD OF THE INVENTION Applied Studies, 2005, p. 50), in 2004, the number of new non-medical users of OxyContin R) was 615,000, with an 0003. The present invention is generally in the field of average age at first use of 24.5 years. Comparable data on past pharmaceutical compositions, and specifically compositions year Oxycontin R initiation are not available for prior years, that are designed to reduce the potential for improper admin but calendar year estimates of Oxycontin R initiation show a istration of drugs, such as those subject to abuse. steady increase in the number of initiates from 1995, the year this product was first available, through 2003 BACKGROUND OF THE INVENTION 0008 Oxycodone is a controlled substance in Schedule H 0004 Oxycodone, morphine, and other opioid analgesics of the Controlled Substances Act (CSA), which is adminis are successful and therapeutically useful medications, e.g., as tered by the Drug Enforcement Administration (DEA). pain killers, when administered orally. Unfortunately, they Despite the fact that Schedule II provides the maximum also pose a severe threat for willful abuse due to their ability amount of control possible under the CSA for approved drug to alter mood and/or cause a sense of euphoria. Currently products, in practice it is difficult for law enforcement agen available Sustained release formulations of such drugs, which cies to control the diversion or misuse of legitimate prescrip contain a relatively large amount of drug meant to be released tions. Although abuse, misuse, and diversion are potential from the formulation over an extended time period, are par problems for all opioids; including Oxycodone, opioids are a ticularly attractive to abusers since the Sustained release very important part of the medical armamentarium for the action can be destroyed by crushing or grinding the formula management of pain when used appropriately under the care tion. The resulting material (i.e., the crushed formulation) can ful Supervision of a physician. no longer control the release of drug. Depending on the drug, 0009 Currently available formulations for such drugs are abusers can then (1) Snort the material. (2) Swallow the mate designed for oral administration but are vulnerable to alter rial or (3) dissolve the material in water and subsequently ations in their dissolution characteristics by physical manipu inject it intravenously. The dose of drug contained in the lation of the formulation as discussed above. Such formula formulation is absorbed immediately through the nasal or GI tions are also vulnerable due to the inherently high water mucosa (for Snorting or Swallowing, respectively) or is solubility of the API contained therein. Because of their administered in a bolus to the systemic circulation (for IV nature, these formulations do not prevent or deter improper injection). These abuse methods result in the rapid bioavail methods of administration Such as chewing, injection and ability of relatively high doses of drug, giving the abuser a Snorting. This represents a serious problem given the large “high”. Since relatively simple methods (crushing, grinding, number of legitimate prescriptions written in the US; for chewing and/or dissolution in water) can be used to transform example, the medical use of opioids within the US increased US 2014/O 105987 A1 Apr. 17, 2014

400% from 1996 to 2000. The problems with abuse are sig chemically modified to increase its lipophilicity and is for nificant and longstanding, and efforts to design new abuse mulated as microparticles. In other embodiments, the formu resistant or abuse-deterrent formulations have been largely lation contains lipophilic or water-insoluble materials or is unsuccessful. made using a process which increases the lipophilicity and/or 0010 U.S. Pat. No. 3,980,766 to Shaw et al. (“Shaw), water-insolubility of the composition. In some embodiments, U.S. Pat. No. 4,070,494 to Hoffmeisteretal. (“Hoffmeister'), the composition additionally contains one or more antioxi and U.S. Pat. No. 6,309,668 to Bastin et al. (“Bastin') dants. describe formulations designed to prevent the injection of 0020. The abuse-deterrent composition retards the release compositions meant for oral administration. of drug, even if the physical integrity of the dosage form is 0011 Shaw describes the incorporation of an ingestible compromised (for example, by chopping with a blade or Solid which causes a rapid increase in viscosity upon concen crushing) and the resulting material is placed in water, tration of an aqueous solution thereof. snorted, or swallowed. However, when administered as 0012 Hoffmeister describes the incorporation of a non directed, the drug is released slowly (typically over a period toxic, water getable material in an amount Sufficient to render of 4-18 hours) from the composition by diffusion as the the drug resistant to aqueous extraction. composition is broken down or dissolved gradually within the 0013 Bastin describes a tablet for oral administration con GI tract by a combination of surfactant action of bile acids, taining two or more layers containing one or more drugs and mechanical erosion and/or enzymatic degradation. one or more gelling agents within separate layers of the tablet. 0021. In some embodiments, the individual drug-contain The resulting tablet forms a gel when combined with the ing microparticles or drug particles are coated With one or Volume of water necessary to dissolve the drug allegedly more independent coating layers. At least one of the coating reducing the extractability of the drug from the tablet. materials is water-insoluble and/or organic solvent-insoluble, 0014. It should be noted that although these compositions so that in vitro degradation of the formulation will require allegedly preclude abuse by injection, this approach fails to more than one step. Thus, the drug is not easily extractable prohibit rapid dissolution of the drug once the dosage form is from the formulations by conventional chemical means. In crushed into Smaller particles or pieces. Thus, these formula contrast, when administered to the gastrointestinal tract via tions are Vulnerable to abuse by crushing and Swallowing or swallowing, the drug will gradually be released from the Snorting the formulation, which are commonly reported coated microparticles as a consequence of diffusion, the methods of abuse associated with OxyContinR). gradual breakdown of the formulation via Surfactant action of 0.015 U.S. Pat. Nos. 3,773.955 and 3,966,940 to Pachteret bile acids, mechanical erosion and/or enzymatic degradation. al. describe formulations containing a combination of opioid 0022. The pharmaceutical composition, when adminis agonists and antagonists, in which the antagonist does not tered orally, results in a desired drug release profile. The block the therapeutic effect when the admixture is adminis release profile provides a therapeutic effect for an extended tered orally, but which does not produce analgesia, euphoria period of time, typically from 6 to 24 hours, preferably from orphysical dependence when administered parenterally by an 12 to 24 hours. Additional compositions are provided which abuser. achieve a small immediate release dose that precedes the 0016 U.S. Pat. No. 4,457.933 to Gordon etal, describes a Sustained release of drug. The compositions disclosed herein method for decreasing both the oral and parenteral abuse may optionally contain a drug having no appreciable abuse potential of strong analgetic agents by combining an analge potential. sic dose of the analgetic agent with an antagonist in specific, relatively narrow ratios. DETAILED DESCRIPTION OF THE INVENTION 0017 U.S. Pat. Nos. 6,277,384, 6,375,957 and 6,475,494 to Kaiko et al. describe oral dosage forms including a com 0023 Disclosed herein are an abuse-deterrent pharmaceu bination of an orally active opioid agonistand an orally active tical compositions and the method of making and using the opioid antagonist in a ratio that, when delivered orally, is compositions. analgesically effective but that is aversive in a physically dependent subject. While such a formulation may be success I. Compositions ful in deterring abuse, it also has the potential to produce 0024. As used herein, "composition” refers to the drug adverse effects in legitimate patients. dosage unit for administration to a patient. "Composition” 0018. It is therefore an object of the present invention to may also be used in reference solely to the active ingredient, provide a pharmaceutical composition that significantly or to a formulation containing the active ingredient. reduces the potential for improper administration or use of 0025. The currently available sustained release dosage drugs but which, when administered as directed, is capable of forms containing narcotic analgesics and other drugs are Sub delivering a therapeutically effective dose. ject to misuse, in part, because mechanical destruction of the dosage form exposes the encapsulated drug and allows for SUMMARY OF THE INVENTION immediate dissolution of the drug into aqueous media. Three 0019. An abuse-deterrent pharmaceutical composition properties of the dosage form that contribute to this outcome and methods of making and using thereof have been devel are, (1) the high water solubility of the drug salt form; (2) the oped. The compositions can be used to reduce the likelihood lack of protection offered by the hydrophilic and/or water of improper administration of drugs, especially drugs prone soluble excipients in the formulation; and (3) the ease with to abuse Such as oxycodone. The technology is useful for a which the surface area of the formulation is increased by number of other drugs where sustained release oral delivery is simple chewing or crushing. Susceptibility to simple methods desired, and there is potential for abuse if the drug dose is Such as chewing or crushing is particularly problematic for made immediately available for nasal, intravenous (IV) or monolithic controlled-release dosage forms. For monolithic oral administration. In a preferred embodiment, the drug is dosage forms, such as tablets, even splitting the unit into a few US 2014/O 105987 A1 Apr. 17, 2014

pieces (without completely crushing it) can result in a dra trointestinal tract, and immediate or burst release, for matic increase in the dissolution rate. example, by inhalation or injection, is undesirable. As used 0026. In the compositions disclosed herein, one or more of herein, drugs prone to abuse refer to controlled Substance these properties are altered in order to achieve an abuse specified as schedule II, III, IV and V drugs. deterrent composition. Specifically, in the one embodiment, 0031. The terms “drug”, “active agent, and “pharmaco the drug is modified to increase its lipophilicity which logically active agent” are used interchangeably herein to reduces its water solubility. The modified drug is then homo refer to a chemical compound that induces a desired pharma geneously dispersed within one or more carrier materials that cological, physiological effect. The terms also encompass are either slowly soluble or not soluble in water. Dispersion pharmaceutically acceptable derivatives of those active within these materials further reduces the accessibility of the agents specifically mentioned herein, including, but not lim drug when crushed and exposed to an aqueous media. In some ited to, salts, Solvates, hydrates, complexes with one or more embodiments, the drug may be partially or fully dispersed in molecules, prodrugs, active metabolites, analogs, and the the carrier materials on a molecular level. The intimate mix like. When the terms “active agent”, “pharmacologically ture of modified drug and carrier materials is Subsequently active agent” and "drug are used, or when a particular drug, formulated into microparticles, producing a formulation Such as oxycodone, is identified, it is to be understood as whose Surface area is minimally influenced by chewing or including the active agent per seas well as pharmaceutically crushing. acceptable salts, Solvates, hydrates, complexes with one or 0027. The terms “abuse-deterrent composition” or more molecules, prodrugs, active metabolites, and analogs. “abuse-deterrent formulation” are used interchangeably 0032 Examples of preferred drugs include, 1-phenylcy herein to refer to compositions that reduce the potential for clohexylamine, 1-piperidinocyclohexanecarbonitrile, alfen improper administration of drugs but that deliver a therapeu tanil, alphacetylmethadol, alphaprodine, alprazolam, tically effective dose when administered as directed. amobarbital, amphetamine, anileridine, apomorphine, Improper administration includes tampering with the dosage aprobarbital, barbital, barbituric acid derivative, bemidone, form and/or administering the drug by any route other than benzoylecgonine, benzphetamine, betacetylmethadol, betap instructed. For example, for a tablet or capsule, methods of rodine, bezitramide, bromazepam, buprenorphine, butabar tampering with the dosage form may include, but are not bital, butalbital, butorphanol, camazepam, cathine, chloral, limited to, breaking, crushing, grinding, chewing and/or dis chlordiazepoxide, clobazam, clonazepam, cloraZepate, clo solving the tablet or the contents of the capsule. For oral tiazepam, cloxazolam, cocaine, codeine, chlorphentermine, administration, improper administration includes administer delorazepam, dexfenfluramine, dextromoramide, dextropro ing the drug by any route other than via Swallowing. poxyphen, dezocine, diazepam, diethylpropion, difenoxin, 0028. The abuse deterrent compositions preferably con dihydrocodeine, dihydromorphine, dioxaphentyl butyrate, tain a drug modified to increase its lipophilicity. In some dipanone, diphenoxylate, diprenorphine, ecgonine, enado embodiments, the drug is homogenously dispersed within line, eptazocine, estaZolam, ethoheptazine, ethyl loflazepate, microparticles composed of a material that is either slowly ethylmorphine, etorphine, femproponex, fencamfamin, fen soluble in water or water insoluble. The compositions main fluramine, fentanyl, fludiazepam, flunitrazepam, flurazepam, tain the slow the release of drug if the dosage form is chopped glutethimide, halazepam, haloxazolam, hexalgon, hydroc or crushed and the resulting material is placed in water, odone, hydromorphone, isomethadone, hydrocodone, ket Snorted, or Swallowed since most of the drug will remain amine, ketazolam, ketobemidone, levanone, levoalphacetyl associated with or entrapped within portions of the core mate methadol, levomethadone, levomethadyl acetate, rial of the microparticles. In other embodiments, the drug levomethorphan, levorphanol, lofentanil, loperamide, lopra containing microparticles or individual drug particles are Zolam, lorazepam, lormetazepam, lysergic acid, lysergic acid coated with one or more coating layers, where at least one amide, mazindol, medazepam, mefenorex, meperidine, coating is water insoluble and/or organic solvent insoluble. meptazinol, metazocine, methadone, methamphetamine, The components of the resulting coated microparticles are not methohexital, methotrimeprazine, methyldihydromorphi mutually soluble in water or organic solvents. Such that no none, methylphenidate, methylphenobarbital, metopon, mor one solvent or enzyme solution is capable of dissolving the phine, nabilone, nalbuphine, nalbupine, nalorphine, narceline, formulation in its entirety invitro. Therefore, extraction of the nefopam, nicomorphine, nimetazepam, nitrazepam, nordiaz drug from the formulation cannot be carried out in one step. epam, normethadone, normorphine, oxazepam, oxazolam, However, when administered as directed, the drug is slowly oxycodone, oxymorphone, pentazocine, pentobarbital, phen released from the formulation via diffusion and erosion adoxone, phenazocinc, phencyclidine, phendimetrazine, within the environment of the gastrointestinal tract. phenmetrazine, pheneridine, piminodine, prodilidine, prope 0029. A. Drugs to be Formulated ridine, propoxyphene, racemethorphan, racemorphan, 0030 There are many drugs which can be delivered using racemoramide, remifentanil, secobarbital, Sufentanil, talb the compositions described herein. The Controlled Sub utal, thebaine, thiamylal, thiopental, tramadol, trimeperidine, stances Act (CSA), Title II of the Comprehensive Drug Abuse and vinbarbital. Prevention and Control Act of 1970, places all substances that 0033. In addition to the compounds above, the following are regulated under existing federal law into one offive sched scheduled drugs may be incorporated into the composition: ules based upon the Substance's medicinal value, harmful allobarbitone, alprazolam, amylobarbitone, aprobarbital, ness, and potential for abuse or addiction. Drugs that are barbital, barbitone, benzphetamine, brallobarbital, bro preferred include those classified as Schedule II, III, IV and V mazepam, brotizolam, buspirone, butalbital, butobarbitone, drugs. Drugs that are most preferable include those, like butorphanol, camazepam, captodiame, carbromal, carfenta oxycodone, that are currently formulated as Sustained or con nil, carpipramine, cathine, chloral, chloral betaine, chloral trolled release compositions, where drug release is intended hydrate, chloralose, chlordiazepoxide, chlorhexadol, chlo to occur over a prolonged period of time through the gas rmethiazole edisylate, chlormeZanone, cinolazepam, cloba US 2014/O 105987 A1 Apr. 17, 2014

Zam, potassium cloraZepate, clotiazepam, cloxazolam, cyclo 0037 B. Drug Solubility Modification barbitone, delorazepam, dexfenfluramine, diazepam, 0038. In some embodiments, the solubility characteristics diethylpropion, difebarbamate, difenoxin, enciprazine, esta of a drug are altered. Modification of the drug to produce a Zolam, ethyl loflazepate, etizolam, febarbamate, fencam more lipophilic derivative serves to reduce the water solubil famin, fenfluramine, fenproporex, fluianisone, fludiazepam, ity of the drug and thus reduce the aqueous extractability of flunitraam, flunitrazepam, flurazepam, flutoprazepam, the drug. Furthermore, if the drug is made more lipophilic, it gepirone, glutethimide, halazepam, haloxazolam, hexobarbi can be solubilized in a molten fatty substance or wax like tone, ibomal, ipsapirone, ketazolam, loprazolam mesylate, mixture, rather than physically dispersed in a particulate lorazepam, lormetazepam, mazindol, mebutamate, form. Solubilization of the drug enhances the abuse-deterrent medazepam, inefenorex, mephobarbital, meprobamate, properties of microparticles formulated from the mixture as it metaclazepam, methaqualone, methohexital, methylpen is difficult to extract drug from an intimately dispersed com tynol, methylphenobarbital, midazolam, milaZolam, mor position. Furthermore, such a composition is capable of con phine, nimetazepam, nitrazepam, nordiazepam, oxazepam, trolling the release of drug, even when formulated into rela oxazolam, paraldehyde, pemoline, pentabarbitone, pentazo tively small microparticles. Microparticulate compositions, cine, pentobarbital, phencyclidine, phenobarbital, phendime in contrast to monolithic compositions, are inherently less trazine, phenmetrazine, phenprobamate, phentermine, phen Susceptible to tampering by mechanisms that are intended to yacetone, pinazepam, pipradol, prazepam, proxibarbal, increase the Surface area and, consequently, the release rate of quazepam, quinalbaritone, secobarbital, secbutobarbitone, drug (such as chewing or crushing). Sibutramine, temazepam, tetrazepam, triazolam, triclofos, Zalepan, Zaleplon, Zolazepam, Zolpidem, and Zopiclone. Cer 0039. The terms “lipophilic derivative” and “lipophililic tain compounds described herein may exist in particular geo drug derivative', as used herein, refer to derivatives of the metric or stereoisomeric forms. The composition disclosed drug that are less soluble or dissolve less rapidly in water than herein contemplates all such compounds, including cis- and the most soluble salt of the drug; the most soluble salt being trans-isomers, R- and S-enantiomers, diastereomers, (D)-iso selected from either base addition salts (for acidic drugs) or mers, (L)-isomers, the racemic mixtures thereof, compounds acid addition salts (for basic drugs). Such as by the addition of of different spacial conformations, and other mixtures inorganic acids. The examples of the latter include but are not thereof, as falling within the scope of the invention. Addi limited to hydrohalates, sulfates, and nitrates. Some of the tional asymmetric carbon atoms may be present in a Substitu methods that can be used to alter the drug's lipophilicity are ent such as an alkyl group. All such isomers, as well as outlined below. It is understood that two or more approaches mixtures thereof, are intended to be included in this invention. can be combined to achieve a desired solubility profile. 0034. As used herein, “pharmaceutically acceptable salts' 0040 Methods for Increasing Lipophilicity refer to derivatives of the disclosed compounds wherein the 0041. In one embodiment, the drug is made more lipo parent compound is modified by making acid or base salts philic by eliminating or reducing the overall charge of the thereof. Examples of pharmaceutically acceptable salts drug molecule. For example, for a basic drug, a water soluble include, but are not limited to, mineral or organic acid salts of salt (Such as hydrochloride, Sulfate, or maleate) can be con basic residues such as amines; alkali or organic salts of acidic Verted to a free base using techniques known in the art. In the residues such as carboxylic acids; and the like The pharma case of an acidic drug, a water Soluble salt (such as Sodium, ceutically acceptable salts include the conventional non-toxic potassium, or the like) can be converted to a free acid. salts or the quaternary ammonium salts of the parent com 0042. In another embodiment, the drugs lipophilicity is pound formed, for example, from non-toxic inorganic or increased by forming a salt between a drug molecule and a organic acids. For example. Such conventional non-toxic salts charged lipophilic compound. In this case the lipophilicity of include those derived from inorganic acids such as hydro the resulting salt can be manipulated by varying the lipophi chloric, hydrobromic, Sulfuric, Sulfamic, phosphoric, nitric licity of the counter-ion. In general, lipophilic acids oramines and the like; and the salts prepared from organic acids such as with chain lengths between Cs-Co are lipophilic counter-ion acetic, propionic, Succinic, glycolic, Stearic, myristic, palm candidates. Some specific examples include, but are not lim itic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, ited to, linoleic acid, octanoic acid, lauric acid, Stearic acid, hydroxymaleic, phenylacetic, glutamic, benzoic, Salicylic, palmitic acid, myristic acid, oleic acid, octyl amine, lauryl Sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic, meth amine, Stearyl amine, palmityl amine, linoleyl amine, and anesulfonic, ethane disulfonic, oxalic, and isethionic. oleylamine. Other salts which may increase lipophilicity and, 0035. The pharmaceutically acceptable salts of the com hence, lipid solubility relative to the parent drug compound pounds can be synthesized from the parent compound, which include, but are not limited to, pectinate, tannate, phytate, contains a basic or acidic moiety, by conventional chemical salicylate, Saccharinate, acesulfamate, gallate, and terephtha methods. Generally, such salts can be prepared by reacting the late salts. free acid or base forms of these compounds with a stoichio 0043. In still a further embodiment, drug lipophilicity is metric amount of the appropriate base or acid in water or in an increased via complexation with poorly water-soluble cyclo organic solvent, or in a mixture of the two: generally, non dextrin. For example, ethylated beta-cyclodextrin has been aqueous media like ether, ethyl acetate, ethanol, isopropanol, shown to decrease aqueous solubility of complexed drug oracetonitrile are preferred. Lists of suitable salts are found in molecules. Remington’s Pharmaceutical Sciences, 20th ed., Lippincott 0044. In another embodiment, a drug is covalently modi Williams & Wilkins, Baltimore, Md., 2000, p. 704, the dis fied to increase its lipophilicity. For example, a lipophilic closure of which is hereby incorporated by reference. compound can be covalently attached to a drug molecule via 0036) Optionally, the composition described herein can an ester oramide linkage. Such drug derivatives are cleaved in further include a drug having no appreciable abuse potential. Vivo, thus releasing the parent compound. US 2014/O 105987 A1 Apr. 17, 2014

0045 C. Drug Containing Microparticles lated with drug into microparticles and Subsequently cross 0046. In some embodiments, the drug is formulated with a linked to form an insoluble network. For example, cyclodex carrier material to form microparticles. As used herein, the trins can be complexed with individual drug molecules and term “microparticle' refers to a composition containing a Subsequently cross-linked. drug dispersed within a carrier material and "coated micro 0051 Certain polymers may also be used as carrier mate particle' refers to a composition containing a drug containing rials in the formulation of drug containing microparticles. microparticle or a drug particle coated with one or more Suitable polymers include ethylcellulose and other natural or coating layers of material. Microparticles and coated micro synthetic cellulose derivatives. Polymers which are slowly particles have a size range of 10 to 3000 microns in diameter, soluble and form a gel in an aqueous environment, Such as more preferably from 10 to 1000 microns. hydroxypropyl methylcellulose or polyethylene oxide may 0047. Within microparticles, the drug is preferably homo also be suitable as carrier materials for drug containing geneously dispersed in the form of fine particles within the microparticles. carrier material. More preferably, the drug is partially solu 0.052 Encapsulation or incorporation of drug into carrier bilized in a molten carrier material or partially dissolved with materials to produce drug containing microparticles can be the carrier material in a mutual solvent during the formulation achieved through known pharmaceutical formulation tech of the microparticles. Most preferably, the drug is completely niques. To create a composition that protects drug from expo solubilized in the molten carrier material or completely dis Sure upon mechanical disruption (eg., grinding, chewing, or solved with the carrier material in a co-solvent during the chopping), the drug is intimately dispersed within the carrier formulation of the microparticles. This is accomplished material. In the case of formulation in fats, waxes or wax-like through the selection of materials and the manner in which materials, the carrier material is heated above its melting they are processed. temperature and the drug is added to form a mixture contain 0048 Carrier materials appropriate for the fabrication of ing drug particles Suspended in the carrier material, drug drug containing microparticles either dissolve slowly in water dissolved in the carrier material, or a mixture thereof. Micro or are insoluble in water. As used herein, the term “dissolves particles can be subsequently formulated through several slowly in water refers to materials that are not completely methods including, but not limited to, congealing, extrusion, dissolved in water within a period of 30 minutes. Suitable spray chilling or aqueous dispersion. In a preferred process, materials include fats, fatty Substances, waxes, wax-like Sub one or more carrier materials are heated above its melting stances and mixtures thereof. Suitable fats and fatty sub temperature, the drug is added, and the molten carrier mate stances include fatty alcohols (such as lauryl, myristyl rial-drug mixture is congealed to form solid, spherical par Stearyl, cetyl or cetostearyl alcohol), fatty acids and deriva ticles via a spraying or spinning cylinder or disk processes. tives, including but not limited, to fatty acid esters, fatty acid Alternatively, the molten carrier material-drug mixture can be glycerides (mono-, di- and tri-glycerides), and hydrogenated extruded and pelletized to form pellets or beads. Detailed fats. Specific examples include, but are not limited to hydro descriptions of these processes can be found in "Reming genated vegetable oil, hydrogenated cottonseed oil, hydroge ton The science and practice of pharmacy”. 20" Edition, nated castor oil, hydrogenated oils available under the trade Jennaro et. Al. (Phila, Lippencott, Williams, and Wilkens, name SteroteX(R), Stearic acid, cocoa butter, glyceryl behenate 2000. Spinning disk processes are described in U.S. Pat. Nos. (available under the trade name COMPRITOL 888(R), glyc 3,015,128 and 7,261,529. eryl dipalmitostearate (available under the trade name PRE 0053. In a preferred process, spherical particles are pro CIROL(R), and stearyl alcohol. Mixtures of mono-, di- and duced. Spherical particles may introduce an additional barrier tri-glycerides and mono- and di-fatty acid esters of polyeth to deter tampering with the composition. Smaller, round par ylene glycol, available under the trade name GELUCIRER) ticles act as “ball bearings” that are more difficult to crush or are also suitable fatty materials. Suitable waxes and wax-like grind, and if crushed, do not allow for significant decrease in materials include natural or synthetic waxes, hydrocarbons, particle size or surface areas of the particles in order to effect and normal waxes. Specific examples of waxes include bees an increase in release rate. wax, glycowax, castor wax, carnauba wax, paraffins and can 0054 For compositions containing salts composed of a delilla wax. As used herein, a wax-like material is defined as pharmaceutically active agent and one or more fatty acids or any material which is normally solid at room temperature and amines, the salt may be formed during the formulation pro has a melting point of from about 30 to 300° C. cess itself. To accomplish this, the one or more fatty acids or 0049. In some cases, it may be desirable to alter the rate of amines are melted and mixed with the free base or acid form water penetration into the hydrophobic drug containing of the active agentata temperature above the melting point(s) microparticles. To this end, rate-controlling (wicking) agents of the fatty acid(s) or amine(s). Once a homogeneous mixture may beformulated along with the fats or waxes listed above. is formed, one or more additional carrier materials, such as Examples of rate-controlling materials include certain starch fat, fatty Substance(s), wax or wax-like Substance(s) can be derivatives (e.g., waxy maltodextrin and drum dried corn added to the molten mixture to yield a single phase compo starch), cellulose derivatives (e.g., hydroxypropylmethylcel sition. The molten solution is then solidified into micropar lulose, hydroxypropylcellulose, methylcellulose, and car ticles using one of the techniques described above. boxymethylcellulose), alginic acid, lactose and talc. Addi 0055. The molar concentration offatty acid or amine may tionally, a pharmaceutically acceptable Surfactant (for need to be higher than that of the drug in order to achieve a example, lecithin) may be added to facilitate the degradation homogeneous single phase. For example, it has been found and/or dissolution of the microparticles. that, for oxycodone, a molar ratio in excess of about 7:1 (fatty 0050. Proteins which are water insoluble, such as Zein, are acid to drug) results in a homogeneous melt using this tech Suitable carrier materials for the formation of drug containing nique. The molar ratio needed to obtain a homogeneous melt microparticles. Additionally, proteins, polysaccharides and may depend on the type and quantity of additional carrier combinations thereof which are water soluble can be formu materials added. In one embodiment, the molar ratio offatty US 2014/O 105987 A1 Apr. 17, 2014

acid or fatty amine is from about 1:1 to about 15:1, preferably nyl acetate (available under the trade name KOLLICOATR), from about 6:1 to about 15:1. However, molar ratios greater can also be used to form water-insoluble but permeable coat than 15:1, for example 15:1 to 25:1, preferably 15:1-20:1, ings. may be required depending on the fatty acid or fatty amine, 0063. The coating may also include a water-insoluble but the drug to be formulated, and/or the carrier material(s). enzymatically degradable material. In some instances the 0056. For some carrier materials it may be desirable to use Substrates of digestive enzymes are naturally water-insoluble a solvent evaporation technique to produce drug containing and can be utilized in the formulation without further pro microparticles. In this case drug and carrier material are co cessing. Solid esters of fatty acids, which are hydrolyzed by dissolved in a mutual solvent and microparticles can Subse lipases, can be spray coated onto microparticles or drug par quently be produced by several techniques including, but not ticles. Mixtures of waxes (beeswax, carnauba wax, etc.) with limited to, forming an emulsion in water or other appropriate glyceryl monostearate, Stearic acid, palmitic acid, glyceryl media, spray drying or by evaporating off the solvent from the monopalmitate and cetyl alcohol will also form films that are bulk solution and milling the resulting material. dissolved slowly or broken down in the GI tract. Zein is an 0057. In addition to modification of the drug itself, pro example of a naturally water-insoluble protein. It can be cessing conditions can be used to influence the dispersion of coated onto drug containing microparticles or drug particles the drug within water-insoluble or slowly water soluble mate by spray coating or by wet granulation techniques. In addition rials. For example, in the case where the water in-soluble or to naturally water-insoluble materials, some Substrates of slowly soluble material is melted and the drug is fully or digestive enzymes can be treated with cross-linking proce partially dissolved under Stirring conditions, the temperature, dures, resulting in the formation of non-soluble networks. agitation rate and time of processing will influence the degree Many methods of cross-linking proteins, initiated by both of dissolution achieved. More specifically, a more homog chemical and physical means, have been reported. In some enous dispersion may be achieved with a higher temperature, embodiments, chemical cross-linking agents are used. faster stirring rate and/or longer processing time. Ultrasound Examples of chemical cross-linking agents include aldehydes can also be applied to the molten mixture to increase the (gluteraldehyde and formaldehyde), epoxy compounds, car degree of dispersion and/or the rate of dissolution of the drug. bodiimides, and genipin. In addition to these cross-linking 0058. In some embodiments, the drug in a particulate form agents, oxidized and native Sugars have been used to cross is homogeneously dispersed in a water-insoluble or slowly link gelatin (Cortesi, R., et al., Biomaterials 19 (1998) 1641 water soluble material. To minimize the size of the drug 1649). Cross-linking can also be accomplished using enzy particles within the composition, the drug powder itself may matic means; for example, transglutaminase has been be milled to generate fine particles prior to formulation. The approved as a GRAS Substance for cross-linking seafood process ofjet milling, known in the pharmaceutical art, can be products. Finally, cross-linking can be initiated by physical used for this purpose. In some embodiments drug in a par means such as thermal treatment, UV irradiation and gamma ticulate form is homogeneously dispersed in a wax or wax irradiation. like Substance by heating the wax or wax like Substance above 0064. To produce a coating layer of cross-linked protein its melting point and adding the drug particles while stirring Surrounding drug containing microparticles or drug particles, the mixture. In this case a pharmaceutically acceptable Sur a water Soluble protein can be spray coated onto the micro factant may be added to the mixture to facilitate the dispersion particles and Subsequently cross-linked by one of the meth of the drug particles. ods described above. Alternatively, drug containing micro 0059) D. Coated Drug Containing Microparticles particles can be microencapsulated within protein by 0060. In Sonic embodiments, drug containing micropar coacervation-phase separation (for example, by the addition ticles or drug particles are encapsulated. Drug containing of salts) and Subsequently cross-linked. Some Suitable pro microparticles can be encapsulated in water insoluble mate teins for this purpose include gelatin, albumin, casein, and rials, slowly water Soluble materials, organic insoluble mate gluten. rials and/or materials with pH dependent solubilities. 0065 Polysaccharides can also be cross-linked to form a 0061. In general, any coating procedure which provides a water-insoluble network. For many polysaccharides, this can contiguous coating on each microparticle can be used. Coat be accomplished by reaction with calcium salts or multivalent ing procedures known in the pharmaceutical arts include, but cations which cross-link the main polymer chains. Pectin, are not limited to, fluid bed coating processes and microen alginate, dextran, amylose and guar gum are Subject to cross capsulation may be used to obtain appropriate coatings. linking in the presence of multivalent cations. Complexes Detailed descriptions of these processes can be found in between oppositely charged polysaccharides can also be “Remington The science and practice of pharmacy”, 20" formed; pectin and chitosan, for example, can be complexed Edition, Jennaro et. Al. (Phila, Lippencott, Williams, and via electrostatic interactions. Insoluble coatings can be Wilkens, 2000. formed on particles in this fashion. It should be noted that in 0062. The water-insoluble coating materials may be many cases polysaccharides are broken down specifically by selected from natural or synthetic film-formers used singly, in enzymes produced by bacteria within the colon. admixture with each other, and in admixture with plasticizers, 0066. In some cases a water-insoluble but enzymatically pigments and other Substances to alter the characteristics of degradable coating including both a protein and a polysac the coating. A water-insoluble but water-permeable diffusion charide can be produced if the components are oppositely barrier may contain ethyl cellulose, methyl cellulose and charged polyelectrolytes. Under the proper temperature, pH, mixtures thereof. The water-permeable diffusion barrier may and concentrations, the two polymers can interact through also include ammonia methacrylate copolymers sold under their opposite electrical charges and form a water-insoluble the trade name EUDRAGITR (Rohm Pharma), such as complex. If a core particle is present at the time the complex EUDRAGITRS, EUDRAGITRL, EUDRAGITNE and mix phase separates, it will be coated. For example, gelatin and tures thereof. Other synthetic polymers, for example, polyvi gum arabic can be coated onto a core particle utilizing this US 2014/O 105987 A1 Apr. 17, 2014

process. Optionally, the complex can be made irreversibly the one or more inactive carrier materials in the composition. insoluble by Subsequent cross-linking induced by chemical or Oxidation of one or more components may occur during the physical means. formulation process itself or during the shelf-life of the com 0067 Coating materials may also include a pH sensitive position. Oxidation may result from exposure to the oxygen polymer which is insoluble in the acid environment of the content of air or, alternatively, may be related to impurities in stomach, and soluble in the more basic environment of the GI the carrier materials. For example, highly reactive species tract. These coatings, referred to as enteric coatings, create a Such as peroxides, Superoxides, hypochlorites and formic dosage form designed to prevent drug release in the stomach. acid may be present in carrier materials as manufacturing Preventing drug release in the stomach has the advantage of related impurities. Also, trace metal impurities in carrier reducing side effects associated with irritation of the gastric materials, such as iron and copper, can catalyze oxidation mucosa and/or of minimizing exposure of drug to very low reactions. An antioxidant may be included in the composition pH. Avoiding release within the stomach can be achieved to mitigate the degradation of the drug in Such cases. If the using enteric coatings known in the art. The enteric coated Source of oxidation is a reactive manufacturing-related impu formulation remains intact or Substantially intact in the stom rity in one or more of the carrier materials, the anti-oxidant ach, however, once the formulation reaches the Small intes can be co-melted with the carrier materials prior to the intro tines, the enteric coating dissolves and exposes either drug duction of the drug into the formulation in order to protect the containing carrier particles or drug-containing carrier drug from these reactive species. particles coated with extended release coating. 0075. The concentration of the antioxidant is generally 0068 Enteric coated particles can be prepared as from about 0.001% to about 1% w/w, preferably from about described in “Pharmaceutical dosage form tablets’, eds. 0.01% to about 0.5% w/w. However, concentrations of less Liberman et. al. (New York, Marcel Dekker, Inc., 1989), than 0.001% or greater than 0.5% may be used, provided the “Remington The science and practice of pharmacy”. 20th concentration is sufficient to stabilize the formulation and is ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000, non-toxic. and "Pharmaceutical dosage forms and drug delivery sys (0076 F. Dosage Forms tems’, 6th Edition, Ansel et. al., (Media, Pa.; Williams and 0077. In one embodiment a drug is partially dissolved Wilkins, 1995). Examples of suitable coating materials within a water-insoluble or slowly water soluble material include, but are not limited to, cellulose polymers, such as during the manufacturing process, for example, by mixing at cellulose acetate phthalate, hydroxypropyl cellulose, hydrox a temperature above the melting point of the carrier material, ypropyl methylcellulose phthalate and hydroxypropyl meth and the mixture is formulated into microparticles. In another ylcellulose acetate Succinate; polyvinyl acetate phthalate, embodiment a drug is fully dissolved withina water-insoluble acrylic acid polymers and copolymers, and certain meth or slowly water Soluble material during the manufacturing acrylic resins that are commercially available under the trade process, for example, by mixing at a temperature above the name EUDRAGIT (Rohm Pharma). Additionally the coating melting point of the carrier material, and the mixture is for material may contain conventional carriers such as plasticiz mulated into microparticles. Instill a further embodiment, the ers, pigments, colorants, glidants, stabilization agents, and drug containing microparticles, where the drug is homoge Surfactants. neously dispersed in a particulate form, or has been partially 0069. In some cases it may be desirable to coat the par or fully dissolved within the carrier material during the manu ticles with a coating which is soluble in aqueous solutions but facturing process, are coated with one or more coatings to insoluble in hydroalcoholic Solutions. In this case the coating form coated microparticles. In a further embodiment, drug material may or may not have pH sensitive solubility in aque particles are coated directly with one or more coatings to form ous solutions. coated microparticles. 0070. In other cases it may be desirable to combine coat 0078. The microparticles, coated microparticles, or a mix ing materials to produce a tailored release of drug. For ture thereofare formed into a solid dosage form suitable for example, combinations of insoluble polymers and pH depen oral administration. For example, microparticles or coated dent polymers can produce a pH dependent Sustained release microparticles can be incorporated into hard shell capsules, profile. Combinations of insoluble polymers (eg, ethylcellu dispersed within a soft gelatin capsule, or combined with lose), water-soluble polymers (eg. HPMC or PEG) and pH appropriate excipients such as magnesium Stearate as lubri dependent Swellable polymers (eg. carboxyvinylpolymer) cant, colloidal silicon dioxide as glidant, Sodium starch gly have also been reported to produce pH dependent Sustained collide, Sodium croScarmellose or crospovidone as disinte release profiles (See, for example, Journal of Controlled grant, sodium dodecyl sulfate or Polyoxyethylene (20) Release, 2006, 111:309-315). Sorbitan monooleate, polyvinyl pyrrolidone or hydroxypro 0071. In one embodiment, the particles are coated with pylmethylcellulose as crystallization inhibitor, and lactose cellulose acetate phthalate. Cellulose acetate phthalate is and microcrystalline cellulose as fillers, and tableted by com typically used as an enteric coating. pression. 0072 E. Antioxidants 0079. In some embodiments, the compositions are coated 0073. In some embodiments, the composition includes with an enteric coating. Enteric coatings known in the art are one or more anti-oxidants. Suitable antioxidants include, but applied directly to the abuse-deterrent microparticle or coated are not limited to, butylated hydroxytoluene (BHT); ascorbic microparticle compositions or are applied to the Surface of a acid, its salts and esters; Vitamin E, tocopherol and its salts; capsule or tablet containing the abuse deterrent microparticle Sulfites such as Sodium metabisulphite; cysteine and its and/or coated microparticle compositions. Enteric coatings derivatives; citric acid; propyl gallate, and butylated known in the art include, for example, acrylic polymers that hydroxyanisole (BHA). are commercially available under the trade name 0074 Antioxidants may be necessary to prevent oxidative EUDRAGITR), cellulose acetate phthalate, hydroxypropylm degradation of the active pharmaceutical ingredient and/or ethyl-cellulosephthalate, polyvinylacetate phthalate, shellac, US 2014/O 105987 A1 Apr. 17, 2014 hydroxypropylmethylcellulose Succinate, cellulose acetate lating tablets. For example, ingredients can be added to deter trimelliate or mixtures thereof. In one embodiment, the par chewing or Snorting of the final formulation. For example, an ticles are coated with cellulose acetate phthalate. intensely bitter Substance may deter chewing, while an 0080 Dosage forms can include one or more drugs. When intensely spicy ingredient, Such as capsaicin, may deter Snort the dosage form includes two or more drugs they can be ing. The addition of a colored dye, which would stain the skin Scheduled drugs or can be a combination of Scheduled and and mucosal Surface of the nose following Snorting may also non-Scheduled drugs. The drugs can be incorporated into serve to reduce this practice. separate microparticle compositions where the Scheduled I0084 Optional excipients present in the oral dosage form drugs are incorporated into abuse deterrent microparticle containing abuse deterrent microparticles or coated micro compositions and the non-Scheduled drugs are incorporated particles include, but are not limited to diluents, binders, into abuse deterrent microparticle compositions, Sustained lubricants, disintigrants, colorants, plasticizers and the like. release compositions known in the art or immediate release I0085 Diluents, also termed “fillers.” are typically neces compositions known in the art. The compositions containing sary to increase the bulk of a solid dosage form so that a the different drugs are formulated into a single Solid dosage practical size is provided for compression of tablets. form suitable for oral administration, for example, they can be Examples of diluents include cellulose, dry starch, microc incorporated into a gelatin capsule, or combined with appro rystalline cellulose, dicalcium phosphate, calcium sulfate, priate excipients and compressed into a tablet form. Sodium chloride confectioner's Sugar, compressible Sugar, Examples of non-scheduled drugs that may be included in dextrates, dextrin, dextrose, Sucrose, mannitol, powdered cel dosage forms described herein include, but are not limited to, lulose, Sorbitol, and lactose. Binders are used to impart cohe aspirin, acetaminophen, non-steroidal anti-inflammatory sive qualities powdered materials and can include materials drugs, cyclooxygenase II inhibitors, N-methyl-D-aspartate Such as starch, gelatin, Sugars, natural and synthetic gums, receptor antagonists, glycine receptor antagonists, triptans, polyethylene glycol, ethylcellulose, methylcellulose, dextromethorphan, promethazine, fiorinal, guaifenesin, hydroxypropylmethylcellulose, carboxymethylcellulose, butalbital, and caffeine. waxes and polyvinyl pyrrolidone. Lubricants are used to 0081. An immediate release dose can be incorporated into facilitate tablet manufacture; examples of lubricants include the formulation in several ways. Immediate release micropar talc, magnesium Stearate, calcium Stearate, hydrogenated ticles can be made utilizing standard methodologies and for Vegetable oils Stearic acid, Sodium Stearyl fumarate, sodium mulated along with abuse-deterrent microparticle and/or benzoate, sodium acetate, leucine, Sodium oleate, sodium coated microparticle compositions in a Suitable oral dosage lauryl Sulfate, magnesium lauryl Sulfate and polyethylene form. Alternatively, a coating containing drug which is avail glycol. Disintegrants can be added to pharmaceutical formu able for immediate release can be placed on a tablet contain lations in order to facilitate “breakup” or disintegration after ing abuse-deterrent microparticle and/or coated microparticle administration. Materials used for this purpose include compositions plus appropriate excipients. Additionally, an starches, clays, celluloses, aligns, gums, and cross-linked immediate dose of drug can be granulated or blended with polymers. A plasticizer may be included in coating materials rapidly dissolving excipients and Subsequently compressed to alter their mechanical properties. Examples of plasticizers (1) as one layer of bi-layer tablets in which the abuse-deter include benzyl benzoate, chlorobutanol, dibutyl sebacate, rent microparticle and/or coated microparticle compositions diethyl phthalate, glycerin, mineral oil, polyethylene glycol, are compressed as the other layer, or (2) as the outer layer of Sorbitol, triacetin, triethylcitrate, glycerol, etc. In addition to compression-coated tablets in which the abuse-deterrent the additives above, coloring and flavoring agents may also be microparticle and/or coated microparticle compositions are incorporated into the composition. compressed as the inner core, or (3) into tablets in which abuse-deterrent microparticle and/or coated microparticle II. Methods of Administration compositions are embedded. I0086. In addition to providing a deterrent to common 0082 In some embodiments, the immediate release por methods of abuse/diversion, the formulation can provide a tion of the dosage form contains a lipophilic drug derivative. Sustained release of drug over an extended time period. This For example, salt derivatives or complexes that are insoluble is a natural consequence of the fact that, in the present for at a neutral pH but dissociate, thereby releasing the parent mulation, drug is slowly released from a predominantly compound, at an acidic pH are ideal for immediate release water-insoluble, hydrophobic matrix as it passes through the within the stomach. In the case of oxycodone some salts that GI tract. The barrier components may be degraded as the may exhibit this property include, but are not limited to, the matrix passes through the GI tract, for example, by enzymes, tannate, phthalate, salicylate, gallate, pectinate, phytate, sac the Surfactant action of bile acids and mechanical erosion. charinate, asesulfamate and terephthalate salts. Complexes of I0087. In some embodiments, an immediate release of drug drug with one or more metalions and, optionally, one or more is achieved within the stomach in order to provide rapid lipophilic counter-ions may also be used for immediate drug therapeutic onset. release. Use of salts or complexes in the immediate release I0088. The pharmaceutical drug composition is adminis portion of the dosage form reduces the abuse potential of the tered orally. The appropriate dosage formulations can be immediate release dose if the formulation is crushed and (1) obtained by calculation of the pharmacokinetics of the for snorted or (2) dissolved in water since these salts will be mulation, then adjusting using routine techniques to yield the poorly soluble under these conditions. It is understood by the appropriate drug levels based on the approved dosage forms. one of ordinary skill in the art that Such salts or complexes Any suitable amount of drug containing microparticles or may also be used to formulate an immediate release dosage coated microparticles can be included in the final formula form without a Sustained release portion. tion. The selection of a Suitable amount of drug containing 0083. Additional mechanisms to reduce the potential for microparticles depends on the dosage desired and is readily abuse can also be incorporated during the process of formu determined by those skilled in the art. US 2014/O 105987 A1 Apr. 17, 2014

0089. In addition to oral administration, some embodi 0100 Microparticles (Formulations A, B, C or D, all 20-40 ments may also be administered by other routes, including: mesh in starting particle size) or tablets were crushed using a but not limited to, rectal and nasal administration. Some glass mortar & pestle. The resulting crushed material was embodiments may also be suitable for formulation as oral placed in a dissolution vessel equipped with paddles (USP liquids. Apparatus II).900 mL of 0.1NHC1 pre-warmed to 37°C. was 0090 The present composition and method of making and added to the vessels and stirred for 15 minutes. After 15 using the composition will be further understood by reference minutes the amount of oxycodone released was determined. to the following non-limiting examples. The results are shown in Table 2.

EXAMPLES TABLE 2 Example 1 Drug Release from Crushed Compositions % Released in Preparation of Drug Containing Microparticles 15 minutes in O.1NHCI 0091 Sample (n = 3) TABLE 1. Oxycontin (R) (40 mg Tablet) 95.6+f- 2.7 Formulation A 31.6 +/- 2.6 Compositions (microparticles containing 40 mg oxycodone HCl equivalent) Composition Composition Composition Composition Formulation B 19.7 +/- 1.4 of of of of (microparticles containing 40 mg Formulation Formulation Formulation Formulation oxycodone HCl equivalent) Ingredient A. B C D Formulation C 14.8 +/- 1.1 (microparticles containing 20 mg Oxycodone 5g 5g 10 g 5g oxycodone HCl equivalent) Base Formulation D 18.2 +/- 1.6 Myristic Acid 50 g 30 g (microparticles containing 20 mg Stearic Acid 34g 34g oxycodone HCl equivalent) Yellow 10 g 10 g 10 g Beeswax Carnauba wax 5g 10 g 20 g 10 g 01.01. As illustrated in the table above, the microparticle compositions of Example 1 release only a fraction of the total drug load in simulated Stomach conditions when crushed. In Procedure: contrast, a currently marketed Sustained release composition, OxyContin R, releases approximately 96% of the drug load 0092] 1. Fatty acid (myristic or stearic acid) was melted in when crushed and exposed to identical conditions. an erlenmeyer flask in a silicone oil bath at 100° C. The mixture was stirred and kept under an argonblanket for this Example 3 and all Subsequent steps. 0093. 2. Oxycodone base was introduced into the molten Preparation of Oxycodone Containing Microparticles fatly acid and the melt was stirred until the oxycodone base Using a Spinning Disk Atomization Process was completely dissolved and a clear liquid was formed. 0094 3. Yellow beeswax was added and dissolved under constant stirring. Batch Size: 1000 g 0.095 4. Carnauba wax was added and dissolved under 01.02 constant stirring. 0096 5. The resulting homogeneous molten solution was poured onto aluminum foil and allowed to solidify at room temperature. Component Quantity(g) Batch 0097 6. The bulk material obtained was combined with Oxycodone base 91 Small quantities of dry ice and Subjected to size reduction in Myristic acid 545 a mortar and pestle. Beeswax 182 0098 7. The dry ice was allowed to dissipate and the Carnauba Wax 182 particles were sieved to obtain various size ranges. Par Total 1OOO.O ticles 20-40 mesh in size (400-84.1 micron) were subjected to testing. Example 2 Procedure: 0103 1. Myristic acid was melted at 85°C. in a silicone oil Release of Drug From Crushed Microparticles bath while constantly flowing argon above the surface of 0099. In vitro testing was conducted in order to assess the the solution. influence of crushing of the microparticles produced in 0104 2. Beeswax was added to the molten fatty acid and Example 1 on the release in simulated stomach conditions. A mixed until a clear, homogeneous Solution was obtained. currently marketed Sustained release formulation of oxyc 0105 3. Carnauba wax was added to the molten solution odone, OxyContin R, was also subjected to crushing and dis and mixed until a clear, homogeneous Solution was Solution for comparison purposes. obtained. US 2014/O 105987 A1 Apr. 17, 2014

0106 4. Oxycodone base was added to the molten solution patient in need thereof an abuse-deterrent oral dosage form and mixed until a clear, homogeneous Solution was comprising a plurality of microparticles, where each micro obtained. particle comprises: 0107 5. The resulting molten solution was transferred to a a fatty acid salt of one or more drugs prone to abuse; and feed kettle and continuously metered onto a spinning disk one or more carrier material(s) comprising fats, fatty Sub atomizer in order to form solid, spherical microparticles. stances, waxes, wax-like Substances or mixtures thereof Example 4 wherein the oral dosage form retards the release of the one or more drugs prone to abuse, even if the physical integrity of the Preparation of Coated Drug Containing dosage form is compromised and the compromised dosage Microparticles form is placed in water. 0108. The drug-containing particles from Example 3 can 31. A method of administering an abuse-deterrent pharma be spray coated with cellulose acetate phthalate ceutical composition comprising orally administering to a patient in need thereof an abuse-deterrent oral dosage form Example 5 comprising a plurality of microparticles, where each micro particle comprises: Preparation of Oxymorphone Containing Microparticles a solidified solution of a fatty acid salt of one or more drugs prone to abuse; and Batch Size: 630.6 g. one or more carrier material(s) comprising fats, fatty Sub 0109 stances, waxes, wax-like Substances or mixtures thereof. 32. The method of claim 31, wherein the oral dosage form retards the release of the one or more drugs prone to abuse, even if the physical integrity of the dosage form is compro Component Quantity(g), Batch mised and the compromised dosage form is placed in water. Oxymorphone base 60 33. The method of claim 30 or 31, wherein the one or more Stearic Acid 420 drugs prone to abuse is an opioid. Beeswax 30 Carnauba Wax NF 120 34. The method of claim33, wherein the opioid is an opioid Butylated Hydroxyanisole O.6 agonist. 35. The method of claim 34, wherein the opioid agonist is Total 630.6 hydrocodone, hydromorphone, morphine, oxycodone, oxy morphone or tramadol. 36. The method of claim 30 or 31, wherein the fatty acid Procedure: salt is the Stearate, palmitate or the myristate fatty acid salt. 0110 1. Stearic acid was melted in an erlenmeyer flaskin 37. The method of claim 30 or 31, wherein the one or more a silicone oil bath at 100° C. Note the composition was carrier materials comprise myristic acid, Stearic acid, palmitic Subjected to stirring and was kept under an argon blanket acid, beeswax, carnauba wax, hydrogenated oil or mixtures for this and all Subsequent steps. thereof. 0111 2. Butylated hydroxyanisole was added to the mol 38. The method of claim 30 or 31, wherein the oral dosage ten Stearic acid while mixing. form is a capsule or a tablet. 0112. 3. Oxymorphone base was introduced into the mol 39. The method of claim 30 or 31, wherein the oral dosage ten fatty acid and the melt was stirred until all oxymor form further comprises an antioxidant. phone base dissolved and a clear liquid was formed. 40. The method of claim 39, wherein the antioxidant com 0113 4. Beeswax was added and dissolved under constant prises butylated hydroxytoluene (BHT); ascorbic acid, its stirring. salts and esters; Vitamin E, tocopherol and its salts; sodium 0114 5. Carnauba wax was added and dissolved under metabisulphite; cysteine; citric acid; propyl gallate; butylated constant stirring. 0115 6. The resulting homogeneous molten solution was hydroxyanisole (BHA); or combinations thereof poured onto aluminum foil and allowed to solidify at room 41. The method of claim 30 or 31, wherein each micropar temperature. ticle further comprises an enteric coat. 0116 7. The bulk wax obtained was combined with dry ice 42. The method of claim 30 or 31, wherein the oral dosage and Subjected to size reduction in a mortar and pestle. form is a controlled-release oral dosage form. 0117 8. The dry ice was allowed to dissipate and the 43. The method of claim 30 or 31, wherein each micropar particles were sieved to obtain particles in the 40-80 mesh ticle further comprises a pharmaceutically acceptable Surfac size range. tant. 44. The method of claim 30 or 31, wherein the micropar Example 6 ticles are spherical. Preparation of Capsules for Oral Administration 45. The method of claim 30 or 31, wherein the one or more 0118. The drug containing mieroparticles from Examples drugs prone to abuse is a stimulant. 1, 3, 4, or 5 can be blended with a lubricant and incorporated 46. The method of claim 45, wherein the stimulant is into standard hard gelatin capsules amphetamine, methamphetamine or methylphenidate. 1-29. (canceled) 47. The method of claim 31, wherein the one or more drugs 30. A method of administering an abuse-deterrent pharma prone to abuse is uniformly dispersed in the carrier material of ceutical composition comprising orally administering to a each microparticle. US 2014/O 105987 A1 Apr. 17, 2014 11

48. The method of claim 31, wherein each microparticle comprises one or more fatty acids as carrier materials in an amount Sufficient to Solubilize the one or more drugs prone to abuse in the carrier material(s). 49. A method for the management of pain comprising administering to a patient in need thereof an abuse-deterrent oral dosage form comprising a plurality of microparticles, where each microparticle comprises: a fatty acid salt of one or more drugs prone to abuse; and one or more carrier material(s) comprising fats, fatty Sub stances, waxes, wax-like Substances or mixtures thereof wherein the oral dosage form retards the release of the one or more drugs prone to abuse, even if the physical integrity of the dosage form is compromised and the compromised dosage form is placed in water; and wherein the one or more drugs prone to abuse is an opioid. 50. The method of claim 49, wherein the opioid is an opioid agonist. 51. The method of claim 50, wherein the opioid agonist is hydrocodone, hydromorphone, morphine, oxycodone, oxy morphone or tramadol. k k k k k