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 opiods. In the preferred embodiment, a drug is modified to increase its lipophilicity. In preferred embodiments the modified drug is homogeneously dispersed within 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 preferably organic solvent insoluble, but enzymatically degradable by enzymes present in the human gastrointestinal tract. 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 broken down or dissolved gradually within the tract by a combination of enzymatic degradation, surfactant action of bile acids, and mechanical erosion.

We claim: 
     
         1 . An orally administerable abuse-deterrent pharmaceutical composition comprising a therapeutically effective amount of a drug prone to abuse selected from the group of compositions consisting of
 (a) a composition comprising a therapeutically effective amount of a lipophilic derivative of a drug prone to abuse, and   (b) a water-insoluble, preferably lipophilic, formulation comprising a therapeutically effective amount of a drug prone to abuse.   
     
     
         2 . The composition of  claim 1  comprising a therapeutically effective amount of a lipophilic derivative of a drug prone to abuse in one or more pharmaceutically acceptable excipients. 
     
     
         3 . The composition of  claim 1 , wherein the composition is a controlled-release pharmaceutical composition. 
     
     
         4 . The composition of  claim 1 , wherein the composition prevents the immediate release of a substantial portion of incorporated drug when the physical integrity of the composition is compromised and the resulting material is exposed to an aqueous medium. 
     
     
         5 . The composition of  claim 4 , wherein the portion of the drug released immediately is less than 80% of the total amount of drug incorporated into formulation. 
     
     
         6 . The composition of  claim 1 , wherein the composition prevents the immediate release of a substantial portion of incorporated drug when the physical integrity of the composition is compromised and the resulting material is exposed to a non-aqueous medium. 
     
     
         7 . The composition of  claim 6 , wherein the portion of the drug released immediately is less than 80% of the total amount of the drug incorporated into the composition. 
     
     
         8 . The composition of  claim 1  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 amide, mazindol, medazepam, mefenorex, meperidine, meptazinol, metazocine, methadone, methamphetamine, methohexital, methotrimeprazine, methyldihydromorphinone, methylphenidate, methylphenobarbital, metopon, morphine, nabilone, nalbuphine, nalbupine, nalorphine, narceine, nefopam, nicomorphine, nimetazepam, nitrazepam, nordiazeparn, 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, chloral, chloral betaine, chloral hydrate, chloralose, chlordiazepoxide, chlorhexadol, chlormethiazole 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. 
     
     
         9 . The composition of  claim 2 , wherein the lipophilic derivative of a drug is a free base or a free acid of the drug. 
     
     
         10 . The composition of  claim 2 , wherein the lipophilic derivative of a drug is a salt comprising the ionized drug and a lipophilic counter-ion. 
     
     
         11 . The composition of  claim 2 , wherein the lipophilic derivative of a drug is a complex comprising one or more components selected from the group consisting of drug molecules, metal cations, and lipophilic counter-ions. 
     
     
         12 . The composition of  claim 2 , wherein the lipophilic derivative of a drug is a complex comprising one or more components selected from the group consisting of drug molecules, metal cations, and cyclodextrin molecules. 
     
     
         13 . The composition of  claim 2  wherein the drug is complexed with a metal cation selected from the group cmisisting of zinc, calcium, magnesium, bismuth and combinations thereof. 
     
     
         14 . The composition of  claim 11  wherein the drug is oxycodone, and
 wherein the metal cation is selected from the group consisting of zinc, calcium, magnesium, and bismuth and the lipophilic counter-ion is selected from the group consisting of stearate, oleate, palmitate, laurate and linoleate. 
 
     
     
         15 . The composition of  claim 2 , wherein the lipophilic derivative of a drug is a complex comprising the drug and a cyclodextrin. 
     
     
         16 . The composition of  claim 2 , wherein the lipophilic derivative of a drug is an ester or amide formed between the drug and a fatty acid. 
     
     
         17 . The composition of  claim 1 , wherein the drug is incorporated into a plurality of individual microparticles comprising a material that is either slowly soluble in water or water insoluble. 
     
     
         18 . The composition of  claim 17  wherein the microparticles comprise a wax or wax-like material. 
     
     
         19 . The composition of  claim 17  wherein the microparticles comprise a fat or a fatty substance. 
     
     
         20 . The composition of  claim 17  wherein the microparticles comprise a material selected from the group consisting of naturally water insoluble proteins, naturally water insoluble polysaccharides, naturally water insoluble lipids and phospholipids, cross-linked water soluble proteins, cross-linked water soluble polysaccharides, cross-linked water soluble cyclodextrins and combinations thereof. 
     
     
         21 . The composition of  claim 17  wherein the individual microparticles are coated with one or more independent layers, where at least one of the layers is water insoluble and is degraded by enzymes of the human gastrointestinal tract. 
     
     
         22 . The composition of  claim 1  wherein the drug is in the form of individual drug particles coated with one or more independent layers where at least one of the layers is water insoluble and is degraded by enzymes of the human gastrointestinal tract. 
     
     
         23 . The composition of  claim 21  wherein at least one of the layers is water-insoluble, organic solvent-insoluble, and degradable by enzymes present in the human gastrointestinal tract. 
     
     
         24 . The composition of  claim 21  comprising materials wherein a combination of these materials is not soluble in water, organic solvent, or any combination thereof. 
     
     
         25 . The composition of  claim 21  wherein the composition is not completely soluble, and
 wherein the drug is not fully released in a single solvent or enzyme solution. 
 
     
     
         26 . The composition of  claim 21  wherein the enzymatically degradable layer(s) comprise a material selected from the group consisting of naturally water insoluble proteins, naturally water insoluble polysaccharides, naturally water insoluble lipids and phospholipids, cross-linked proteins, cross-linked polysaccharides, and combinations thereof. 
     
     
         27 . The composition of  claim 1  wherein the drug prone to abuse is co-administered with a drug that has no appreciable abuse potential. 
     
     
         28 . The composition of  claim 1  formulated for the drug to be immediately released upon oral administration. 
     
     
         29 . The composition of  claim 1  wherein the drug prone to abuse is oxycodone. 
     
     
         30 . A method of manufacturing an abuse-resistant pharmaceutical composition comprising homogeneously dispersing a therapeutically effective amount of a drug prone to abuse, in one or more pharmaceutically acceptable carrier(s), diluent(s), and/or additives, to form an orally administerable, abuse-deterrent pharmaceutical composition comprising a therapeutically effective amount of a drug prone to abuse selected from the group of compositions consisting of
 (a) a composition comprising a therapeutically effective amount of a lipophilic derivative of a drug prone to abuse, and   (b) a water-insoluble, preferably lipophilic, formulation comprising a therapeutically effective amount of a drug prone to abuse, as defined by any of  claim 1 .   
     
     
         31 . The method of  claim 30  further comprising formulating the composition into a capsule or tablet. 
     
     
         32 . 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 drug prone to abuse selected from the group of compositions consisting of
 (a) a composition comprising a therapeutically effective amount of a lipophilic derivative of a drug prone to abuse, and   (b) a water-insoluble, preferably lipophilic, formulation comprising a therapeutically effective amount of a drug prone to abuse, as defined by any of  claim 1 .