Pravastatin pharmaceutical formulations and methods of their use

1. A method of treating hypercholesterolemia comprising administering, to a subject in need of such treatment, a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation, wherein the formulation inhibits release of the pravastatin in the stomach of the subject, releases a therapeutic amount of pravastatin in the small intestine of the subject over a period of less than 6 hours and achieves a relative systemic bioavailability, as compared to an equally effective dose of a conventional rapid release pravastatin formulation, of less than about 90%.

2. The method of claim 1 , wherein the formulation releases greater than about 80% of its pravastatin content in the small intestine.

3. The method of claim 2 , wherein the formulation releases greater than 85% of its pravastatin content in the small intestine.

4. The method of claim 2 , wherein the formulation release greater than 80% of its pravastatin content in the small intestine over a period of from about 3 hours to less than 6 hours.

5. The method of claim 4 , wherein the formulation releases greater than 80% of its pravastatin content in the small intestine over a period of from about 4 hours to about 5 hours.

6. The method according to claim 1 , wherein the administration achieves a relative systemic bioavailability, as compared to a conventional rapid release pravastatin formulation, of less than about 80%.

7. The method according to claim 1 , wherein the administration achieves a relative Cmax, as compared to a conventional rapid release pravastatin formulation, of less than about 80%.

8. The method according to claim 7 , wherein the administration achieves a relative Cmax, as compared to a conventional rapid release pravastatin formulation, of less than about 70%.

9. The method according top claim 1 , wherein the formulation is administered to the subject to treat one or more cardiovascular diseases that are secondary to the hypercholesterolemia.

10. The method according to claim 2 , wherein the administration reduces the low density lipoprotein-cholesterol (LDL-C) levels in a subject following administration of the formulation.

11. The method according to claim 2 , wherein the administration increases high density lipoprotein-cholesterol (HDL-C) levels in a subject following administration of the formulation.

12. The method according to claim 1 , wherein said pharmaceutical formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a 0.1N HCl media for 2 hours, followed by pH 6.8 buffer for the remainder of the test of the following:

2 hours, in HCl media: less than or equal to about 20%;

2 hours, in pH 6.8: greater than or equal to about 20%;

4 hours, in pH 6.8: greater than or equal to about 40%;

6 hours, in pH 6.8: greater than or equal to about 60%; and

12 hours, in pH 6.8: greater than or equal to about 80%.

13. The method according to claim 12 , wherein said pharmaceutical formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a 0.1 N HCl media for 2 hours, followed by pH 6.8 buffer for the remainder of the test, of the following:

2 hours, in HCl media: less than or equal to about 20%;

1 hour, in pH 6.8: 0 to about 50%;

2 hours, in pH 6.8: about 20% to about 80%;

4 hours, in pH 6.8: greater than or equal to about 50%;

6 hours, in pH 6.8: greater than or equal to about 70%;

12 hours, in pH 6.8: greater than or equal to about 80%.

14. The method according to claim 12 , wherein said pharmaceutical formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a 0.1 N HCl media for 2 hours, followed by pH 6.8 buffer for the remainder of the test, of the following:

2 hours, in HCl media: less than or equal to about 10%;

1 hour, in pH 6.8: about 10 to about 40%;

2 hours, in pH 6.8: about 30% to about 70%;

3 hours, in pH 6.8: greater than or equal to about 45%;

4 hours, in pH 6.8: greater than or equal to about 60%;

5 hours, in pH 6.8: greater than or equal to about 75%; and

6 hours, in pH 6.8: greater than or equal to about 80%.

15. The method according to claim 14 , wherein said pharmaceutical formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a 0.1 N HCl media for 2 hours, followed by pH 6.8 buffer for the remainder of the test, of the following:

2 hours, in HCl media: less than or equal to about 5%;

1 hour, in pH 6.8: about 10 to about 40%;

2 hours, in pH 6.8: about 30% to about 70%;

3 hours, in pH 6.8: greater than or equal to about 45%;

4 hours, in pH 6.8: greater than or equal to about 60%; and

5 hours, in pH 6.8: greater than or equal to about 80%.

16. The method according to claim 15 , wherein said pharmaceutical formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following:

2 hours, in pH 6.8: greater than or equal to about 20%;

4 hours, in pH 6.8: greater than or equal to about 40%;

6 hours, in pH 6.8: greater than or equal to about 60%; and

12 hours, in pH 6.8: greater than or equal to about 80%.

17. The method according to claim 16 , wherein said pharmaceutical formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following:

1 hour, in pH 6.8: 0 to about 50%;

2 hours, in pH 6.8: about 20% to about 80%;

4 hours, in pH 6.8: greater than or equal to about 50%;

6 hours, in pH 6.8: greater than or equal to about 70%;

12 hours, in pH 6.8: greater than or equal to about 80%.

18. The method according to claim 17 , wherein said pharmaceutical formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following:

1 hour, in pH 6.8: about 10 to about 40%;

2 hours, in pH 6.8: about 30% to about 70%;

3 hours, in pH 6.8: greater than or equal to about 45%;

4 hours, in pH 6.8: greater than or equal to about 60%;

5 hours, in pH 6.8: greater than or equal to about 75%; and

6 hours, in pH 6.8: greater than or equal to about 80%.

19. The method according to claim 18 , wherein said pharmaceutical formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following:

1 hour, in pH 6.8: about 10 to about 40%;

2 hours, in pH 6.8: about 30% to about 70%;

3 hours, in pH 6.8: greater than or equal to about 45%;

4 hours, in pH 6.8: greater than or equal to about 60%; and

5 hours, in pH 6.8: greater than or equal to about 80%.

20. A modified-release pravastatin formulation comprising pravastatin, or a pharmaceutically acceptable salt thereof, and a pH-independent coating, which formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following:

1 hour, in pH 6.8: less than or equal to about 20%;

3 hours, in pH 6.8: greater than or equal to about 20%;

5 hours, in pH 6.8: greater than or equal to about 40%;

7 hours, in pH 6.8: greater than or equal to about 60%; and

12 hours, in pH 6.8: greater than or equal to about 80%.

21. The modified-release pravastatin formulation according to claim 20 , which exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following:

1 hour, in pH 6.8: less than or equal to about 20%;

2 hours, in pH 6.8: about 20 to about 80%;

5 hours, in pH 6.8: greater than or equal to about 50%;

7 hours, in pH 6.8: greater than or equal to about 70%; and

12 hours, in pH 6.8: greater than or equal to about 80%.

22. The modified-release pravastatin formulation according to claim 21 , which exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following:

1 hour, in pH 6.8: less than or equal to about 10%;

2 hours, in pH 6.8: about 10 to about 40%;

3 hours, in pH 6.8: about 30 to about 70%;

4 hours, in pH 6.8: greater than or equal to about 45%;

5 hours, in pH 6.8: greater than or equal to about 60%;

6 hours, in pH 6.8: greater than or equal to about 75%; and

7 hours, in pH 6.8: greater than or equal to about 80%.

23. The modified-release pravastatin formulation according to claim 22 , which exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following:

1 hour, in pH 6.8: less than or equal to about 5%;

2 hours, in pH 6.8: about 10 to about 40%;

3 hours, in pH 6.8: about 30 to about 70%;

4 hours, in pH 6.8: greater than or equal to about 45%;

5 hours, in pH 6.8: greater than or equal to about 60%; and

6 hours, in pH 6.8: greater than or equal to about 80%.

24. A method for treating one or more cardiovascular diseases that are not secondary to hypercholesterolemia comprising administering, to a subject in need of such treatment, a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation, and releases a therapeutic amount of pravastatin in the small intestine of the subject over a period of less than 6 hours, and achieves a relative systemic bioavailability, as compared to an equally effective dose of a conventional rapid release pravastatin formulation, of less than about 90%.

25. A method for increasing the hepatic availability of pravastatin comprising administering to a subject a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, in a non-enteric coated pharmaceutical formulation exhibiting a pravastatin release rate, as measured in a Type II dissolution apparatus, in a 0.1N HCl media for 2 hours, followed by pH 6.8 buffer for the remainder of the test, of the following:

2 hours, in HCl media: less than or equal to about 10%;

1 hour, in pH 6.8: about 10 to about 40%;

2 hours, in pH 6.8: about 30% to about 70%;

3 hours, in pH 6.8: greater than or equal to about 45%;

4 hours, in pH 6.8: greater than or equal to about 60%;

5 hours, in pH 6.8: greater than or equal to about 75%; and

6 hours, in pH 6.8: greater than or equal to about 80%.

26. The formulation of claim 25 , wherein the therapeutically effective amount of pravastatin ranged from about 1 to about 200 mg.

27. The formulation of claim 26 , wherein the therapeutically effective amount of pravastatin ranged from about 5 to about 80 mg.

28. A method for increasing the hepatic availability of pravastatin comprising administering to a subject a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, in a non-enteric coated pharmaceutical formulation exhibiting a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following:

1 hour, in pH 6.8: less than or equal to about 10%;

2 hours, in pH 6.8: about 10 to about 40%;

3 hours, in pH 6.8: about 30 to about 70%;

4 hours, in pH 6.8: greater than or equal to about 45%;

5 hours, in pH 6.8: greater than or equal to about 60%;

6 hours, in pH 6.8: greater than or equal to about 75%; and

7 hours, in pH 6.8: greater than or equal to about 80%.

29. The formulation of claim 28 , wherein the therapeutically effective amount of pravastatin ranges from about 1 to about 200 mg.

30. The formulation of claim 29 , wherein the therapeutically effective amount of pravastatin ranges from about 5 to about 80 mg.

31. A method of reducing one or more side effects associated with the administration of pravastatin, comprising administering a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation to a subject in need of such reduction in side effects, wherein the formulation inhibits release of the pravastatin in the stomach of the subject, releases a therapeutic amount of pravastatin in the small intestine of the subject over a period of less than 6 hours, achieves a relative systemic bioavailability, as compared to an equally effective dose of a conventional rapid release formulation, of less than about 90%, and wherein one or more side-effects are reduced relative to those resulting from the administration of an equivalent amount of a conventional rapid release formulation of pravastatin.

32. The method according to claim 31 , wherein the formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a 0.1N HCl media for 2 hours, followed by a pH 6.8 buffer for the remainder of the test, of the following:

2 hours, in HCl media: less than or equal to about 10%;

1 hour, in pH 6.8: about 10 to about 40%;

2 hours, in pH 6.8: about 30% to about 70%;

3 hours, in pH 6.8: greater than or equal to about 45%;

4 hours, in pH 6.8: greater than or equal to about 60%;

5 hours, in pH 6.8: greater than or equal to about 75%; and

6 hours, in pH 6.8: greater than or equal to about 80%.

33. The method according to claim 31 , wherein the formulation exhibits a pravastatin release rate, as measured in a Type II dissolution apparatus, in a pH 6.8 buffer, of the following:

1 hour, in pH 6.8: less than or equal to about 10%;

2 hours, in pH 6.8: about 10% to about 40%;

3 hours, in pH 6.8: about 30 to about 70%;

4 hours, in pH 6.8: greater than or equal to about 45%;

5 hours, in pH 6.8: greater than or equal to about 60%;

6 hours, in pH 6.8: greater than or equal to about 75%; and

7 hours, in pH 6.8: greater than or equal to about 80%.

34. A method of reducing one or more drug interactions associated with administration of conventional rapid release pravastatin formulations comprising administering a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, to a subject in need of such a reduction, wherein one or more drug interactions are reduced relative to those resulting from the administration of an equivalent amount of pravastatin from a conventional rapid release pravastatin formulational;

and wherein the pravastatin is administered in a fomulation that inhibits release of the pravastatin in the stomach of the subject over a period of less than 6 hours, achieves a relative systemic bioavailability, as compared to an equally effective dose of a convention rapid release pravastatin formulation, of less than about 90%.

35. A method of reducing one or more side effects associated with the administration of pravastatin, or associated with the co-administration of pravastatin with other lipid lowering drugs, comprising:

administering a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, in a pharmaceutical formulation to a subject in need of such reduction in side effects, in combination with a different lipid-lowering drug chosen from HMG-CoA reductase inhibitors, fibrates, modifiers of cholesterol absorption, and bile acid-binding resins,

wherein the formulation inhibits release of the pravastatin in the stomach of the subject over a period of less than 6 hours, achieves a relative systemic bioavailability, as compared to an equally effective dose of a conventional rapid release pravastatin formulation, of less than about 90%, and

wherein one or more side-effects are reduced relative to those resulting from co-administration of an equivalent amount of a conventional rapid release formulation of pravastatin and said lipid-lowering drug.

36. The method of claim 1 , wherein the therapeutically effective amount of pravastatin ranges from about 1 to about 200 mg.

37. The method of claim 36 , wherein the therapeutically effective amount of pravastatin ranges from about 5 to about 80 mg.

38. The method of claim 12 , wherein the formulation comprises an amount of pravastatin ranging from about 1 to about 200 mg.

39. The method of claim 38 , wherein the formulation comprises an amount of pravastatin ranging from about 5 to about 80 mg.

40. The method of claim 16 , wherein the formulation comprises an amount of pravastatin ranging from about 1 to about 200 mg.

41. The method of claim 40 , wherein the formulation comprises an amount of pravastatin ranging from about 5 to about 80 mg.

42. The formulation of claim 20 , wherein the therapeutically effective amount of pravastatin ranges from about 1 to about 200 mg.

43. The formulation of claim 42 , wherein the therapeutically effective amount of pravastatin ranges from about 5 to about 80 mg.

44. The method of claim 31 , wherein the therapeutically effective amount of pravastatin ranges from about 1 to about 200 mg.

45. The method of claims 44 , wherein the therapeutically effective amount of pravastatin ranges from about 5 to about 80 mg.

46. A method of treating hypercholesterolemia comprising administering, to a subject in need of such treatment, a therapeutically effective amount of pravastatin, or a pharmaceutically acceptable salt thereof, in a non-enteric coated phannaceutical formulation, wherein the formulation inhibits release of the pravastatin in the stomach of the subject, and releases a therapeutic amount of pravastatin in the small intestine of the subject over a period of less than 6 hours.

47. The method of claim 46 , wherein the formulation releases greater than about 80% of its pravastatin content in the small intestine.

48. The method of claim 47 , wherein the formulation releases greater than 85% of its pravastatin content in the small intestine.

49. The method of claim 47 , wherein the formulation release greater than 80% of its pravastatin content in the small intestine over a period of from about 3 hours to less than 6 hours.

50. The method of claim 49 , wherein the formulation releases greater than 80% of its pravastatin content in the small intestine over a period of from about 4 hours to about 5 hours.

51. The method of claim 46 , wherein the administration achieves a relative systemic bioavailability, as compared to a conventional rapid release pravastatin formulation, of less than about 90%.

52. The method according to claim 51 , wherein the administration achieves a relative systemic bioavailability, as compared to a conventional rapid release pravastatin formulation, of less than about 80%.

53. The method according to claim 46 , wherein the administration achieves a relative Cmax, as compared to a conventional rapid release pravastatin formulation, of less than about 80%.

54. The method according to claim 53 , wherein the administration achieves a relative Cmax, as compared to a conventional rapid release pravastatin formulation, of less than about 70%.

55. The method according top claim 46 , wherein the formulation is administered to the subject to treat one or more cardiovascular diseases that are secondary to the hypercholesterolemia.

56. The method according to claim 46 , wherein the administration reduces the low density lipoprotein-cholesterol (LDL-C) levels in a subject following administration of the formulation.

57. The method according to claim 47 , wherein the administration increases high density lipoprotein-cholesterol (HDL-C) levels in a subject following administration of the formulation.