PHARMACEUTICAL COMPOSITIONS AND METHODS FOR MITIGATING RISK OF ALCOHOL INDUCED DOSE DUMPING OR DRUG ABUSE

• US 20100291205A1
• Filed: 01/16/2008
• Published: 11/18/2010
• Est. Priority Date: 01/16/2007
• Status: Abandoned Application

• Current Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Original Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Inventors: Haahr, Anne-Mette, Downie, Ken, Bar-Shalom, Daniel, Hemmingsen, Pernille Hoyrup, Pedersen, Anders Vagno
• Application Number:
  US12/523,045
• Publication Number:
  US 20100291205A1
• Time in Patent Office: Days
• US Class Current: 424/457
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids

Abstract

Abuse resistant polyglycol-based pharmaceutical compositions are disclosed. The composition contains one or more polyglycols and one or more active substances and it is resistant to crushing, melting and/or extraction. Moreover, such compositions have the same or lower solubility in ethanolic-aqueous medium, i.e. they are not subject to ethanol-induced dose dumping effect.

Claims

1-26. -26. (canceled)

27. A composition providing controlled release of one or more drug substances, the composition comprising:

a matrix comprising one or more drug substances and one or more polyglycols selected from polyethylene glycol and polyethylene oxides; and

a coating that is substantially insoluble, non-erodible and non-permeable to water, said coating partly covering the matrix;

wherein the composition is formulated such that the one or more drug substances are released from the composition by erosion of the matrix and said composition does not exhibit ethanol-induced dose dumping of the one or more active agents.

28. A composition according to claim 27, wherein one or both of the polyethylene glycol and the polyethylene oxide is a substantially water soluble crystalline or semi-crystalline polymer.

29. A composition according to claim 27, wherein the matrix further comprises a polyglycol co-polymer.

30. A composition according to claim 27, wherein the total concentration of polyglycols in the composition is selected from about 5% w/w to about 99.9% w/w, about 10% w/w to about 95% w/w, about 15% w/w to about 90% w/w, about 20% w/w to about 85% w/w, about 30% w/w to about 85% w/w, about 30% w/w to about 99% w/w, about 35% w/w to about 95% w/w, about 35% w/w to about 90% w/w, about 35% w/w to about 85% w/w, about 35% w/w to about 80% w/w, about 40% w/w to about 75% w/w, about 45% w/w to about 70% w/w, about 45% w/w to about 65% w/w, about 55% w/w to about 85% w/w, and about 60% w/w to about 85% w/w.

31. A composition according to claim 27, wherein one or both of the polyethylene glycol and the polyethylene oxide has a molecular weight of at least about 20,000.

32. A composition according to claim 27, wherein one or both of the polyethylene glycol and the polyethylene oxide has a molecular weight selected from about 20,000 daltons, about 20,000 to about 700,000 daltons, about 20,000 to about 600,000 daltons, about 35,000 to about 500,000 daltons, about 35,000 to about 400,000 daltons, about 35,000 to about 300,000 daltons, about 50,000 to about 300,000 daltons, about 35,000 daltons, about 50,000 daltons, about 75,000 daltons, about 100,000 daltons, about 150,000 daltons, about 200,000 daltons, about 250,000 daltons, about 300,000 daltons, and about 400,000 daltons.

33. A composition according to claim 27, wherein one or both of the polyethylene glycol and the polyethylene oxide has a molecular weight selected from about 35,000 daltons, about 50,000 daltons, about 100,000 daltons, about 200,000 daltons and about 300,000 daltons.

34. A composition according to claim 29, wherein the polyglycol co-polymer has a molecular weight of at least about 2,000 daltons.

35. A composition according to claim 34, wherein the polyglycol co-polymer is a polaxmer that has the formula HO(C₂H₄O)_a(C₃H₆O)_b(C₂H₄O)_aH, and a is an integer selected from about 10 to about 150, from about 30 to about 140, from about 50 to about 100, from about 65 to about 90, and from about 70 to about 90, and b is an integer selected from about 10 to about 80, from about 15 to about 80, from about 20 to about 60, and from about 25 to about 55.

36. A composition according to claim 29, wherein the polyglycol co-polymer is a polaxmer that has a molecular weight selected from about 2,000 to about 30,000 daltons, from about 2,000 daltons to about 20,000 daltons, from about 4,000 daltons to about 18,000 daltons, and from about 6,000 daltons to about 10,000 daltons.

37. A composition according to claim 29, wherein the polyglycol co-polymer has a HLB value of at least about 18.

38. A composition according to claim 29, wherein the concentration of the polyglycol co-polymer in the pharmaceutical composition is selected from about 2.5% w/w to about 99.5% w/w, about 5% w/w to about 99.5% w/w, about 5% w/w to about 95% w/w, about 5% w/w to about 90% w/w, about 5% w/w to about 85% w/w, about 10% w/w to about 80% w/w, about 10% w/w to about 70% w/w, about 10% w/w to about 60% w/w, about 10% w/w to about 50% w/w, about 15% w/w to about 50% w/w, about 10% w/w to about 45% w/w, about 10% w/w to about 40% w/w, about 15% w/w to about 40% w/w, about 15% w/w to about 35% w/w, and about 15% w/w to about 30% w/w.

39. A composition according to claim 27, wherein the composition further exhibits a release rate of the one or more drug substances in ethanol that is equal to or lower than the release rate of the one or more drug substances exhibited in water.

40. A composition according to claim 27, wherein the composition further exhibits a release rate of the one or more drug substances in ethanol that is 1.5 times lower than the release rate of the one or more drug substances exhibited in water.

41. A composition according to claim 27, wherein the composition further exhibits a ratio (R₅₀) between t_{50% w/w}(40% ethanol in medium 1) and t_{50% w/w} (medium 1) that is 1 or more.

42. A composition according to claim 41, wherein the ratio R₅₀ is selected from at the most 5, at the most 4, at the most 3 and at the most 2.

43. A composition according to claim 41, wherein the ratio R₅₀ is selected from 1 to 1.5, from 1 to 1.4, from 1 to 1.3, from 1 to 1.2, from 1 to 1.1, from 1 to 1.05, and about 1.

44. A composition according to claim 27, wherein the composition is a solid dosage form.

45. A composition according to claim 27, wherein the composition is designed for oral administration.

46. A composition according to claim 45, wherein the composition is in the form of tablets, capsules or sachets.

47. A composition according to claim 27, wherein the pharmaceutical composition is an injection molded or extruded composition.

48. A composition according to claim 27, wherein the composition is compressed.

49. A composition according to claim 27, wherein the composition is resistant to crushing, whereby the composition is resistant to drug abuse.

50. A composition according to claim 27, wherein the composition is resistant to isolation of the drug substance by melting or ethanol extraction.

51. A composition according to claim 27, wherein the composition is resistant to isolation of the drug substance by crushing, melting or ethanol extraction.

52. A method for delivery of one or more drug substances to a subject in need thereof, the method comprising:

providing a composition for the controlled release of the one or more drug substances, the composition comprising,

a matrix comprising one or more drug substances and one or more polyglycols selected from polyethylene glycol and polyethylene oxides; and

a coating that is substantially insoluble, non-erodible and non-permeable to water, said coating partly covering the matrix;

wherein the composition is formulated such that the one or more drug substances are released from the composition by erosion of the matrix and said composition does not exhibit ethanol-induced dose dumping of the one or more active agents; and

administering said composition to the subject.

53. A method according to claim 52, wherein one or both of the polyethylene glycol and the polyethylene oxide included in the composition for controlled release is a substantially water soluble crystalline or semi-crystalline polymer.

54. A method according to claim 52, wherein the matrix included in the composition for controlled release further comprises a polyglycol co-polymer.

55. A method according to claim 52, wherein the total concentration of polyglycols in the composition for controlled release is selected from about 5% w/w to about 99.9% w/w, 10% w/w to about 95% w/w, about 15% w/w to about 90% w/w, about 20% w/w to about 85% w/w, about 30% w/w to about 85% w/w, about 30% w/w to about 99% w/w, about 35% w/w to about 95% w/w, about 35% w/w to about 90% w/w, about 35% w/w to about 85% w/w, about 35% w/w to about 80% w/w, about 40% w/w to about 75% w/w, about 45% w/w to about 70% w/w, about 45% w/w to about 65% w/w, about 55% w/w to about 85% w/w, and about 60% w/w to about 85% w/w.

56. A method according to claim 52, wherein one or both of the polyethylene glycol and the polyethylene oxide included in the composition for controlled release has a molecular weight of at least about 20,000.

57. A method according to claim 52, wherein one or both of the polyethylene glycol and the polyethylene oxide included in the composition for controlled release has a molecular weight selected from about 20,000 daltons, about 20,000 to about 700,000 daltons, about 20,000 to about 600,000 daltons, about 35,000 to about 500,000 daltons, about 35,000 to about 400,000 daltons, about 35,000 to about 300,000 daltons, about 50,000 to about 300,000 daltons, about 35,000 daltons, about 50,000 daltons, about 75,000 daltons, about 100,000 daltons, about 150,000 daltons, about 200,000 daltons, about 250,000 daltons, about 300,000 daltons, and about 400,000 daltons.

58. A method according to claim 52, wherein one or both of the polyethylene glycol and the polyethylene oxide included in the composition for controlled release has a molecular weight selected from about 35,000 daltons, about 50,000 daltons, about 100,000 daltons, about 200,000 daltons, and about 300,000 daltons.

59. A method according to claim 54, wherein the polyglycol co-polymer has a molecular weight of at least about 2,000 daltons.

60. A method according to claim 59, wherein the polyglycol co-polymer is a poloxamer that has the formula HO(C₂H₄O)_a(C₃H₆O)_b(C₂H₄O)_aH, and a is an integer selected from about 10 to about 150, about 30 to about 140, about 50 to about 100, about 65 to about 90, about 70 to about 90, and b is an integer selected from about 10 to about 80, about 15 to about 80, about 20 to about 60, and about 25 to about 55.

61. A method according to claim 54, wherein the polyglycol copolymer is a poloxamer that has a molecular weight selected from about 2,000 daltons to about 30,000 daltons, about 2,000 daltons to about 20,000 daltons, about 4,000 daltons to about 18,000 daltons, and about 6,000 daltons to about 10,000 daltons.

62. A method according to claim 54, wherein the polyglycol co-polymer has a HLB value of at least about 18.

63. A method according to claim 54, wherein the concentration of the polyglycol co-polymer in the composition for controlled release is selected from about 2.5% w/w to about 99.5% w/w, about 5% w/w to about 99.5% w/w, about 5% w/w to about 95% w/w, about 5% w/w to about 90% w/w, about 5% w/w to about 85% w/w, about 10% w/w to about 80% w/w, about 10% w/w to about 70% w/w, about 10% w/w to about 60% w/w, about 10% w/w to about 50% w/w, about 15% w/w to about 50% w/w, about 10% w/w to about 45% w/w, about 10% w/w to about 40% w/w, about 15% w/w to about 40% w/w, about 15% w/w to about 35% w/w, and about 15% w/w to about 30% w/w.

64. A method according to claim 52, wherein the composition for controlled release further exhibits a release rate of the one or more drug substances in ethanol that is equal to or lower than the release rate of the one or more drug substances exhibited in water.

65. A method according to claim 52, wherein the composition for controlled release further exhibits a release rate of the one or more drug substances in ethanol that is 1.5 times lower than the release rate of the one or more drug substances exhibited in water.

66. A method according to claim 52, wherein the composition for controlled release further exhibits a ratio (R₅₀) between t_{50% w/w}(40% ethanol in medium 1) and t_{50% w/w} (medium 1) that is 1 or more.

67. A method according to claim 66, wherein the ratio R₅₀ is selected from at the most 5, at the most 4, at the most 3, and at the most 2.

68. A method according to claim 66, wherein the ratio R₅₀ is selected from 1 to 1.5, from 1 to 1.4, from 1 to 1.3, from 1 to 1.2, from 1 to 1.1, from 1 to 1.05, and about 1.

69. A method according to claim 52, wherein the composition for controlled release is a solid dosage form.

70. A method according to claim 52, wherein the composition for controlled release is designed for oral administration.

71. A method according to claim 52, wherein the composition for controlled release is in the form of tablets, capsules or sachets.

72. A method according to claim 52, wherein the composition for controlled release is an injection molded or extruded composition.

73. A method according to claim 52, wherein the composition for controlled release is compressed.

74. A method according to claim 52, wherein the composition for controlled release is resistant to crushing, whereby the composition is resistant to drug abuse.

75. A method according to claim 52, wherein the composition for controlled release is resistant to isolation of the drug substance by melting or ethanol extraction.

76. A method according to claim 52, wherein the composition for controlled release is resistant to isolation of the drug substance by crushing, melting or ethanol extraction.