Therapeutic composition

• US 8,735,345 B2
• Filed: 02/26/2010
• Issued: 05/27/2014
• Est. Priority Date: 02/27/2009
• Status: Expired due to Fees

• Current Assignee: Pharmasset Incorporated (Gilead Sciences Inc.), Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Pharmasset Incorporated (Gilead Sciences Inc.), Hoffmann-La Roche Incorporated (Roche Holding AG), Roche Palo Alto LLC (Roche Holding AG)
• Inventors: Porter, Steven B., Bradford, Williamson Ziegler, Smith, Patrick F., Yetzer, Ellen S., De La Rosa, Abel, Symonds, William T., Rogers, Michael D.
• Primary Examiner(s): JARRELL, NOBLE E
• Application Number:
  US12/713,497
• Publication Number:
  US 20100221217A1
• Time in Patent Office: 1,551 Days
• Field of Search: None
• US Class Current: 514/4.3
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Embodiments disclosed in the present application relate to a composition that can include a hepatitis C viral polymerase inhibitor, or pharmaceutically acceptable salt or prodrug thereof and a hepatitis C viral protease inhibitor, or pharmaceutically acceptable salt or prodrug thereof. Additional embodiments disclosed relate to methods for treating a disease condition such as a hepatitis C virus infection, liver fibrosis and/or impaired liver function with a hepatitis C viral polymerase inhibitor, or pharmaceutically acceptable salt or prodrug thereof and a hepatitis C viral protease inhibitor, or pharmaceutically acceptable salt or prodrug thereof.

Claims

1. A composition comprising a first compound, or a pharmaceutically acceptable salt thereof, wherein the first compound is

3. The composition of claim 1, further comprising a pharmaceutically acceptable excipient, diluent or carrier.

4. The composition of claim 1, wherein the composition comprises an amount of the first compound, or a pharmaceutically acceptable salt thereof, in the range of about 9000 mg to about 50 mg.

5. The composition of claim 1, wherein the composition comprises an amount of the first compound, or a pharmaceutically acceptable salt thereof, in the range of about 5000 mg to about 150 mg.

6. The composition of claim 1, wherein the composition comprises an amount of the first compound, or a pharmaceutically acceptable salt thereof, in the range of about 2000 mg to about 300 mg.

7. The composition of claim 1, wherein the composition comprises an amount of the first compound, or a pharmaceutically acceptable salt thereof, in the range of about 1000 mg to about 450 mg.

8. The composition of claim 1, wherein the composition comprises an amount of the first compound, or a pharmaceutically acceptable salt thereof, in the range of about 1000 mg to about 500 mg.

9. The composition of claim 1, wherein the composition comprises an amount of the second compound, or a pharmaceutically acceptable salt thereof, in the range of about 2000 mg to about 2 mg.

10. The composition of claim 1, wherein the composition comprises an amount of the second compound, or a pharmaceutically acceptable salt thereof, in the range of about 1600 mg to about 25 mg.

11. The composition of claim 1, wherein the composition comprises an amount of the second compound, or a pharmaceutically acceptable salt thereof, in the range of about 500 mg to about 50 mg.

12. The composition of claim 1, wherein the composition comprises an amount of the second compound, or a pharmaceutically acceptable salt thereof, in the range of about 200 mg to about 100 mg.

13. The composition of claim 1, wherein the composition comprises a total amount of the first compound, or a pharmaceutically acceptable salt thereof, in the range of about 1% to about 99% (weight/weight) based on the sum of the total amount of the first compound, or a pharmaceutically acceptable salt thereof, and the total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the composition.

14. The composition of claim 1, wherein the composition comprises a total amount of the first compound, or a pharmaceutically acceptable salt thereof, in the range of about 5% to about 90% (weight/weight) based on the sum of the total amount of the first compound, or a pharmaceutically acceptable salt thereof, and the total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the composition.

15. The composition of claim 1, wherein the composition comprises a total amount of the first compound, or a pharmaceutically acceptable salt thereof, in the range of about 10% to about 80% (weight/weight) based on the sum of the total amount of the first compound, or a pharmaceutically acceptable salt thereof, and the total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the composition.

16. The composition of claim 1, wherein the composition comprises a total amount of the first compound, or a pharmaceutically acceptable salt thereof, in the range of about 20% to about 70% (weight/weight) based on the sum of the total amount of the first compound, or a pharmaceutically acceptable salt thereof, and the total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the composition.

17. The composition of claim 1, wherein the composition comprises a total amount of the first compound, or a pharmaceutically acceptable salt thereof, in the range of about 30% to about 60% (weight/weight) based on the sum of the total amount of the first compound, or a pharmaceutically acceptable salt thereof, and the total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the composition.

18. The composition of claim 1, wherein the composition comprises a total amount of the first compound, or a pharmaceutically acceptable salt thereof, in the range of about 40% to about 50% (weight/weight) based on the sum of the total amount of the first compound, or a pharmaceutically acceptable salt thereof, and the total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the composition.

19. The composition of claim 13, wherein the composition comprises a total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the range of about 1% to about 99% (weight/weight) based on the sum of the total amount of the first compound, or a pharmaceutically acceptable salt thereof, and the total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the composition.

20. The composition of claim 13, wherein the composition comprises a total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the range of about 5% to about 90% (weight/weight) based on the sum of the total amount of the first compound, or a pharmaceutically acceptable salt thereof, and the total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the composition.

21. The composition of claim 13, wherein the composition comprises a total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the range of about 10% to about 80% (weight/weight) based on the sum of the total amount of the first compound, or a pharmaceutically acceptable salt thereof, and the total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the composition.

22. The composition of claim 13, wherein the composition comprises a total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the range of about 20% to about 70% (weight/weight) based on the sum of the total amount of the first compound, or a pharmaceutically acceptable salt thereof, and the total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the composition.

23. The composition of claim 13, wherein the composition comprises a total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the range of about 30% to about 60% (weight/weight) based on the sum of the total amount of the first compound, or a pharmaceutically acceptable salt thereof, and the total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the composition.

24. The composition of claim 13, wherein the composition comprises a total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the range of about 40% to about 50% (weight/weight) based on the sum of the total amount of the first compound, or a pharmaceutically acceptable salt thereof, and the total amount of the second compound, or a pharmaceutically acceptable salt thereof, in the composition.

25. The composition of claim 1, wherein the amount of the first compound, or a pharmaceutically acceptable salt thereof, in the composition is less than the amount of the first compound, or a pharmaceutically acceptable salt thereof, needed to achieve substantially the same viral load reduction as when the first compound, or a pharmaceutically acceptable salt thereof, is administered as monotherapy.

26. The composition of claim 1, wherein the amount of the second compound, or a pharmaceutically acceptable salt thereof, in the composition is less than the amount of the second compound, or a pharmaceutically acceptable salt thereof, needed to achieve substantially the same viral load reduction as when the second compound, or a pharmaceutically acceptable salt thereof, is administered as monotherapy.

27. The composition of claim 1, wherein the composition further comprises one or more additional therapeutic agents.

28. The composition of claim 27, wherein the one or more additional therapeutic agents are selected from the group consisting of a nucleoside analog, pirfenidone, a pirfenidone analog, an NS5B RNA-dependent RNA polymerase inhibitor, a tumor necrosis factor antagonist, thymosin-α

, interferon-gamma (IFN-γ

), interferon-alpha (IFN-α

), 3′

-azidothymidine, 2′

,3′

-dideoxyinosine, 2′

,3′

-dideoxycytidine, 2-,3-didehydro-2′

,3′

-dideoxythymidine, combivir, abacavir, adefovir dipivoxil, cidofovir, ritonavir, an inosine monophosphate dehydrogenase inhibitor, an interferon, an additional NS3 protease inhibitor, a NS5B polymerase inhibitor, and an NS3 helicase inhibitor.

29. The composition of claim 28, wherein the nucleoside analog is selected from the group consisting of ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

30. The composition of claim 28, wherein the tumor necrosis factor antagonist is selected from the group consisting of etanercept, infliximab, and adalimumab.

31. The composition of claim 28, wherein the thymosin-α

is in an amount in the range of from about 1.0 mg to about 1.6 mg.

32. The composition of claim 28, wherein the IFN-γ

is in an amount in the range of from about 10 μ

g to about 300 μ

g.

33. The composition of claim 28, wherein the IFN-α

is monoPEG (30 kD, linear)-ylate consensus.

34. The composition of claim 28, wherein the IFN-α

is selected from the group consisting of a 40 kD branched mono-methoxy PEG conjugate of interferon α

-2b and a 12 kD mono-methoxy PEG conjugate of interferon α

-2b.

35. The composition of claim 28, wherein the IFN-α

is INFERGEN consensus IFN-α

.

36. The composition of claim 28, wherein the additional NS3 protease inhibitor is selected from

37. The composition of claim 1, wherein the composition does not comprise ribavirin.

38. The composition of claim 1, wherein the composition does not comprise an interferon.

39. The composition of claim 38, wherein the interferon is a pegylated interferon.

40. A method for ameliorating a disease condition in a patient population, comprising administering a therapeutically effective amount of one or more compositions of claim 1 to a subject suffering from the disease condition, wherein the disease condition is selected from the group consisting of a hepatitis C virus infection, and liver fibrosis.

47. The method of claim 40, wherein the disease condition is a hepatitis C viral infection.

48. The method of claim 40, wherein the method further comprises administering an effective amount of an additional nucleoside analog.

49. The method of claim 48, wherein the additional nucleoside analog is selected from the group consisting of ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

50. The method of claim 40, wherein the method further comprises administering an effective amount of pirfenidone or a pirfenidone analog.

51. The method of claim 40, wherein the method further comprises administering an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.

52. The method of claim 40, wherein the method further comprises administering an effective amount of a tumor necrosis factor antagonist selected from the group consisting of etanercept, infliximab, and adalimumab.

53. The method of claim 40, wherein the method further comprises administering an effective amount of thymosin-α

.

54. The method of claim 53, wherein the thymosin-α

is in an amount in the range of from about 1.0 mg to about 1.6 mg.

55. The method of claim 40, wherein the method further comprises administering an effective amount of interferon-gamma (IFN-γ

).

56. The method of claim 55, wherein the IFN-γ

is administered subcutaneously in an amount in the range of from about 10 μ

g to about 300 μ

g.

57. The method of claim 40, wherein the method further comprises administering an effective amount of interferon-alpha (IFN-α

).

58. The method of claim 57, wherein the IFN-α

is monoPEG (30 kD, linear)-ylate consensus administered at a dosing interval in the range of every 8 days to every 14 days.

59. The method of claim 57, wherein the IFN-α

is monoPEG (30 kD, linear)-ylated consensus IFN-α

administered at a dosing interval of once every 7 days.

60. The method of claim 57, wherein the IFN-α

is selected from the group consisting of a 40 kD branched mono-methoxy PEG conjugate of interferon α

-2b and a 12 kD mono-methoxy PEG conjugate of interferon α

-2b.

61. The method of claim 57, wherein the IFN-α

is INFERGEN consensus IFN-α

.

62. The method of claim 40, wherein the method further comprises administering an effective amount of an agent selected from 3′

-azidothymidine, 2′

,3′

-dideoxyinosine, 2′

,3′

-dideoxycytidine, 2-,3-didehydro-2′

,3′

-dideoxythymidine, combivir, abacavir, adefovir dipivoxil, cidofovir, ritonavir, and an inosine monophosphate dehydrogenase inhibitor.

63. The method of claim 40, wherein the method further comprises administering an effective amount of an interferon, an additional NS3 protease inhibitor, an NS5B polymerase inhibitor, or an NS3 helicase inhibitor.

64. The method of claim 63, wherein the additional NS3 protease inhibitor is selected from

65. The method of claim 40, wherein the patient population is administered pegylated interferon after administration of the first compound, or a pharmaceutically acceptable salt thereof, and the second compound, or a pharmaceutically acceptable salt thereof, is complete.

66. The method of claim 40, wherein the patient population is administered ribavirin after administration of the first compound, or a pharmaceutically acceptable salt thereof, and the second compound, or a pharmaceutically acceptable salt thereof, is complete.

67. The method of claim 40, wherein the method does not include administering an additional agent.

68. The method of claim 67, wherein the additional agent is ribavirin.

69. The method of claim 67, wherein the additional agent is an interferon.

70. The method of claim 69, wherein the interferon is a pegylated interferon.

2. A composition consisting essentially of a first compound, or a pharmaceutically acceptable salt thereof, wherein the first compound is

41. A method for ameliorating a disease condition in a patient population comprising administering a therapeutically effective amount of a first compound, or a pharmaceutically acceptable salt thereof, wherein the first compound is

42. The method of claim 41, wherein the first compound, or a pharmaceutically acceptable salt thereof, is administered before the second compound, or a pharmaceutically acceptable salt thereof.

43. The method of claim 41, wherein the first compound, or a pharmaceutically acceptable salt thereof, is administered after the second compound, or a pharmaceutically acceptable salt thereof.

44. The method of claim 41, wherein the first compound, or a pharmaceutically acceptable salt thereof, is administered at approximately the same time as the second compound, or a pharmaceutically acceptable salt thereof.

45. The method of claim 41, wherein the first compound, or a pharmaceutically acceptable salt thereof, and the second compound, or a pharmaceutically acceptable salt thereof, are together in one dosage form.

46. The method of claim 41, wherein the first compound, or a pharmaceutically acceptable salt thereof, and the second compound, or a pharmaceutically acceptable salt thereof, are in separate dosage forms.