Compositions and Methods for the Treatment of Heart Failure

• US 20100178269A1
• Filed: 04/04/2008
• Published: 07/15/2010
• Est. Priority Date: 04/05/2007
• Status: Active Grant

• Current Assignee: Phrixus Pharmaceuticals, Inc.
• Original Assignee: Phrixus Pharmaceuticals, Inc.
• Inventors: Markham, Bruce Edward
• Granted Patent: US 8,372,387 B2
• Time in Patent Office: Days
• US Class Current: 424/78.180
• CPC Class Codes: A61K 31/77 of oxiranes
• CPC Class Codes: A61K 31/785 Polymers containing nitrogen
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The invention provides a therapeutic composition comprising an aqueous buffer, and a therapeutic agent that improves the functioning of a diseased heart by decreasing left ventricular end-diastolic pressure and simultaneously increasing left ventricular ejection without affecting the blood pressure or heart rate.

Claims

1. A therapeutic composition comprising:

an aqueous buffer, and

a therapeutic agent that improves the functioning of a diseased heart by decreasing left ventricular end-diastolic pressure or increasing left ventricular ejection without significantly affecting the blood pressure or heart rate.

3. The therapeutic composition of claim 1, wherein the therapeutic composition improves the functioning of the diseased heart continuously for at least 24 hours following each administration of the therapeutic composition.

7. The therapeutic composition of claim 1, wherein the therapeutic agent improves the functioning of a diseased heart independently of its concentration in the blood for at least 24 hours following each single administration of the therapeutic composition.

9. The therapeutic composition of claim 1, wherein the therapeutic agent is a polyoxyalkylene block copolymer.

10. The therapeutic composition of claim 9, wherein the therapeutic agent has a molecular weight in the range of 3,000 to 18,000.

11. The therapeutic composition of claim 10, wherein the therapeutic agent is a poloxamer or poloxamine.

12. The therapeutic composition of claim 11, wherein the therapeutic agent is one or more compounds selected from the group consisting of Poloxamer 188, Poloxamer 407, Poloxamer 338, and Poloxamine 1107.

13. The therapeutic composition of claim 12, wherein the therapeutic agent is Poloxamer 188.

17. The therapeutic composition of claim 1, wherein the therapeutic composition is injectable or infusible.

18. The therapeutic composition of claim 1, wherein the disease of the heart is heart failure.

19. The therapeutic composition of claim 18, wherein the disease of the heart is chronic heart failure or acute heart failure.

21. The therapeutic composition of claim 18, wherein the disease of the heart is ischemic heart failure.

22. The therapeutic composition of claim 1, further comprising an agent selected from the group consisting of angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs);

beta-blockers, diuretics, digoxin, and anti-arrhythmic drugs.

23. The therapeutic composition of claim 22, wherein the ACE inhibitors consist of captopril, benazepril, enalapril, lisinopril, fosinopril, ramipril, perindopril, quinapril, moexipril, and trandolapril;

ARBs consist of losartan, candesartan, irbesartan, and valsartan;

beta-blockers consist of alprenolol, carteolol, levobunolol, mepindolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol, nebivolol, carvedilol, celiprolol, labetalol, and butaxamine;

diuretics consist of calcium chloride, ammonium chloride, amphotericin B, lithium citrate, Goldenrod, Juniper, dopamine, acetazolamide, dorzolamide, bumetanide, ethacrynic acid, furosemide, torsemide, glucose, mannitol, amiloride, spironolactone, triamterene, bendroflumethiazide, hydrochlorothiazide, caffeine, and theophylline;

anti-arrhythmic drugs consist of disopyramide, procainamide, quinidine, lidocaine, phenyloin, flecamide, propafenone, propranolol, timolol, metoprolol, sotalol, atenolol, amiodarone, sotalol, bretylium, verapamil, and diltiazem.

2. (canceled)

4-6. -6. (canceled)

8. (canceled)

14-16. -16. (canceled)

20. (canceled)

24. A method of treating, ameliorating, or preventing heart failure in a subject, comprising administering to the subject in need thereof a therapeutic composition comprising

an aqueous buffer, and

a therapeutic agent that improves the functioning of a diseased heart by decreasing left ventricular end-diastolic pressure or increasing left ventricular ejection without substantially affecting the blood pressure or heart rate.

26. The method of claim 24, wherein the therapeutic composition improves the functioning of the diseased heart continuously for at least 24 hours following each administration of the therapeutic composition.

30. The method of claim 24, wherein the therapeutic agent improves the functioning of a diseased heart independently of its concentration in the blood for at least 24 hours following each single administration of the therapeutic composition.

32. The method of claim 24, wherein the therapeutic agent is a polyoxyalkylene block copolymer.

33. The method of claim 32, wherein the therapeutic agent has a molecular weight in the range of 3,000 to 18,000.

34. The method of claim 33, wherein the therapeutic agent is a poloxamer or poloxamine.

35. The method of claim 34, wherein the therapeutic agent is one or more compounds selected from the group consisting of Poloxamer 188, Poloxamer 407, Poloxamer 338, and Poloxamine 1107.

36. The method of claim 35, wherein the therapeutic agent is Poloxamer 188.

40. The method of claim 24, wherein the heart failure is acute heart failure.

41. The method of claim 24, wherein the heart failure is chronic heart failure.

42. The method of claim 41, wherein the heart failure is ischemic heart failure.

43. The method of claim 24, wherein the therapeutic composition is administered by injection or infusion.

44. The method of claim 24, wherein the therapeutic agent in the composition is administered to the patient in the amount of 0.15 mg/kg to about 480 mg/kg.

45. The method of claim 44, wherein the therapeutic agent in the composition is administered to the patient in the amount of about 460 mg/kg.

46. The method of claim 44, wherein the therapeutic agent in the composition is administered to the patient in the amount of about 250 mg/kg.

47. The method of claim 44, wherein the therapeutic agent in the composition is administered to the patient in the amount of about 15.3 mg/kg.

48. The method of claim 44, wherein the therapeutic agent in the composition is administered to the patient in the amount of about 4.6 mg/kg.

49. The method of claim 44, wherein the therapeutic agent in the composition is administered to the patient in the amount of about 1.5 mg/kg.

50. The method of claim 44, wherein the therapeutic agent in the composition is administered to the patient in the amount of about 0.46 mg/kg.

51. The method of claim 24, further comprising administering to the subject an agent selected from a group consisting of angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, diuretics, digoxin, and anti-arrhythmic drugs.

52. The method of claim 51, wherein the ACE inhibitors consist of captopril, benazepril, enalapril, lisinopril, fosinopril, ramipril, perindopril, quinapril, moexipril, and trandolapril;

ARBs consist of losartan, candesartan, irbesartan, and valsartan;

beta-blockers consist of alprenolol, carteolol, levobunolol, mepindolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol, nebivolol, carvedilol, celiprolol, labetalol, and butaxamine;

diuretics consist of calcium chloride, ammonium chloride, amphotericin B, lithium citrate, Goldenrod, Juniper, dopamine, acetazolamide, dorzolamide, humetanide, ethacrynic acid, furosemide, torsemide, glucose, mannitol, amiloride, spironolactone, triamterene, bendroflumethiazide, hydrochlorothiazide, caffeine, and theophylline;

anti-arrhythmic drugs consist of disopyramide, procainamide, quinidine, lidocaine, phenyloin, flecamide, propafenone, propranolol, timolol, metoprolol, sotalol, atenolol, amiodarone, sotalol, bretylium, verapamil, and diltiazem.

25. (canceled)

27-29. -29. (canceled)

31. (canceled)

37-39. -39. (canceled)