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Claims for Patent: 7,399,488

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Claims for Patent: 7,399,488

Title:Abuse-deterrent pharmaceutical compositions of opiods 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 GI tract by a combination of enzymatic degradation, surfactant action of bile acids, and mechanical erosion.
Inventor(s): Hirsh; Jane (Wellesley, MA), Kibanov; Alexander M. (Newton, MA), Swager; Timothy M. (Newton, MA), Buchwald; Stephen L. (Newton, MA), Lo; Whe Yong (Canton, MA), Fleming; Alison B. (Marshfield, MA), Rariy; Roman V. (Allston, MA)
Assignee: Collegium Pharmaceutical, Inc. (Cumberland, RI)
Application Number:10/614,866
Patent Claims: 1. An orally administrable abuse-deterrent pharmaceutical composition comprising a therapeutically effective amount of microparticles consisting of (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 consisting of a lipophilic derivative of a drug prone to abuse dispersed within one or more carrier materials which are either slowly soluble in water or insoluble in water, 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 release of a portion of incorporated drug is substantially retarded.

5. The composition of claim 1 or 2, wherein the portion of the drug released immediately when the physical integrity of the composition is compromised is less than 80% of the total amount of drug incorporated into the formulation.

6. The composition of claim 1 or 2, 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 an aqueous medium.

7. The composition of claim 6, wherein the portion of the drug released immediately when the physical integrity of the composition is compromised 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, 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, choral, 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 1 or 2, wherein the lipophilic derivative of a drug is a free base or a free acid of the drug.

10. The composition of claim 1 or 2, wherein the lipophulic derivative of a drug is a salt comprising the ionized drug and a lipophilic counter-ion.

11. The composition of claim 1 or 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 1 or 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 1 or 2 wherein the drug is complexed with a metal cation selected from the group consisting of zinc, calcium, magnesium, bismuth and combinations thereof.

14. The composition of claim 1 or 2, wherein the lipophilic derivative of a drug is a complex comprising the drug and a cyclodextrin.

15. The composition of claim 1 or 2, wherein the lipophilic derivative of a drug is an ester or amide formed between the drug and a fatty acid.

16. The composition of claim 2 wherein the microparticles consist of drug dispersed in a carrier material selected from the group consisting of fats, fatty substances, waxes, wax-like substances and combinations thereof.

17. The composition of claim 16 wherein the microparticles consist of drug dispersed in a fat or a fatty substance.

18. The composition of claim 2 wherein the microparticles consist of a drug dispersed in a carrier 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.

19. The composition of claim 1 or 2 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.

20. The composition of claim 19 wherein at least one of the layers is water-insoluble, organic solvent-insoluble, and degradable by enzymes present in the human gastrointestinal tract.

21. The composition of claim 19 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.

22. 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.

23. The composition of claim 1 or 2 wherein the drug prone to abuse is oxycodone.

24. The composition of claim 2 wherein the drug prone to abuse is selected from the group consisting of 1-phenylcyclohexytamine, 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, nordiazepam, normethadone, normorphine, oxazepam, oxazolam, oxycodone, oxymorphone, pentazocine, pentobarbital, phenadoxone, phenazoeme, 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, 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.

25. The composition of claim 1 or 2 wherein the lipophilic drug and the lipophilic derivative is dissolved in the carrier material in a molten state to result in a uniform dispersion within the carrier material.

26. The composition of claim 1 or 2 wherein the lipophilic drug and the lipophilic derivative is dissolved in a co-solvent along with a carrier material to result in a uniform dispersion within the carrier material.

27. The composition of claim 10 wherein the lipophilic counter-ion is selected from the group consisting of stearic acid, palmitic acid, myristic acid, and mixtures thereof.

28. The composition of claim 9, 10 or 27 wherein one or more carrier materials is selected from the group consisting of stearic acid, palmitic acid, beeswax, carnauba wax, hydrogenated oil, and mixtures thereof.

29. The composition of claim 1 or 2, wherein the individual microparticles are further formulated into a tablet or capsule for oral administration.

30. The composition of claim 28 wherein the drug prone to abuse is selected from the group consisting of oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, tramadol, methylphenidate, and amphetamine.
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