Combination dosage form containing individual dosage units of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin

• US 6,669,955 B2
• Filed: 08/28/2001
• Issued: 12/30/2003
• Est. Priority Date: 08/28/2001
• Status: Expired due to Term

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Longwood Pharmaceutical Research, Inc.
• Inventors: Chungi, Shubha, Iorio, Theodore L.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): TRAN, SUSAN T
• Application Number:
  US09/941,948
• Publication Number:
  US 20030068366A1
• Time in Patent Office: 854 Days
• Field of Search: 424/451, 424/452, 424/464, 424/465, 424/468, 424/472, 514/85, 514/91
• US Class Current: 424/464
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/485 Inorganic compounds
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 9/08 Vasodilators for multiple indications
• 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

An orally administrable pharmaceutical formulation is provided that combines, as active agents, a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, aspirin, and optionally at least one of vitamin B₆, B₁₂, and folate; the active agents are each present in a unit dose appropriate for once-daily dosing, and at least one of the active agents is contained in a dosage unit within the dosage form that physically separates it from the other active agents. The formulation is provided as a simple and convenient therapy to reduce the risk of cardiovascular events in individuals who are at elevated cardiovascular risk, including individuals who have systemic lupus erythematosus. The formulation is also therapeutic for individuals during or immediately following an occurrence of acute myocardial infarction.

Claims

1. An orally administrable pharmaceutical dosage form for treating a patient at an elevated cardiovascular risk, comprising a combination of:

(a) a therapeutically effective daily dosage of a cholesterol-lowering agent, as a first active agent;

(b) a therapeutically effective daily dosage of an inhibitor of the renin-angiotensin system, as a second active agent; and

(c) a therapeutically effective daily dosage of aspirin, as a third active agent;

wherein at least one of the active agents is present in a dosage unit that physically separates the at least one active agent from the other active agents, and

wherein the effective daily dosage units of each of the active agents of the combination have different release profiles.

2. The dosage form of claim 1, wherein at least two of the active agents are present in dosage units that physically separate the at least two active agents from the other active agents and from each other.

3. The dosage form of claim 1, wherein the cholesterol-lowering agent is present in a first dosage unit, the inhibitor of the renin-angiotensin system is present in a second dosage unit, and the aspirin is present in a third dosage unit.

4. The dosage form of claim 3, wherein the dosage form is a capsule, and the dosage units each comprise a plurality of beads or granules contained therein.

5. The dosage form of claim 3, wherein the dosage form is a capsule, and the dosage units each comprise a tablet contained therein.

6. The dosage form of claim 3, wherein the dosage form is a compressed tablet, and the dosage units each comprise a physically isolated segment thereof.

7. The dosage form of claim 6, wherein the compressed tablet is a layered tablet, and the dosage units each comprise a layer thereof.

8. The dosage form of claim 3, wherein the dosage form is a compressed tablet, and each dosage unit comprises a plurality of beads or granules contained in an admixture therein.

9. The dosage form of claim 3, wherein the dosage form is comprised of an inner core coated with at least two concentric layers.

10. The dosage form of claim 9, containing two concentric layers.

11. The dosage form of claim 10, wherein the inner core is comprised of one of the dosage units and each concentric layer contains one of the dosage units.

12. The dosage form of claim 9, wherein the inner core is comprised of an inert material.

13. The dosage form of claim 12, containing three concentric layers.

14. The dosage form of claim 13, wherein each concentric layer contains one of the dosage units.

15. The dosage form of claim 3, wherein at least one of the dosage units is an immediate release dosage unit.

16. The dosage form of claim 15, wherein all of the dosage units are immediate release dosage units.

17. The dosage form of claim 15, wherein at least one of the dosage units is a delayed release dosage unit.

18. The dosage form of claim 15, wherein at least one of the dosage units is a sustained release dosage unit.

19. The dosage form of claim 3, wherein at least one of the dosage units is a delayed release dosage unit.

20. The dosage form of claim 19, wherein at least one of the dosage units is a sustained release dosage unit.

21. The dosage form of claim 1, further comprising at least one of vitamin B₆, vitamin B₁₂, and folic acid.

22. The dosage form of claim 1, wherein the cholesterol-lowering agent is selected from the group consisting of HMG CoA reductase inhibitors, bile acid sequestrants, probucol, fibric acid agents, and combinations thereof.

23. The dosage form of claim 1, wherein the cholesterol-lowering agent is an HMG CoA reductase inhibitor.

24. The dosage form of claim 23, wherein the HMG CoA reductase inhibitor is selected from the group consisting of atorvastatin, cerivistatin, fluindostatin, fluvastatin, lovastatin, mevastatin, pravastatin, simvastatin, and velostatin.

25. The dosage form of claim 24, wherein the HMG CoA reductase inhibitor is selected from the group consisting of lovastatin and pravastatin.

26. The dosage form of claim 25, wherein the HMG CoA reductase inhibitor is lovastatin.

27. The dosage form of claim 1, wherein the inhibitor of the renin-angiotensin system is selected from the group consisting of angiotensin converting enzyme (ACE) inhibitors and angiotensin II antagonists.

28. The dosage form of claim 27, wherein the inhibitor of the renin-angiotensin system is an ACE inhibitor.

29. The dosage form of claim 28, wherein the ACE inhibitor is selected from the group consisting of captopril, cilazapril, delapril, enalapril, fentiapril, fosinopril, indolapril, lisinopril, perindopril, pivopril, quinapril, ramipril, spirapril, trandolapril, and zofenopril.

30. The dosage form of claim 29, wherein the ACE inhibitor is selected from the group consisting of captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril, and trandolapril.

31. The dosage form of claim 30, wherein the ACE inhibitor is enalapril.

32. The dosage form of claim 27, wherein the inhibitor of the renin-angiotensin system is an angiotensin II antagonist.

33. The dosage form of claim 32, wherein the angiotensin II antagonist is selected from the group consisting of losartan, irbesartan, eprosartan, candesartan, valsartan, telmisartan, zolasartin, and tasosartan.

34. The dosage form of claim 33, wherein the angiotensin II antagonist is losartan.

35. An orally administrable pharmaceutical dosage form for treating a patient at an elevated cardiovascular risk, comprising:

(a) a first dosage unit containing approximately 10 to approximately 120 mg of an HMG CoA reductase inhibitor selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin, as a first active agent;

(b) a second dosage unit containing approximately 1 to approximately 60 mg of an ACE inhibitor selected from the group consisting of captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril, and trandolapril, as a second active agent; and

(c) a third dosage unit containing approximately 20 to approximately 600 mg aspirin, as a third active agent,

wherein each dosage unit provides physical separation between each of the active agents, thereby preventing contact therebetween, and

wherein the effective daily dosage units of each of the active agents of the combination have different release profiles.

36. The dosage form of claim 35, wherein the first and second dosage units are sustained release dosage units, and the third dosage unit is an immediate release dosage unit.

37. The dosage form of claim 35, wherein the dosage form is a capsule, and the dosage units each comprise a plurality of beads or granules contained therein.

38. The dosage form of claim 35, wherein the dosage form is a capsule, and the dosage units each comprise a tablet contained therein.

39. The dosage form of claim 35, wherein the dosage form is a compressed tablet, and the dosage units each comprise a physically isolated segment thereof.

40. The dosage form of claim 39, wherein the compressed tablet is a layered tablet, and the dosage units each comprise a layer thereof.

41. The dosage form of claim 35, wherein the dosage form is a compressed tablet, and each dosage unit comprises a plurality of beads or granules contained in an admixture therein.

42. The dosage form of claim 35, wherein the dosage form is comprised of an inner core coated with at least two concentric layers.

43. The dosage form of claim 42, containing two concentric layers.

44. The dosage form of claim 43, wherein the inner core is comprised of one of the dosage units and each concentric layer contains one of the dosage units.

45. The dosage form of claim 42, wherein the inner core is comprised of an inert material.

46. The dosage form of claim 45, containing three concentric layers.

47. The dosage form of claim 46, wherein each concentric layer contains one of the dosage units.

48. The dosage form of claim 47, wherein at least one of the dosage units is an immediate release dosage unit.

49. The dosage form of claim 48, wherein all of the dosage units are immediate release dosage units.

50. The dosage form of claim 48, wherein at least one of the dosage units is a delayed release dosage unit.

51. The dosage form of claim 48, wherein at least one of the dosage units is a sustained release dosage unit.

52. The dosage form of claim 35, wherein at least one of the dosage units is a delayed release dosage unit.

53. The dosage form of claim 50, wherein at least one of the dosage units is a sustained release dosage unit.

54. The dosage form of claim 35, further comprising at least one of vitamin B₆, vitamin B₁₂, and folic acid.

55. A packaged kit for a patient at an elevated cardiovascular risk to use in the self-administration of multiple oral dosage forms, the kit including a container housing a plurality of oral dosage forms and instructions for carrying out drug administration therewith, the improvement comprising incorporating in said oral dosage forms a combination of active agents comprised of:

a therapeutically effective daily dose of a cholesterol-lowering agent, a therapeutically effective daily dose of an inhibitor of the renin-angiotensin system, a therapeutically effective daily dose of aspirin,

wherein the active agents are present in a dosage unit that physically separates at least one active agent from the other active agents, and

wherein the effective daily dose of each of the active agents of the combination have different release profiles.

56. The packaged kit of claim 55, wherein said oral dosage forms each comprise:

(a) approximately 10 to approximately 120 mg of an MMG CoA reductase inhibitor as the cholesterol-lowering agent, wherein the HMG CoA reductase inhibitor is selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin;

(b) approximately 1 to approximately 60 mg of an ACE inhibitor as the inhibitor of the renin-angiotensin system, wherein the ACE inhibitor is selected from the group consisting of captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril, and trandolapril;

(c) approximately 20 to approximately 600 mg aspirin; and

(d) a pharmaceutically acceptable carrier.

57. The packaged kit of claim 56, wherein each of said oral dosage forms further comprises:

(e) at least one of

(i) approximately 25 mg to approximately 75 mg vitamin B6,

(ii) approximately 0.25 to approximately 2 mg vitamin B12, and

(iii) approximately 1 mg to approximately 8 mg folic acid.

58. The packaged kit of claim 57, wherein the HMG CoA reductase inhibitor is lovastatin and the ACE inhibitor is enalapril.

59. The packaged kit of claim 58, wherein each of said oral dosage forms contains approximately 25 mg to approximately 75 mg vitamin B6, approximately 0.25 mg to approximately 2 mg vitamin B12, and approximately 1 mg to approximately 8 mg folic acid.