Compositions comprising nebivolol

• US 20080161296A1
• Filed: 11/15/2005
• Published: 07/03/2008
• Est. Priority Date: 06/04/2004
• Status: Active Grant

• Current Assignee: Mylan Laboratories Incorporated (Pfizer Inc.)
• Original Assignee: Forest Laboratories Holdings Limited (Abbvie Incorporated)
• Inventors: Shaw, Andrew, O'Donnell, John P., Mason, R. Preston, Davis, Eric, Bottini, Peter Bruce
• Granted Patent: US 7,838,552 B2
• Time in Patent Office: Days
• US Class Current: 514/223.5
• 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 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/54 having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

Nebivolol has been shown to be beneficial in the treatment of cardiovascular diseases such hypertension, congestive heart failure, arterial stiffness and endothelial dysfunction. The present invention features a pharmaceutical composition comprising nebivolol and at least one other active agent, wherein the at least one other active agent is a cardiovascular agent.

Claims

1. ) A composition comprising nebivolol and at least one other active agent.

2. ) The composition of claim 1 wherein at least one of the other active agents is a cardiovascular agent.

3. ) The composition of claim 2 wherein the cardiovascular agent is selected from the group consisting of ACE inhibitors, ARB'"'"'s, adrenergic blockers, adrenergic agonists, agents for pheochromocytoma, antiarrhythmics, antiplatelet agents, anticoagulants, antihypertensives, antilipemic agents, antidiabetics, antiinflammatory agents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, rennin inhibitors, vasodilators, vasopressors, AGE crosslink breakers, AGE formation inhibitors, and mixtures thereof.

4. ) The composition of claim 2, wherein the cardiovascular agent is selected from the group consisting of an ACE inhibitor, an ARB, and mixtures thereof.

5. ) The composition of claim 4, wherein the cardiovascular agent is an ACE inhibitor.

6. ) The composition of claim 5 wherein the ACE inhibitor is selected from the group consisting of alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, spirapril, temocapril, trandolapril, and mixtures thereof.

7. ) The composition of claim 5 wherein the ACE inhibitor is selected from the group consisting of enalapril, ramipril and ramiprilat and mixtures thereof.

8. ) The composition of claim 4 wherein the cardiovascular agent is an ARB.

9. ) The composition of claim 8 wherein the ARB is selected from the group consisting of candesartan, eprosartan, irbesartan, losartan, valsartan, and mixtures thereof.

10. ) The composition of claim 2, wherein the cardiovascular agent is selected from the group consisting of AGE crosslink breakers, AGE formation inhibitors, and mixtures thereof.

37. ) The composition of claim 2, wherein the cardiovascular agent is a vasodilator.

38. ) The composition of claim 37, wherein the vasodilator is selected from the group consisting of isosorbide dinitrate, isosorbide mononitrate, and a hydralazine compound, and mixtures thereof

39. ) The composition of claim 1 wherein at least one of the other active agents is a flavonoid.

40. ) The composition of claim 39 wherein the flavonoid is selected from the group consisting of (−

)-epictechin, (+)-catechin, procyanidin B2, quercetin dehydrate, taxifolin and resveratrol, and mixtures thereof.

41. ) The composition of claim 1 wherein at least one other active agent is selected from the group consisting of flavonoids, cartenoids, sulfonylureas, and niacin and related derivatives, and mixtures thereof.

42. ) The composition of claim 41 wherein at least one other active agent is a carotenoid.

43. ) The composition of claim 42 wherein the carotenoid is selected from the group consisting of astaxanthin, zeaxanthin, lutein, lycopene, beta-carotene, and mixtures thereof.

44. ) The composition of claim 41 wherein the at least one other active agent is a sulfonylurea.

45. ) The composition of claim 44 wherein the sulfonylurea is selected from the group consisting of acetohexamide, DiaBeta, glibenclamide, gliclazide, glipizide, glyclopyramide, chlorpropamide, tolazamide, tolbutamide, glimepiride, tolbutamide and meglitinide analogues, and mixtures thereof.

11. ) A composition comprising nebivolol and only one other active agent.

12. ) The composition of claim 11 wherein the other active agent is a cardiovascular agent.

13. ) The composition of claim 12 wherein the cardiovascular agent is selected from the group consisting of ACE inhibitors, ARB'"'"'s, adrenergic blockers, adrenergic agonists, agents for pheochromocytoma, antiarrhythmics, antiplatelet agents, anticoagulants, antihypertensives, antilipemic agents, antidiabetics, antiinflammatory agents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, rennin inhibitors, vasodilators, vasopressors, AGE crosslink breakers, AGE formation inhibitors, and mixtures thereof.

14. ) The composition of claim 12 wherein the cardiovascular agent is selected from the group consisting of ACE inhibitors and ARB'"'"'s.

15. ) The composition of claim 12 wherein the cardiovascular agent is an ACE inhibitor selected from the group consisting of alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, spirapril, temocapril, and trandolapril.

16. ) The composition of claim 12, wherein the cardiovascular agent is an ARB selected from the group consisting of candesartan, eprosartan, irbesartan, losartan and valsartan.

17. ) The composition of claim 12 wherein the cardiovascular agent is selected from the group consisting of AGE crosslink breakers and AGE formation inhibitors.

18. ) A pharmaceutical composition comprising nebivolol and at least one other active agent, and a pharmaceutically-acceptable carrier.

19. ) The pharmaceutical composition of claim 18 wherein at least one of the other active agents is a cardiovascular agent.

20. ) The pharmaceutical composition of claim 19 wherein the cardiovascular agent is selected from the group consisting of ACE inhibitors, ARB'"'"'s, adrenergic blockers, adrenergic agonists, agents for pheochromocytoma, antiarrhythmics, antiplatelet agents, anticoagulants, antihypertensives, antilipemic agents, antidiabetics, antiinflammatory agents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, rennin inhibitors, vasodilators, vasopressors, AGE crosslink breakers, AGE formation inhibitors, and mixtures thereof.

21. ) The pharmaceutical composition of claim 19, wherein the cardiovascular agent is selected from the group consisting of ACE inhibitors, an ARB'"'"'s, and mixtures thereof.

22. ) The pharmaceutical composition of claim 21, wherein the cardiovascular agent is an ACE inhibitor.

23. ) The pharmaceutical composition of claim 22 wherein the ACE inhibitor is selected from the group consisting of alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, spirapril, temocapril, trandolapril, and mixtures thereof.

24. ) The pharmaceutical composition of claim 23 wherein the ACE inhibitor is selected from the group consisting of enalapril, ramipril and rarniprilat and mixtures thereof

25. ) The pharmaceutical composition of claim 21 wherein the cardiovascular agent is an ARB.

26. ) The pharmaceutical composition of claim 25 wherein the ARB is selected from the group consisting of candesartan, eprosartan, irbesartan, losartan, valsartan, and mixtures thereof.

27. ) The pharmaceutical composition of claim 19, wherein the cardiovascular agent is selected from the group consisting of AGE crosslink breakers, AGE formation inhibitors, and mixtures thereof.

36. ) The pharmaceutical composition as set forth in claims 18, wherein said composition comprises a pharmaceutical kit.

28. ) A method of treating and/or preventing a cardiovascular disorder comprising administering to a subject a therapeutically safe and effective amount of nebivolol and at least one other active agent, sufficient to treat said condition.

29. ) The method of claim 28 wherein the at least one other active agent is a cardiovascular agent.

30. ) The method of claim 29 wherein the cardiovascular agent is selected from the group consisting of ACE inhibitors, ARB'"'"'s, adrenergic blockers, adrenergic agonists, agents for pheochromocytoma, antiarrhythmics, antiplatelet agents, anticoagulants, antihypertensives, antilipemic agents, antidiabetics, antiinflammatory agents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, rennin inhibitors, vasodilators, vasopressors, AGE crosslink breakers, AGE formation inhibitors, and mixtures thereof.

31. ) The method of claim 28 wherein the cardiovascular disorder is selected from the group consisting of congestive heart failure, hypertension, pulmonary hypertension, myocardial and cerebral infarctions, atherosclerosis, atherogenesis, thrombosis, ischemic heart disease, post-angioplasty restenosis, coronary artery diseases, renal failure, stable, unstable and variant (Prinzmetal) angina, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, transient ischemic attacks, cerebrovascular accidents, restenosis, controlling blood pressure in hypertension, platelet adhesion, platelet aggregation, smooth muscle cell proliferation, pulmonary edema, vascular complications associated with the use of medical devices, wounds associated with the use of medical devices, pulmonary thromboembolism, cerebral thromboembolism, thrombophlebitis, thrombocytopenia and bleeding disorders.

32. ) The method of claim 30 wherein the wherein the cardiovascular agent is selected from the group consisting of ACE inhibitors, an ARB'"'"'s, and mixtures thereof.

33. ) The method of claim 32 wherein the cardiovascular agent is an ACE inhibitor.

34. ) The method of claim 32 wherein the cardiovascular agent is an ARB.

35. ) The method of claim 30 wherein the cardiovascular agent is selected from the group consisting of AGE crosslink breakers, AGE formation inhibitors, and mixtures thereof.

46. ) The method of claim 29 wherein the cardiovascular agent is a vasodilator.

47. ) The method of claim 46 wherein the vasodilator is selected from the group consisting of isosorbide dinitrate, isosorbide mononitrate, isosorbide mononitrate and a hydralazine compound, and mixtures thereof

48. ) The method of claim 47 wherein the hydralazine compound is selected from the group consisting of budralazine, cadralazine, dihydralazine, endralazine, hydralazine, pildralazine and todralazine, or pharmaceutically acceptable salts thereof, and mixtures thereof.

49. ) The method of claim 28 wherein at least one other active agent is a flavonoid.

50. ) The method of claim 49 wherein the flavonoid is selected from the group consisting of (−

)-epictechin, (+)-catechin, procyanidin B2, quercetin dehydrate, taxifolin and resveratrol, and mixtures thereof.

51. ) The method of claim 28 wherein at least one other active agent is selected from the group consisting of flavonoids, cartenoids, sulfonylureas, and niacin and related derivatives, and mixtures thereof.

52. ) A method of improving NO release in a black patient in need thereof comprising administering to the black patient a therapeutically safe and effective amount of nebivolol or a pharmaceutically acceptable salt thereof and at least one other cardiovascular agent, sufficient to improve NO release.

53. ) The method of claim 52 wherein the at least one other cardiovascular agent is selected from the group consisting of ACE inhibitors, ARB'"'"'s, adrenergic blockers, adrenergic agonists, agents for pheochromocytoma, antiarrhythmics, antiplatelet agents, anticoagulants, antihypertensives, antilipemic agents, antidiabetics, antiinflammatory agents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, rennin inhibitors, vasodilators, vasopressors, AGE crosslink breakers, AGE formation inhibitors, and mixtures thereof.

54. ) The method of claim 53 wherein the at least one other cardiovascular agent is a vasodilator.

55. ) The method of claim 54 wherein the vasodilator is selected from the group consisting of isosorbide dinitrate, isosorbide mononitrate, a hydralazine compound, and mixtures thereof.

56. ) The method of claim 55 wherein the hydralazine compound is selected from the group consisting of budralazine, cadralazine, dihydralazine, endralazine, hydralazine, pildralazine and todralazine, or pharmaceutically acceptable salts thereof, and mixtures thereof.

57. ) A method of reducing mortality associated with cardiovascular disease in a black patient comprising administering to the black patient a therapeutically effective amount of:

(i) nebivolol or a pharmaceutically salt thereof;

(ii) at least one hydralazine compound or a pharmaceutically acceptable salt thereof;

(iii) at least one of isosorbide dinitrate and/or isosorbide mononitrate; and

(iv) optionally, one or more compounds selected from the group consisting of a digitalis compound, a diuretic compound, potassium, an angiotensin-converting enzyme inhibitor, a beta-adrenergic blocker, a cholesterol reducer, a calcium channel blocker, an angiotensin II receptor antagonist, and an endothelin antagonist.

58. ) The method of claim 57 wherein the cardiovascular disorder is selected from the group consisting of congestive heart failure, hypertension, pulmonary hypertension, myocardial and cerebral infarctions, atherosclerosis, atherogenesis, thrombosis, ischemic heart disease, post-angioplasty restenosis, coronary artery diseases, renal failure, stable, unstable and variant (Prinzmetal) angina, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, transient ischemic attacks, cerebrovascular accidents, restenosis, controlling blood pressure in hypertension, platelet adhesion, platelet aggregation, smooth muscle cell proliferation, pulmonary edema, vascular complications associated with the use of medical devices, wounds associated with the use of medical devices, pulmonary thromboembolism, cerebral thromboembolism, thrombophlebitis, thrombocytopenia and bleeding disorders.

59. ) The method of claim 58, wherein the cardiovascular disorder is hypertension.

60. ) The method of claim 59, wherein the hydralazine compound is budralazine, cadralazine, dihydralazine, endralazine, hydralazine, pildralazine, todralazine or a pharmaceutically acceptable salt thereof, and mixtures thereof.

61. ) The method of claim 57 wherein the nebivolol is administered in an amount of from about 1 mg per day to about 10 mg per day.

62. ) A method for improving NO release in a black patient in need thereof comprising administering to the black patient a safe and therapeutically effective amount of:

(i) nebivolol or a pharmaceutically salt thereof;

(ii) at least one hydralazine compound or a pharmaceutically acceptable salt thereof;

(iii) at least one of isosorbide dinitrate and/or isosorbide mononitrate; and

(iv) optionally, one or more compounds selected from the group consisting of a digitalis compound, a diuretic compound, potassium, an angiotensin-converting enzyme inhibitor, a beta-adrenergic blocker, a cholesterol reducer, a calcium channel blocker, an angiotensin II receptor antagonist, and an endothelin antagonist.

63. ) The method of claim 62, wherein the cardiovascular disorder is hypertension.

64. ) The method of claim 62, wherein the hydralazine compound is budralazine, cadralazine, dihydralazine, endralazine, hydralazine, pildralazine, todralazine or a pharmaceutically acceptable salt thereof, and mixtures thereof.

65. ) The method of claim 64, wherein the hydralazine compound is hydralazine hydrochloride.

66. ) A method for improving exercise tolerance or for improving the quality of life in a black patient in need thereof comprising administering to the black patient a therapeutically effective amount of:

(i) nebivolol or a pharmaceutically salt thereof;

(ii) at least one hydralazine compound or a pharmaceutically acceptable salt thereof;

(iii) at least one of isosorbide dinitrate and/or isosorbide mononitrate; and

(iv) optionally, one or more compounds selected from the group consisting of a digitalis compound, a diuretic compound, potassium, an angiotensin-converting enzyme inhibitor, a beta-adrenergic blocker, a cholesterol reducer, a calcium channel blocker, an angiotensin II receptor antagonist, and an endothelin antagonist.

67. ) The method of claim 66, wherein the hydralazine compound is budralazine, cadralazine, dihydralazine, endralazine, hydralazine hydrochloride, pildralazine, todralazine or a pharmaceutically acceptable salt thereof, and mixtures thereof.

68. ) The method of claim 67, wherein the hydralazine compound is hydralazine hydrochloride.

69. ) A method of improving NO release in a black patient in need thereof comprising administering to the black patient nebivolol or a pharmaceutically acceptable salt in an amount of about 1 mg per day to about 10 mg per day, and at least one other cardiovascular agent.

70. ) The method of claim 69 wherein the cardiovascular agent is selected from the group consisting of isosorbide dinitrate, isosorbide mononitrate, a hydralazine compound, and mixtures thereof.

71. ) A method for the treatment and/or prevention of cardiovascular diseases characterized by nitric oxide insufficiency, wherein said method comprises administering to a patient nebivolol, or a pharmaceutically acceptable salt, in an amount of about 1 mg per day to about 10 mg per day, and at least one other cardiovascular agent selected from the group consisting of isosorbide dinitrate, isosorbide mononitrate, a hydralazine compound, and mixtures thereof.

72. ) A method for improving exercise tolerance or for improving the quality of life in a black patient in need thereof comprising administering to the black patient a therapeutically effective amount of:

(i) nebivolol or a pharmaceutically salt thereof in the amount of about 1 mg to about 10 mg per day;

(ii) at least one cardiovascular agent; and

(iii) optionally, one or more compounds selected from the group consisting of a digitalis compound, a diuretic compound, potassium, an angiotensin-converting enzyme inhibitor, a beta-adrenergic blocker, a cholesterol reducer, a calcium channel blocker, an angiotensin II receptor antagonist, and an endothelin antagonist.

73. ) The method of claim 72 wherein the cardiovascular agent is selected from the group consisting of ACE inhibitors, ARB'"'"'s, adrenergic blockers, adrenergic agonists, agents for pheochromocytoma, antiarrhythmics, antiplatelet agents, anticoagulants, antihypertensives, antilipemic agents, antidiabetics, antiinflammatory agents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, rennin inhibitors, vasodilators, vasopressors, AGE crosslink breakers, AGE formation inhibitors, and mixtures thereof.

74. ) A composition comprising nebivolol, hydrochlorothiazide and at least one other additional active agent.