Drug formulations having reduced abuse potential

• US 20040228802A1
• Filed: 05/12/2003
• Published: 11/18/2004
• Est. Priority Date: 05/12/2003
• Status: Active Grant

• Current Assignee: Supernus Pharmaceuticals Incorporated
• Original Assignee: Supernus Pharmaceuticals Incorporated
• Inventors: Couch, Richard A., Chang, Rong-Kun, Burnside, Beth A.
• Granted Patent: US 8,906,413 B2
• Time in Patent Office: Days
• US Class Current: 424/10.2
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2853 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61K 9/7061 Polyacrylates
• CPC Class Codes: A61K 9/7069 obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
• CPC Class Codes: A61P 25/30 for treating abuse or dependence

Abstract

Drug formulations having reduced abuse potential which contain one or more of (1) a bittering agent, (2) a bright deterrent/indicator dye and (3) fine insoluble particulate matter. The bittering agent and dye are in a form which does not affect proper administration of the drug, but the bittering agent creates a bitter side effect when the dosage form is crushed or chemically extracted and nasally, orally, buccally or sublingually administered and the dye produces a bright color when crushed and contacted. The fine insoluble particulate matter hinders extraction of the drug from the dosage form and, when crushed, can deter intravenous injection because of the presence of the insoluble particles or hinder injection by blocking an intravenous needle. The bright color of the dye, when extracted, also has a psychologically deterrent effect on intravenous abusers.

Claims

1. A dosage form having reduced abuse potential comprising a psychoactive drug as an active pharmaceutical ingredient, and one or more of:

(1) a bittering agent in a form which does not create a bitter taste when the dosage form of the drug is properly administered, but which creates a bitter side effect when crushed or extracted and nasally, orally, buccally or sublingually administered;

(2) an indicator dye in a form which does not create color when the dosage form of the drug is properly administered, but which colors or stains human tissue when crushed or extracted; and

(3) fine insoluble particulate matter.

2. The dosage form according to claim 1, wherein said one or more bittering agent, indicator dye and fine insoluble particulate matter is contained in a granule, bead or tablet.

3. The dosage form according to claim 2, wherein said granule, bead or tablet is coated with a pharmaceutically acceptable protective coating, enteric coating or sustained release coating.

4. The dosage form according to claim 3, wherein said protective coating is selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, and pH dependent cationic polymers soluble in gastric fluid up to pH 5.0.

5. The dosage form according to claim 3, wherein said enteric coating is a pH-sensitive polymer which dissolves at a pH greater than 4.5, after a selected delayed time, or after the coated unit passes through the stomach.

6. The dosage form according to claim 3, wherein said pH sensitive polymer is selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, and co-polymerized methacrylic acid/methacrylic acid methyl esters.

7. The dosage form according to claim 2, wherein said granule, bead or tablet is coated with a coating that does not dissolve in the gastrointestinal tract.

8. The dosage form according to claim 7, wherein the coating that does not dissolve in the gastrointestinal tract is selected from the group consisting of cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, poly(ethyl acrylate), poly (methyl methacrylate), and poly(trimethylammonioethylmethacrylate chloride).

9. The dosage form according to claim 1, wherein said bittering agent is selected from the group consisting of sugar octaacetate, denatonium benzoate, denatonium saccharide, caffeine, quinine or a quinine salt, bitter orange peel oil, pepper extract and capsicum.

10. The dosage form according to claim 9, wherein said bittering agent is selected from the group consisting of sugar octaacetate, denatonium benzoate and denatonium saccharide.

11. The dosage form according to claim 1, wherein said indicator dye is selected from the group consisting of allura red, amaranth, brilliant blue, canthaxanthin, carmine, carmoisine, carotene, curcumin, erythrosine, green S, indigo carmine, iron oxide black, iron oxide red, iron oxide yellow, patent blue, phloxine O, ponceau 4R, quinoline yellow, riboflavin, sunset yellow, tartrazine, titanium dioxide, vegetable carbon black, annatto, beet, black carrot, black currant, caramel, carmine, carmine lake, chlorophyll, cochineal, elderberry, grapeskin/grape juice, malt, paprika, red cabbage, turmeric, and anthocyanins.

12. The dosage form according to claim 11, wherein said indicator dye is tartrazine.

13. The dosage form according to claim 1, wherein said fine insoluble particulate matter is selected from the group consisting of polycarbophil, methacrylic acid copolymer, microcrystalline cellulose, sodium starch glycolate, crospovidone, croscarmellose sodium, talcum, and silicon dioxide.

14. The dosage form according to claim 1 which is a capsule.

15. The dosage form according to claim 14, wherein said one or more bittering agent, indicator dye and fine insoluble particulate matter is contained in a granule, bead or tablet.

16. The dosage form according to claim 15, wherein said granule, bead or tablet is coated with a pharmaceutically acceptable protective coating, enteric coating or sustained release coating.

17. The dosage form according to claim 16, wherein said protective coating is selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, and pH dependent cationic polymers soluble in gastric fluid up to pH 5.0.

18. The dosage form according to claim 16, wherein said enteric coating is a pH-sensitive polymer which dissolves at a pH greater than 4.5, after a selected delayed time, or after the coated unit passes through the stomach.

19. The dosage form according to claim 16, wherein said pH sensitive polymer is selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, and co-polymerized methacrylic acid/methacrylic acid methyl esters.

20. The dosage form according to claim 15, wherein said granule, bead or mini-tablet is coated with a coating that does not dissolve in the gastrointestinal tract.

21. The dosage form according to claim 20, wherein the coating that does not dissolve in the gastrointestinal tract is selected from the group consisting of cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, poly(ethyl acrylate), poly (methyl methacrylate), and poly(trimethylammonioethylmethacrylate chloride).

22. The dosage form according to claim 14, wherein said bittering agent is selected from the group consisting of sugar octaacetate, denatonium benzoate, denatonium saccharide, caffeine, quinine or a quinine salt, bitter orange peel oil, pepper extract and capsicum.

23. The dosage form according to claim 22, wherein said bittering agent is selected from the group consisting of sugar octaacetate, denatonium benzoate and denatonium saccharide.

24. The dosage form according to claim 14, wherein said indicator dye is selected from the group consisting of allura red, amaranth, brilliant blue, canthaxanthin, carmine, carmoisine, carotene, curcumin, erythrosine, green S, indigo carmine, iron oxide black, iron oxide red, iron oxide yellow, patent blue, phloxine O, ponceau 4R, quinoline yellow, riboflavin, sunset yellow, tartrazine, titanium dioxide, vegetable carbon black, annatto, beet, black carrot, black currant, caramel, carmine, carmine lake, chlorophyll, cochineal, elderberry, grapeskin/grape juice, malt, paprika, red cabbage, turmeric, and anthocyanins.

25. The dosage form according to claim 24, wherein said indicator dye is tartrazine.

26. The dosage form according to claim 14, wherein said fine insoluble particulate matter is selected from the group consisting of polycarbophil, methacrylic acid copolymer, microcrystalline cellulose, sodium starch glycolate, crospovidone, croscarmellose sodium, talcum, and silicon dioxide.

27. The dosage form according to claim 1 which is a tablet.

28. The dosage form according to claim 27, wherein said one or more bittering agent, indicator dye and fine insoluble particulate matter is contained in a granule or bead.

29. The dosage form according to claim 28, wherein said granule or bead is coated with a pharmaceutically acceptable protective coating, enteric coating or sustained release coating.

30. The dosage form according to claim 29, wherein said protective coating is selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, ethyl cellulose aqueous dispersions and pH dependent cationic polymers soluble in gastric fluid up to pH 5.0.

31. The dosage form according to claim 29, wherein said enteric coating is a pH-sensitive polymer which dissolves at a pH greater than 4.5, after a selected delayed time, or after the coated unit passes through the stomach.

32. The dosage form according to claim 29, wherein said pH sensitive polymer is selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, and co-polymerized methacrylic acid/methacrylic acid methyl esters.

33. The dosage form according to claim 28, wherein said granule, bead or mini-tablet is coated with a coating that does not dissolve in the gastrointestinal tract.

34. The dosage form according to claim 33, wherein the coating that does not dissolve in the gastrointestinal tract is selected from the group consisting of cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, poly(ethyl acrylate), poly (methyl methacrylate), and poly(trimethylammonioethylmethacrylate chloride).

35. The dosage form according to claim 27, wherein said bittering agent is selected from the group consisting of sugar octaacetate, denatonium benzoate, denatonium saccharide, caffeine, quinine or a quinine salt, bitter orange peel oil, pepper extract and capsicum.

36. The dosage form according to claim 35, wherein said bittering agent is selected from the group consisting of sugar octaacetate, denatonium benzoate and denatonium saccharide.

37. The dosage form according to claim 27, wherein said indicator dye is selected from the group consisting of allura red, amaranth, brilliant blue, canthaxanthin, carmine, carmoisine, carotene, curcumin, erythrosine, green S, indigo carmine, iron oxide black, iron oxide red, iron oxide yellow, patent blue, phloxine O, ponceau 4R, quinoline yellow, riboflavin, sunset yellow, tartrazine, titanium dioxide, vegetable carbon black, annatto, beet, black carrot, black currant, caramel, carmine, carmine lake, chlorophyll, cochineal, elderberry, grapeskin/grape juice, malt, paprika, red cabbage, turmeric, and anthocyanins.

38. The dosage form according to claim 37, wherein said indicator dye is tartrazine.

39. The dosage form according to claim 27, wherein said fine insoluble particulate matter is selected from the group consisting of polycarbophil, methacrylic acid copolymer, microcrystalline cellulose, sodium starch glycolate, crospovidone, croscarmellose sodium, talcum, and silicon dioxide.

40. The dosage form according to claim 1 which is a transdermal patch.

41. The dosage form according to claim 1 which is a liquid suspension.

42. A deterrent particle to be incorporated into a capsule or tablet containing a drug of abuse and comprising a bittering agent contained in a granule, bead or tablet coated with a pharmaceutically acceptable substance which when digested dissolves, if at all, after reaching the small intestine.

43. A deterrent particle to be incorporated into a capsule or tablet containing a drug of abuse and comprising a dye contained in a granule, bead or tablet coated with a pharmaceutically acceptable substance which when ingested dissolves, if at all, after reaching the small intestine.