US 2010.0260834A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0260834 A1 Hirsh et al. (43) Pub. Date: Oct. 14, 2010

(54) ABUSE-DETERRENT A69/48 (2006.01) FORMULATIONS A6IP 25/04 (2006.01) (75) Inventors: Jane C. Hirsh, Wellesley, MA (52) U.S. Cl...... 424/451; 514/282; 424/490; 424/498: (US); Alison B. Fleming, 424/491; 424/493 Mansfield, MA (US); Roman V. Rariy, Philadelphia, PA (US); (57) ABSTRACT Alexander M. Klibanov, Boston, MA (US) An abuse-deterrent pharmaceutical composition has been developed to reduce the likelihood of improper administra Correspondence Address: tion of , especially drugs such as opiods. In the preferred Pabst Patent Group LLP embodiment, the drug is modified to increase its lipophilicity 1545 PEACHTREE STREET NE, SUITE 320 by forming a salt between the drug and one or more fatty acids ATLANTA, GA 30309 (US) wherein the concentration of the one or more fatty acids is one to 15 times the molar amount of the active agent, preferably (73) Assignee: Collegium Pharmaceutical, Inc. two to ten times the molar amount of the active agent. In one embodiment the modified drug is homogeneously dispersed (21) Appl. No.: 12/823,628 within microparticles composed of a material that is either slowly soluble or not soluble in water. In some embodiments (22) Filed: Jun. 25, 2010 the drug containing microparticles or drug particles are coated with one or more coating layers, where at least one Related U.S. Application Data coating is water insoluble and preferably organic solvent (63) Continuation of application No. 1 1/149.867, filed on insoluble. The abuse-deterrent composition prevents the Jun. 10, 2005, now Pat. No. 7,771,707. immediate release of a Substantial portion of drag, even if the physical integrity of the formulation is compromised (for (60) Provisional application No. 60/579,191, filed on Jun. example, by chopping with a blade or crushing) and the 12, 2004. resulting material is placed in water, Snorted, or Swallowed. However, when administered as directed, the drug is slowly Publication Classification released from the composition as the composition is broken (51) Int. C. down or dissolved gradually within the GI tract by a combi A 6LX 9/50 (2006.01) nation of enzymatic degradation, Surfactant action of bile A6 IK 3/485 (2006.01) acids, and mechanical erosion. Patent Application Publication Oct. 14, 2010 Sheet 1 of 2 US 2010/0260834 A1

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Sunou21ÁqpasD3|94%,O6:436IDL• Patent Application Publication Oct. 14, 2010 Sheet 2 of 2 US 2010/0260834 A1

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A/6. 2 US 2010/0260834 A1 Oct. 14, 2010

ABUSE-DETERRENT DRUG 0005. In recent years, there have been numerous reports of FORMULATIONS Oxycodone diversion and abuse in several states. For example, DEA's Office of Diversion Control reported 700 CROSS-REFERENCE TO RELATED OxyContin R thefts in the U.S. between January 2000 and APPLICATIONS June 2001. Some of these reported cases have been associated with serious consequences including death. 0001. This application claims priority under 35 U.S.C. 0006. Oxycodone is a controlled substance in Schedule II S119 to U.S. Provisional Application No. 60/579,191, filed of the Controlled Substances Act (CSA), which is adminis Jun. 12, 2004 entitled “Abuse-Deterrent Drug Formulations'. tered by the Drug Enforcement Administration (DEA). Despite the fact that Schedule II provides the maximum FIELD OF THE INVENTION amount of control possible under the CSA for approved drug 0002 The present invention is generally in the field of products, in practice, it is difficult for law enforcement agen pharmaceutical compositions, specifically compositions cies to control the diversion or misuse of legitimate prescrip tions. Although abuse, misuse, and diversion are potential designed to reduce the potential for improper administration problems for all opioids, including Oxycodone, opioids are a of drugs that are Subject to abuse. very important part of the medical arsenal for the manage ment of pain when used appropriately under the careful Super BACKGROUND OF THE INVENTION vision of a physician. 0003 Oxycodone, morphine, and other opioid analgesics 0007 Currently available formulations for such drugs are are therapeutically useful and effective , e.g., as designed for oral administration but do not include mecha pain killers, when administered orally. Unfortunately, they nisms to prevent or retard improper methods of administra also pose a severe threat for willful abuse due to their ability tion Such as chewing, injection and Snorting. This represents to alter mood and/or cause a sense of euphoria. Currently a serious problem given the large number of legitimate pre available Sustained release formulations of such drugs, which scriptions written in the U.S.; for example, the medical use of contain a relatively large amount of drug intended to be opioids within the U.S. increased 400% from 1996 to 2000. released from the formulation over an extended period of The problems with abuse are significant and longstanding, time, are particularly attractive to abusers since the Sustained and efforts to design new abuse-resistant or abuse-deterrent release coating can be destroyed by crushing or grinding the formulations have been largely unsuccessful. U.S. Pat. Nos. formulation. The crushed material no longer controls the 3,980,766, 4,070,494 and 6,309,668 describe formulations release of drug. Depending on the drug, abusers can then (1) designed to prevent the injection of compositions meant for snort the material, (2) swallow the material or (3) dissolve the oral administration. U.S. Pat. No. 3,980,766 describes the material in water and Subsequently inject it intravenously. incorporation of an ingestible solid which causes a rapid The dose of drug contained in the formulation is thus increase in Viscosity upon concentration of an aqueous solu absorbed immediately through the nasal or GI mucosa (for tion thereof. U.S. Pat. No. 4,070,494 describes the incorpo Snorting or Swallowing, respectively) or is administered sys ration of a non-toxic, water gelable material in an amount temically in a bolus via the circulatory system (for IV injec Sufficient to render the drug resistant to aqueous extraction. tion). These abuse methods result in the rapid bioavailability U.S. Pat. No. 6,309,668 describes a tablet for oral adminis of relatively high doses of drug, giving the abuser a "high”. tration containing two or more layers comprising one or more Since relatively simple methods (crushing, grinding, chewing drugs and one or more gelling agents within separate layers of and/or dissolution in water) can be used to transform Such the tablet. The resulting tablet forms a gel when combined formulations into an abusable form, they provide virtually no with the volume of water necessary to dissolve the drug; this deterrent to a potential abuser. formulation thus reduces the extractability of the drug from 0004 For example, the FDA recently strengthened the the tablet. It should be noted that although these compositions warnings and precautions sections in the labeling of OxyCon preclude abuse by injection, this approach fails to prevent tin R (oxycodone HC1 controlled-release) tablets, a narcotic abuse by crushing and Swallowing or Snorting the formula drug approved for the treatment of moderate to severe pain, tion, which are commonly reported methods of abuse associ because of continuing reports of abuse and diversion. Oxy ated with OxyContin R. ContinR contains oxycodone HCl (available in 10, 20, 40 and 0008 U.S. Pat. Nos. 3,773.955 and 3,966,940 describe 80 mg strengths), an opioid agonist with an addiction poten formulations containing a combination of opioid agonists and tial similar to that of morphine. Opioid agonists are Sub antagonists, in which the antagonist does not block the thera stances that act by attaching to specific proteins called opioid peutic effect when the admixture is administered orally, but receptors, which are found in the brain, spinal cord, and which does not produce analgesia, euphoria or physical gastrointestinal tract. When these drugs attach to certain dependence when administered parenterally by an abuser. opioid receptors in the brain and spinal cord they can effec U.S. Pat. No. 4,457.933 describes a method for decreasing tively block the transmission of pain messages to the brain. both the oral and parenteral abuse potential of strong analge OxyContin R is supplied in a controlled-release dosage form sic agents by combining an analgesic dose of the analgesic and is intended to provide up to 12 hours of relief from agent with an antagonist in specific, relatively narrow ratios. moderate to severe pain. The warning specifically states that U.S. Pat. Nos. 6,277,384, 6,375,957 and 6,475,494 describe the tablet must be taken whole and only by mouth. When the oral dosage forms including a combination of an orally active tablet is chewed or crushed and its contents are swallowed, opioidagonist and an orally active opioidantagonist in a ratio Snorted into the nostrils or dissolved and Subsequently that, when delivered orally, is analgesically effective but that injected intravenously, the controlled release mechanism is is aversive in a physically dependent subject. While such a destroyed and a potentially lethal dose of oxycodone formulation may be successful in deterring abuse, it also has becomes bioavailable. the potential to produce adverse effects in legitimate patients. US 2010/0260834 A1 Oct. 14, 2010

0009. It is therefore an object of the present invention to less soluble in water than the most soluble salt of the drug. provide a pharmaceutical composition that significantly The most soluble salt is selected from either alkaline metal reduces the potential for improper administration or use of salts (for acidic drugs) or acid addition salts of (for basic drugs but which, when administered as directed, is capable of drugs). delivering a therapeutically effective dose. 0017 “Microparticle' as used herein refers to a composi tion comprising a drug dispersed within a carrier material. BRIEF SUMMARY OF THE INVENTION “Coated microparticle' as used herein refers to a composition comprising a drug containing microparticle or a drug particle 0010. An abuse-deterrent pharmaceutical composition coated with one or more coating layers. Microparticles and has been developed to reduce the likelihood of improper coated microparticles have a size range of 10 to 3000 microns administration of drugs, especially drugs such as opioids. In in diameter. the preferred embodiment, the drug is modified to increase its lipophilicity by forming a salt between the drug and one or II. Compositions more fatty acids or amines, wherein the concentration of the one or more fatty acids or amines is one to fifteen times the 0018. The currently available sustained release dosage molar amount of the active agent, preferably two to ten times forms containing narcotic analgesics and other drugs are Sub the molar amount of the active agent. In one embodiment the ject to misuse, in part, because mechanical destruction of the modified drug is homogeneously dispersed within micropar dosage form exposes the encapsulated drug and allows for ticles composed of a material that is either slowly soluble or immediate dissolution of the drug into aqueous media. Two insoluble in water. In some embodiments the drug containing properties of the dosage form that contribute to this outcome microparticles or drug particles are coated with one or more are (1) the ease with which drug is exposed to the extraction coating layers. The abuse-deterrent composition prevents the media and (2) the high water solubility of the drug salt form. immediate release of a Substantial portion of drug, even if the 0019. In the composition disclosed herein, one or both of physical integrity of the formulation is compromised (for these properties are altered in order to achieve an abuse example, by chopping with a blade or crushing) and the deterrent composition. Specifically, in the preferred embodi resulting material is placed in water, Snorted, or Swallowed. ment, the drug is modified to increase its lipophilicity and, in However, when administered as directed, the drug is slowly additional preferred embodiments, is then homogeneously released from the composition as the composition is broken dispersed within a material that is either slowly soluble or not down or dissolved gradually within the GI tract by a combi soluble in water and Subsequently formulated into micropar nation of enzymatic degradation, surfactant action of bile ticles. The drug may be present in the form of discrete par acids, and mechanical erosion. ticles or may be partially or fully dispersed in the carrier material on a molecular level. BRIEF DESCRIPTION OF THE DRAWINGS 0020. The abuse deterrent composition preferably com prises a drug modified to increase its lipophilicity. In other 0011 FIG. 1 is an illustration of the testing procedures for preferred embodiments, the drug is homogenously dispersed determining abuse resistance of the formulations. within microparticles composed of a material that is either 0012 FIG. 2 is a graph showing the percentage of oxyc slowly soluble in water or water insoluble. The compositions odone released in Oral Abuse Testing as a function of com slow the release of drug if the dosage form is chopped or position. crushed and the resulting material is placed in water, Snorted, or Swallowed since most of the drug will remain associated DETAILED DESCRIPTION OF THE INVENTION with or entrapped within portions of the core material of the I. Definitions microparticles. In some embodiments the drug containing microparticles or individual drug particles are coated with 0013 “Composition” as used herein refers to the drug one or more coating layers, where at least one coating is water dosage unit for administration to a patient. It may also be used insoluble and preferably organic solvent insoluble, but enzy in reference solely to the active ingredient, or to the formu matically degradable. The components of the resulting coated lation containing the active ingredient. microparticles are not mutually soluble in water, organic Sol 0014 Abuse-deterrent composition” or “abuse-deterrent vents, or any combination thereof. Such that no one solvent or formulation” are used interchangeably herein to refer to com enzyme solution is capable of dissolving the formulation in positions that reduce the potential for improper administra its entirety in vitro. It follows that extraction of the drug from tion of drugs but that deliver a therapeutically effective dose the formulation cannot be carried out in one step. However, when administered as directed. Improper administration when administered as directed, the drug is slowly released includes tampering with the dosage form and/or administer from the formulation since it is eroded within the environ ing the drug by any route other than instructed. ment of the gastrointestinal tract. 00.15 “Drug”, “active agent, and “pharmacologically 0021 A. Drugs to be Formulated active agent” are used interchangeably herein to refer to a 0022. There are many drugs that it is desirable to deliver chemical compound that induces a desired pharmacological using the compositions described herein. The Controlled and/or physiological effect. The terms also encompass phar Substances Act (CSA), Title II of the Comprehensive Drug maceutically acceptable derivatives of those active agents Abuse Prevention and Control Act of 1970, places all sub specifically mentioned herein, including, but not limited to, stances that are regulated under existing federal law into one salts, Solvates, hydrates, complexes with one or more mol offive schedules based upon the substance's medicinal value, ecules, prodrugs, active metabolites, lipophilic derivatives, harmfulness, and potential for abuse or addiction. Drugs that analogs, and the like. are preferred include those classified as Schedule II, III, IV 0016 “Lipophilic derivative' and “lipophilic drug deriva and V drugs. Drugs that are most preferable include those, tive', as used herein, refer to derivatives of the drug that are like oxycodone, that are currently formulated as Sustained or US 2010/0260834 A1 Oct. 14, 2010

controlled release compositions, where drug release is nil, , cathine, , , chloral intended to occur over a prolonged period of time through the hydrate, , , chlorhexadol, chlo gastrointestinal tract, and immediate or burst release, for rmethiazole edisylate, , , cloba example, by inhalation or injection, is undesirable. As used Zam, potassium , , , cyclo herein, drugs prone to abuse refer to controlled Substance barbitone, , dexfenfluramine, , specified as schedule II, II, IV and V drugs. diethylpropion, , difenoxin, enciprazine, esta 0023 The terms “drug”, “active agent, and “pharmaco Zolam, , , , fencam logically active agent” are used interchangeably herein to famin, fenfluramine, fenproporex, fluianisone, , refer to a chemical compound that induces a desired pharma flunitraam, , , , cological, physiological effect. The terms also encompass , , , , hexobarbi pharmaceutically acceptable derivatives of those active tone, ibomal, , , mesylate, agents specifically mentioned herein, including, but not lim , , mazindol, , ited to, salts, Solvates, hydrates, complexes with one or more , mefenorex, mephobarbital, , molecules, prodrugs, active metabolites, lipophilic deriva , , , methylpen tives, analogs, and the like. When the terms “active agent'. tynol, , , milaZolam, mor “pharmacologically active agent' and "drug” are used, or phine, , , nordiazepam, , when a particular drug, Such as Oxycodone, is identified, it is , , pemoline, pentabarbitone, pentaZo to be understood as including the active agent perse as well as cine, , phencyclidine, , phendime pharmaceutically acceptable salts, Solvates, hydrates, com trazine, phenmetrazine, , phentermine, phen plexes with one or more molecules, prodrugs, active metabo yacetone, , pipradol, , proxibarbal, lites, and lipophilic derivatives and analogs. , quinalbaritone, , secbutobarbitone, 0024 Examples of preferred drugs include, 1-phenylcy Sibutramine, , , , , clohexylamine, 1-piperidinocyclohexanecarbonitrile, alfen Zalepan, , , , and . In a tanil, alphacetylmethadol, alphaprodine, , preferred embodiment, the pharmaceutically active agent is , amphetamine, anileridine, apomorphine, oxycodone. , , barbituric acid derivative, bemidone, Certain compounds described herein may exist in particular benzoylecgonine, benzphetamine, betacetylmethadol, betap geometric or Stereoisomeric forms. The compositions dis rodine, bezitramide, , buprenorphine, butabar closed herein contemplate all Such compounds, including cis bital, , butorphanol, , cathine, chloral, and trans-isomers, R- and S-enantiomers, diastereomers, (D)- chlordiazepoxide, , , cloraZepate, clo isomers, (L)-isomers, the racemic mixtures thereof, com tiazepam, cloxazolam, cocaine, codeine, chlorphentermine, pounds of different spatial conformations, and other mixtures delorazepam, dexfenfluramine, dextromoramide, dextropro thereof Additional asymmetric carbon atoms may be present poxyphen, dezocine, diazepam, diethylpropion, difenoxin, in a substituent Such as an alkyl group. dihydrocodeine, dihydromorphine, dioxaphentyl butyrate, 0026. As used herein, “pharmaceutically acceptable salts' dipanone, diphenoxylate, diprenorphine, ecgonine, enado refer to derivatives of the disclosed compounds wherein the line, eptazocine, , ethoheptazine, ethyl loflazepate, parent compound is modified by making acid or base salts ethylmorphine, etorphine, femproponex, fencamfamin, fen thereof. Examples of pharmaceutically acceptable salts fluramine, fentanyl, fludiazepam, flunitrazepam, flurazepam, include, but are not limited to, mineral or organic acid salts of glutethimide, halazepam, haloxazolam, hexylgon, hydroc basic residues such as amines; alkali or organic salts of acidic odone, hydromorphone, isomethadone, hydrocodone, ket residues such as carboxylic acids; and the like. The pharma amine, ketazolam, ketobemidone, levanone, levoalphacetyl ceutically acceptable salts include the conventional non-toxic methadol, levomethadone, levomethadyl acetate, salts or the quaternary ammonium salts of the parent com , , lofentanil, loperamide, lopra pound formed, for example, from non-toxic inorganic or Zolam, lorazepam, lormetazepam, lysergic acid, lysergic acid organic acids. For example, Such conventional non-toxic salts amide, mazindol, medazepam, mefenorex, meperidine, include those derived from inorganic acids such as hydro meptazinol, metazocine, methadone, methamphetamine, chloric, hydrobromic, Sulfuric, Sulfamic, phosphoric, nitric methohexital, methotrimeprazine, methyldihydromorphi and the like; and the salts prepared from organic acids such as none, methylphenidate, methylphenobarbital, metopon, mor acetic, propionic, Succinic, glycolic, Stearic, lactic, malic, phine, nabilone, nalbuphine, nalbupine, nalorphine, narceline, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phe nefopam, nicomorphine, nimetazepam, nitrazepam, nordiaz nylacetic, glutamic, benzoic, Salicylic, Sulfanilic, 2-acetoxy epam, normethadone, normorphine, oxazepam, oxazolam, benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane oxycodone, oxymorphone, pentazocine, pentobarbital, phen disulfonic, oxalic, and isethionic. adoxone, phenazocine, phencyclidine, phendimetrazine, 0027. The pharmaceutically acceptable salts of the com phenmetrazine, pheneridine, piminodine, prodilidine, prope pounds can be synthesized from the parent compound, which ridine, propoxyphene, racemethorphan, racemorphan, contains a basic or acidic moiety, by conventional chemical racemoramide, remifentanil, secobarbital, Sufentanil, talb methods. Generally, Such salts can be prepared by reacting the utal, thebaine, , thiopental, tramadol, trimeperidine, free acid or base forms of these compounds with a stoichio and . metric amount of the appropriate base or acid in water or in an 0025. In addition to the compounds above, the following organic solvent, or in a mixture of the two: generally, non scheduled drugs may be incorporated into the composition: aqueous media like ether, ethyl acetate, ethanol, isopropanol, allobarbitone, alprazolam, amylobarbitone, aprobarbital, oracetonitrile are preferred. Lists of suitable salts are found in barbital, barbitone, benzphetamine, , bro Remington's Pharmaceutical Sciences, 20th ed., Lippincott mazepam, , , butalbital, butobarbitone, Williams & Wilkins, Baltimore, Md., 2000, p. 704, the dis butorphanol, camazepam, , , carfenta closure of which is hereby incorporated by reference. US 2010/0260834 A1 Oct. 14, 2010

0028 Optionally, the composition described herein can ceutically active agent. The mass of fatty acid or amine further include a drug having no appreciable abuse potential. required to dissolve the active agent is a function of the chain 0029. In preferred embodiments, the solubility character length of the fatty acid or amine. For example, oxycodone istics of a drug are altered prior to incorporation into the base can be dissolved in a molten mixture of Stearic and formulation. Modification of the drug to produce a more plamitic acids at a ratio of 1:5, by weight, or in molten myris lipophilic derivative serves to reduce the water solubility of tic acid at a ratio of 1:4, by weight. The factors determining the drug and thus reduces the aqueous extractability. Further the amount offatty acid oramine required to dissolve a given more, if the drug is made more lipophilic, it can be solubilized amount of base include but are not limited to base strength, in a fatty Substance or wax like mixture, rather than physically acid strength, Steric hindrance of the portions of the acid dispersed in a particulate form. Solubilization of drug and/or base molecule involved in salt formation, and the enhances the abuse-deterrent properties of microparticles for ability of the base to form non-ionic interactions (i.e. hydro mulated from the mixture as it is difficult to extract drug from gen bonds), with the acid molecules. an intimately dispersed composition. 0035. Other salts which may increase lipophilicity and, 0030. Some of the methods that can be used to alter the hence, lipid solubility relative to the parent drug compound drug's lipophilicity are outlined below. It is understood that include, but are not limited to, pectinate, tannate, phytate, two or more approaches can be combined to achieve a desired salicylate, Saccharinate, acesulfamate, gallate, and terephtha solubility profile. late salts. 0031 B. Lipophilic Drug Formulations 0036. In another embodiment, a drug is covalently modi 0032. In one embodiment, drug is made more lipophilic by fied to increase its lipophilicity. For example, a lipophilic eliminating or reducing the overall charge of the drug mol compound can be covalently attached to a drug molecule via ecule. For example, for a basic drug, a water soluble salt (Such an ester oramide linkage. Such drug derivatives are cleaved in as hydrochloride, Sulfate, or maleate) can be converted to a Vivo, thus releasing the parent compound. free base using techniques known in the art. Correspondingly, 0037 C. Drug Containing Microparticles in the case of an acidic drug, a water Soluble salt (Such 0038. In preferred embodiments, drugs are formulated Sodium, potassium, or the like) can be converted to a free acid. with a carrier material to form microparticles. As used herein, 0033. In another embodiment, the drug's lipophilicity is the term “microparticle' refers to a composition comprising a increased by forming a salt between a drug molecule and one drug dispersed within a carrier material and "coated micro or more charged lipophilic compounds. In this case the lipo particle' refers to a composition comprising a drug contain philicity of the resulting salt can be manipulated by varying ing microparticle or a drug particle coated with one or more the lipophilicity of the counter-ion. In general lipophilic coating layers of material. Microparticles and coated micro (fatty) acids oramines with chain lengths between Cs-Co are particles have a size range of 10 to 3000 microns in diameter. suitable lipophilic counter-ion candidates. Suitable (fatty) 0039. Within microparticles, drug is preferably homoge acids and amines include, but are not limited to, pentanoic neously dispersed in the form of fine particles within the acid, hexanoic (caproic) acid, heptanoic acid, octanoic (ca carrier material. More preferably, drug is partially solubilized prylic) acid, nonanoic acid, decanoic (capric) acid, unde in molten carrier material or partially dissolved with the car canoic acid, dodecanoic (lauric) acid, tridecanoic acid, tet rier material in a mutual solvent during the formulation of the radecanoic (myristic) acid, pentadecanoic acid, hexadecanoic microparticles. Most preferably, drug is completely solubi (palmitic) acid, heptadecanoic (margaric) acid, octadecanoic lized in the carrier material or completely dissolved with the (Stearic) acid, nonadecanoic acid, eicosanoic (arachidic) acid, carrier material in a co-solvent during the formulation of the heneicosanoic acid, docosanoic (behenic) acid, tricosanoic microparticles. This is accomplished through the selection of acid, tetracosanoic (lignoceric) acid, pentacosanoic acid, materials and the manner in which they are processed. hexacosanoic acid, heptacosanoic acid, octacosanoic acid, 0040 Carrier materials appropriate for the fabrication of nonacosanoic acid, triacontanoic acid, linoleic acid, oleic drug containing microparticles are either slowly soluble in acid, octyl amine, lauryl amine, Stearyl amine, palmityl water or insoluble in water, but capable of degrading within amine, linoleylamine, and oleylamine and mixtures thereof. the GI tract by means including enzymatic degradation, Sur In a preferred embodiment, the fatty acid is myristic acid or a factant action of bile acids and mechanical erosion. As used mixture of stearic and palmitic acid. The fatty acid oramine is herein, the term “slowly soluble in water refers to materials present in an amount from about one to about fifteen times the that are not dissolved in water within a period of 30 minutes. molar amount of the pharmaceutically active agent, prefer Preferred examples include fats, fatty Substances, waxes, ably two to ten times the molar of amount of the pharmaceu wax-like substances and mixtures thereof. Suitable fats and tically acceptable agent. fatty Substances include fatty (such as lauryl, myri 0034. The formation of a salt composed of a pharmaceu styl Stearyl, cetyl or cetostearyl ), fatty acids and tically active agent and a fatty acid or amine can be accom derivatives, including but not limited to fatty acid esters, fatty plished by a melt process, with or without the use of a solvent. acid glycerides (mono-, di- and tri-glycerides), and hydroge One or more fatty acids or amines are heated above their nated fats. Specific examples include, but are not limited to melting point and the pharmaceutically active agent, in free castor oil, safflower oil, olive oil, canola oil, sunflower oil, base or acid form, is added to the molten fatty acid or amine Vegetable oil, corn oil, hydrogenated vegetable oil, hydroge either directly or after dissolution of the active agent in an nated cottonseed oil, hydrogenated castor oil, hydrogenated appropriate solvent, Such as methylene chloride. The lipo oils available under the trade name SteroteXCR), stearic acid, philic compound is present in excess (on a molar basis) rela cocoa butter, and Stearyl alcohol. Oils and hydrogenated oils tive to the pharmaceutically active agent. The lipophilic com in admixture with one another may also be used as carrier pound is present, preferably, in an amount one to fifteen times materials. Suitable waxes and wax-like materials include the molar amount of the pharmaceutically active agent, more natural or synthetic waxes, hydrocarbons, and normal waxes. preferably, two to ten times the molar amount of the pharma Specific examples of waxes include beeswax, glycowax, cas US 2010/0260834 A1 Oct. 14, 2010

tor wax, carnauba wax, paraffins and candelilla wax. As used ton The science and practice of pharmacy”. 20" Edition, herein, a wax-like material is defined as any material which is Jennaro et. Al. (Phila, Lippencott, Williams, and Wilkens, normally solid at room temperature and has a melting point of 2000). from about 30 to 300° C. In a preferred embodiment, the 0045. For some carrier materials it may be desirable to use carrier is beeswax, carnauba wax or a mixture thereof. a solvent evaporation technique to produce drug containing 0041. In some cases, it may be desirable to alter the rate of microparticles. In this case drug and carrier material are co water penetration into the hydrophobic drug containing dissolved in a mutual solvent and microparticles can Subse microparticles. To this end, rate-controlling (wicking) agents quently be produced by several techniques including, but not may beformulated along with the fats or waxes listed above. limited to, forming an emulsion in water or other appropriate Examples of rate-controlling materials include certain starch media, spray drying or by evaporating off the solvent from the derivatives (eg, waxy maltodextrin and drum dried corn bulk solution and milling the resulting material. starch), cellulose derivatives (eg. hydroxypropylmethylcellu 0046. In addition to modification of the drug itself, pro lose, hydroxypropylcellulose, methylcellulose, and car cessing conditions can be used to influence the dispersion of boxymethylcellulose), alginic acid, lactose and talc. Addi the drug within water-insoluble or slowly water soluble mate tionally, a pharmaceutically acceptable Surfactant (for rial. For example, in the case where the water in-soluble or example, lecithin) may be added to facilitate the degradation slowly soluble material is melted and drug is fully or partially of Such microparticles. dissolved under Stirring conditions, the temperature, agitation 0.042 Proteins which are water insoluble, such as Zein, are rate and time of processing will influence the degree of dis preferred carrier materials for the formation of drug contain Solution achieved. More specifically, a more homogenous ing microparticles. Additionally, proteins, polysaccharides dispersion may be achieved with a higher temperature, faster and combinations thereof which are water soluble can be stirring rate and longer processing time. Ultrasound can also formulated with drug into microparticles and Subsequently be applied to the molten mixture to increase the degree of cross-linked to form an insoluble network. For example, dispersion and/or the rate of dissolution of the drug. cyclodextrins can be complexed with individual drug mol 0047. In some embodiments, drug in a particulate form is ecules and Subsequently cross-linked. homogeneously dispersed in a water-insoluble or slowly 0043. Certain polymers may also be used as carrier mate water soluble material. To minimize the size of the drug rials in the formulation of drug containing microparticles. particles within the composition, the drug powder itself may Suitable polymers include ethylcellulose and other natural or be milled to generate fine particles prior to formulation. The synthetic cellulose derivatives. Polymers which are slowly process ofjet milling, known in the pharmaceutical art, can be soluble and form a gel in an aqueous environment, Such as used for this purpose. In some embodiments drug in a par hydroxypropyl methylcellulose or polyethylene oxide may ticulate form is homogeneously dispersed in a wax or wax also be suitable as carrier materials for drug containing like Substance by heating the wax or wax like Substance above microparticles. its melting point and adding the drug particles while stirring 0044) Encapsulation or incorporation of drug into carrier the mixture. In this case a pharmaceutically acceptable Sur materials to produce drug containing microparticles can be factant may be added to the mixture to facilitate the dispersion achieved through known pharmaceutical formulation tech of the drug particles. niques. To create a composition that protects drug from expo 004.8 D. Coated Drug Containing Microparticles Sure upon mechanical disruption (eg, grinding, chewing, or 0049. In some embodiments, drug containing micropar chopping), the drug is intimately dispersed within the carrier ticles or drug particles are encapsulated within at least one material. In the case of formulation in fats, waxes or wax-like water-insoluble enzymatically degradable material. In some materials, the carrier material is heated above its melting instances the Substrates of digestive enzymes are naturally temperature and the drug is added to form a mixture compris water-insoluble and can be utilized in the formulation without ing drug particles Suspended in the carrier material, drug further processing. Solid esters of fatty acids, which are dissolved in the carrier material, or a mixture thereof. Micro hydrolyzed by lipases, can be spray coated onto micropar particles can be subsequently formulated through several ticles or drug particles. Zein is an example of a naturally methods including, but not limited to, the processes of con water-insoluble protein. It can be coated onto drug containing gealing, extrusion, spray chilling or aqueous dispersion. In a microparticles or drug particles by spray coating or by wet preferred process, wax is heated above its melting tempera granulation techniques. In addition to naturally water-in ture, drug is added, and the molten wax-drug mixture is soluble materials, some Substrates of digestive enzymes can congealed under constant stirring as the mixture cools. Alter be treated with cross-linking procedures, resulting in the for natively, the molten wax-drug mixture can be extruded and mation of non-soluble networks. Many methods of cross spheronized to form pellets or beads. For formulations com linking proteins, initiated by both chemical and physical prising salts composed of a pharmaceutically active agent and means, have been reported. One of the most common meth one or more fatty acids or amines, the one or more fatty acids ods to obtain cross-linking is the use of chemical cross-link or amines are melted and mixed with the free base or acid ing agents. Examples of chemical cross-linking agents form of the active agent at a temperature above the melting include aldehydes (gluteraldehyde and formaldehyde), epoxy point(s) of the fatty acid(s) or amine(s) but below the melting compounds, carbodiimides, and genipin. In addition to these point of the active agent. Once a homogeneous mixture is cross-linking agents, oxidized and native Sugars have been formed, a carrier material Such as a fat, fatty Substance, wax or used to cross-link gelatin (Cortesi, R., et al., Biomaterials 19 wax-like substance can be added to the molten mixture to (1998) 1641-1649). Cross-linking can also be accomplished yield a single phase composition. The molten solution is using enzymatic means; for example, transglutaminase. solidified and formulated into microparticles. Detailed Finally, cross-linking can be initiated by physical means Such descriptions of these processes can be found in "Reming as thermal treatment, UV irradiation and gamma irradiation. US 2010/0260834 A1 Oct. 14, 2010

0050. To produce a coating layer of cross-linked protein 0055 As used herein, the term water-permeable is used to Surrounding drug containing microparticles or drug particles, indicate that the fluids of the alimentary canal will permeate a water Soluble protein can be spray coated onto the micro or penetrate the coating film with or without dissolving the particles and Subsequently cross-linked by the one of the film or parts of the film. Depending on the permeability or methods described above. Alternatively, drug containing solubility of the chosen coating (polymer or polymer mix microparticles can be microencapsulated within protein by ture) a lighter or heavier application thereof is required to coacervation-phase separation (for example, by the addition obtain the desired release rate. of salts) and Subsequently cross-linked. Some Suitable pro teins for this purpose include gelatin, albumin, casein, and 0056 E. Dosage Forms gluten. 0057 There are a number of drug compositions that meet 0051 Polysaccharides can also be cross-linked to form a the abuse deterrent criteria outlined above. In one embodi water-insoluble network. For many polysaccharides, this can ment a drug is homogeneously dispersed, in a fine particulate be accomplished by reaction with calcium salts or multivalent form, within a water-insoluble or slowly water soluble mate cations which cross-link the main polymer chains. Pectin, rial and the mixture is formulated into microparticles. In alginate, dextran, amylose and guar gum are Subject to cross another embodiment a drug is partially dissolved within a linking in the presence of multivalent cations. Complexes water-insoluble or slowly water soluble material during the between oppositely charged polysaccharides can also be manufacturing process, for example, by mixing at a tempera formed; pectin and chitosan, for example, can be complexed ture above the melting point of the carrier material, and the via electrostatic interactions. Insoluble coatings can be mixture is formulated into microparticles. In yet another formed on particles in this fashion. It should be noted that in embodiment a drug is fully dissolved withina water-insoluble many cases polysaccharides are broken down specifically by or slowly water Soluble material during the manufacturing enzymes produced by bacteria within the colon. process, for example, by mixing at a temperature above the 0052. In some cases a water-insoluble but enzymatically melting point of the carrier material, and the mixture is for degradable coating comprising both a protein and a polysac mulated into microparticles. Instill a further embodiment, the charide can be produced if the components are oppositely drug containing microparticles, where the drug is homoge charged polyelectrolytes. Under the proper temperature, pH, neously dispersed in a particulate form, or has been partially and concentrations, the two polymers can interact through or fully dissolved within the carrier material during the manu their opposite electrical charges and form a water-insoluble complex. If a core particle is present at the time the complex facturing process, are coated with one or more coatings to phase separates, it will be coated. For example, gelatin and form coated microparticles. In a further embodiment, drug gum arabic can be coated onto a core particle utilizing this particles are coated directly with one or more coatings to form process. Optionally, the complex can be made irreversibly coated microparticles. insoluble by Subsequent cross-linking induced by chemical or 0058. The microparticles, coated microparticles, or a mix physical means. ture thereofare formed into a solid dosage form suitable for 0053. In some embodiments it may be desirable to coat the oral administration. For example, microparticles or coated drug containing microparticles with a non-enzymatically microparticles can be incorporated into hard capsules, dis degradable coating. Such coatings generally release drug via persed within a softgelatin capsule, or combined with appro diffusion through pores in the coating. priate excipients and tableted by compression. The micropar 0054. In general, any coating procedure which provides a ticles, coated microparticles, or a mixture thereof could also coating on each particle of drug containing microparticle be further dispersed in a semisolid hydrophobic material, for without significant agglomeration of particles may be used. example, a mixture of castor oil and hydrogenated castor oil. Coating procedures known in the pharmaceutical art includ 0059. In some embodiments, the compositions are coated ing, but not limited to, fluid bed coating processes, granula with an enteric coating. Enteric coatings known in the art are tion and microencapsulation may be used to obtain appropri applied directly to the abuse-deterrent microparticle or coated ate coatings. The coating materials may be any of a large microparticle compositions or are applied to the Surface of a number of natural or synthetic film-formers used singly, in capsule ortablet comprising the abuse deterrent microparticle admixture with each other, and in admixture with plasticizers and/or coated microparticle compositions. Enteric coatings (for example, Durkex 500 vegetable oil), pigments and other Substances to alter the characteristics of the coating. In gen known in the art include, for example, acrylic polymers that eral, the major components of the coating should be insoluble are commercially available under the trade name in, and permeable to, water. However, it might be desirable to EUDRAGITR), cellulose acetate phthalate, hydroxypropylm incorporate a water-soluble Substance, Such as methyl cellu ethylcellulose phthalate, polyvinylacetate phthalate, shellac, lose, to alter the permeability of the coating. The coating hydroxypropylmethylcellulose Succinate, cellulose acetate materials may be applied as a suspension in an aqueous fluid trimelliate or mixtures thereof. or as a solution in organic solvents. The water-permeable 0060 Dosage forms can include one or more drugs. When diffusion barrier may consist of ethyl cellulose, methyl cel the dosage form includes two or more drugs they can be lulose and mixtures thereof. The water-permeable diffusion Scheduled drugs or can be a combination of Scheduled and barrier may also consist of water insoluble synthetic poly non-Scheduled drugs. The drugs can be incorporated into mers sold under the trade name Eudragit(R) (Rohm Pharma), separate microparticle compositions where the Scheduled such as Eudragit RA, Eudragit RL, Eudragit NE and mixtures drugs are incorporated into abuse deterrent microparticle thereof. Other examples of Such coating materials can be compositions and the non-Scheduled drugs are incorporated found in the Handbook of Pharmaceutical Excipients, Ed. By into abuse deterrent microparticle compostions, Sustained A. Wade and P. J. Weller, (1994), incorporated by reference release compositions known in the art or immediate release herein. compositions known in the art. The compositions comprising US 2010/0260834 A1 Oct. 14, 2010

the different drugs are formulated into a single Solid dosage increase the bulk of a Solid dosage form so that a practical size form suitable for oral administration, for example, they can be is provided for compression of tablets. Examples of diluents incorporated into a gelatin capsule, or combined with appro include cellulose, dry starch, microcrystalline cellulose, priate excipients and compressed into a tablet form. dicalcium phosphate, calcium Sulfate, Sodium chloride con Examples of non-scheduled drugs that may be included in fectioner's Sugar, compressible Sugar, dextrates, dextrin, dex dosage forms described herein include, but are not limited to, trose, Sucrose, mannitol, powdered cellulose, Sorbitol, and aspirin, acetaminophen, non-steroidal anti-inflammatory lactose. Binders are used to impart cohesive qualities pow drugs, cyclooxygenase II inhibitors, N-methyl-D-aspartate dered materials and can include materials such as starch, receptor antagonists, glycine receptor antagonists, triptans, gelatin, Sugars, natural and synthetic gums, polyethylene gly dextromethorphan, promethazine, fiorinal, guaifenesin, col, ethylcellulose, methylcellulose, hydroxypropylmethyl butalbital, and caffeine. cellulose, carboxymethylcellulose, waxes and polyvinyl pyr 0061 An immediate release dose can be incorporated into rolidone. Lubricants are used to facilitate tablet manufacture; the formulation in several ways. Immediate release micropar examples of lubricants include talc, magnesium Stearate, cal ticles can be made utilizing standard methodologies and for cium Stearate, hydrogenated vegetable oils Stearic acid, mulated along with abuse-deterrent microparticle and/or Sodium Stearyl fumarate, sodium benzoate, sodium acetate, coated microparticle compositions in a Suitable oral dosage leucine, Sodium oleate, Sodium lauryl Sulfate, magnesium form. Alternatively, a coating containing drug which is avail lauryl Sulfate and polyethylene glycol. Disintegrants can be able for immediate release can be placed on a tablet compris added to pharmaceutical formulations in order to facilitate ing abuse-deterrent microparticle and/or coated microparticle “breakup” or disintegration after administration. Materials compositions plus appropriate excipients. Additionally, an used for this purpose include starches, clays, celluloses, immediate dose of drug can be granulated or blended with aligns, gums, and cross-linked polymers. A plasticizer may be rapidly dissolving excipients and Subsequently compressed included in coating materials to alter their mechanical prop (1) as one layer of bi-layer tablets in which the abuse-deter erties. Examples of plasticizers include benzyl benzoate, rent microparticle and/or coated microparticle compositions , dibutyl sebacate, diethyl phthalate, glycerin, are compressed as the other layer, or (2) as the outer layer of mineral oil, polyethylene glycol, Sorbitol, triacetin, triethyl compression-coated tablets in which the abuse-deterrent citrate, glycerol, etc. In addition to the additives above, col microparticle and/or coated microparticle compositions are oring and flavoring agents may also be incorporated into the compressed as the inner core, or (3) into tablets in which composition. abuse-deterrent microparticle and/or coated microparticle 0065 Optionally, the composition disclosed herein com compositions are embedded. prises materials wherein a combination of the materials is not 0062. In some embodiments, the immediate release por soluble in water, organic solvent, or any combination thereof. tion of the dosage form comprises a lipophilic drug derivative. For example, salt derivatives or complexes that are insoluble EXAMPLES at a neutral pH but dissociate, thereby releasing the parent compound, at an acidic pH are ideal for immediate release Example 1 within the stomach. In the case of oxycodone some salts that may exhibit this property include, but are not limited to, the Preparation and Testing of Abuse-Resistant Compo tannate, phthalate, salicylate, gallate, pectinate, phytate, sac sitions charinate, asesulfamate and terephthalate salts. Use of salts in the immediate release portion of the dosage form reduces the 0066 Compositions comprising oxycodone base, a fatty abuse potential of the immediate release dose if the formula acid and a third wax component were prepared at several tion is crushed and (1) Snorted or (2) dissolved in water since different ratios in the following manner. Oxycodone base (0.2 these salts will be poorly soluble under these conditions. It is g) and Butylated Hydroxytoluene (-4 mg) were dissolved in understood by the one of ordinary skill in the art that such methylene chloride (0.7 ml). The fatty acid(s) and wax(es) salts may also be used to formulate an immediate release were melted together at 95°C. on a heating block until clear dosage form without a Sustained release portion. solutions were obtained. The oxycodone solution was added 0063 Additional mechanisms to reduce the potential for to the molten fatty acids/waxes and mixed well. The resulting abuse can also be incorporated during the process of formu clear solutions were incubated for 20 minutes to remove the lating tablets. For example, ingredients can be added to deter solvent. The mixtures were then solidified and re-melted at chewing or Snorting of the final formulation. For example, an 95° C. as an informal test of stability (i.e. to check for base intensely bitter Substance may deter chewing, while an precipitation). Finally, the molten solutions were poured onto intensely spicy ingredient, such as capsaicin, may deter Snort sheets of aluminum foil and rapidly cooled to form solid ing. The addition of a colored dye, which would stain the skin wafers. Note that only formulations that did not show base and mucosal Surface of the nose following Snorting may also precipitation were cast into wafers and subjected to further serve to reduce this practice. analysis. 0064 Optional excipients present in the oral dosage form 0067. The wafer compositions described above were comprising abuse deterrent microparticles or coated micro crushed into particles. Sample particles were subjected to the particles include, but are not limited to diluents, binders, Oral Abuse Test (see FIG. 1 for protocol). Samples were lubricants, disintigrants, colorants, plasticizers and the like. analyzed with a UV spectrophotometer. Results are presented Diluents, also termed “fillers.” are typically necessary to in FIG. 2. US 2010/0260834 A1 Oct. 14, 2010

Example 2 0071 (3) The clear solution was poured onto a sheet of Oxycodone with Myristic Acid as a Lipophilic aluminum foil and allowed to cool rapidly to form solid Counter-Ion wafers 0068. Small batches of each microparticle composition 0072 The solid wafers produced above were crushed with were prepared with the following amounts of reagents: a mortar and pestle (Oxycodone base/Myristic Acid/Car nauba wax) or cut with a razor blade followed by crushing with a mortar and pestle (Oxycodone base/Myristic Acid/ Oxycodone base/Myristic acid/Beeswax (1:5:2 Beeswax). Crushing was carried out with the goal of reducing Ingredient Amount (g) the particle size to less than 25 mesh. For Oxycodone base/ Oxycodone base 2.2 g Myristic Acid/Beeswax, crushing was stopped prior to reach Myristic acid 11 g ing this endpoint due to the difficulty in reducing the particle Beeswax, NF 4.4 g BHT 0.011 g size of this "gummy” material. total 17.611 g Example 3 Abuse Resistance and Bioavailability Screen

Oxycodone base/Myristic Acid Carnauba wax (1:5:2 0073. The microparticles comprising oxycodone base/ Ingredient Amount (g) myristic acid/wax (1:5:2 by weight ratio) described above were subjected to a battery of Abuse Tests and a Bioavailabil Oxycodone base 2.2 g Myristic acid 11 g ity Screen (see FIG. 1 for protocols). Samples were analyzed via HPLC. The results are shown in Table 1.

TABLE 1 Testing Results for Particles made from oxycodone/myristic acid?wax at a ratio of 1:5:2

OAT OAT Oil OAT OAT IVAT Bioavail Water Pre- Alcohol Result Result Screen Pre-treat treat Pre-treat Sample ID (%) (%) (%) (%) (%) (%) Oxycodone 15.215 21 O2 107.3 2.4 15.9 1.O. 12.00.4 27.8 2.3 Base/Myrisitic acid carnauba (1:5:2) Oxycodone 17.7 O.7 24 O2 101.1 - 0.6 24.O. 13 14.6 0.6 25.0 - 1.6 Base/Myrisitic acid/beeswax (1:5:2)

0074 Differential Scanning Calorimetry was conducted -continued on the samples and on Oxycodone base. The results are sum marized in Table 2. Oxycodone base/Myristic Acid Carnauba wax (1:5:2 Ingredient Amount (g) TABLE 2 Carnauba wax, NF 4.4 g Summary of DSC analysis on Pre-formulations made from BHT 0.011 g oxycodone myristic acid wax at a ratio of 1:5:2. total 17.611 g Peak Temps Onset of Peaks AH Sample (° C.) (° C.) (J/g) Oxycodone 48.5 43.1 88.2 0069 (1) Myristic acid, Oxycodone base (solid), and Base/Myristic BHT were heated to form a homogeneous mixture free acid/beeswax (1:5:2) of drug crystals. Note that no solvent was used in this Oxycodone 31.5 30.3 2.0 Stage. Base/Myristic 51.6 49.4 78.O acid carnauba (1:5:2) 73.6 71.8 23.0 0070 (2) Solid wax was added to the clear solution and Oxycodone Base 222.8 22O.O 116.7 allowed to dissolve. The clear mixture was stirred for 5 minutes US 2010/0260834 A1 Oct. 14, 2010

0075 No peak was observed at the melting point of oxy 0084. It is understood that the disclosed invention is not codone base, demonstrating that no discrete base particles limited to the particular methodology, protocols, and reagents were present in the compositions. described as these may vary. Those skilled in the art will recognize, or be able to ascertain using no more than routine Example 4 experimentation, many equivalents to the specific embodi ments of the invention described herein. Such equivalents are Preparation of Drug Containing Microparticles intended to be encompassed by the following claims. It is also 0076 to be understood that the terminology used herein is for the purpose of describing particular embodiments only. Publica tions cited herein and the material for which they are cited are specifically incorporated by reference. Sr. No. Ingredients % Quantity Batch (g) 1 Oxycodone base 1O.OO 12S.OO 1. An orally administrable controlled release abuse-deter 2 Myristic acid SO.OO 625.00 rent pharmaceutical composition of a pharmaceutically 3 Yellow Beeswax 2O.OO 2SO.OO active agent prone to abuse, the composition comprising: 4 Carnauba wax 2O.OO 2SO.OO a therapeutically effective amount of the pharmaceutically active agent prone to abuse, in free base or free acid total 1OOOO 12SO.OO form, one or more fatty acids or fatty amines, wherein the concentration of the one or more fatty acids or Procedure: fatty amines is one to fifteen times the molar amount of 0077. 1. Myristic acid was melted under constant stir the active agent. ring while continuously sparging with 2. (canceled) (0078 2. When Step 1 temperature reaches 70° C., Oxy 3. The composition of claim 1 wherein the one or more codone base was added and mixing is continued until a fatty acids is present in an amount from about two to about ten clear molten liquid was formed. times the molar amount of the pharmaceutically active agent. 0079. 3. Yellow Beeswax is melted in a separate con 4. The composition of claim 1 wherein the one or more tainer. When it reached 70° C., it is added slowly to Step fatty amines is present in an amount from about two to about 2 molten liquid and mixed for 5 minutes. ten times the molar amount of the pharmaceutically active 0080. 4. Carnauba wax is melted in a separate container. agent. When it reached 90° C., it is added slowly to Step 3 5. The composition of claim 1 wherein the one or more molten liquid and mixed for 5 minutes. A uniform homo fatty acids is selected from the group consisting of Cs to Co geneous mixture was formed. monovalent fatty acids, Cs to Cao divalent fatty acids and The molten mixture was solidified and subsequently was mixtures thereof. milled in a Fitzmill in the presence of dry ice in order to obtain 6. The composition of claim 5 wherein the Cs to Co microparticles less than 16 mesh. It is expected that the mol monovalent fatty acid is selected from the group consisting of ten homogeneous mixture formed in step 4 could be spray pentanoic acid, hexanoic (caproic) acid, heptanoic acid, congealed as an alternative method to form microparticles octanoic (caprylic) acid, nonanoic acid, decanoic (capric) with a uniform particle size distribution. acid, undecanoic acid, dodecanoic (lauric) acid, tridecanoic acid, tetradecanoic (myristic) acid, pentadecanoic acid, hexa Example 5 decanoic (palmitic) acid, heptadecanoic (margaric) acid, Preparation of Coated Drug Containing Micropar octadecanoic (Stearic) acid, nonadecanoic acid, eicosanoic (arachidic) acid, heneicosanoic acid, docosanoic (behenic) ticles acid, tricosanoic acid, tetracosanoic (lignoceric) acid, penta 0081. Drug-containing particles formulated in a mariner cosanoic acid, hexacosanoic acid, heptacosanoic acid, octa similar to that described in Example 3 were sieved to obtain cosanoic acid, nonacosanoic acid, triacontanoic acid, linoleic particles from 20-40 mesh in size. These particles were acid, oleic acid, and mixtures thereof. coated with an insoluble coating comprising Eudragit RS 7. The composition of claim 6 wherein the Cs to Co 30D in a fluidized bed apparatus. monovalent fatty acid is a mixture of palmitic and Stearic acid. 8. The composition of claim 6 wherein the Cs to Co Example 6 monovalent fatty acid is myristic acid. 9. The composition of claim 6 wherein the Cs to Co Preparation of Tablets for Oral Administration monovalent fatty acid is Stearic acid. 0082 Drug-containing particles formulated in a manner 10. The composition of claim 1 further comprising a phar similar to that described in Example 3 were sieved to obtain maceutically acceptable carrier. particles from 20-40 mesh in size. These particles were 11. The composition of claim 10 wherein the carrier is tableted with the addition of an appropriate amount of filler, present in an amount from 0.25 to about eighttimes by weight disintegrant and lubricant. of the amount of the pharmaceutically active agent. 12. The composition of claim 10 wherein the carrier is Example 7 present in an amount from two to about six times by weight of Preparation of Capsules for Oral Administration the amount of the pharmaceutically active agent. 13. The composition of claim 10 wherein the carrier is 0083. The drug containing microparticles from Example 3 selected from the group consisting of waxes, fats, and mix were loaded into gelatin capsules. tures thereof. US 2010/0260834 A1 Oct. 14, 2010

14. The composition of claim 13 wherein the carrier is a diethylpropion, difebarbamate, difenoxin, enciprazine, esta Wax. Zolam, ethyl loflazepate, etizolam, febarbamate, fencam 15. The composition of claim 14 wherein the wax is famin, fenfluramine, fenproporex, fluianisone, fludiazepam, selected from the group consisting of carnauba wax, bees flunitraam, flunitrazepam, flurazepam, flutoprazepam, wax, microcrystalline wax and mixtures thereof. gepirone, glutethimide, halazepam, haloxazolam, hexobarbi 16. The composition of claim 14 wherein the wax is bees tone, ibomal, ipsapirone, ketazolam, loprazolam mesylate, Wax. lorazepam, lormetazepam, mazindol, mebutamate, 17. The composition of claim 14 wherein the wax is car medazepam, mefenorex, mephobarbital, meprobamate, nauba wax. metaclazepam, methaqualone, methohexital, methylpen 18. The composition of claim 1 wherein the pharmaceuti tynol, methylphenobarbital, midazolam, milaZolam, mor cally active agent prone to abuse is selected from the group phine, nimetazepam, nitrazepam, nordiazepam, oxazepam, consisting of 1-phenylcyclohexylamine, 1-piperidinocyclo oxazolam, paraldehyde, pemoline, pentabarbitone, pentaZo hexanecarbonitrile, alfentanil, alphacetylmethadol, cine, pentobarbital, phencyclidine, phenobarbital, phendime alphaprodine, alprazolam, amobarbital, amphetamine, anile trazine, phenmetrazine, phenprobamate, phentermine, phen ridine, apomorphine, aprobarbital, barbital, barbituric acid yacetone, pinazepam, pipradol, prazepam, proxibarbal, derivative, bemidone, benzoylecgonine, benzphetamine, quazepam, quinalbaritone, secobarbital, secbutobarbitone, betacetylmethadol, betaprodine, bezitramide, bromazepam, Sibutramine, temazepam, temazepam, triazolam, triclofos, buprenorphine, , butalbital, butorphanol, Zalepan, Zaleplon, Zolazepam, Zolpidem, and Zopiclone. camazepam, cathine, chloral, chlordiazepoxide, clobazam, 19. The composition of claim 18 wherein the pharmaceu clonazepam, cloraZepate, clotiazepam, cloxazolam, cocaine, tically active agent is oxycodone. codeine, chlorphentermine, delorazepam, dexfenfluramine, 20. The composition of claim 1 further comprising a phar dextromoramide, dextropropoxyphen, dezocine, diazepam, maceutically active agent that has no abuse potential. diethylpropion, difenoxin, dihydrocodeine, dihydromor 21. The composition of claim 1, wherein the drug is incor phine, dioxaphentyl butyrate, dipanone, diphenoxylate, porated into a plurality of individual microparticles compris diprenorphine, ecgonine, enadoline, eptazocine, estazolam, ing a material that is either slowly soluble in water or water ethoheptazine, ethyl loflazepate, ethylmorphine, etorphine, insoluble. femproponex, fencamfamin, fenfluramine, fentanyl, fludiaz 22. The composition of claim 21 wherein the micropar epam, flunitrazepam, flurazepam, glutethimide, halazepam, ticles comprise a wax or wax-like material. haloxazolam, hexylgon, hydrocodone, hydromorphone, 23. The composition of claim 21 wherein the micropar isomethadone, hydrocodone, ketamine, ketazolam, ketobe ticles comprise a fat or a fatty Substance. midone, levanone, levoalphacetylmethadol, levomethadone, 24. The composition of claim 21 wherein the micropar levomethadyl acetate, levomethorphan, levorphanol, lofenta ticles comprise a material selected from the group consisting nil, loperamide, loprazolam, lorazepam, lormetazepam, of naturally water insoluble proteins, naturally water lysergic acid, lysergic acid amide, mazindol, medazepam, insoluble polysaccharides, naturally water insoluble lipids mefenorex, meperidine, meptazinol, metazocine, methadone, and phospholipids, cross-linked water Soluble proteins, methamphetamine, methohexital, methotrimeprazine, meth cross-linked water soluble polysaccharides, cross-linked yldihydromorphinone, methylphenidate, methylphenobar water soluble cyclodextrins and combinations thereof. bital, metopon, morphine, nabilone, nalbuphine, nalbupine, 25. The composition of claim 21 wherein the individual nalorphine, narceline, nefopam, nicomorphine, nimetazepam, microparticles are coated with one or more independent lay nitrazepam, nordiazepam, normethadone, normorphine, ers, where at least one of the layers is water insoluble. oxazepam, oxazolam, oxycodone, oxymorphone, pentaZo 26. The composition of claim 25 wherein at least one of the cine, pentobarbital, phenadoxone, phenazocine, phencyclid layers is alcohol-insoluble. ine, phendimetrazine, phenmetrazine, pheneridine, piminod 27. The composition of claim 25 wherein the composition ine, prodilidine, properidine, propoxyphene, is not completely soluble, and wherein the drug is not fully racemethorphan, racemorphan, racemoramide, remifentanil, released in a single solvent solution. secobarbital, Sufentanil, , thebaine, thiamylal, thio 28. The composition of claim 1 administered in a tablet or pental, tramadol, trimeperidine, vinbarbital, allobarbitone, capsule. alprazolam, amylobarbitone, aprobarbital, barbital, barbi 29. A method of manufacturing an abuse-deterrent phar tone, benzphetamine, bralobarbital, bromazepam, broti maceutical formulation of a drug prone to abuse, the method Zolam, buspirone, butalbital, butobarbitone, butorphanol, comprising mixing together a therapeutically effective camazepam, captodiame, carbromal, carfentanil, amount of a pharmaceutically active agent prone to abuse and carpipramine, cathine, chloral, chloral betaine, chloral one or more fatty acids, wherein the concentration of the one hydrate, chloralose, chlordiazepoxide, chlorhexadol, chlo or more fatty acids is one to fifteen times the molar amount of rmethiazole edisylate, chlormeZanone, cinolazepam, cloba the active agent. Zam, potassium cloraZepate, clotiazepam, cloxazolam, cyclo barbitone, delorazepam, dexfenfluramine, diazepam,