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(12) United States Patent (10) Patent No.: US 7,399,488 B2 Hirsh Et Al

(12) United States Patent (10) Patent No.: US 7,399,488 B2 Hirsh Et Al

US007399488B2

(12) United States Patent (10) Patent No.: US 7,399,488 B2 Hirsh et al. (45) Date of Patent: Jul. 15, 2008

(54) ABUSE-DETERRENT PHARMACEUTICAL 5,958,452 A 9, 1999 OShlack et al. COMPOSITIONS OF OPODS AND OTHER 5,965,161. A 10/1999 Oshlack et al. 5,965,163 A 10/1999 Miller et al. 5,968,551 A 10, 1999 Oshlack et al.

(75) Inventors: Jane Hirsh, Wellesley, MA (US); 6,048,736 A * 4/2000 Kosak ------436,536 6,068,855 A 5, 2000 Leslie et al. Alexander M. Kibanov, Newton, MA 6.103.261J. W - A 8, 2000 Chasiasin et al. (US); Timothy M. Swager, Newton, 6,162,467 A 12/2000 Miller et al. MA (US); Stephen L. Buchwald, 6,261,599 B1 7/2001 Oshlack et al. Newton, MA (US); Whe Yong Lo, 6,277.384 B1 8/2001 Kaiko et al. Canton, MA (US); Alison B. Fleming, 6,294,195 B1 9, 2001 Oshlack et al. Marshfield, MA (US); Roman V. Rariy, 6,309.668 B1 10/2001 Bastin et al. Allston, MA (US) 6,310,072 B1 * 10/2001 Smith et al...... 514,282 6,335,033 B2 1/2002 Oshlack et al.

(73) Assignee: Collegium Pharmaceutical, Inc., 87.6- R r38: akOs C. a. Cumberland, RI (US) 6,696,088 B2 * 2/2004 Oshlack et al...... 424/465 (*) Notice: Subject to any disclaimer, the term of this 2. R ck 23. E" 424/479 patent is extended or adjusted under 35 6,743.442 B2 6/2004 Oshlack et al. U.S.C. 154(b) by 626 days. 2002/0081333 A1 6/2002 Oshlack et al. 2006/0104909 A1* 5/2006 Vaghefi et al...... 424,102 (21) Appl. No.: 10/614,866 OTHER PUBLICATIONS (22) Filed: Jul. 7, 2003 Cortesi, et al., “Sugar cross-linked gelatin for controlled release: O O microspheres and disks.” Biomaterials 19:1641-1649 (1998). (65) Prior Publication Data Gennaro, ed., Remington. The Science and Practice of Pharmacol US 2004/OO52731 A1 Mar. 18, 2004 ogy, 20" ed., Lipincott: Baltimore, MD, pp. 704–706 (2000). Related U.S. Application Data * cited by examiner (60) Provisional application No. 60/463,518, filed on Apr. Primary Examiner-Lakshmi S. Channavaljala 15, 2003, provisional application No. 60/463,514, (74) Attorney, Agent, or Firm Pabst Patent Group LLP filed on Apr. 15, 2003, provisional application No. 60/443,226, filed on Jan. 28, 2003, provisional appli- (57) ABSTRACT cation No. 60/436,523, filed on Dec. 23, 2002, provi sional application No. 60/393,876, filed on Jul. 5 An abuse-deterrent pharmaceutical composition has been 2002. sy- Ys s developed to reduce the likelihood of improper administra tion of drugs, especially drugs such as opiods. In the preferred (51) Int. Cl. embodiment, a is modified to increase its lipophilicity. In A6 IK 9/14 (2006.01) preferred embodiments the modified drug is homogeneously A61 K9/50 (2006.01) dispersed within microparticles composed of a material that (52) U.S. Cl...... 424/489: 424/464; 424/451 is either slowly soluble or not soluble in Water. In some s s 424/502 embodiments the drug containing microparticles or drug par (58) Field of Classification Search 424/489 ticles are coated with one or more coating layers, where at See application file for com lete search histo least one coating is water insoluble and preferably organic pp p ry. Solvent insoluble, but enzymatically degradable by enzymes (56) References Cited present in the human gastrointestinal tract. The abuse-deter rent composition retards the release of drug, even if the physi U.S. PATENT DOCUMENTS cal integrity of the formulation is compromised (for example, 3,773.955 A 11, 1973 Pachter by chopping with a blade or crushing) and the resulting mate 3,966,940 A 6, 1976 Pachter et al. rial is placed in water, snorted, or swallowed. However, when 3,980,766 A 9, 1976 Shaw et al. administered as directed, the drug is slowly released from the 4,070,494 A 1/1978 Hoffmeister et al. composition as the composition is broken down or dissolved 4,457.933 A 7, 1984 Gordon et al. gradually within the GI tract by a combination of enzymatic 5,508,042 A * 4, 1996 Oshlack et al...... 424/468 degradation, Surfactant action of bile acids, and mechanical 5,756.483. A 5, 1998 Merkus 514/58 erosion. 5,849,240 A 12/1998 Miller et al. 5,891,471 A 4/1999 Miller et al. 5,952,005 A * 9/1999 Olsson et al...... 424/458 30 Claims, No Drawings US 7,399,488 B2 1. 2 ABUSE-DETERRENT PHARMACEUTICAL injected intravenously, the controlled release mechanism is COMPOSITIONS OF OPODS AND OTHER destroyed and a potentially lethal dose of DRUGS becomes bioavailable. In recent years, there have been numerous reports of Oxy BACKGROUND OF THE INVENTION codone diversion and abuse in several states. For example, DEA's Office of Diversion Control reported 700 OxyCon The present invention is generally in the field of pharma tin R thefts in the US between January 2000 and June 2001. ceutical compositions, and specifically relates to composi Some of these reported cases have been associated with seri tions that are designed to reduce the potential for improper ous consequences including death. administration of drugs that are subject to abuse. 10 Oxycodone is a controlled substance in Schedule II of the Controlled Substances Act (CSA), which is administered by This application claims priority to U.S. Ser. No. 60/393, the Drug Enforcement Administration (DEA). Despite the 876 filed Jul. 5, 2002 entitled “Abuse-Resistant Formulations of Oxycontin and Other Drugs” by Alexander M. Klibanov, fact that Schedule II provides the maximum amount of con Stephen L. Buchwald, Timothy M. Swager, and Whe-Yong trol possible under the CSA for approved drug products, in 15 practice it is difficult for law enforcement agencies to control Lo: U.S. Ser. No. 60/436,523 filed Dec. 23, 2002 by Alison B. the diversion or misuse of legitimate prescriptions. Although Fleming, Roman V. Rariy, Alexander M. Klibanov, Whe abuse, misuse, and diversion are potential problems for all Yong Lo, and Jane Hirsh; U.S. Ser. No. 60/443.226 filed Jan. , including Oxycodone, opioids are a very important 28, 2003 by Jane Hirsh, Alison B. Fleming, Alexander M. part of the medical armamentarium for the management of Klibanov, and Whe-Yong Lo: U.S. Ser. No. 60/463,514 filed pain when used appropriately under the careful Supervision of Apr. 15, 2003 by Jane C. Hirsh, Alison B. Fleming, Roman V. a physician. Rariy, Stephen L. Buchwald, and Timothy M. Swager; and Currently available formulations for such drugs are U.S. Ser. No. 60/463,518 filed Apr. 15, 2003 by Jane C. Hirsh, designed for oral administration but do not include mecha Alison B. Fleming and Roman V. Rariy. nisms to prevent or retard improper methods of administra Oxycodone, , and other opiod are suc 25 tion Such as chewing, injection and Snorting. This represents cessful and therapeutically useful , e.g., as pain a serious problem given the large number of legitimate pre killers, when administered orally. Unfortunately, they also scriptions written in the US; for example, the medical use of pose a severe threat for willful abuse due to their ability to opiods within the US increased 400% from 1996 to 2000. The alter mood and/or cause a sense of euphoria. Currently avail problems with abuse are significant and longstanding, and able Sustained release formulations of such drugs, which con 30 efforts to design new abuse-resistant or abuse-deterrent for tain a relatively large amount of drug meant to be released mulations have been largely unsuccessful. U.S. Pat. Nos. from the formulation over an extended time period, are par 3,980,766, 4,070,494 and 6,309,668 describe formulations ticularly attractive to abusers since the Sustained release designed to prevent the injection of compositions meant for action can be destroyed by crushing or grinding the formula oral administration. U.S. Pat. No. 3,980,766 describes the tion. The resulting material (ie, the crushed formulation) can 35 incorporation of an ingestible solid which causes a rapid no longer control the release of drug. Depending on the drug, increase in Viscosity upon concentration of an aqueous solu abusers can then (1) Snort the material. (2) Swallow the mate tion thereof. U.S. Pat. No. 4,070,494 describes the incorpo rial or (3) dissolve the material in water and subsequently ration of a non-toxic, water gelable material in an amount inject it intravenously. The dose of drug contained in the Sufficient to render the drug resistant to aqueous extraction. formulation is thus absorbed immediately through the nasal 40 U.S. Pat. No. 6,309,668 describes a tablet for oral adminis or GI mucosa (for Snorting or Swallowing, respectively) or is tration containing two or more layers comprising one or more administered in a bolus to the systemic circulation (for IV drugs and one or more gelling agents within separate layers of injection). These abuse methods result in the rapid bioavail the tablet. The resulting tablet forms a gel when combined ability of relatively high doses of drug, giving the abuser a with the volume of water necessary to dissolve the drug; this “high”. Since relatively simple methods (crushing, grinding, 45 formulation thus reduces the extractability of the drug from chewing and/or dissolution in water) can be used to transform the tablet. It should be noted that although these compositions such formulations into an abusable form, they provide virtu preclude abuse by injections, this approach fails to prevent ally no deterrent to a potential abuser. abuse by crushing and Swallowing or Snorting the formula For example, the FDA recently strengthened the warnings tion, which are commonly reported methods of abuse associ and precautions sections in the labeling of OxyContin R (oxy 50 ated with OxyContin R. codone HC1 controlled-release) Tablets, a narcotic drug U.S. Pat. Nos. 3,773,955 and 3,966,940 describe formula approved for the treatment of moderate to severe pain, tions containing a combination of opiod and antago because of continuing reports of abuse and diversion. Oxy nists, in which the antagonist does not block the therapeutic ContinR contains oxycodone HCl (available in 10, 20, 40 and effect when the admixture is administered orally, but which 80 mg strengths), an with an addiction poten 55 does not produce analgesia, euphoria or physical dependence tial similar to that of morphine. Opioid agonists are Sub when administered parenterally by an abuser. U.S. Pat. No. stances that act by attaching to specific proteins called opioid 4,457.933 describes a method for decreasing both the oral and receptors, which are found in the brain, spinal cord, and parenteral abuse potential of strong analgetic agents by com gastrointestinal tract. When these drugs attach to certain bining an dose of the analgetic agent with an opioid receptors in the brain and spinal cord they can effec 60 antagonist in specific, relatively narrow ratios. U.S. Pat. Nos. tively block the transmission of pain messages to the brain. 6,277.384, 6,375,957 and 6,475,494 describe oral dosage OxyContin R is supplied in a controlled-release dosage form forms including a combination of an orally active opiod ago and is intended to provide up to 12 hours of relief from nistand an orally active opiod antagonist in a ratio that, when moderate to severe pain. The warning specifically states that delivered orally, is analgesically effective but that is aversive the tablet must be taken whole and only by mouth. When the 65 in a physically dependent subject. While such a formulation tablet is chewed or crushed and its contents are swallowed, may be successful in deterring abuse, it also has the potential Snorted into the nostrils or dissolved and Subsequently to produce adverse effects in legitimate patients. US 7,399,488 B2 3 4 It is therefore an object of the present invention to provide reference solely to the active ingredient, or to the formulation a pharmaceutical composition that significantly reduces the containing the active ingredient. potential for improper administration or use of drugs but The currently available Sustained release dosage forms which, when administered as directed, is capable of deliver containing narcotic analgesics and other drugs are subject to ing a therapeutically effective dose. misuse, in part, because mechanical destruction of the dosage form exposes the encapsulated drug and allows for immediate SUMMARY OF THE INVENTION dissolution of the drug into aqueous media. Two properties of the dosage form that contribute to this outcome are (1) the An abuse-deterrent pharmaceutical composition and the ease with which drug is exposed to the extraction media and method of making and using the composition have been 10 (2) the high water solubility of the drug salt form. developed. The composition can be used to reduce the likeli In the composition disclosed herein, one or both of these hood of improper administration of drugs, especially drugs properties are altered in order to achieve an abuse-deterrent Such as oxycodone. The technology is useful for a number of composition. Specifically, in the preferred embodiment, the other drugs where sustained release oral delivery is desired, drug is modified to increase its lipophilicity and, in additional and there is the potential for abuse if the drug dose is made 15 preferred embodiments, is then homogeneously dispersed immediately available for nasal, IV or oral administration. In within a material that is either slowly soluble or not soluble in the preferred embodiment, the drug is chemically modified to water and Subsequently formulated into microparticles. The increase its lipophilicity. In other embodiments, the formula drug may be present in the form of discrete particles or may be tion contains lipophilic or water-insoluble materials or is partially or fully dispersed in the carrier material on a molecu made using a process which increases the lipophilicity and/or lar level. water-insolubility of the composition. The terms “abuse-deterrent composition' or “abuse-deter The abuse-deterrent composition retards the release of rent formulation' are used interchangeably herein to refer to drug, even if the physical integrity of the dosage form is compositions that reduce the potential for improper adminis compromised (for example, by chopping with a blade or tration of drugs but that deliver a therapeutically effective crushing) and the resulting material is placed in water, 25 dose when administered as directed. Improper administration Snorted, or Swallowed. The composition thus provides a includes tampering with the dosage form and/or administer deterrent to common methods of improper administration ing the drug by any route other than instructed. For example, including IV injection of drug dissolved in water and nasal or for a tablet or capsule, methods of tampering with the dosage oral administration of the crushed formulation since drug will form may include, but are not limited to, breaking, crushing, not be immediately released from the formulation. However, 30 grinding, chewing and/or dissolving the tablet or the contents when administered as directed, the drug is slowly released of the capsule. For oral administration, improper administra (typically over a period of 4-18 hours) from the composition tion includes administering the drug by any route other than as the composition is broken down or dissolved gradually via Swallowing. within the GI tract by a combination of enzymatic degrada The abuse deterrent composition preferably comprises a tion, Surfactant action of bile acids, and mechanical erosion. 35 drug modified to increase its lipophilicity. In other preferred In some embodiments, the individual drug-containing embodiments, the drug is homogenously dispersed within microparticles or drug particles are coated with one or more microparticles composed of a material that is either slowly independent coating layers. At least one of the coating mate soluble in water or water insoluble. The compositions slow rials is water-insoluble and preferably organic Solvent-in the release of drug if the dosage form is chopped or crushed soluble, but enzymatically degradable. The components of 40 and the resulting material is placed in water, Snorted, or Swal the resulting coated microparticles are not mutually soluble in lowed since most of the drug will remain associated with or water, organic solvents, or any combination thereof. So that in entrapped within portions of the core material of the micro vitro degradation of the formulation will require more than particles. In some embodiments the drug containing micro one step. Hence the drug is not easily extractable from Such a particles or individual drug particles are coated with one or formulation by conventional chemical means. In contrast, 45 more coating layers, where at least one coating is water when administered to the gastrointestinal tract via Swallow insoluble and preferably organic solvent insoluble, but enzy ing, the drug gradually will be released from the coated matically degradable. The components of the resulting coated microparticles as a consequence of enzymatic degradation, microparticles are not mutually soluble in water, organic Sol Surfactant action of bile acids and mechanical erosion within vents, or any combination thereof. Such that no one solvent or the GI tract. 50 enzyme solution is capable of dissolving the formulation in The pharmaceutical composition, when administered its entirety in vitro. It follows that extraction of the drug from orally, results in a desired drug release profile. Such a release the formulation cannot be carried out in one step. However, profile provides a therapeutic effect for an extended period of when administered as directed, the drug is slowly released time, typically from 6 to 24 hours. Additional compositions from the formulation since it is eroded within the environ are provided which achieve a small immediate dose that pre 55 ment of the gastrointestinal tract. cedes the Sustained release of drug. The compositions dis A. Drugs to be Formulated closed herein may optionally comprise a drug having no There are many drugs that it is desirable to deliver using the appreciable abuse potential. compositions described herein. The Controlled Substances DETAILED DESCRIPTION OF THE INVENTION Act (CSA), Title II of the Comprehensive Drug Abuse Pre 60 vention and Control Act of 1970, places all substances that are regulated under existing federal law into one offive schedules Disclosed herein are an abuse-deterrent pharmaceutical based upon the Substance's medicinal value, harmfulness, composition and the method of making and using the com and potential for abuse or addiction. Drugs that are preferred position. include those classified as Schedule II, III, IV and V drugs. I. Compositions 65 Drugs that are most preferable include those, like oxycodone, As used herein, "composition” refers to the drug dosage that are currently formulated as sustained or controlled unit for administration to a patient. This may also be used in release compositions, where drug release is intended to occur US 7,399,488 B2 5 6 over a prolonged period of time through the gastrointestinal diethylpropion, , difenoxin, enciprazine, esta tract, and immediate or burst release, for example, by inhala Zolam, , , , fencam tion or injection, is undesirable. As used herein, drugs prone famin, fenfluramine, fenproporex, fluianisone, , to abuse refer to controlled substance specified as schedule II, flunitraam, , , , III, IV and V drugs. , , , , hexobarbi The terms “drug”, “active agent, and “pharmacologically tone, ibomal, , , mesylate, active agent” are used interchangeably herein to refer to a , , mazindol, , chemical compound that induces a desired pharmacological, , mefenorex, mephobarbital, , physiological effect. The terms also encompass pharmaceu , , , methylpen tically acceptable derivatives of those active agents specifi 10 tynol, , , milaZolam, mor cally mentioned herein, including, but not limited to, salts, phine, , , nordiazepam, , Solvates, hydrates, complexes with one or more molecules, , , pemoline, pentabarbitone, pentaZo , active metabolites, analogs, and the like. When the cine, , , , phendime terms 'active agent”, “pharmacologically active agent” and trazine, phenmetrazine, , phentermine, phen 'drug are used, or when a particular drug, Such as oxyc 15 yacetone, , pipradol, , proxibarbal, odone, is identified, it is to be understood as including the , quinalbaritone, , secbutobarbitone, active agent per se as well as pharmaceutically acceptable Sibutramine, , , , , salts, Solvates, hydrates, complexes with one or more mol Zalepan, , , , and . Cer ecules, prodrugs, active metabolites, and analogs. tain compounds described herein may exist in particular geo Examples of preferred drugs include, 1-phenylcyclohexy metric or stereoisomeric forms. The composition disclosed lamine, 1-piperidinocyclohexanecarbonitrile, , herein contemplates all such compounds, including cis- and alphacetylmethadol, alphaprodine, , , trans-isomers, R- and S-enantiomers, diastereomers, (D)-iso amphetamine, anilleridine, apomorphine, , bar mers, (L)-isomers, the racemic mixtures thereof, compounds bital, barbituric acid derivative, bemidone, benzoylecgonine, of different spacial conformations, and other mixtures benzphetamine, , betaprodine, bezitra 25 thereof, as falling within the scope of the invention. Addi mide, , , , , tional asymmetric carbon atoms may be presentina Substitu , , cathine, , , ent such as an alkyl group. All Such isomers, as well as , , , , clox mixtures thereof, are intended to be included in this invention. aZolam, , , chlorphentermine, , As used herein, “pharmaceutically acceptable salts' refer dexfenfluramine, , dextropropoxyphen, 30 to derivatives of the disclosed compounds wherein the parent , , diethylpropion, difenoxin, dihydroco compound is modified by making acid or base salts thereof. deine, , dioxaphentyl butyrate, dipanone, Examples of pharmaceutically acceptable salts include, but , , ecgonine, , eptaZo are not limited to, mineral or organic acid salts of basic cine, , , ethyl loflazepate, ethylmor residues such as amines; alkali or organic salts of acidic phine, , femproponex, fencamfamin, fenfluramine, 35 residues such as carboxylic acids; and the like. The pharma , fludiazepam, flunitrazepam, flurazepam, glutethim ceutically acceptable salts include the conventional non-toxic ide, halazepam, haloxazolam, hexalgon, , salts or the quaternary ammonium salts of the parent com , , hydrocodone, , pound formed, for example, from non-toxic inorganic or ketazolam, , levanone, levoalphacetylmeth organic acids. For example, Such conventional non-toxic salts adol, , levomethadyl acetate, levomethor 40 include those derived from inorganic acids such as hydro phan, , , , loprazolam, chloric, hydrobromic, Sulfuric, Sulfamic, phosphoric, nitric lorazepam, lormetazepam, lysergic acid, lysergic acid amide, and the like; and the salts prepared from organic acids such as mazindol, medazepam, mefenorex, meperidine, , acetic, propionic, Succinic, glycolic, Stearic, lactic, malic, , , methamphetamine, methohexital, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phe methotrimeprazine, methyldihydromorphinone, meth 45 nylacetic, glutamic, benzoic, Salicylic, Sulfanilic, 2-acetoxy ylphenidate, methylphenobarbital, , morphine, benzoic, fumaric, tolunesulfonic, methanesulfonic, ethane , , nalbupine, , narceline, nefo disulfonic, oxalic, and isethionic. pam, , nimetazepam, nitrazepam, nordiaz The pharmaceutically acceptable salts of the compounds epam, normethadone, normorphine, oxazepam, oxazolam, can be synthesized from the parent compound, which con oxycodone, , , pentobarbital, phen 50 tains a basic oracidic moiety, by conventional chemical meth adoxone, , phencyclidine, phendimetrazine, ods. Generally, such salts can be prepared by reacting the free phenmetrazine, pheneridine, , prodilidine, prope acid or base forms of these compounds with a stoichiometric ridine, propoxyphene, racemethorphan, , amount of the appropriate base or acid in water or in an racemoramide, , secobarbital, , talb organic solvent, or in a mixture of the two: generally, non utal, , , thiopental, , trimeperidine, 55 aqueous media like ether, ethyl acetate, ethanol, isopropanol, and . oracetonitrile are preferred. Lists of suitable salts are found in In addition to the compounds above, the following sched Remington’s Pharmaceutical Sciences, 20th ed., Lippincott uled drugs may be incorporated into the composition: allo Williams & Wilkins, Baltimore, Md., 2000, p. 704, the dis barbitone, alprazolam, amylobarbitone, aprobarbital, bar closure of which is hereby incorporated by reference. bital, barbitone, benZphetamnine, , 60 Optionally, the composition described herein can further bromazepam, , , butalbital, butobarbi include a drug having no appreciable abuse potential. tone, butorphanol, camazepam, , , B. Drug Solubility Modification , , cathine, chloral, , In preferred embodiments, the solubility characteristics of , , chlordiazepoxide, chlorhexadol, a drug are altered prior to incorporation into the formulation. chlormethiazole edisylate, , , 65 Modification of the drug to produce a more lipophilic deriva clobazam, potassium cloraZepate, clotiazepam, , tive serves to reduce the water solubility of the drug and thus cyclobarbitone, delorazepam, dexfenfluramine, diazepam, reduces the aqueous extractability. Furthermore, if the drug is US 7,399,488 B2 7 8 made more lipophilic, it can be solubilized in a molten fatty ing microparticle or a drug particle coated with one or more Substance or wax like mixture, rather than physically dis coating layers of material. Microparticles and coated micro persed in a particulate form. Solubilization of drug enhances particles have a size range of 10 to 3000 microns in diameter. the abuse-deterrent properties of microparticles formulated Within microparticles, drug is preferably homogeneously from the mixture as it is difficult to extract drug from an dispersed in the form of fine particles within the carrier mate intimately dispersed composition. rial. More preferably, drug is partially solubilized in molten The terms "lipophilic derivative' and “lipophililic drug carrier material or partially dissolved with the carrier material derivative', as used herein, refer to derivatives of the drug that in a mutual solvent during the formulation of the micropar are less soluble in water than the most soluble salt of the drug. ticles. Most preferably, drug is completely solubilized in the The most soluble salt being selected from either drug alkaline 10 molten carrier material or completely dissolved with the car metal salts (for acidic drugs) or salts of the drug with inor rier material in a co-solvent during the formulation of the ganic acids (for basic drugs). The examples of the latter microparticles. This is accomplished through the selection of include but are not limited to hydrohalates, sulfates, and materials and the manner in which they are processed. nitrates. Carrier materials appropriate for the fabrication of drug Some of the methods that can be used to alter the drugs 15 containing microparticles are either slowly soluble in water or lipophilicity are outlined below. It is understood that two or insoluble in water, but capable of degrading within the GI more approaches can be combined to achieve a desired solu tract by means including enzymatic degradation, Surfactant bility profile. action of bile acids and mechanical erosion. As used herein, Methods for Increasing Lipophilicity the term “slowly soluble in water refers to materials that are In one embodiment, drug is made more lipophilic by elimi not dissolved in water within a period of 30 minutes. Pre nating or reducing the overall charge of the drug molecule. ferred examples include fats, fatty Substances, waxes, wax For example, for a basic drug, a water soluble salt (such as like substances and mixtures thereof. Suitable fats and fatty hydrochloride, sulfate, or maleate) can be converted to a free Substances include fatty (such as lauryl, myristyl base using techniques known in the art. Correspondingly, in Stearyl, cetyl or cetostearyl ), fatty acids and deriva the case of an acidic drug, a water soluble salt (such sodium, 25 tives, including but not limited to fatty acid esters, fatty acid potassium, or the like) can be converted to a free acid. glycerides (mono-, di- and tri-glycerides), and hydrogenated In another embodiment, the drugs lipophilicity is fats. Specific examples include, but are not limited to hydro increased by forming a salt between a drug molecule and a genated vegetable oil, hydrogenated cottonseed oil, hydroge charged lipophilic compound. In this case the lipophilicity of nated castor oil, hydrogenated oils available under the trade the resulting salt can be manipulated by varying the lipophi 30 name SteroteXR), Stearic acid, cocoa butter, and Stearyl alco licity of the counter-ion. In general lipophilic acids oramines hol. Suitable waxes and wax-like materials include natural or with chain lengths between Cs-Co are lipophilic counter-ion synthetic waxes, hydrocarbons, and normal waxes. Specific candidates. Some specific examples include, but are not lim examples of waxes include beeswax, glycowax, castor wax, ited to, linoleic acid, octanoic acid, lauric acid, Stearic acid, carnauba wax, paraffins and candelilla wax. As used herein, a palmitic acid, oleic acid, octyl amine, lauryl amine, Stearyl 35 wax-like material is defined as any material which is normally amine, palmityl amine, linoleyl amine, and oleyl amine. Solid at room temperature and has a melting point of from Other salts which may increase lipophilicity and, hence, lipid about 30 to 300° C. solubility relative to the parent drug compound include, but In some cases, it may be desirable to alter the rate of water are not limited to, pectinate, tannate, phytate, salicylate, sac penetration into the hydrophobic drug containing micropar charinate, acesulfamate, gallate, and terephthalate salts. 40 ticles. To this end, rate-controlling (wicking) agents may be In yet another embodiment the lipophilicity of the drug is formulated along with the fats or waxes listed above. increased by fanning a stable complex between a drug mol Examples of rate-controlling materials include certain starch ecule (either charged or uncharged) and a metal cation Such as derivatives (eg, waxy maltodextrin and drum dried corn Zinc, magnesium, calcium, bismuth or the like. This complex starch), cellulose derivatives (eg. hydroxypropylmethylcellu may consist of one or more drug molecules, one or more metal 45 lose, hydroxypropylcellulose, methylcellulose, and car cations, and, optionally, one or more lipophilic charged spe boxymethylcellulose), alginic acid, lactose and talc. Addi cies. The aforementioned charged lipophilic species are tionally, a pharmaceutically acceptable Surfactant (for incorporated into the complex if necessary to bring the charge example, ) may be added to facilitate the degradation of the final complex to zero and increase its overall lipophi of such microparticles. licity. In general lipophilic acids oramines with chain lengths 50 Proteins which are water insoluble, such as Zein, are pre between Cs-Co are lipophilic counter-ion candidates. ferred carrier materials for the formation of drug containing In still a further embodiment, drug lipophilicity is microparticles. Additionally, proteins, polysaccharides and increased via complexation with poorly water-soluble cyclo combinations thereof which are water soluble can be formu dextrin. For example, ethylated beta-cyclodextrin has been lated with drug into microparticles and Subsequently cross shown to decrease aqueous solubility of complexed drug 55 linked to form an insoluble network. For example, cyclodex molecules. trins can be complexed with individual drug molecules and In another embodiment, a drug is covalently modified to Subsequently cross-linked. increase its lipophilicity. For example, a lipophilic compound Certain polymers may also be used as carrier materials in can be covalently attached to a drug molecule via an ester or the formulation of drug containing microparticles. Suitable amide linkage. Such drug derivatives are cleaved in Vivo, thus 60 polymers include ethylcellulose and other natural or synthetic releasing the parent compound. cellulose derivatives. Polymers which are slowly soluble and C. Drug Containing Microparticles form a gel in an aqueous environment, such as hydroxypropyl In preferred embodiments, drugs are formulated with a methylcellulose or polyethylene oxide may also be suitable as carrier material to form microparticles. As used herein, the carrier materials for drug containing microparticles. term “microparticle' refers to a composition comprising a 65 Encapsulation or incorporation of drug into carrier mate drug dispersed within a carrier material and "coated micro rials to produce drug containing microparticles can be particle' refers to a composition comprising a drug contain achieved through known pharmaceutical formulation tech US 7,399,488 B2 10 niques. To create a composition that protects drug from expo linking proteins, initiated by both chemical and physical Sure upon mechanical disruption (eg, grinding, chewing, or means, have been reported. One of the most common meth chopping), the drug is intimately dispersed within the carrier ods to obtain cross-linking is the use of chemical cross-link material. In the case of formulation in fats, waxes or wax-like ing agents. Examples of chemical cross-linking agents materials, the carrier material is heated above its melting include aldehydes (gluteraldehyde and formaldehyde), epoxy temperature and the drug is added to form a mixture compris compounds, carbodiimides, and genipin. In addition to these ing drug particles Suspended in the carrier material, drug cross-linking agents, oxidized and native Sugars have been dissolved in the carrier material, or a mixture thereof. Micro used to cross-link gelatin (Cortesi, R., et al., Biomaterials 19 particles can be subsequently formulated through several (1998) 1641-1649). Cross-linking can also be accomplished methods including, but not limited to, the processes of con 10 using enzymatic means; for example, transglutaminase has gealing, extrusion, spray chilling or aqueous dispersion. In a been approved as a GRAS substance for cross-linking sea preferred process, wax is heated above its melting tempera food products. Finally, cross-linking can be initiated by ture, drug is added, and the molten wax-drug mixture is physical means such as thermal treatment, UV irradiation and congealed under constant stirring as the mixture cools. Alter gamma irradiation. natively, the molten wax-drug mixture can be extruded and 15 To produce a coating layer of cross-linked protein Sur spheronized to form pellets or beads. Detailed descriptions of rounding drug containing microparticles or drug particles, a these processes can be found in “Remington The Science water soluble protein can be spray coated onto the micropar and practice of pharmacy”, 20" Edition, Jennaro et. Al. ticles and subsequently cross-linked by the one of the meth (Phila, Lippencott, Williams, and Wilkens, 2000). ods described above. Alternatively, drug containing micro For some carrier materials it may be desirable to use a particles can be microencapsulated within protein by Solvent evaporation technique to produce drug containing coacervation-phase separation (for example, by the addition microparticles. In this case drug and carrier material are co of salts) and Subsequently cross-linked. Some Suitable pro dissolved in a mutual solvent and microparticles can Subse teins for this purpose include gelatin, albumin, casein, and quently be produced by several techniques including, but not gluten. limited to, forming an emulsion in water or other appropriate 25 Polysaccharides can also be cross-linked to form a water media, spray drying or by evaporating off the solvent from the insoluble network. For many polysaccharides, this can be bulk solution and milling the resulting material. accomplished by reaction with calcium salts or multivalent In addition to modification of the drug itself, processing cations which cross-link the main polymer chains. Pectin, conditions can be used to influence the dispersion of the drug alginate, dextran, amylose and guar gum are Subject to cross within water-insoluble or slowly water soluble material. For 30 linking in the presence of multivalent cations. Complexes example, in the case where the water in-soluble or slowly between oppositely charged polysaccharides can also be soluble material is melted and drug is fully or partially dis formed; pectin and chitosan, for example, can be complexed Solved under stirring conditions, the temperature, agitation via electrostatic interactions. Insoluble coatings can be rate and time of processing will influence the degree of dis formed on particles in this fashion. It should be noted that in Solution achieved. More specifically, a more homogenous 35 many cases polysaccharides are broken down specifically by dispersion may be achieved with a higher temperature, faster enzymes produced by bacteria within the colon. stirring rate and longer processing time. Ultrasound can also In some cases a water-insoluble but enzymatically degrad be applied to the molten mixture to increase the degree of able coating comprising both a protein and a polysaccharide dispersion and/or the rate of dissolution of the drug. can be produced if the components are oppositely charged In some embodiments, drug in a particulate form is homo 40 polyelectrolytes. Under the proper temperature, pH, and con geneously dispersed in a water-insoluble or slowly water centrations, the two polymers can interact through their oppo soluble material. To minimize the size of the drug particles site electrical charges and form a water-insoluble complex. If within the composition, the drug powder itself may be milled a core particle is present at the time the complex phase sepa to generate fine particles prior to formulation. The process of rates, it will be coated. For example, gelatin and gum arabic jet milling, known in the pharmaceutical art, can be used for 45 can be coated onto a core particle utilizing this process. this purpose. In some embodiments drug in a particulate form Optionally, the complex can be made irreversibly insoluble is homogeneously dispersed in a wax or wax like Substance by Subsequent cross-linking induced by chemical or physical by heating the wax or wax like Substance above its melting CaS. point and adding the drug particles while stirring the mixture. E. Dosage Forms In this case a pharmaceutically acceptable surfactant may be 50 There are a number of drug compositions that meet the added to the mixture to facilitate the dispersion of the drug abuse deterrent criteria outlined above. In one embodiment a particles. drug is homogeneously dispersed, in a fine particulate form, D. Coated Drug Containing Microparticles within a water-insoluble or slowly water soluble material and In some embodiments, drug containing microparticles or the mixture is formulated into microparticles. In another drug particles are encapsulated within at least one water 55 embodiment a drug is partially dissolved within a water insoluble enzymatically degradable material. In some insoluble or slowly water soluble material during the manu instances the Substrates of digestive enzymes are naturally facturing process, for example, by mixing at a temperature water-insoluble and can be utilized in the formulation without above the melting point of the carrier material, and the mix further processing. Solid esters of fatty acids, which are ture is formulated into microparticles. In yet another embodi hydrolyzed by lipases, can be spray coated onto micropar 60 ment a drug is fully dissolved within a water-insoluble or ticles or drug particles. Zein is an example of a naturally slowly water soluble material during the manufacturing pro water-insoluble protein. It can be coated onto drug containing cess, for example, by mixing at a temperature above the microparticles or drug particles by spray coating or by wet melting point of the carrier material, and the mixture is for granulation techniques. In addition to naturally water-in mulated into microparticles. Instill a further embodiment, the soluble materials, some Substrates of digestive enzymes can 65 drug containing microparticles, where the drug is homoge be treated with cross-linking procedures, resulting in the for neously dispersed in a particulate form, or has been partially mation of non-soluble networks. Many methods of cross or fully dissolved within the carrier material during the manu US 7,399,488 B2 11 12 facturing process, are coated with one or more coatings to the stomach. In the case of oxycodone some salts tat may form coated microparticles. In a further embodiment, drug exhibit this property include, but are not limited to, the tan particles are coated directly with one or more coatings to form nate, phthalate, salicylate, gallate, pectinate, phytate, saccha coated microparticles. rinate, aseSulfamate and terephthalate salts. Complexes of The microparticles, coated microparticles, or a mixture drug with one or more metalions and, optionally, one or more thereof are formed into a solid dosage form suitable for oral lipophilic counter-ions may also be used for immediate drug administration. For example, microparticles or coated micro release. Use of salts or complexes in the immediate release particles can be incorporated into hard capsules, dispersed portion of the dosage form reduces the abuse potential of the within a soft gelatin capsule, or combined with appropriate immediate release dose if the formulation is crushed and (1) excipients and tableted by compression. 10 snorted or (2) dissolved in water since these salts will be In some embodiments, the compositions are coated with an poorly soluble under these conditions. It is understood by the enteric coating. Enteric coatings known in the art are applied one of ordinary skill in the art that Such salts or complexes directly to the abuse-deterrent microparticle or coated micro may also be used to formulate an immediate release dosage particle compositions or are applied to the Surface of a capsule form without a Sustained release portion. or tablet comprising the abuse deterrent microparticle and/or 15 Additional mechanisms to reduce the potential for abuse coated microparticle compositions. Enteric coatings known can also be incorporated during the process of formulating in the art include, for example, acrylic polymers that are tablets. For example, ingredients can be added to deter chew commercially available under the trade name EUDRAGITR), ing or Snorting of the final formulation. For example, an cellulose acetate phthalate, hydroxypropylmethylcellulose intensely bitter Substance may deter chewing, while an phthalate, polyvinylacetate phthalate, shellac, hydroxypro intensely spicy ingredient, Such as , may deter Snort pylmethylcellulose Succinate, cellulose acetate trimelliate or ing. The addition of a colored dye, which would stain the skin mixtures thereof. and mucosal Surface of the nose following Snorting may also Dosage forms can include one or more drugs. When the serve to reduce this practice. dosage form includes two or more drugs they can be Sched Optional excipients present in the oral dosage form com uled drugs or can be a combination of Scheduled and non 25 prising abuse deterrent microparticles or coated micropar Scheduled drugs. The drugs can be incorporated into separate ticles include, but are not limited to diluents, binders, lubri microparticle compositions where the Scheduled drugs are cants, disintigrants, colorants, plasticizers and the like. incorporated into abuse deterrent microparticle compositions Diluents, also termed “fillers.” are typically necessary to and the non-Scheduled drugs are incorporated into abuse increase the bulk of a Solid dosage form so that a practical size deterrent microparticle compostions, Sustained release com 30 is provided for compression of tablets. Examples of diluents positions known in the art or immediate release compositions include cellulose, dry starch, microcrystalline cellulose, known in the art. The compositions comprising the different dicalcium phosphate, calcium sulfate, sodium chloride con drugs are formulated into a single solid dosage form Suitable fectioner's Sugar, compressible Sugar, dextrates, dextrin, dex for oral administration, for example, they can be incorporated trose, Sucrose, mannitol, powdered cellulose, Sorbitol, and into a gelatin capsule, or combined with appropriate excipi 35 lactose. Binders are used to impart cohesive qualities pow ents and compressed into a tablet form. Examples of non dered materials and can include materials such as starch, scheduled drugs that may be included in dosage forms gelatin, Sugars, natural and synthetic gums, polyethylene gly described herein include, but are not limited to, , col, ethylcellulose, methylcellulose, hydroxypropylmethyl acetaminophen, non-steroidal anti-inflammatory drugs, cellulose, carboxymethylcellulose, waxes and polyvinyl pyr cyclooxygenase II inhibitors, N-methyl-D-aspartate receptor 40 rolidone. Lubricants are used to facilitate tablet manufacture; antagonists, glycine receptor antagonists, triptans, dex examples of lubricants include talc, magnesium Stearate, cal tromethorphan, , fiorinal, , butalbi cium Stearate, hydrogenated vegetable oils Stearic acid, tal, and caffeine. Sodium Stearyl fumarate, sodium benzoate, sodium acetate, An immediate release dose can be incorporated into the leucine, Sodium oleate, Sodium lauryl Sulfate, magnesium formulation in several ways. Immediate release micropar 45 lauryl Sulfate and polyethylene glycol. Disintegrants can be ticles can be made utilizing standard methodologies and for added to pharmaceutical formulations in order to facilitate mulated along with abuse-deterrent microparticle and/or “breakup” or disintegration after administration. Materials coated microparticle compositions in a Suitable oral dosage used for this purpose include starches, clays, celluloses, form. Alternatively, a coating containing drug which is avail aligns, gums, and cross-linked polymers. A plasticizer may be able for immediate release can be placed on a tablet compris 50 included in coating materials to alter their mechanical prop ing abuse-deterrent microparticle and/or coated microparticle erties. Examples of plasticizers include benzyl benzoate, compositions plus appropriate excipients. Additionally, an , dibutyl sebacate, diethyl phthalate, glycerin, immediate dose of drug can be granulated or blended with mineral oil, polyethylene glycol, Sorbitol, triacetin, triethyl rapidly dissolving excipients and Subsequently compressed citrate, glycerol, etc. In addition to the additives above, col (1) as one layer of bi-layer tablets in which the abuse-deter 55 oring and flavoring agents may also be incorporated into the rent microparticle and/or coated microparticle compositions composition. are compressed as the other layer, or (2) as the outer layer of Optionally, the composition disclosed herein comprises compression-coated tablets in which the abuse-deterrent materials wherein a combination of the materials is not microparticle and/or coated microparticle compositions are soluble in water, organic solvent, or any combination thereof. compressed as the inner core, or (3) into tablets in which 60 abuse-deterrent microparticle and/or coated microparticle II. Methods of Administration compositions are embedded. It is assumed that upon oral ingestion of the intact compo In some embodiments, the immediate release portion of the sition, drug is released as the formulation is gradually broken dosage form comprises a lipophilic drug derivative. For down or dissolved within the GI tract by a combination of example, salt derivatives or complexes that are insoluble at a 65 enzymatic degradation, Surfactant action of bile acids, and neutral pH but dissociate, thereby releasing the parent com mechanical erosion. This is a result of the unique ability of the pound, at an acidic pH are ideal for immediate release within human digestive system to efficiently break down or solubi US 7,399,488 B2 13 14 lize a variety of materials. The process within the GI tract that Methylene chloride was added in order to extract the formed results in the digestion of food and the absorption of nutrients oxycodone free base. The obtained organic layer was dried is well known. Following mastication within the mouth, food over sodium sulfate and methylene chloride was evaporated passes into the stomach where it is mixed with digestive using rotary evaporator. The obtained oxycodone free base juices. This fluid contains the proteolytic enzyme pepsin 5 was purified by crystallization. which, following activation by the low pH within the stom B. Oxycadone Terephthalate Oxycodone terephthalate is ach, begins the process of cleaving ingested proteins into commercially available and can be used without further pro Smaller peptide fragments. Food then enters the Small intes cessing. tine in the form of macromolecular aggregates, where it is digested into molecules near or in a form capable of being 10 EXAMPLE 2 absorbed. This digestion is accomplished through the action of various enzymes which are produced in the pancreas and Preparation of Drug Containing Microparticles flow into the upper portion of the large intestine, the duode num. The enzymes synthesized in the pancreas include pro The free base, or sal from Example 1 are added to molten teases, amylases and lipases; these enzymes are capable of 15 hydrogenated vegetable oil, mixed, extruded and spheronized breaking down proteins, starches and fats, respectively. The to form drug containing microparticles. digestion of fats is further facilitated by the secretion of bile into the duodenum since bile salts, which contain both hydro EXAMPLE 3 phobic and hydrophilic portions, are capable of emulsifying lipids into minute droplets in order to increase the Surface area Preparation of Coated Drug Containing available for digestion by lipases. The material which remains Microparticles following passage through the Small intestine enters the large intestine. Bacteria capable of breaking down carbohydrates The drug-containing particles from Example 2 are spray not digested in the Small intestine (such as cellulose) are coated with Zein in a fluidized bed apparatus. present in large numbers this region of the digestive tract. 25 Finally, in addition to microbial fermentation, the large intes EXAMPLE 4 tine functions to absorb water and electrolytes and to form and store feces until they are excreted. Preparation of Capsules for Oral Administration In addition to providing a deterrent to common methods of abuse/diversion, the formulation can provide a Sustained 30 The drug containing microparticles from Example 2 and/or release of drug over an extended time period. This is a natural the coated microparticles from Example 3 are incorporated consequence of the fact that, in the present formulation, drug into standard gelatin capsules. is slowly released from a predominantly water-insoluble, hydrophobic matrix following the degradation of the matrix. EXAMPLE 5 The barrier components are degraded, for example, by 35 enzymes, the Surfactant action of bile acids and mechanical Preparation of Capsules for Oral Administration erosion. Containing a Dose of Drug for Immediate Release In some embodiments, an immediate release of drug is achieved within the stomach in order to provide rapid thera The drug containing microparticles from Example 2 and/or peutic onset. 40 the coated microparticles from Example 3 are combined with The pharmaceutical drug composition is administered immediate release drug particles, and incorporated into stan orally. The appropriate dosage formulations can be obtained dard gelatin capsules. by calculation of the of the formulation, We claim: then adjusting using routine techniques to yield the appropri 1. An orally administrable abuse-deterrent pharmaceutical ate drug levels based on the approved dosage forms. Any 45 composition comprising atherapeutically effective amount of Suitable amount of drug containing microparticles or coated microparticles consisting of microparticles can be included in the final formulation. The (a) a lipophilic drug prone to abuse or lipophilic derivative selection of a Suitable amount of drug containing micropar of a drug prone to abuse, and ticles depends on the dosage desired and is readily deter (b) one or more carrier materials selected from the group mined by those skilled in the art. 50 consisting of fats, fatty Substances, waxes, wax-like Sub In addition to oral administration, some embodiments may stances and mixtures thereof, also be administered by other routes, including, but not lim wherein the drug is dispersed within the one or more carrier ited to, rectal and nasal administration. Some embodiments materials, and the release of a portion of incorporated may also be suitable for formulation as oral liquids. drug is retarded when the physical integrity of the com The present composition and method of making and using 55 position is compromised and the compromised compo the composition will be further understood by reference to the sition is exposed to water. following non-limiting examples. 2. An orally administrable abuse-deterrent pharmaceutical composition comprising atherapeutically effective amount of EXAMPLE1 microparticles consisting of a lipophilic derivative of a drug 60 prone to abuse dispersed within one or more carrier materials Preparation of Lipophilic Oxycodone Derivatives which are either slowly soluble in water or insoluble in water, wherein the release of a portion of incorporated drug is A. Oxycodone Free Base retarded when the physical integrity of the composition is The free base of oxycodone was prepared from its hydro compromised and the compromised composition is exposed chloride salt by the following method: Oxycodone hydro 65 to Water. chloride was dissolved in water and sodium carbonate was 3. The composition of claim 1 or 2, wherein the composi added in the amount required to neutralize hydrochloric acid. tion is a controlled-release pharmaceutical composition. US 7,399,488 B2 15 16 4. The composition of claim 1 or 2, wherein release of a medazepam, mefenorex, mephobarbital, meprobamate, portion of incorporated drug is Substantially retarded. metaclazepam, methaqualone, methohexital, methylpen 5. The composition of claim 1 or 2, wherein the portion of tynol, methylphenobarbital, midazolam, milaZolam, mor the drug released immediately when the physical integrity of phine, nimetazepam, nitrazepam, nordiazepam, oxazepam, the composition is compromised is less than 80% of the total 5 oxazolam, paraldehyde, pemoline, pentabarbitone, pentaZo amount of drug incorporated into the formulation. cine, pentobarbital, phencyclidine, phenobarbital, phendime 6. The composition of claim 1 or 2, wherein the release of trazine, phenmetrazine, phenprobamate, phentermine, phen a portion of incorporated drug is retarded when The physical yacetone, pinazepam, pipradol, prazepam, proxibarbal, integrity of the composition is compromised and the compro quazepam, quinalbaritone, secobarbital, secbutobarbitone, mised composition is exposed to an aqueous medium. 10 Sibutramine, temazepam, tetrazepam, triazolam, triclofos, 7. The composition of claim 6, wherein the portion of the Zalepan, Zaleplon, Zolazepam, Zolpidem, and Zopiclone. drug released immediately when the physical integrity of the 9. The composition of claim 1 or 2, wherein the lipophilic composition is compromised is less than 80% of the total derivative of a drug is a free base or a free acid of the drug. amount of the drug incorporated into the composition. 10. The composition of claim 1 or 2, wherein the lipophulic 8. The composition of claim 1 wherein the drug prone to 15 derivative of a drug is a salt comprising the ionized drug and abuse is selected from the group consisting of 1-phenylcyclo a lipophilic counter-ion. hexylamine, 1-piperidinocyclohexanecarbonitrile, alfentanil, 11. The composition of claim 1 or 2, wherein the lipophilic alphacetylmethadol, alphaprodine, alprazolam, amobarbital, derivative of a drug is a complex comprising one or more amphetamine, anilleridine, apomorphine, aprobarbital, bar components selected from the group consisting of drug mol bital, barbituric acid derivative, bemidone, benzoylecgonine, ecules, metal cations, and lipophilic counter-ions. benzphetamine, betacetylmethadol, betaprodine, bezitra 12. The composition of claim 1 or 2, wherein the lipophilic mide, bromazepam, buprenorphine, butabarbital, butalbital, derivative of a drug is a complex comprising one or more butorphanol, camazepam, cathine, chloral, chlordiazepoxide, components selected from the group consisting of drug mol clobazam, clonazepam, cloraZepate, clotiazepam, clox ecules, metal cations, and cyclodextrin molecules. aZolam, cocaine, codeine, chlorphentermine, delorazepam, 25 13. The composition of claim 1 or 2 wherein the drug is dexfenfluramine, dextromoramide, dextropropoxyphen, complexed with a metal cation selected from the group con dezocine, diazepam, diethylpropion, difenoxin, dihydroco sisting of Zinc, calcium, magnesium, bismuth and combina deine, dihydromorphine, dioxaphentyl butyrate, dipanone, tions thereof. diphenoxylate, diprenorphine, ecgonine, enadoline, eptaZo 14. The composition of claim 1 or 2, wherein the lipophilic cine, estaZolam, ethoheptazine, ethyl loflazepate, ethylmor 30 derivative of a drug is a complex comprising the drug and a phine, etorphine, femproponex, fencamfamin, fenfluramine, cyclodextrin. fentanyl, fludiazepam, flunitrazepam, flurazepam, glutethim 15. The composition of claim 1 or 2, wherein the lipophilic ide, halazepam, haloxazolam, hexalgon, hydrocodone, derivative of a drug is an ester or amide formed between the hydromorphone, isomethadone, hydrocodone, ketamine, drug and a fatty acid. ketazolam, ketobemidone, levanone, levoalphacetylmeth 35 16. The composition of claim 2 wherein the microparticles adol, levomethadone, levomethadyl acetate, levomethor consist of drug dispersed in a carrier material selected from phan, levorphanol, lofentanil, loperamide, loprazolam, the group consisting of fats, fatty Substances, waxes, wax-like lorazepam, lormetazepam, lysergic acid, lysergic acid amide, Substances and combinations thereof. mazindol, medazepam, mefenorex, meperidine, meptazinol, 17. The composition of claim 16 wherein the micropar metazocine, methadone, methamphetamine, methohexital, 40 ticles consist of drug dispersed in a fat or a fatty Substance. methotrimeprazine, methyldihydromorphinone, meth 18. The composition of claim 2 wherein the microparticles ylphenidate, methylphenobarbital, metopon, morphine, consist of a drug dispersed in a carrier material selected from nabilone, nalbuphine, nalbupine, nalorphine, narceline, nefo the group consisting of naturally water insoluble proteins, pam, nicomorphine, nimetazepam, nitrazepam, nordiaz naturally water insoluble polysaccharides, naturally water epam, normethadone, normorphine, oxazepam, oxazolam, 45 insoluble lipids and phospholipids, cross-linked water oxycodone, oxymorphone, pentazocine, pentobarbital, phen soluble proteins, cross-linked water soluble polysaccharides, adoxone, phenazocine, phencyclidine, phendimetrazine, cross-linked water Soluble cyclodextrins and combinations phenmetrazine, pheneridine, piminodine, prodilidine, prope thereof. ridine, propoxyphene, racemethorphan, racemorphan, 19. The composition of claim 1 or 2 wherein the individual racemoramide, remifentanil, secobarbital, Sufentanil, talb 50 microparticles are coated with one or more independent lay utal, thebaine, thiamylal, thiopental, tramadol, trimeperidine, ers, where at least one of the layers is water insoluble and is Vinbarbital, allobarbitone, alprazolam, amylobarbitone, degraded by enzymes of the human gastrointestinal tract. aprobarbital, , barbitone, benzphetamine, brallobar 20. The composition of claim 19 wherein at least one of the bital, bromazepam, brotizolam, buspirone, butalbital, buto layers is water-insoluble, organic solvent-insoluble, and barbitone, butorphanol, camazepam, captodiame, carbromal, 55 degradable by enzymes present in the human gastrointestinal carfentanil, carpipramine, cathine, choral, chloral betaine, tract. chloral hydrate, chloralose, chlordiazepoxide, chlorhexadol, 21. The composition of claim 19 wherein the enzymati chlormethiazole edisylate, chlormeZanone, cinolazepam, cally degradable layer(s) comprise a material selected from clobazam, potassium cloraZepate, clotiazepam, cloxazolam, the group consisting of naturally water insoluble proteins, cyclobarbitone, delorazepam, dexfenfluramine, diazepam, 60 naturally water insoluble polysaccharides, naturally water diethylpropion, difebarbamate, difenoxin, enciprazine, esta insoluble lipids and phospholipids, cross-linked proteins, Zolam, ethyl loflazepate, etizolam, febarbamate, fencam cross-linked polysaccharides, and combinations thereof. famin, fenfluramine, fenproporex, fluianisone, fludiazepam, 22. The composition of claim 1 or 2 wherein the drug prone flunitraam, flunitrazepam, flurazepam, flutoprazepam, to abuse is co-administered with a drug that has no appre gepirone, glutethimide, halazepam, haloxazolam, hexobarbi 65 ciable abuse potential. tone, ibomal, ipsapirone, ketazolam, loprazolam mesylate, 23. The composition of claim 1 or 2 wherein the drug prone lorazepam, lormetazepam, mazindol, mebutamate, to abuse is oxycodone. US 7,399,488 B2 17 18 24. The composition of claim 2 wherein the drug prone to clobazam, potassium cloraZepate, clotiazepam, cloxazolam, abuse is selected from the group consisting of 1-phenylcyclo cyclobarbitone, delorazepam, dexfenfluramine, diazepam, hexytamine, 1-piperidinocyclohexanecarbonitrile, alfentanil, diethylpropion, difebarbamate, difenoxin, enciprazine, esta alphacetylmethadol, alphaprodine, alprazolam, amobarbital, Zolam, ethyl loflazepate, etizolam, febarbamate, fencam amphetamine, anilleridine, apomorphine, aprobarbital, bar 5 famin, fenfluramine, fenproporex, fluianisone, fludiazepam, bital, barbituric acid derivative, bemidone, benzoylecgonine, flunitraam, flunitrazepam flurazepam, flutoprazepam, benzphetamine, betacetylmethadol, betaprodine, bezitra gepirone, glutethimide, halazepam, haloxazolam, hexobarbi mide, bromazepam, buprenorphine, butabarbital, butalbital, tone, ibomal, ipsapirone, ketazolam, loprazolam mesylate, butorphanol, camazepam, cathine, chloral, chlordiazepoxide, lorazepam, lormetazepam, mazindol, mebutamate, clobazam, clonazepam, cloraZepate, clotiazepam, clox 10 medazepam, mefenorex, mephobarbital, meprobamate, aZolam, cocaine, codeine, chlorphentermine, delorazepam, metaclazepam, methaqualone, methohexital, methylpen dexfenfluramine, dextromoramide, dextropropoxyphen, tynol, methylphenobarbital, midazolam, milaZolam, mor dezocine, diazepam, diethylpropion, difenoxin, dihydroco phine, nimetazepam, nitrazepam, nordiazepam, oxazepam, deine, dihydromorphine, dioxaphentyl butyrate, dipanone, oxazolam, paraldehyde, pemoline, pentabarbitone, pentaZo diphenoxylate, diprenorphine, ecgonine, enadoline, eptaZo 15 cine, pentobarbital, phencyclidine, phenobarbital, phendime cine, estaZolam, ethoheptazine, ethyl loflazepate, ethylmor trazine, phenmetrazine, phenprobamate, phentermine, phen phine, etorphine, femproponex, fencamfamin, fenfluramine, yacetone, pinazepam, pipradol, prazepam, proxibarbal, fentanyl, fludiazepam, flunitrazepam, flurazepam, glutethim quazepam, quinalbaritone, secobarbital, secbutobarbitone, ide, halazepam, haloxazolam, hexalgon, hydrocodone, Sibutramine, temazepam, tetrazepam, triazolam, triclofos, hydromorphone, isomethadone, hydrocodone, ketamine, Zalepan, Zaleplon, Zolazepam, Zolpidem, and Zopiclone. ketazolam, ketobemidone, levanone, levoalphacetylmeth 25. The composition of claim 1 or 2 wherein the lipophilic adol, levomethadone, levomethadyl acetate, levomethor drug and the lipophilic derivative is dissolved in the carrier phan, levorphanol, lofentanil, loperamide, loprazolam, material in a molten state to result in a uniform dispersion lorazepam, lormetazepam, lysergic acid, lysergic acid amide, within the carrier material. mazindol, medazepam, mefenorex, meperidine, meptazinol, 25 26. The composition of claim 1 or 2 wherein the lipophilic metazocine, methadone, methamphetamine, methohexital, drug and the lipophilic derivative is dissolved in a co-solvent methotrimeprazine, methyldihydromorphinone, meth along with a carrier material to result in a uniform dispersion ylphenidate, methylphenobarbital, metopon, morphine, within the carrier material. nabilone, nalbuphine, nalbupine, nalorphine, narceline, nefo 27. The composition of claim 10 wherein the lipophilic pam, nicomorphine, nimetazepam, nitrazepam, nordiaz 30 counter-ion is selected from the group consisting of Stearic epam, normethadone, normorphine, oxazepam, oxazolam, acid, palmitic acid, myristic acid, and mixtures thereof. oxycodone, oxymorphone, pentazocine, pentobarbital, phen 28. The composition of claim 9, 10 or 27 wherein one or adoxone, phenaZoeme, phencyclidine, phendimetrazine, more carrier materials is selected from the group consisting of phenmetrazine, pheneridine, piminodine, prodilidine, prope Stearic acid, palmitic acid, beeswax, carnauba wax, hydroge ridine, propoxyphene, racemethorphan, racemorphan, 35 nated oil, and mixtures thereof. racemoramide, remifentanil, secobarbital, Sufentanil, talb 29. The composition of claim 1 or 2, wherein the individual utal, thebaine, thiamylal, thiopental, tramadol, trimeperidine, microparticles are further formulated into a tablet or capsule Vinbarbital, allobarbitone; alprazolam, amylobarbitone, for oral administration. aprobarbital, barbital, barbitone, benzphetamine, brallobar 30. The composition of claim 28 wherein the drug prone to bital, bromazepam, brotizolam, buspirone, butalbital, buto 40 abuse is selected from the group consisting of oxycodone, barbitone, butorphanol, camazepam, captodiame, carbromal, oxymorphone, hydrocodone, hydromorphone, morphine, tra carfentanil, carpipramine, cathine, chloral, chloral betaine, madol, methylphenidate, and amphetamine. chloral hydrate, chloralose, chlordiazepoxide, chlorhexadol, chlormethiazole edisylate, chlormeZanone, cinolazepam,

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 7,399,488 B2 Page 1 of 1 APPLICATION NO. : 10/614866 DATED : July 15, 2008 INVENTOR(S) : Jane Hirsh et al.

It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Claim 6, column 15, line 8, replace “The with--the--.

Signed and Sealed this Twenty-first Day of October, 2008 WDJ

JON. W. DUDAS Director of the United States Patent and Trademark Office

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 7,399,488 B2 Page 1 of 1 APPLICATION NO. : 10/614866 DATED : July 15, 2008 INVENTOR(S) : Jane Hirsh et al.

It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Title page, item 54, second line, replace “opiods with --opioids--. Title page, item 57, third line, replace “opiods with -opioids--. Column 1, title, second line, replace “opiods with -opioids--. Column 1, line 25, replace “opiod with -opioid--. Column 2, line 52, replace “opiods with -opioids--. Column 2, line 62, replace “opiods with -opioids--. Column 2, line 63, replace “opiods with -opioids--. Column 7, line 2, replace “wax like with --wax-like--. Column 7, line 42, replace “fanning with --forming--. Column 9, line 47, replace “wax like with --wax-like--. Column 9, line 47, replace “wax like with --wax-like--. Column 12, line 32, replace “chloride confectioner's with --chloride, confectioners--. Column 12, line 35, replace “qualities powdered with --qualities to powdered--. Column 12, line 42, replace “oils stearic with --oils, stearic--. Column 14, line 6, replace “B. Oxycodone Terephthalate Oxycodone terephthalate with --B. Oxycodone Terephthalate Oxycodone terephthalate--. Column 14, line 14, replace “sal with --salt--. Column 18, line 22, replace “is with --are--. Column 18, line 26, replace “is with --are--.

Signed and Sealed this Twenty-first Day of April, 2009 4 (O-e-

JOHN DOLL Acting Director of the United States Patent and Trademark Office

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