Europäisches Patentamt *EP001293195A1* (19) European Patent Office

Office européen des brevets (11) EP 1 293 195 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.7: A61K 9/20, A61K 9/50, 19.03.2003 Bulletin 2003/12 A61K 45/06, A61K 31/485 // (A61K31/485, 31:165), (21) Application number: 02256157.5 (A61K31/485, 31:12) (22) Date of filing: 05.09.2002

(84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • Hugues, Lyn IE IT LI LU MC NL PT SE SK TR Harleysville, Pennsylvania 19438 (US) Designated Extension States: • Bellamy, Simon Andrew AL LT LV MK RO SI Redhill, Surrey RH1 6DD (GB)

(30) Priority: 17.09.2001 US 322624 P (74) Representative: Kent, Venetia Katherine 02.11.2001 US 16336 Rohm and Haas (UK) Ltd European Operations Patent Dept. (71) Applicant: ROHM AND HAAS COMPANY Lennig House Philadelphia, Pennsylvania 19106-2399 (US) 2 Mason’s Avenue Croydon, CR9 3NB (GB)

(54) Oral pharmaceutical dosage forms with reduced potential for drug abuse, comprising respiratory irritants or bitter substances

(57) Solid oral dosage forms of controlled substances containing aversive agents are useful in reducing abuse by chewing or inhaling. EP 1 293 195 A1

Printed by Jouve, 75001 PARIS (FR) 1 EP 1 293 195 A1 2

Description the potential for abuse of controlled substances. These methods have focussed on the parenteral and oral BACKGROUND routes of administration. [0007] US3,773,955, US3,966,940, and US4,457, [0001] Abuse of controlled substances is a serious 5 933 describe oral dosage forms containing a combina- and growing problem throughout the world. For exam- tion of opioid agonists and antagonists, in which the ef- ple, the abuse of an extended release form of oxyco- fect of the antagonist when administered according to done has been the recent subject of many articles such the correct procedure does not affect the therapeutic as 'Playing With Pain Killers' and 'How One Town Got pain management value of the agonist. However, when Hooked'. See, Newsweek, April 9, 2001, pages 45-51. 10 the agonist and antagonist are extracted for parenteral Further, The New York Times profiled the problem of ox- administration by an addict the effect of the agonist de- ycodone abuse by inhalation of the crushed pill. See, sired by the addict is decreased. This approach was fur- The New York Times, July 29, 2001. It is estimated that ther adopted in WO9004965 where it was incorporated in America four million people over the age of 12 used into a transdermal delivery device, and in US 6,228,863 prescription painkillers and stimulants for non-medical 15 where it was developed into a dosage form from which reasons in the space of just one month, approximately the agonist could not be separated from the antagonist half of them saying they'd done it for the first time. Emer- except by using a sophisticated multi-step procedure. gency room visits related to such abuse approximately [0008] In US 3,980,766 multiple methods for reducing doubled between 1992 and 1999. abuse potential are described. One method is to include [0002] There are three main routes that drug abusers 20 a thickening agent such that the concentrated extract use for administering the drug substances: parenteral, containing the drug can not be injected with a syringe. oral, and inhalation. The parenteral route is commonly Another is the incorporation of agents that cause the called 'mainlining' and requires the drug substance to precipitation of the drug during isolation, thus rendering be in solution such that it can be injected intravenously it unsuitable for injection. The addition of a thickener has with a syringe. For solid dosage form drugs this requires 25 also been used in US 4,070,494, WO9107950, and some type of extraction and concentration procedure to WO9520947. render the drug substance suitable for injection. Inhala- [0009] In WO0033835 additives are included in the tion of a solid drug substance through the nose is com- dosage forms such that when added to drinks create a monly called 'snorting'. For solid dosage form drugs this visible change in the drink. This invention reduces the requires only that the dosage form be crushed into a 30 potential for abuse by oral administration of the sub- powder, or emptied from a capsule. Breathing in vapors stance by one person to another without their knowl- is frequently known as 'huffing'. Both snorting and huff- edge. ing result in the rapid absorption of the drug substance [0010] The use of bitter and sour agents to minimize through the mucosa of the respiratory system. the risk of ingestion of poisonous compounds is well [0003] The potential for abuse is increased by the use 35 known in the art. For example, see US 3,268,577, GB of extended release formulations because they typically 2358585, JP 2000026260, and Chemistry and Industry contain more than the immediate release single dose of (London), volume 22, 721-723, 1998). In all such cases active ingredient. Circumventing the extended release the purpose of the bitter or sour agent is to prevent in- mechanism delivers the full dose, which is intended to gestion. be delivered over a longer time period, immediately. For 40 [0011] However, none of the cited references solve example, crushing an extended release oxycodone tab- the problem of potential abuse of therapeutic com- let separates a gelling matrix from the oxycodone active pounds via inhalation or chewing. Now, Applicants have ingredient, such that when inhaled through the nose the surprisingly discovered a dosage form useful in reduc- gelling matrix cannot exert the extended release effect. ing the potential for drug abuse via inhalation or chew- Similarly it is sometimes possible to circumvent the ex- 45 ing. tended release effect by chewing the dosage form. [0012] The term "high," as used herein means the [0004] The use of coatings to extend the release of non-therapeutic effect desired by drug addicts and rec- drug substances is very well known in the art (Reming- reational drug users ton's Pharmaceutical Sciences, 16th Edition, Chapter [0013] The term "respiratory mucosal membrane" as 90). Such dosage forms are also subject to said modes 50 used herein means the mucous membrane lining the na- of abuse because the coating can be damaged by sal and pharyngeal cavities, the bronchial tubes, and the crushing or chewing. lungs. Typically, snorting into the nasal cavity is the com- [0005] WO0108661 describes an extended release mon, preferred route of abuse for a solid oral dosage dosage form of opioids that uses an ion exchange resin. form which has been crushed by one intending to inhale This dosage form is also subject to said modes of abuse 55 said crushed dosage form to obtain the high. because the ion exchange resin and the active ingredi- [0014] The term "respiratory irritant' as use herein ent can be separated by crushing. means substances that cause irritation when adminis- [0006] Various methods have been used to reduce tered to the respiratory mucosal membrane. Said irrita-

2 3 EP 1 293 195 A1 4 tion can include, but is not limited to, coughing, dyspnea, substance. When the oral dosage form is used as pre- rhinitis, nasal congestion, eye irritation, lachrymation, scribed, i.e. swallowed whole, said irritant causes no and sneezing. aversive response. However, if the oral dosage form is [0015] When describing dosage forms the term "im- rendered into a powder and inhaled, said irritant creates mediate release" as used herein means a dosage form 5 intense discomfort in the user, including coughing, dys- from which the active ingredient is dissolved as quickly pnea, rhinitis, nasal congestion, eye irritation, lachryma- as possible after administration. In the pharmaceutical tion, and sneezing. This intense discomfort has the ef- arts said immediate release dosage forms are frequent- fect of deterring people from using said inhalation route ly referred to as "conventional" dosage forms. as a means of administration, i.e. it elicits an aversive [0016] When describing dosage forms the term "mod- 10 response. ified release" as used herein means a dosage form [0025] In the practice of another embodiment of the whose drug-release characteristics of time course and/ invention, a bitter tasting agent such as denatonium or location are chosen to accomplish therapeutic or con- benzoate (Bitr venience objectives not offered by conventional dosage ex®) or a sour tasting agent such as citric acid , is forms. Said modified release dosage forms include dos- 15 incorporated into the solid oral dosage form of the con- age forms commonly known in the art as, delayed, sus- trolled substance. When the oral dosage form is used tained, extended, targeted, prolonged, pulsatile, zero- as prescribed, i.e. swallowed whole, said bitter or sour order, constant rate, and controlled. substance causes no aversive response. However, if [0017] The term "aversive response" as used herein the oral dosage form is chewed, said bitter or sour sub- means a response in a person, resulting from adminis- 20 stance creates an intensely unpleasant . This un- tration of a dosage form containing a controlled sub- pleasant taste has the effect of deterring people from stance, via any of the known routes of administration, chewing the dosage form, i.e. it elicits an aversive re- sufficiently unpleasant that said person decides not to sponse. administer said dosage form by the same route of ad- [0026] The Controlled Substances Act of 1970 regu- ministration again 25 lates the manufacturing, distribution, and dispensing of [0018] The term "aversive agent" as used herein drugs that have abuse potential. The Drug Enforcement means any substance that is included in a dosage form Agency (DEA) within the US Department of Justice is that creates an aversive response. the chief agency responsible for enforcing said act. [0019] The term "nociceptive" as used herein means Drugs under the jurisdiction of said Act are divided into a response characterized by pain. For example the term 30 five schedules (I thru V) based on their medical utility, 'nociceptive efficacy' when applied to an irritant refers potential for abuse, and physical and psychological de- to the quantification of the ability of said irritant to cause pendence. Schedule I substances have high abuse po- pain. tential and no accepted medical use. Schedule II also have high abuse potential, but also have medical utility. SUMMARY OF THE INVENTION 35 Schedules III, IV, and V have progressively lower abuse potential. [0020] The present invention relates to an oral phar- [0027] Because the DEA rates abuse potential based maceutical dosage form not susceptible to abuse by res- on specific dosage forms it is not uncommon for a drug piratory mucosal membrane administration comprising to be rated in multiple schedules. For example codeine one or more aversive agents. 40 appears as Schedule II, Schedule III, and Schedule IV, [0021] The present invention further relates to an oral depending on the specific dosage form and dosage pharmaceutical dosage form not susceptible to abuse amount. To avoid duplication in the list of controlled sub- by chewing comprising one or more aversive agents. stance below, multiple occurrences have been removed and any controlled substance that had multiple occur- DETAILED DESCRIPTION OF THE INVENTION 45 rences is placed in the highest abuse potential category for which is has been scheduled. For example, codeine [0022] The present invention relates to an oral phar- has been included as Schedule II, but not Schedule III maceutical dosage form not susceptible to abuse by res- or Schedule IV. This is not intended to limit the scope of piratory mucosal membrane administration comprising the invention. The utility of the Applicant's invention lies one or more aversive agents. 50 in the fact that any controlled substance, regardless of [0023] The present invention further relates to an oral what schedule it appears on, is suitable for formulating pharmaceutical dosage form not susceptible to abuse into the Applicant's dosage form. by chewing comprising one or more aversive agents. [0028] Controlled substances useful in the practice of [0024] In the practice of one embodiment of the inven- the invention are those categorized by the DEA as tion, a respiratory irritant such as powdered chili pep- 55 Schedule II, III, IV, and V controlled substances. pers, or concentrated extracts of such products that con- [0029] Schedule II substances include, but are not tain or capsaicin-like components, is incorpo- limited to, 1-1-Phenylcyclohexylamine, 1-Piperidinocy- rated into the solid oral dosage form of the controlled clohexanecarbonitrile, Alfentanil, Alphaprodine, Amo-

3 5 EP 1 293 195 A1 6 barbital, Amphetamine, Anileridine, Benzoylecgonine, Diphenoxylate, Pyrovalerone. Bezitramide, Carfentanil, Coca Leaves, Cocaine, Co- [0033] Preferred controlled substances useful in the deine, Dextropropoxyphene, Dihydrocodeine, Diphe- practice of the invention are those categorized by the noxylate, Diprenorphine, Ecgonine, Ethylmorphine, DEA as Schedule II, III, and IV controlled substances. Etorphine HCl, Fentanyl, Glutethimide, Hydrocodone, 5 [0034] More preferred controlled substance useful in Hydromorphone, Isomethadone, Levo-alphacetylmeth- the practice of the invention are those categorized by adol, Levomethorphan, Levorphanol, Meperidine, the DEA as Schedule II and III controlled substances. Meperidine intermediate-A, Meperidine intermediate-B, [0035] Most preferred controlled substance useful in Meperidine intermediate-C, Metazocine, Methadone, the practice of the invention are those categorized by Methadone intermediate, Methamphetamine, Methyl- 10 the DEA as Schedule II controlled substances. The most phenidate, Metopon, Moramide-intermediate, Mor- preferred Schedule II substance is oxycodone. phine, Nabilone, Opium extracts, Opium fluid extract, [0036] Aversive agents useful in the practice of this Opium poppy, Opium tincture, Opium, granulated, Opi- invention include, but are not limited to, respiratory irri- um, powdered, Opium, raw, Oxycodone, Oxymorphone, tants, bitter substances, and sour substances. Pentobarbital, Phenazocine, Phencyclidine, Phenme- 15 [0037] Aversive agents useful in the practice of this trazine, Phenylacetone, Piminodine, Poppy Straw, Pop- invention are solids. Said solid can be said agent in pure py Straw Concentrate, Racemethorphan, Racemor- form or a solid containing said agent. phan, Remifentanil, Secobarbital, Sufentanil, Thebaine [0038] Aversive agents useful in the practice of this [0030] Schedule III substances include, but are not invention are of natural or synthetic origin. limited to, Amobarbital, Anabolic steroids, Aprobarbital, 20 [0039] An important aspect of this invention is the use Barbituric acid derivative, Benzphetamine, Boldenone, of capsaicinoids as an aversive agent which acts as a Butabarbital, Butalbital, Chlorhexadol, Chlorotestoster- respiratory irritant to create an aversive response. Cap- one, Chlorphentermine, Clortermine, Clostebol, Co- saicinoids are alkaloid substances which occur naturally deine, Dehydrochlormethyltestosterone, Dihydroco- in the fruit of various chile pepper plants. The principal deine, Dihydrotestosterone, Dronabinol, Drostanolone, 25 capsaicinoids found in most pepper plants are capsai- Ethylestrenol, Ethylmorphine, Fluoxymesterone, cin, , capsico, and capsacutin. The Formebolone, Hydrocodone, Ketamine, Lysergic acid, principal capsaicinoid is capsaicin. There can be multi- Lysergic acid amide, Mesterolone, Methandienone, ple capsaicinoids in one pepper and different peppers Methandranone, Methandriol, Methandrostenolone, have different concentrations of capsaicinoids. The pro- Methenolone, Methyltestosterone, Methyprylon, Mibo- 30 duction of capsaicinoids is a form of chemical defense lerone, Morphine, Nalorphine, Nandrolone, against being eaten and thus acts naturally as an animal Norethandrolone, Oxandrolone, Oxymesterone, repellant. See, Smith, R. L., Ecology and Field Biology, Oxymetholone, Pentobarbital, Phendimetrazine, Seco- p. 562 (3d Ed. 1980). Capsaicinoids are the chemicals barbital, Stanolone, Stanozolol, Sulfondiethylmethane, responsible for the "hot" sensation associated with pep- Sulfonethylmethane, Sulfonmethane, Talbutal, Testol- 35 pers. The hotness of the various is directly actone, Testosterone, Thiamylal, Thiopental, Tileta- attributable to their capsaicinoid content. Capsaicinoids mine, Trenbolone, Vinbarbital. generate a spicy flavor in the mouth but are irritants [0031] Schedule IV substances include, but are not when applied to mucous membranes. limited to, Alprazolam, Barbital, Bromazepam, Butorph- [0040] is the formal term used to refer to anol, Camazepam, Cathine, Chloral betaine, Chloral hy- 40 the dried ripe fruit of the various species of chili peppers. drate, Chlordiazepoxide, Clobazam, Clonazepam, [0041] Therapeutically, capsaicin is listed as a coun- Clorazepate, Clotiazepam, Cloxazolam, Cocaine, terirritant (Merck Index, 9th Ed., p. 224). Capsicum has Delorazepam, Dexfenfluramine, Dextropropoxyphene, Generally Regarded as Safe (GRAS) status in the USA. Diazepam, Diethylpropion, Difenoxin, Estazolam, Eth- Capsaicin, capsicum, and capsicum oleoresin have chlorvynol, Ethinamate, Ethyl loflazepate, Fencamfam- 45 monographs in the US Pharmacopeia 24. in, Fenfluramine, Fenproporex, Fludiazepam, Fluni- [0042] Respiratory irritants useful in the practice of trazepam, Flurazepam, Halazepam, Haloxazolam, Ket- this invention include, but are not limited to, pure com- azolam, Loprazolam, Lorazepam, Lormetazepam, Maz- pounds and mixtures of capsaicin, capsico, capsacutin, indol, Mebutamate, Medazepam, Mefenorex, Mep- dihydrocapsaicin, nordihydrocapsaicin, homocapsai- robamate, Methohexital, Methylphenobarbital, Mida- 50 cin, , capsaicinoids, , zolam, Modafinil, Nimetazepam, Nitrazepam, Nor- chemical , , isochavicine, isopiperine, pip- diazepam, Oxazepam, Oxazolam, Paraldehyde, Pemo- eridine, chavicine, piperettine, zingerone, , line, Pentazocine, Petrichloral, Phenobarbital, valleral, isovallerals, vanyllylamide, nonoyl vanyllamide, Phentermine, Pinazepam, Pipradrol, Prazepam, vanyllylamide derivatives, synthetic derivatives of cap- Quazepam, Sibutramine, Temazepam,Tetrazepam,Tri- 55 saicinoids, and extracts, capsicums, and powders of, azolam, Zaleplon, Zolpidem Capsicum frutescens varieties, Capsicum anuum vari- [0032] Schedule V substances include, but are not eties, Capsicum chinense varieties, Capsicum bacca- limited to Buprenorphine, Difenoxin, Dihydrocodeine, tum varieties, Capsicum pubescens varieties, Capsi-

4 7 EP 1 293 195 A1 8 cum species, Piper migrum varieties, Piper longum va- amount of active ingredient in said irritant. The following rieties, Piper retrofractum varieties, Piper officinarum amounts of respiratory irritants are provided as exam- varieties, Piperaceae species, Brassica juncea varie- ples. Effective amounts of other respiratory irritants can ties, Brassica. nigra varieties, Sinapis alba varieties, Si- be determined using techniques well known to those napis arvensis varieties, Zingiber officinale varieties, 5 skilled in the art. and Lactarius vellereus varieties and mixtures thereof. [0049] The preferred amount of the respiratory irri- [0043] Preferred respiratory irritants useful in the tants capsaicin and dihydrocapsaicin is a combined total practice of the invention are pure compounds and mix- of 0.002-100mg per dose. tures of capsaicin, capsico, capsacutin, dihydrocapsai- [0050] The preferred amount of the respiratory irritant cin, nordihydrocapsaicin,, homodihydro- 10 zingerone is 0.04-200mg per dose. capsaicin, capsaicinoids, gingerol, chemical mace, pip- [0051] The preferred amount of the respiratory irritant erine, isochavicine, isopiperine, piperidine, chavicine, shogaol is 0.04-200mg per dose piperettine, zingerone, shogaol, valleral, isovallerals, [0052] The preferred amount of the respiratory irritant vanyllylamide, nonoyl vanyllamide, vanyllylamide deriv- piperine is 0.04-200mg per dose atives, synthetic derivatives of capsaicinoids, and ex- 15 [0053] The preferred amount of the respiratory irri- tracts, capsicums, and powders of, Capsicum frutes- tants capsicums of Capsicum annum, Capsicum frutes- cens varieties, Capsicum anuum varieties, Capsicum cens, and Capsicum chinense is 0.1 - 450mg per dose. chinense varieties, Piper migrum varieties, Piper [0054] The more preferred amount of the respiratory longum varieties, Piper retrofractum varieties, Piper of- irritants capsaicin and dihydrocapsiacin is a combined ficinarum varieties, Brassica juncea varieties, Brassica. 20 total of 0.004-25mg per dose. nigra varieties, Sinapis alba varieties, Sinapis arvensis [0055] The more preferred amount of the respiratory varieties, and Zingiber officinale varieties and mixtures irritant zingerone 0.2-150mg per dose. thereof. [0056] The more preferred amount of the respiratory [0044] More preferred respiratory irritants useful in irritant shogaol 0.2-150mg per dose the practice of the invention are pure compounds and 25 [0057] The more preferred amount of the respiratory mixtures of capsaicin, capsico, capsacutin dihydrocap- irritant piperine is 0.2-150mg per dose saicin, nordihydrocapsaicin,homocapsaicin, homodihy- [0058] The more preferred amount of the respiratory drocapsaicin, capsaicinoids, gingerol, piperine, isopi- irritants capsicums of Capsicum annum, Capsicum perine, piperidine, piperettine, zingerone, shogaol, frutescens, and Capsicum chinense is 0.4-350mg per valleral, isovallerals, vanyllylamide, vanyllylamide deriv- 30 dose atives, and extracts, capsicums, and powders of, Cap- [0059] The most preferred amount of the respiratory sicum frutescens varieties, Capsicum anuum varieties, irritants capsaicin and dihydrocapsiacin is a combined Capsicum chinense varieties, Piper migrum varieties, total of 0.02-15mg per dose. Piper longum varieties, Piper retrofractum varieties, Pip- [0060] The most preferred amount of the respiratory er officinarum varieties, Brassica juncea varieties, 35 irritant zingerone 0.2-100mg per dose. Brassica. nigra varieties, Sinapis alba varieties, Sinapis [0061] The most preferred amount of the respiratory arvensis varieties, and Zingiber officinale varieties and irritant shogaol 0.2-100mg per dose mixtures thereof. [0062] The most preferred amount of the respiratory [0045] Most preferred respiratory irritants useful in the irritant piperine is 0.2-100mg per dose practice of the invention are pure compounds and mix- 40 [0063] The most preferred amount of the respiratory tures of capsaicin, capsacutin dihydrocapsaicin, nordi- irritants capsicums of Capsicum annum, Capsicum hydrocapsaicin, homocapsaicin, homodihydrocapsai- frutescens, and Capsicum chinense is 0.6-250mg per cin, capsaicinoids, gingerol, piperine, isopiperine, dose zingerone, shogaol, and vanyllylamide derivatives and [0064] Bitter agents also create an aversive re- mixtures thereof. 45 sponse. The use of bitter agents is particularly useful in [0046] The use of capsaicin with cocaine is contra- preventing abuse of controlled substances by chewing indicated. the oral dosage form. Bitter agents useful in the practice [0047] The amount of respiratory irritant useful in the of this invention include, but are not limited to, agaricic practice of this invention is that which is sufficient to elicit acid, benzyl acetate, brucine, brucine sulfate, caffeine, an aversive response in the user when said irritant is 50 capsaicin, catechin, dadzein, denatonium benzoate (Bi- inhaled through the respiratory mucosa but that which trex®) and other denatonium salts, denatonium capsa- is not sufficient to elicit an aversive response or an ad- icinate, denatonium chloride, denatonium saccharide, verse medical response in the user when said irritant is diethyl phthalate, epicatechin, genistein, gentian violet, swallowed as a solid oral dosage form in the manner gerianol, hydroxytyrosol, kashin, limonin, , lina- prescribed. 55 lool acetate, methyl anthranilate, naringin, nobiletin, [0048] The nociceptive efficacy of the respiratory irri- oleuropin, phenylethyl alcohol, polyphenols, quassin, tants varies greatly depending both on chemical struc- quebracho, quercitin, quinine, quinine sulfate, quinine ture of the active ingredient of said irritant, and the hydrochloride, sinensetin, benzoate, sucrose

5 9 EP 1 293 195 A1 10 octaacetate, and tangeretin and mixtures thereof. of benzoic acid, cetylpyridinium chloride, methyl pa- [0065] Preferred bitter agents useful in the practice of raben and propyl paraben. The compositions of the this invention are, denatonium benzoate (Bitrex®) and present invention generally include from 0-2% preserv- other denatonium salts, denatonium capsaicinate, den- atives. atonium chloride, denatonium saccharide, limonin, lina- 5 [0074] Preferred viscosity agents include, but are not lool, linalool acetate, naringin, quassin, quercitin, su- limited to, methylcellulose, sodium carboxymethylcellu- crose benzoate, and sucrose octaacetate and mixtures lose, hydroxypropyl-methylcellulose, hydroxypropylcel- thereof. lulose, sodium alginate, carbomer, povidone, acacia, [0066] Most preferred bitter agents useful in the prac- guar gum, xanthan gum and tragacanth. Particularly tice of this invention are denatonium benzoate (Bitrex®), 10 preferred are methylcellulose, carbomer, xanthan gum, denatonium capsaicinate, denatonium saccharide, and guar gum, povidone, sodium carboxymethylcellulose, sucrose octaacetate and mixtures thereof. and magnesium aluminum silicate. Compositions of the [0067] Further, sour agents also create an aversive present invention include 0-25% viscosity agents. response. The use of sour agents is particularly useful [0075] Preferred fillers include, but are not limited to, in preventing abuse of controlled substances by chew- 15 lactose, mannitol, sorbitol, tribasic calcium phosphate, ing the oral dosage form. Sour agents useful in the prac- dibasic calcium phosphate, compressible sugar, starch, tice of this invention include, but are not limited to, acidic calcium sulfate, dextro and microcrystalline cellulose. organic compounds that contain one or more acidic pro- The compositions of the present invention contain from tons per molecule and mixtures thereof. 0-75% fillers. [0068] Preferred sour agent useful in the practice of 20 [0076] Preferred lubricants include, but are not limited the invention are acidic organic compounds that contain to, magnesium stearate, stearic acid, and talc. The phar- two or more acidic protons per molecule and mixtures maceutical compositions of the present invention in- thereof. clude 0-2% lubricants. [0069] Most preferred sour agents useful in the prac- [0077] Preferred glidants include, but are not limited tice of the invention are citric acid and tartaric acid and 25 to, talc and colloidal silica. The compositions of the mixtures thereof. present invention include from 0-5% glidants. [0070] The controlled substance and aversive agent [0078] Preferred disintegrants include, but are not lim- are incorporated into the dosage form using any of the ited to, starch, sodium starch glycolate, crospovidone, methods known in the art for preparation of solid oral croscarmelose sodium, polacrilin potassium, and micro- dosage forms. See, Remington's Pharmaceutical Sci- 30 crystalline cellulose. The pharmaceutical compositions ences, 16th Edition. of the present invention include from 0-30% disintegran- [0071] Further, different combinations of aversive ts. agents can be combined in the same dosage form. For [0079] Preferred binders include, but are not limited example, if it is desired to reduce the potential for abuse to, acacia, tragacanth, hydroxypropylcellulose, prege- via both inhalation and chewing, it may be desirable to 35 latinized starch, gelatin, povidone, hydroxypropylcellu- combine both a respiratory irritant and a bitter agent in lose, hydroxypropyl-methylcellulose, methylcellulose, the same formulation. Further, combination of avervise sugar solutions, such as sucrose and sorbitol, and ethyl- agents can sometime have a synergistic effect, such cellulose. The compositions of the present invention in- that the combination has a greater effect than the sum clude 0.1-10% binders. of the individuals taken separately. Still further, people 40 [0080] Encapsulants useful in the practice of the have different responses to taste, such that a mixture of present invention include, but are not limited to perma- bitter agents may be needed to be effective in a larger ble coatings, impermeable coatings, and matrices. fraction of the population. [0081] Permeable coatings useful in this invention are [0072] In addition to the controlled substance and well know to one skilled in the art and include Eudragit® aversive agent, excipients are used in the manufacture 45 RL, and Eudragit® RS (Rohm-Pharma Darmstadt, Ger- of the oral dosage forms of the present invention. Ex- many) cipients useful in the practice if this invention include but [0082] Non-permeable coatings useful in this inven- are not limited to preservatives, viscosity agents, fillers, tion are well known to one skilled in the art and include lubricants, glidants, disintegrants, binders, and encap- Aquacoat CPD (FMC Corporation, Philadelphia, PA, sulants. 50 USA), Eudragit® E100, Eudragit® L100, Eudragit® [0073] Preferred preservatives include, but are not S100 (Rohm-Pharma Darmstadt, Germany), Kollicoat® limited to, phenol, alkyl esters of parahydroxybenzoic MA 30 DP (BASF Aktiengesellschaft, Ludwigshafen, acid, o-phenylphenol benzoic acid and the salts thereof, Germany), Opadry light pink. boric acid and the salts thereof, sorbic acid and the salts [0083] Plastizers for use with coatings useful in the thereof, chlorobutanol, benzyl alcohol, thimerosal, phe- 55 practice of the invention include but are not limited to, nylmercuric acetate and nitrate, nitromersol, benzalko- triethyl citrate, 1,2-propylene glycol, polyethylene gly- nium chloride, cetylpyridinium chloride, methyl paraben, cols, and tracetin. and propyl paraben. Particularly preferred are the salts [0084] Matrices for encapsulation useful in the prac-

6 11 EP 1 293 195 A1 12 tice of the invention include, but are not limited to, anion Lactose 79.5 exchange resins, cation exchange resins, polymeric ad- sorbents, carbonaceous adsorbents, cellulosic poly- Eudragit® RL 12 mers, and acrylic polymers. Stearyl aclohol 24 [0085] Dosage forms of the present invention are im- 5 mediate release or modified release. Talc 3 [0086] The following non limiting examples illustrate Magnesium stearate 1.5 the present invention: Capsaicin 10 EXAMPLE 1 30mg Extended release oxycodone tablets 10 using capsaicin [0091] These tablets are prepared according to the following method: [0087] [0092] Morphine sulfate, a Schedule II controlled sub- stance, capsaicin, and lactose are intimately mixed in a Ingredient mg/tabl et 15 suitable mixer. A granulation is then prepared by incor- porating the granulating fluid into the mixing powders Oxycodone HCl 30 using Eudragit® RL. The granulate is then dried and Lactose 200 passed through a 12 mesh screen. The stearyl alcohol is melted and incorporated into the warm granules using Eudragit® RS PM 45 20 a suitable mixer. After cooling, the granules are passed Purified water as needed through a 12 mesh screen. The granules are then lubri- Stearyl alcohol 75 cated by mixing in the talc and stearyl alcohol. Tablets are then compressed on a suitable tabletting machine Talc 7.5 using round biconvex tooling 10/32" in diameter. Magnesium stearate 3.75 25 EXAMPLE 3 8mg extended release Hydromorphone Capsaicin 13.75 capsules using shogaol

[0088] The required quantities of oxycodone hydro- [0093] chloride, a Schedule II controlled substance, spray- 30 dried lactose, capsaicin, and Eudragit® RS PM are Ingredient mg/capsu le placed into an appropriately-sized mixer, and mixed for approximately 5 minutes. While the powders are mixing, Loading the mixture is granulated with enough water to produce Hydromorphone HCl 8 a moist granular mass. The granules are then dried in 35 Opadry light pink (Y-5-1442) 4 a fluid bed dryer at 60° C., and then passed through an 8-mesh screen. Thereafter, the granules are redried and Purified water as needed pushed through a 12-mesh screen. The required quan- 18/20 mesh sugar spheres 148 tity of stearyl alcohol is melted at approximately 60-70° C., and while the granules are mixing, the melted stearyl 40 alcohol is added. The warm granules are returned to the Overcoating mixer. [0089] The coated granules are removed from the Opadry light pink (Y-5-1442) 8.4 mixer and allowed to cool. The granules are then passed Purified water as needed through a 12-mesh screen. The granulate is then lubri- 45 cated by mixing the required quantity of talc and mag- nesium stearate in a suitable blender. Tablets are com- Retardant coating pressed to 375 mg in weight on a suitable tableting ma- Eudragit® RS 30D 7.6 chine. 50 Eudragit® RL 30D 0.8 EXAMPLE 2 30mg Extended release morphine sulfate tablets using capsaicin

[0090] 55 Ingredient mg/tabl et Morphine sulfate 30

7 13 EP 1 293 195 A1 14

(continued) Encapsulation

Ingredient mg/capsu le [0099] The beads are mixed with shogaol in a suitable Retardant coating mixer and the mixture is then hand filled in size #2 clear 5 gelatin capsules. Triethyl citrate 1.68 Talc 3.36 EXAMPLE 4 30 mg extended release oxycodone tablets using piperine Purified water as needed 10 [0100] Tablets are prepared as described in Example 1, except that the respiratory irritiant used is piperine, Second overcoat and the quantities used are as follows: Opadry light pink (Y-5-1442) 9.6 Purified water ass needed Ingredient mg/tabl et 15 Oxycodone HCl 30

Encapsulation Lactose 138.75 Size #2 clear hard gelatin capsules Eudragit® RS PM 45 Shogaol 75 20 Purified water as needed Stearyl alcohol 75 [0094] Hydromorphone beads are prepared by dis- Talc 7.5 solving hydromorphone HCl, a Schedule II controlled substance, in water, adding Opadry Y-5-1442 and mix- Magnesium stearate 3.75 25 ing for about 1 hour to obtain a 20% w/w suspension. Piperine 75 This suspension is then sprayed onto Nu-Pareil® 18/20 mesh beads using a Wurster insert. EXAMPLE 5 30mg Extended release morphine sulfate tablets using denatonium benzoate First Overcoat 30 [0101] These tablets are prepared as described in Ex- [0095] The loaded hydromorphone beads are then ample 2 except that the capsaicin is replaced with 2mg/ overcoated with a 5% w/w gain of Opadry Light Pink us- tablet of denatonium bezoate (available as Bitrex® from ing a Wurster insert. This overcoat is applied as a pro- Macfarlan Smith, Edinburgh, UK). tective coating. 35 EXAMPLE 6 Retardant Coat [0102] A Caucasian female, age 27 , weighing 50 kg [0096] After the first overcoat, the hydromorphone suffering from back pain takes a 30mg tablet of sus- beads are then coated with a 5% weight gain of a re- 40 tained release oxycodone from Example 1 as pre- tardant coating mixture of Eudragit® RS 30D and scribed, by swallowing said tablet whole. She experi- Eudragit® RL 30D at a ratio of 90:10, RS to RL. The ences 15 hours of pain relief without any aversive re- addition of Triethyl Citrate and Talc is also included in sponse. the Eudragit suspension. The Wurster insert is used to apply the coating suspension. 45 EXAMPLE 7

Second Overcoat [0103] A Caucasian male recreational drug user, age 45, weighing 80 kg crushes a 30mg tablet of sustained [0097] Once the retardant coating is complete, the hy- release oxycodone from Example 1 to give a powder. dromorphone beads are given a final overcoat of Opa- 50 He then inhales said powder through the nose. He im- dry Light Pink to a 5% weight gain using a Wurster insert. mediately experiences an aversive response, including This overcoat is also applied as a protective coating. an intense burning sensation in the nasal passages, sneezing, watery eyes and headache. Curing

55 EXAMPLE 8 [0098] After the completion of the final overcoat, the hydromorphone beads are cured in a 45° C. oven for 2 [0104] An African-American male, aged 18, weighing days. 66 kg, who has never abused drugs crushes an extend-

8 15 EP 1 293 195 A1 16 ed release 30mg morphine tablet from Example 2 into stance selected from the group consisting of dena- a powder and then inhales said powder through the tonium benzoate, denatonium capsaicinate, dena- nose. He immediately experiences an aversive re- tonium chloride, denatonium saccharide, limonin, li- sponse, including an intense burning sensation in the nalool, linalool acetate, naringin, quassin, quercitin, nasal passages, coughing, and watery eyes. 5 sucrose benzoate, and sucrose octaacetate, and mixtures thereof. EXAMPLE 9 7. An oral pharmaceutical dosage form according to [0105] An Asian female, recreational drug user, aged Claim 5, wherein said controlled substance is se- 28, weighing 55 kg, breaks an 8mg hydromorhone cap- 10 lected from the group consisting of Schedule II, III, sule from Example 3 and empties out the contents from IV, and V controlled substances. the capsule. She crushes the beads into a fine powder and then inhales said powder through the nose. She im- 8. An oral pharmaceutical dosage form according to mediately experiences an aversive response, including Claim 6, wherein said controlled substance is se- an intense burning sensation in the nasal passages and 15 lected from the group consisting of Schedule II, III, the throat, coughing, and watery eyes. IV, and V controlled substances.

EXAMPLE 10 9. An oral pharmaceutical dosage form according to Claim 7, wherein said controlled substance is a [0106] At a party a Caucasian male recreational drug 20 Schedule II controlled substance. user, aged 17, weighing 65 kg is offered a 30mg mor- phine sulfate tablet, as prepared in Example 5 . He 10. An oral pharmaceutical dosage form according to chews it and he immediately experiences an aversive Claim 8, wherein said controlled substance is a response causing him to spit out the chewed dosage Schedule II controlled substance. form. 25

Claims

1. An oral pharmaceutical dosage form not suscepti- 30 ble to abuse by respiratory mucosal membrane ad- ministration comprising one or more aversive agents.

2. An oral pharmaceutical dosage form not suscepti- 35 ble to abuse by chewing comprising one or more aversive agents.

3. An oral pharmaceutical dosage form not suscepti- ble to abuse by respiratory mucosal membrane ad- 40 ministration comprising one or more aversive agents and a controlled substance.

4. An oral pharmaceutical dosage form not suscepti- ble to abuse by chewing comprising one or more 45 aversive agents and a controlled substance.

5. An oral pharmaceutical dosage form according to Claim 3, wherein said aversive agent is a respirato- ry irritant selected from the group consisting of cap- 50 saicin, capsacutin dihydrocapsaicin, nordihydro- capsaicin, homocapsaicin, homodihydrocapsaicin, capsaicinoids, gingerol, pipeline, isopiperine, zingerone, shogaol, and vanyllylamide derivatives, and mixtures thereof. 55

6. An oral pharmaceutical dosage form according to Claim 4, wherein said aversive agent is a bitter sub-

9 EP 1 293 195 A1

10 EP 1 293 195 A1

11 EP 1 293 195 A1

12 EP 1 293 195 A1

13