Abuse-deterrent pharmaceutical compositions of opioids and other drugs

Abstract

An abuse-deterrent pharmaceutical composition has been developed to reduce the likelihood of improper administration of drugs, especially drugs such as opioids. In a preferred embodiment, a drug is modified to increase its lipophilicity. In some embodiments the modified drug is homogeneously dispersed within spherical microparticles composed of a material that is either slowly soluble or not soluble in water. In some embodiments the drug containing microparticles or drug particles are coated with one or more coating layers, where at least one coating is water insoluble and/or organic solvent insoluble. The abuse-deterrent composition retards the release of drug, even if the physical integrity of the formulation is compromised (for example, by chopping with a blade or crushing) and the resulting material is placed in water, snorted, or swallowed. However, when administered as directed, the drug is slowly released from the composition as the composition is passes through the GI tract.

We claim: 
     
         1 . An orally administrable abuse-deterrent pharmaceutical composition comprising a therapeutically effective amount of microparticles comprising
 (a) a lipophilic drug prone to abuse or lipophilic derivative of a drug prone to abuse, and   (b) one or more carrier materials selected from the group consisting of fats, fatty substances, waxes, wax-like substances and mixtures thereof,   wherein the drug is dispersed within the one or more carrier materials, and the release of a portion of incorporated drug is retarded when the physical integrity of the composition is compromised and the compromised composition is exposed to water.   
     
     
         2 . An orally administrable abuse-deterrent pharmaceutical composition comprising a therapeutically effective amount of microparticles comprising
 (a) a lipophilic derivative of a drug prone to abuse   (b) one or more carrier materials which either dissolve slowly in water or are insoluble in water, and   wherein the lipophilic derivative of the drug is dispersed within the one or more carrier materials which are either slowly soluble in water or insoluble in water, and wherein the release of a portion of incorporated drug is retarded when the physical integrity of the composition is compromised and the compromised composition is exposed to water.   
     
     
         3 . The composition of  claim 1  or  2  wherein the composition is a controlled-release pharmaceutical composition. 
     
     
         4 . The composition of  claim 1  or  2  wherein the drug prone to abuse is selected from the group consisting of 1-phenylcyclohexylamine, 1-piperidinocyclohexanecarbonitrile, alfentanil, alphacetylmethadol, alphaprodine, alprazolam, amobarbital, amphetamine, anileridine, apomorphine, aprobarbital, barbital, barbituric acid derivative, bemidone, benzoylecgonine, benzphetamine, betacetylmethadol; betaprodine, bezitramide, bromazepam, buprenorphine, butabarbital, butalbital, butorphanol, camazepam, cathine, chloral, chlordiazepoxide, clobazam, clonazepam, clorazepate, clotiazepam, cloxazolam, cocaine, codeine, chlorphentermine, delorazepam, dexfenfluramine, dextromoramide, dextropropoxyphen, dezocine, diazepam, diethylpropion, difenoxin, dihydrocodeine, dihydromorphine, dioxaphentyl butyrate, dipanone, diphenoxylate, diprenorphine, ecgonine, enadoline, eptazocine, estazolam, ethoheptazine, ethyl loflazepate, ethylmorphine, etorphine, femproponex, fencamfamin, fenfluramine, fentanyl, fludiazepam, flunitrazepam, flurazepam, glutethimide, halazepam, haloxazolam, hexalgon, hydrocodone, hydromorphone, isomethadone, hydrocodone, ketamine, ketazolam, ketobemidone, levanone, levoalphacetylmethadol, levomethadone, levomethadyl acetate, levomethorphan, levorphanol, lofentanil, loperamide, loprazolam, lorazepam, lormetazepam, lysergic acid, lysergic acid amid; mazindol, medazepam, mefenorex, meperidine, meptazinol, metazocine, methadone, methamphetamine, methohexital, methotrimeprazine, methyldihydromorphinone, methylphenidate, methylphenobarbital, metopon, morphine, nabilone, nalbuphine, nalbupine, nalorphine, narceine, nefopam, nicomorphine, nimetazepam, nitrazepam, nordiazepam, normethadone, normorphine, oxazepam, oxazolam, oxycodone, oxymorphone, pentazocine, pentobarbital, phenadoxone, phenazocine, phencyclidine, phendimetrazine, phenmetrazine, pheneridine, piminodine, prodilidine, properidine, propoxyphene, racemethorphan; racemorphan, racemoramide, remifentanil, secobarbital, sufentanil, talbutal, thebaine, thiamylal, thiopental, tramadol, trimeperidine, vinbarbital, allobarbitone, alprazolam, amylobarbitone, aprobarbital, barbital, barbitone, benzphetamine, brallobarbital, bromazepam, brotizolam, buspirone, butalbital, butobarbitone, butorphanol, camazepam, captodiame, carbromal, carfentanil, carpipramine, cathine, chloral, chloral betaine, chloral hydrate, chloralose, chlordiazepoxide, chlorhexadol, chlormethazole edisylate, chlormezanone, cinolazepam, clobazam, potassium clorazepate, clotiazepam, cloxazolam, cyclobarbitone, delorazepam, dexfenfluramine, diazepam, diethylpropion, difebarbamate, difenoxin, enciprazine, estazolam, ethyl loflazepate, etizolam, febarbamate, fencamfamin, fenfluramine, fenproporex, fluanisone, fludiazepam, flunitraam, flunitrazepam, flurazepam, flutoprazepam, gepirone, glutethimide, halazepam, haloxazolam, hexobarbitone, ibomal, ipsapirone, ketazolam, loprazolam mesylate, lorazepam, lormetazepam, mazindol, mebutamate, medazepam, mefenorex, mephobarbital, meprobamate, metaclazepam, methaqualone, methohexital, methylpentynol, methylphenobarbital, midazolam, milazolam, morphine, nimetazepam, nitrazepam, nordiazepam, oxazepam, oxazolam, paraldehyde, pemoline, pentabarbitone, pentazocine, pentobarbital, phencyclidine, phenobarbital, phendimetrazine, phenmetrazine, phenprobamate, phentermine, phenyacetone, pinazepam, pipradol, prazepam, proxibarbal, quazepam, quinalbaritone, secobarbital, secbutobarbitone, sibutramine, temazepam, tetrazepam, triazolam, triclofos, zalepan, zaleplon, zolazepam, zolpidem, and zopiclone. 
     
     
         5 . The composition of  claim 1  or  2  wherein the lipophilic derivative of a drug is a free base or a free acid of the drug. 
     
     
         6 . The composition of  claim 1  or  2  wherein the lipophilic derivative of a drug is a salt comprising the ionized drug and a lipophilic counter-ion. 
     
     
         7 . The composition of  claim 1  or  2  wherein the lipophilic derivative of a drug is a salt comprising the ionized drug and a one or more fatty acids. 
     
     
         8 . The composition of  claim 2  wherein the microparticles consist of drug dispersed in one or more carrier materials selected from the group consisting of fats, fatty substances, waxes, wax-like-substances and combinations thereof. 
     
     
         9 . The composition of  claim 8  wherein the microparticles consist of drug dispersed in a fat or a fatty substance. 
     
     
         10 . The composition of  claim 2  wherein the microparticles consist of a drug dispersed in a carrier material selected from the group consisting of fats, waxes, natural polymers, synthetic polymers or a mixture thereof. 
     
     
         11 . The composition of  claim 1  or  2  wherein the individual microparticles are coated with one or more independent layers. 
     
     
         12 . The composition of  claim 1  or  2  wherein the drug prone to abuse is co-administered with a drug that has no appreciable abuse potential. 
     
     
         13 . The composition of  claim 1  or  2  wherein the drug prone to abuse is oxycodone. 
     
     
         14 . The composition of  claim 1  or  2  wherein the drug or drug derivative is dissolved in the carrier material in a molten state to result in a uniform dispersion within the carrier material. 
     
     
         15 . The composition of  claim 1  or  2  wherein the drug or drug derivative is dissolved in a co-solvent along with a carrier material to result in a uniform dispersion within the carrier material. 
     
     
         7 . composition of  claim 7  wherein the fatty acid is selected from the group consisting of stearic acid, palmitic acid, myristic acid, and mixtures thereof. 
     
     
         17 . The composition of  claim 1  or  2  wherein one or more carrier materials is selected from the group consisting of stearic acid, palmitic acid, myristic acid, beeswax, carnauba wax, hydrogenated oil, and mixtures thereof. 
     
     
         18 . The composition of  claim 1  or  2 , wherein the individual microparticles are further formulated into a tablet or capsule for oral administration. 
     
     
         19 . The composition of  claim 4  wherein the drug prone to abuse is selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, tramadol, methylphenidate, and amphetamine. 
     
     
         20 . The composition of  claim 1  or  2 , wherein the composition further comprises an antioxidant. 
     
     
         21 . The composition of  claim 20 , wherein the antioxidant is selected from the group consisting of butylated hydroxy anisole (BHT); ascorbic acid, its salts and esters; Vitamin B, tocopherol and its salts; sulfites such as sodium metabisulphite; cysteine and its derivatives; citric acid; propyl gallate; butylated hydroxyanisole (BHA); and combinations thereof. 
     
     
         22 . The composition of  claim 20 , wherein the concentration of the antioxidant is from about 0.001% to about 1% w/w. 
     
     
         23 . The composition of  claim 22 , wherein the concentration of the antioxidant is from about 0.01% to about 0.5% w/w. 
     
     
         24 . The composition of  claim 1  or  2  wherein the microparticles are less than 1000 micron in diameter. 
     
     
         25 . The composition of  claim 1  or  2  wherein the microparticles are spherical. 
     
     
         26 . A method of manufacturing the abuse-resistant pharmaceutical composition of  claim 1  or  2 , the method comprising homogeneously dispersing a therapeutically effective amount of a lipophilic drug prone to abuse or a lipophilic derivative of a drug prone to abuse, in one or more one or more carrier materials,
 wherein the release of a portion of incorporated drug is retarded when the physical integrity of the composition is compromised and the compromised composition is exposed to water. 
 
     
     
         27 . The method of  claim 26 , further comprising incorporating one or more antioxidants into the composition. 
     
     
         28 . A method of administering an abuse-resistant pharmaceutical composition comprising orally administering to a patient in need thereof an abuse-deterrent pharmaceutical composition comprising a therapeutically effective amount of a lipophilic drug prone to abuse or a lipophilic derivative of a drug prone to abuse,
 wherein the drug is homogeneously dispersed one or more one or more carrier materials, and   wherein the release of a portion of incorporated drug is retarded when the physical integrity of the composition is compromised and the compromised composition is exposed to water.   
     
     
         29 . The method of  claim 28 , wherein the composition further comprises one or more antioxidants.