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Details for Patent: 6,534,088

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Details for Patent: 6,534,088

Title: Fibrate-statin combinations with reduced fed-fasted effects
Abstract:This invention discloses an orally administered pharmaceutical composition for the treatment of elevated levels of cholesterol and related conditions comprising a statin and fenofibrate in the form of microparticles of solid fenofibrate that are stabilized by phospholipid as a surface active substance, wherein a therapeutically effective amount of the composition provides the statin and a quantity of fenofibrate to a fasted human patient that is greater than 80% of the quantity of fenofibrate provided by the same amount of the composition when administered to the same patient who has been fed a high fat meal.
Inventor(s): Guivarc'h; Pol-Henri W. (Quebec, CA), Parikh; Indu (Durham, NC), Snow; Robert A. (West Chester, PA)
Assignee: SkyePharma Canada Inc. (Quebec, CA)
Filing Date:Apr 20, 2001
Application Number:09/838,583
Claims:1. A dosage form of a pharmaceutical composition comprising a combination of a statin and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species to said patient when fasted that is at least 80% of the quantity of fenofibrate active species provided by said amount to said patient when fed a meal containing fat.

2. A dosage form of a pharmaceutical composition comprising a combination of a statin and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a human patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species to said patient when fasted that is greater than 80% of the quantity of fenofibrate active species provided by said amount to said patient when fed at least 1000 calories 50% of which are from fat.

3. An oral dosage form of a pharmaceutical composition comprising a combination of a statin and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a human patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species into the blood of said patient when fasted that is between 85% and 115% of the quantity of fenofibrate active species provided by said amount into the blood of said patient when fed at least 1000 calories 50% of which are from fat.

4. An oral dosage form of a pharmaceutical composition comprising a combination of a statin and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a human patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species to said patient when fasted that is at least 85% of the AUC quantity of fenofibrate active species provided by said amount to said patient when fed at least 1000 calories 50% of which are from fat.

5. The dosage form of claim 1 wherein the microparticles of fenofibrate have been prepared in the presence of the phospholipid surface active substance.

6. The dosage form of claim 1 where the statin is water-soluble.

7. The dosage form of claim 1 where the statin is water insoluble or poorly water-soluble.

8. The dosage form of claim 7 where the statin is in the form of a microparticle or is a constituent of a microparticle.

9. The dosage form of any of claim 1 where the statin is in the form of a microparticle that is stabilized by one or more surface active substance or is a constituent of a microparticle that is stabilized by one or more surface active substance.

10. The dosage form of claim 9 where the surface active substance comprises a phospholipid.

11. The dosage form of any of claim 1 where the statin is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin, and cerivastatin.

12. The dosage form of claim 1 where the statin is lovastatin.

13. The dosage form of claim 12 where the lovastatin is present in the range of 2 mg to 50 mg.

14. The dosage form of claim 1 where the statin is pravastatin.

15. The dosage form of claim 14 where the pravastatin is present in the range of 2 mg to 50 mg.

16. The dosage form of claim 1 where the statin is simvastatin.

17. The dosage form of claim 16 where the simvastatin is present in the range of 2 mg to 100 mg.

18. The dosage form of claim 1 where the statin is atorvastatin.

19. The dosage form of claim 18 where the atorvastatin is present in the range of 2 mg to 100 mg.

20. The dosage form of claim 1 where the statin is rosuvastatin.

21. The dosage form of claim 20 where the rosuvastatin is present in the range of 2 mg to 100 mg.

22. The dosage form of claim 1 where the statin is fluvastatin.

23. The dosage form of claim 22 where the fluvastatin is present in the range of 2 mg to 50 mg.

24. The dosage form of claim 1 where the statin is itavastatin.

25. The dosage form of claim 24 where the itavastatin is present in the range of 0.2 mg to 100 mg.

26. The dosage form of claim 1 where the statin is cerivastatin.

27. The dosage form of claim 26 where the cerivastatin is present in the range of 0.05 mg to 2 mg.

28. The dosage form of claim 1 where the fenofibrate is a solid.

29. The dosage form of claim 1 where the fenofibrate is crystalline.

30. The dosage form of claim 1 where the microparticles have a volume weighted mean size smaller than 5 micrometers.

31. The dosage form of claim 1 where the microparticles have a volume weighted mean size smaller than 4 micrometers.

32. The dosage form of claim 1 where the microparticles have a volume weighted mean size smaller than 3 micrometers.

33. The dosage form of claim 1 where the microparticles have a volume weighted mean size smaller than 2 micrometers.

34. The dosage form of claim 1 where the microparticles have a volume weighted mean size smaller than 1 micrometers.

35. The dosage form of claim 1 where the microparticles have a volume weighted mean size smaller than 0.5 micrometers.

36. The dosage form of claim 1 where the microparticles have been prepared by a process selected from the group consisting of homogenization, microfluidization, hot melt microfluidization, and sonication.

37. The dosage form of claim 1 where the microparticles have been prepared by a process selected from the group consisting of a milling process, a precipitation process, an emulsification process, a solvent evaporation spray process, a particle preparation process that utilizes a liquefied gas, and a particle preparation process that utilizes a supercritical fluid.

38. The dosage form of claim 1 that contains a weight of fenofibrate in the range from 40 mg to 300 mg.

39. The dosage form of claim 1 that contains a weight of fenofibrate selected from the group consisting of 40 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 67 mg, 100 mg, 102 mg, 103 mg, 104 mg, 134 mg, 150 mg, 153 mg, 156 mg, 159 mg, 160 mg, 200 mg, 213 mg, 250 mg, and 300 mg of fenofibrate.

40. The dosage form of claim 1 further comprising one or more pharmaceutically acceptable excipient.

41.The dosage form of claim 1 further comprising one or more excipients selected from the group consisting of monosaccharides, disaccharides, trisaccharides, sucrose, raffinose, lactose, mannitol, sorbitol, trehalose, glycerol, dextrose, fructose, pentoses, hexoses, xylitol, and mixtures thereof.

42. The dosage form of claim 1 wherein the phospholipid surface active substance comprises a mixture of phospholipids.

43. The dosage form of claim 1 wherein the phospholipid surface active substance is selected from the group consisting of saturated phospholipids, unsaturated phospholipids, naturally derived phospholipids, synthetic phospholipids, and semisynthetic phospholipids.

44. The dosage form of claim 1 wherein the phospholipid surface active substance is selected from the group consisting of Lipoid E80, Lipoid EPC, Lipoid SPC, DMPG, Phospholipon 100H, a hydrogenated soybean phosphatidylcholine, Phospholipon 90H, Lipoid SPC-3, egg phospholipid, purified egg phopholipid, and mixtures thereof.

45. The dosage form of claim 1 that comprises a capsule.

46. The dosage form of claim 1 that comprises a tablet.

47. The dosage form of claim 1 that comprises a powder dispersible in water or a beverage.

48. The dosage form of claim 1 further comprising a bulking agent.

49. The tablet of claim 46 selected from the group consisting of a film-coated tablet, a moisture resistant tablet, and a tablet coated with a pharmaceutically acceptable polymer.

50. A capsule or tablet dosage form for oral administration comprising a pharmaceutically effective amount of a composition containing a statin and small particles of a fibrate stabilized by a phospholipid stabilizing agent, a sugar, and optionally a carbohydrate-derived alcohol wherein said amount of said dosage form provides a therapeutically effective dose of the statin and a therapeutically effective level of fibrate active species into the blood of a patient in a fasted state that differs by less than 20% of the level of said fibrate active species that said patient receives in a fed state.

51. A dosage form of a pharmaceutical composition comprising a combination of a statin, a carbohydrate bulking agent, and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species to said patient when fasted that is at least 80% of the quantity of fenofibrate active species provided by said amount to said patient when fed a meal containing fat.

52. A dosage form of a pharmaceutical composition comprising a combination of a statin, a carbohydrate bulking agent, and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a human patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species to said patient when fasted that is greater than 80% of the quantity of fenofibrate active species provided by said amount to said patient when fed at at least 1000 calories 50% of which are from fat.

53. An oral dosage form of a pharmaceutical composition comprising a combination of a statin, a carbohydrate bulking agent, and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a human patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species into the blood of said patient when fasted that is between 85% and 115% of the quantity of fenofibrate active species provided by said amount into the blood of said patient when fed at least 1000 calories 50% of which are from fat.

54. An oral dosage form of a pharmaceutical composition comprising a combination of a statin, a carbohydrate bulking agent, and microparticles of fenofibrate that are stabilized by a phospholipid surface active substance, wherein the dosage form provides to a human patient in need of treatment by the statin and fenofibrate a therapeutically effective dose of the statin and a therapeutically effective quantity of fenofibrate active species to said patient when fasted that is at least 85% of the AUC quantity of fenofibrate active species provided by said amount to said patient when fed at least 1000 calories 50% of which are from fat.

55. The dosage form of claim 51 wherein the microparticles of fenofibrate have been prepared in the presence of the phospholipid surface active substance.

56. The dosage form of claim 51 where the statin is water-soluble.

57. The dosage form of claim 51 where the statin is water insoluble or poorly water-soluble.

58. The dosage form of claim 57 where the statin is in the form of a microparticle or is a constituent of a microparticle.

59. The dosage form of claim 51 where the statin is in the form of a microparticle that is stabilized by one or more surface active substance or is a constituent of a microparticle that is stabilized by one or more surface active substance.

60. The dosage form of claim 59 where the surface active substance comprises a phospholipid.

61. The dosage form of claim 51 where the statin is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin, and cerivastatin.

62. The dosage form of claim 51 where the statin is lovastatin.

63. The dosage form of claim 62 where the lovastatin is present in the range of 2 mg to 50 mg.

64. The dosage form of claim 51 where the statin is pravastatin.

65. The dosage form of claim 64 where the pravastatin is present in the range of 2 mg to 50 mg.

66. The dosage form of claim 51 where the statin is simvastatin.

67. The dosage form of claim 66 where the simvastatin is present in the range of 2 mg to 100 mg.

68. The dosage form of claim 51 where the statin is atorvastatin.

69. The dosage form of claim 68 where the atorvastatin is present in the range of 2 mg to 100 mg.

70. The dosage form of claim 51 where the statin is rosuvastatin.

71. The dosage form of claim 70 where the rosuvastatin is present in the range of 2 mg to 100 mg.

72. The dosage form of claim 51 where the statin is fluvastatin.

73. The dosage form of claim 72 where the fluvastatin is present in the range of 2 mg to 50 mg.

74. The dosage form of claim 51 where the statin is itavastatin.

75. The dosage form of claim 74 where the itavastatin is present in the range of 0.2 mg to 100 mg.

76. The dosage form of claim 51 where the statin is cerivastatin.

77. The dosage form of claim 76 where the cerivastatin is present in the range of 0.05 mg to 2 mg.

78. The dosage form of claim 51 where the fenofibrate is a solid.

79. The dosage form of claim 51 where the fenofibrate is crystalline.

80. The dosage form of claim 51 where the microparticles have a volume weighted mean size smaller than 5 micrometers.

81. The dosage form of claim 51 where the microparticles have a volume weighted mean size smaller than 4 micrometers.

82. The dosage form of claim 51 where the microparticles have a volume weighted mean size smaller than 3 micrometers.

83. The dosage form of claim 51 where the microparticles have a volume weighted mean size smaller than 2 micrometers.

84. The dosage form of claim 51 where the microparticles have a volume weighted mean size smaller than 1 micrometers.

85. The dosage form of claim 51 where the microparticles have a volume weighted mean size smaller than 0.5 micrometers.

86. The dosage form of claim 51 where the microparticles have been prepared by a process selected from the group consisting of homogenization, microfluidization, hot melt microfluidization, and sonication.

87. The dosage form of claim 51 where the microparticles have been prepared by a process selected from the group consisting of a milling process, a precipitation process, an emulsification process, a solvent evaporation spray process, a particle preparation process that utilizes a liquefied gas, and a particle preparation process that utilizes a supercritical fluid.

88. The dosage form of claim 51 that contains a weight of fenofibrate in the range from 40 mg to 300 mg.

89. The dosage form of claim 51 that contains a weight of fenofibrate selected from the group consisting of 40 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 67 mg, 100 mg, 102 mg, 103 mg, 104 mg, 134 mg, 150 mg, 153 mg, 156 mg, 159 mg, 160 mg, 200 mg, 213 mg, 250 mg, and 300 mg of fenofibrate.

90. The dosage form of claim 51 further comprising one or more pharmaceutically acceptable excipient.

91. The dosage form of claim 51 where the carbohydrate is a sugar.

92. The dosage form of claim 51 where the carbohydrate is selected from the group consisting of monosaccharides, disaccharides, trisaccharides, sucrose, raffinose, lactose, mannitol, sorbitol, trehalose, glycerol, dextrose, fructose, pentoses, hexoses, xylitol, and mixtures thereof.

93. The dosage form of claim 51 wherein the phospholipid surface active substance comprises a mixture of phospholipids.

94. The dosage form of claim 51 wherein the phospholipid surface active substance is selected from the group consisting of saturated phospholipids, unsaturated phospholipids, naturally derived phospholipids, synthetic phospholipids, and semisynthetic phospholipids.

95. The dosage form of claim 51 wherein the phospholipid surface active substance is selected from the group consisting of Lipoid E80, Lipoid EPC, Lipoid SPC, DMPG, Phospholipon 100H, a hydrogenated soybean phosphatidylcholine, Phospholipon 90H, Lipoid SPC-3, egg phospholipid, purified egg phopholipid, and mixtures thereof.

96. The dosage form of claim 51 that comprises a capsule.

97. The dosage form of claim 51 that comprises a tablet.

98. The dosage form of claim 51 that comprises a powder dispersible in water or a beverage.

99. The dosage form of claim 51 prepared by a process comprising blending dried small particles containing fenofibrate stabilized by a phospholipid surface active substance with a statin.

100. The dosage form of claim 51 further comprising one or more pharmaceutically acceptable excipients.

101. The tablet of claim 97 selected from the group consisting of a film-coated tablet, a moisture resistant tablet, and a tablet coated with a pharmaceutically acceptable polymer.
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