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Claims for Patent: 5,741,512

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Claims for Patent: 5,741,512

Title: Pharmaceutical compositions comprising cyclosporins
Abstract:Pharmaceutical compositions comprising a cyclosporin, e.g. Ciclosporin or [Nva].sup.2 -Ciclosporin, in "microemulsion pre-concentrate" and microemulsion form. The compositions typically comprise (1.1) a C.sub.1-5 alkyl or tetrahydrofurfuryl di- or partial-ether of a low molecular weight mono- or poly-oxy-alkane diol, e.g. Transcutol or Glycofurol, as hydrophilic component. Compositions are also provided comprising a cyclosporin and (1.1) and, suitably, also a saccharide monoester, e.g. raffinose or saccharose monolaurate. Dosage forms include topical formulations and, in particular, oral dosage forms.
Inventor(s): Hauer; Birgit (Lahr, DE), Meinzer; Armin (Freiburg/Munzingen, DE), Posanski; Ulrich (Freiburg, DE), Richter; Friedrich (Schonbuhl-Urtenen, CH)
Assignee: Novartis Corporation (Summit, NJ)
Application Number:08/430,770
Patent Claims: 1. An oral pharmaceutical composition comprising about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component which is a lower alkanol having from one to five carbon atoms, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a surfactant, all weights based on the total weight of the composition, the relative proportion of all cyclosporin A, hydrophilic components, lipophilic components and surfactants in said composition being such that upon dilution with water to a ratio of 1 part by weight of said composition to 5 parts by weight of water, an oil-in-water microemulsion having average particle size of less than about 1,500 .ANG. is spontaneously formed.

2. The composition of claim 1 wherein the average particle size is from about 150 to less than about 1,100 .ANG..

3. The composition of claim 1 wherein the average particle size is less than about 1,000 .ANG..

4. The composition of claim 1 wherein the dilution with water is to a ratio of 1 part by weight of composition to 1 part by weight of water.

5. The composition of claim 1 wherein said lower alkanol is ethanol.

6. The composition of claim 1 wherein said surfactant comprises a polyoxyethylene fatty acid ester.

7. The composition of claim 1 comprising about to about 15% by weight of cyclosporin A, based on the total weight of said cyclosporin A, hydrophilic component, lipophilic component and surfactant.

8. The composition of claim 1 comprising about 2 to about 45% by weight of lipophilic component, based on the total weight of the composition.

9. The composition of claim 1 comprising about to about 90% by weight of surfactant, based on the total weight of the composition.

10. The composition of claim 1 comprising about 0.5 to about 90% by weight of hydrophilic component, about 2 to about 45% by weight of lipophilic component, and about 20 to about 90% by weight of surfactant, all weights based on the total weight of the composition.

11. The composition of claim 1 wherein the ratio of cyclosporin A to surfactant is about 1:1 to about 1:10, based on parts per weight.

12. A method of reducing the variability of bioavailability levels of cyclosporin A for patients during cyclosporin therapy, said method comprising orally administering an oral pharmaceutical composition comprising about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component which is a lower alkanol having from one to five carbon atoms, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a surfactant, all weights based on the total weight of the composition, the relative proportion of all cyclosporin A, hydrophilic components, lipophilic components and surfactants in said composition being such that upon dilution with water to a ratio of 1 part by weight of said composition to 5 parts by weight of water, an oil-in-water microemulsion having average particle size of less than about 1,500 .ANG. is spontaneously formed.

13. The method of claim 12 wherein said composition comprises about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of hydrophilic component, about 2 to about 45% by weight of lipophilic component, and about 20 to about 90% by weight of surfactant, all weights based on the total weight of the composition.

14. A method of orally administering a pharmaceutical composition, said method comprising orally administering to a patient in need of cyclosporin therapy a composition comprising about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component which is a lower alkanol having from one to five carbon atoms, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a surfactant, all weight percents being based on the total weight of composition, the relative proportion of all cyclosporin A, hydrophilic components, lipophilic components and surfactants in said composition being such that upon dilution with water to a ration of 1 part by weight of said composition to 5 parts by weight of water, an oil-in-water microemulsion having average particle size of less than about 1,500 .ANG. is spontaneously formed.

15. The method of claim 14 wherein the average particle size is from about 150 to less than about 1,100 .ANG..

16. The method of claim 14 wherein the average particle size is less than about 1,000 .ANG..

17. The method of claim 14 wherein the dilution with water is to a ratio of 1 part by weight of composition to 1 part by weight of water.

18. The method of claim 14 wherein said lower alkanol is ethanol.

19. The method of claim 14 comprising about 2 to about 45% by weight of lipophilic component, based on the total weight of the composition.

20. The method of claim 14 comprising about 20 to about 90% by weight of surfactant, based on the total weight of the composition.

21. The method of claim 14 comprising about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of hydrophilic component, about 2 to about 45% by weight of lipophilic component, and about 20 to about 90% by weight of surfactant, all weights based on the total weight of the composition.

22. The method of claim 14 wherein the ratio of cyclosporin A to surfactant is about 1:1 to about 1:10, based on parts per weight.

23. The method of claim 12 wherein the average particle size is from about 150 to less than about 1,100 .ANG..

24. The method of claim 12 wherein the average particle size is less than about 1,000 .ANG..

25. The method of claim 12 wherein the dilution with water is to a ratio of 1 part by weight of composition to 1 part by weight of water.

26. The method of claim 12 wherein said lower alkanol is ethanol.

27. The method of claim 12 wherein said surfactant comprises a polyoxyethylene fatty acid ester.

28. The method of claim 12 comprising about 10 to about 15% by weight of cyclosporin A, based on the total weight of said cyclosporin A, hydrophilic component, lipophilic component and surfactant.

29. The method of claim 12 comprising about 2 to about 45% by weight of lipophilic component, based on the total weight of the composition.

30. The method of claim 12 comprising about 20 to about 90% by weight of surfactant, based on the total weight of the composition.

31. The method of claim 12 comprising about 0.5 to about 90% by weight of hydrophilic component, about 2 to about 45% by weight of lipophilic component, and about 20 to about 90% by weight of surfactant, all weights based on the total weight of the composition.

32. The method of claim 12 wherein the ratio of cyclosporin A to surfactant is about 1:1 to about 1:10, based on parts per weight.

33. The composition of claim 1 wherein said surfactant is selected from the group consisting of a polyoxyethylene glycolated natural vegetable oil, a polyoxyethylene glycolated hydrogenated vegetable oil, a polyoxyethylene-sorbitan-fatty acid ester and a polyoxyethylene fatty acid ester.

34. The composition of claim 1 wherein said surfactant comprises a polyoxyethlyene-sorbitan-fatty acid ester.

35. The composition of claim 5 wherein said surfactant comprises a polyoxyethylene-sorbitan-fatty acid ester.

36. The composition of claim 35 wherein said polyoxyethylene-sorbitan-fatty acid ester is selected from the group consisting of

polyoxyethylene(20)sorbitanmonolaurate,

polyoxyethylene(20)sorbitanmonopalmitate,

polyoxyethylene(20)sorbitanmonostearate,

polyoxyethylene(20)sorbitanmonooleate,

polyoxyethylene(20)sorbitantristearate,

polyoxyethylene(20)sorbitantrioleate,

polyoxyethylene(4)sorbitanmonolaurate,

polyoxyethylene(4)sorbitanmonostearate and

polyoxyethylene(5)sorbitanmonooleate.

37. The method of claim 14 wherein said surfactant is selected from the group consisting of a polyoxyethylene glycolated natural vegetable oil, a polyoxyethylene glycolated hydrogenated vegetable oil, a polyoxyethylene-sorbitan-fatty acid ester and a polyoxyethylene fatty acid ester.

38. The method of claim 14 wherein said surfactant comprises a polyoxyethylene-sorbitan-fatty acid ester.

39. The method of claim 18 wherein said surfactant comprises a polyoxyethylene-sorbitan-fatty acid ester.

40. The method of claim 39 wherein said polyoxyethylene-sorbitan-fatty acid ester is selected from the group consisting of

polyoxyethylene(20)sorbitanmonolaurate,

polyoxyethylene(20)sorbitanmonopalmitate,

polyoxyethylene(20)sorbitanmonostearate,

polyoxyethylene(20)sorbitanmonooleate,

polyoxyethylene(20)sorbitantristearate,

polyoxyethylene(20)sorbitantrioleate,

polyoxyethylene(4)sorbitanmonolaurate,

polyoxyethylene(4)sorbitanmonostearate and

polyoxyethylene(5)sorbitanmonooleate.

41. The method of claim 12 wherein said surfactant is selected from the group consisting of a polyoxyethylene glycolated natural vegetable oil, a polyoxyethylene glycolated hydrogenated vegetable oil, a polyoxyethylene-sorbitan-fatty acid ester and a polyoxyethylene fatty acid ester.

42. The method of claim 12 wherein said surfactant comprises a polyoxyethylene-sorbitan-fatty acid ester.

43. The method of claim 26 wherein said surfactant comprises a polyoxyethylene-sorbitan-fatty acid ester.

44. The method of claim 43 wherein said polyoxyethylene-sorbitan-fatty acid ester is selected from the group consisting of

polyoxyethylene(20)sorbitanmonolaurate,

polyoxyethylene(20)sorbitanmonopalmitate,

polyoxyethylene(20)sorbitanmonostearate,

polyoxyethylene(20)sorbitanmonooleate,

polyoxyethylene(20)sorbitantristearate,

polyoxyethylene(20)sorbitantrioleate,

polyoxyethylene(4)sorbitanmonolaurate,

polyoxyethylene(4)sorbitanmonostearate and

polyoxyethylene(5)sorbitanmonooleate.

45. An oral pharmaceutical composition comprising about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component which is a lower alkanol having from one to five carbon atoms, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a surfactant, all weights based on the total weight of the composition, the relative proportion of all cyclosporin A, hydrophilic components, lipophicic components and surfactants in said composition being such that upon dilution with water to a ratio of 1 part by weight of said composition to 5 parts by weight of water, an oil-in-water microemulsion having particles less than 2,000 .ANG. is spontaneously formed.

46. The composition of claim 45 wherein the particles have a maximum size of less than 1,500 .ANG..

47. The composition of claim 45 wherein the maximum size of the particles is from 100 to 1,000 .ANG..

48. The composition of claim 45 wherein the dilution with water is to a ratio of 1 part by weight of composition to 1 part by weight of water.

49. The composition of claim 45 wherein said lower alkanol is ethanol.

50. The composition of claim 45 wherein said surfactant comprises a polyoxyethylene fatty acid ester.

51. The composition of claim 45 comprising about 2 to about 45% by weight of lipophilic component, based on the total weight of the composition.

52. The composition of claim 45 comprising about 20 to about 90% by weight of surfactant, based on the total weight of the composition.

53. The composition of claim 45 comprising about 0.5 to about 90% by weight of hydrophilic component, about 2 to about 45% by weight of lipophilic component, and about 20 to about 90% by weight of surfactant, all weights based on the total weight of the composition.

54. The composition of claim 45 wherein the ratio of cyclosporin A to surfactant is about 1:1 to about 1:10, based on parts per weight.

55. The composition of claim 45 wherein said surfactant is selected from the group consisting of a polyoxyethylene glycolated natural vegetable oil, a polyoxyethylene glycolated hydrogenated vegetable oil, a polyoxyethylene-sorbitan-fatty acid ester and a polyoxyethylene fatty acid ester.

56. The composition of claim 45 wherein said surfactant comprises a polyoxyethlyene-sorbitan-fatty acid ester.

57. The composition of claim 49 wherein said surfactant comprises a polyoxyethylene-sorbitan-fatty acid ester.

58. The composition of claim 57 wherein said polyoxyethylene-sorbitan-fatty acid ester is selected from the group consisting of

polyoxyethylene(20)sorbitanmonolaurate,

polyoxyethylene(20)sorbitanmonopatmitate,

polyoxyethylene(20)sorbitanmonostearate,

polyoxyethylene(20)sorbitanmonooleate,

polyoxyethylene(20)sorbitantristearate,

polyoxyethylene(20)sorbitantrioleate,

polyoxyethylene(4)sorbitanmonolaurate,

polyoxyethylene(4)sorbitanmonostearate and

polyoxyethylene(5)sorbinanmonooleate.

59. A method of reducing the variability of bioavailability levels of cyclosporin A for patients during cyclosporin therapy, said method comprising orally administering an oral pharmaceutical composition comprising about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component which is a lower alkanol having from one to five carbon atoms, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a surfactant, all weights based on the total weight of the composition, the relative proportion of all cyclosporin A, hydrophilic components, lipophilic components and surfactants in said composition being such that upon dilution with water to a ratio of 1 part by weight of said composition to 5 parts by weight of water, an oil-in-water microemulsion having particles of less than 2,000 .ANG. is spontaneously formed.

60. The method of claim 59 wherein the particles have a maximum size of less than 1,500 .ANG..

61. The method of claim 59 wherein the maximum size of the particles is from 100 to 1,000 .ANG..

62. The method of claim 59 wherein the dilution with water is to a ratio of 1 part by weight of composition to 1 part by weight of water.

63. The method of claim 59 wherein said lower alkanol is ethanol.

64. The method of claim 59 wherein said surfactant comprises a polyoxyethylene fatty acid ester.

65. The method of claim 59 comprising about 2 to about 45 by weight of lipophilic component, based on the total weight of the composition.

66. The method of claim 59 comprising about 20 about 90% by weight of surfactant, based on the total weight of the composition.

67. The method of claim 59 comprising about 0.5 to about 90% by weight of hydrophilic component, about 2 about 45% by weight of lipophilic component, and about 20 about 90% by weight of surfactant, all weights based on the total weight of the composition.

68. The method of claim 59 wherein the ratio of cyclosporin A to surfactant is about 1:1 to about 1:10, based on parts per weight.

69. The method of claim 59 wherein said surfactant is selected from the group consisting of a polyoxyethylene glycolated natural vegetable oil, a polyoxyethylene glycolated hydrogenated vegetable oil, a polyoxyethylene-sorbitan-fatty acid ester and a polyoxyethylene fatty acid ester.

70. The method of claim 59 wherein said surfactant comprises a polyoxyethlyene-sorbitan-fatty acid ester.

71. he method of claim 63 wherein said surfactant comprises a polyoxyethylene-sorbitan-fatty acid ester.

72. The composition of claim 71 wherein said polyoxyethylene-sorbitan-fatty acid ester is selected from the group consisting of

polyoxyethylene(20)sorbitanmonolaurate,

polyoxyethylene(20)sorbitanmonopalmitate,

polyoxyethylene(20)sorbitanmonostearate,

polyoxyethylene(20)sorbitanmonooleate,

polyoxyethylene(20)sorbitantristearate,

polyoxyethylene(20)sorbitantrioleate,

polyoxyethylene(4)sorbitanmonolaurate,

polyoxyethylene(4)sorbitanmonostearate and

polyoxyethylene(5)sorbitanmonooleate.

73. A method of orally administering a pharmaceutical composition, said method comprising orally administering to a patient in need of cyclosporin therapy a composition comprising about 5 to about 25% by weight of cyclespetit A, about 0.5 to about 90% by weight of a hydrophilic component which is a lower alkanol having from one to five carbon atoms. about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a surfactant, all weight percents being based on the total weight of the composition, the relative proportion of all cyclesperin A, hydrophilic components, lipophilic components and surfactants in said composition being such that upon dilution with water to a ratio of 1 part by weight of said composition to 5 parts by weight of water, an oil-in-water microemulsion having particles of less than 2,000 .ANG. is spontaneously formed.

74. The method of claim 73 wherein the particles have a maximum size of less than 1,500 .ANG..

75. The method of claim 73 wherein the maximum size of the particles is from 100 to 1,000 .ANG..

76. The method of claim 73 wherein the dilution with water is to a ratio of 1 part by weight of composition to 1 part by weight of water.

77. The method of claim 73 wherein said lower alkanol is ethanol.

78. The method of claim 73 wherein said surfactant comprises a polyoxyethylene fatty acid ester.

79. The method of claim 73 comprising about 2 to about 45% by weight of lipophilic component, based on the total weight of the composition.

80. The method of claim 73 comprising about 20 to about 90% by weight of surfactant, based on the total weight of the composition.

81. The method of claim 73 comprising about 0.5 to about 90% by weight of hydrophilic component, about 2 to about 45% by weight of lipophilic component, and about 20 to about 90% by weight of surfactant, all weights based on the total weight of the composition.

82. The method of claim 73 wherein the ratio of cyclosporin A to surfactant is about 1:1 to about 1:10, based on parts per weight.

83. The method of claim 73 wherein said surfactant is selected from the group consisting of a polyoxyethylene glycolated natural vegetable oil, a polyoxyethylene glycolated hydrogenated vegetable oil, a polyoxyethylene-sorbitan-fatty acid ester and a polyoxyethylene fatty acid ester.

84. The method of claim 73 wherein said surfactant comprises a polyoxyethlyene-sorbitan-fatty acid ester.

85. The method of claim 77 wherein said surfactant comprises a polyoxyethylene-sorbitan-fatty acid ester.

86. The method of claim 85 wherein said polyoxyethylene-sorbitan-fatty acid ester is selected from the group consisting of

polyoxyethylene(20)sorbitanmonolaurate,

polyoxyethylene(20)sorbitanmonopalmitate,

polyoxyenhylene(20)sorbitanmonostearate,

polyoxyethylene(20)sorbitanmonooleate,

polyoxyethylene(20)sorbinantristearate,

polyoxyethylene(20)sorbitantrioleate,

polyoxyethylene(4)sorbitanmonolaurate,

polyoxyethylene(4)sorbitanmonostearate and

polyoxyethylene(5)sorbitanmonooleate.
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