Pharmaceutical formulations, methods, and dosing regimens for the treatment and prevention of acute coronary syndromes

• US 7,435,717 B2
• Filed: 10/15/2004
• Issued: 10/14/2008
• Est. Priority Date: 10/20/2003
• Status: Expired due to Fees

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Bisgaier, Charles L., Johansson, Jan, Hartman, Daniel, Rodrigueza, Wendi V., Lalwani, Narendra D.
• Primary Examiner(s): Mondesi; Robert B.
• Application Number:
  US10/967,061
• Publication Number:
  US 20050142180A1
• Time in Patent Office: 1,460 Days
• Field of Search: None
• US Class Current: 514/1.1
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/544 Phospholipids
• 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: A61K 9/127 Liposomes
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• 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 methods and formulations for treating and preventing acute coronary syndromes. The methods of the instant invention provide safe and effective doses of an Apolipoprotein A-I Milano:phospholipid complex to reduce and stabilize atherosclerotic plaque. Pharmaceutical formulations of the Apo A-I Milano:phospholipid complexes are also provided.

Claims

1. A method of treating coronary atherosclerosis in a subject in need thereof, said method comprising administering an Apolipoprotein A-I Milano:

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine complex (Apo A-IM;

POPC complex) at a dose of about 1 mg of protein/kg to about 100 mg of protein/kg, and wherein said method regresses coronary atherosclerosis.

2. The method of claim 1 wherein the Apo A-1M:

POPC complex is administered to a subject at a dose of about 15 mg/kg or 45 mg/kg.

3. The method of claim 1 wherein the Apo A-IM:

POPC complex is administered to a subject at a dose of about 15 mg/kg to about 45 mg/kg.

4. The method of claim 1 wherein the Apo A-I Milano is recombinant Apo A-I Milano.

5. The method of claim 1 wherein the Apo A-IM:

POPC complex is comprised of Apolipoprotein A-I Milano and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine in a ratio of about 1;

1 wt protein/wt lipid.

6. The method of claim 1 wherein the Apo A-IM:

POPC complex is a sterile liquid pharmaceutical formulation.

7. The method of claim 6 wherein the pharmaceutical formulation is administered to a subject at a dose of about 15 mg/kg or 45 mg/kg.

8. The method of claim 6 wherein the pharmaceutical formulation is administered to a subject once weekly for about 6 months, about 5 months, about 4 months, about 3 months, about 2 months or about 1 month.

9. The method of claim 6 wherein the pharmaceutical formulation is administered to a subject about every day for about 1 month.

10. The method of claim 6 wherein the pharmaceutical formulation is administered to a subject about every 3 days for about 1 month to about 6 months.

11. The method of claim 6 wherein the pharmaceutical formulation is administered about every 10 days for about 1 month to about 6 months.

12. The method of claim 6 wherein the pharmaceutical formulation is administered about every 14 days for about 1 month to about 6 months.

13. The method of claim 1 further comprising surgical intervention.

14. The method of claim 13 wherein the surgical intervention comprises percutaneous transluminal coronary angioplasty or coronary artery bypass grafting.

15. The method of claim 1 further comprising administration of another drug to treat or ameliorate the diseases, disorders, symptoms or pain associated with acute coronary syndromes.

16. The method of claim 1 wherein the percent atheroma volume in a subject'"'"'s affected vessel is reduced by about −

0.73% to about −

1.29%.

17. The method of claim 1 wherein the total atheroma volume in the target vessel of the subject is reduced by about −

15.1 mm³ to about −

12.6 mm³.

18. The method of claim 1 wherein the mean maximum atheroma thickness in the subject'"'"'s target coronary segment is reduced by about −

0.039 mm to −

0.044 mm.

19. The method of claim 6 wherein the pharmaceutical formulation is administered intravenously.

20. The method of claim 19 wherein the pharmaceutical formulation is administered over about one hour.

21. The method of claim 19 wherein the pharmaceutical formulation is administered over about three hours.

22. The method of claim 6 wherein the pharmaceutical formulation comprises Apo A-I Milano, POPC, a sucrose-mannitol carrier and a phosphate buffer.

23. The method of claim 22 wherein the sucrose-mannitol carrier consists of about 6.0% to about 6.4% sucrose and about 0.8% to about 1% mannitol.

24. The method of claim 23 wherein the sucrose-mannitol carrier consists of about 6.2% sucrose and about 0.9% mannitol.

25. The method of claim 6 wherein the pharmaceutical formulation has a pH of about 7.0 to about 7.8.

26. The method of claim 25 wherein the pH is about 7.5.

27. The method of claim 6 wherein the pharmaceutical formulation comprises about 12 mg/ml to about 18 mg/ml Apo A-I Milano.

28. The method of claim 6 wherein the pharmaceutical formulation comprises about 11 mg/ml to about 17 mg/ml of POPC.

29. The method of claim 6 wherein the pharmaceutical formulation comprises less than 6,000 particulates greater than 10 μ

m in size per 50 mL.

30. The method of claim 6 wherein the pharmaceutical formulation comprises less than 600 particulates greater than 25 μ

m in size per 50 mL.

31. The method of claim 6 wherein the pharmaceutical formulation has an Osmolality of about 280 to about 320 mOsm.

32. The method of claim 31 wherein the pharmaceutical formulation has an Osmolality of about 290 mOsm.

33. The method of claim 1, wherein said method provides for the promotion of cholesterol efflux from affected vessels.

34. The method of claim 1, wherein said method provides for reverse cholesterol transport.

35. The method of claim 1, wherein said method provides for decreased atheroma volume in an affected vessel.

36. The method of claim 1, wherein said method provides for a decrease in total plaque volume of an affected vessel.

37. The method of claim 1, wherein said method provides for a decrease in the average maximal plaque thickness in an affected vessel.

38. The method of claim 1, wherein said method provides for a decrease in average maximal atheroma thickness.

39. The method of claim 1, wherein said method provides for a decrease in plaque volume in least percent area.

40. The method of claim 1, wherein said method provides for a decrease in the greatest percent plaque area.

41. The method of claim 1, wherein said method provides for an increase mean coronary luminal diameter in an affected vessel.

42. The method of claim 1, wherein said method provides for decreased angiographic lesions as compared to a subject not receiving said treatment.

43. The method of claim 1, wherein said method provides for achieving patency of an occluded vessel or of maintaining patency of an occluded vessel.

44. A method of treating acute coronary syndromes in a subject in need thereof, said method comprising administering an Apolipoprotein A-I Milano:

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine complex (Apo A-IM;

POPC complex) at a dose of about 1 mg of protein/kg to about 100 mg of protein/kg, and wherein said method ameliorates disorders associated acute coronary syndromes.

45. The method of claim 44, wherein said method provides for the promotion of cholesterol efflux from affected vessels.

46. The method of claim 44, wherein said method provides for reverse cholesterol transport.

47. The method of claim 44, wherein said method provides for decreased atheroma volume in an affected vessel.

48. The method of claim 44, wherein said method provides for a decrease in total plaque volume of an affected vessel.

49. The method of claim 44, wherein said method provides for a decrease in the average maximal plaque thickness in an affected vessel.

50. The method of claim 44, wherein said method provides for a decrease in average maximal atheroma thickness.

51. The method of claim 44, wherein said method provides for a decrease in plaque volume in least percent area.

52. The method of claim 44, wherein said method provides for a decrease in the greatest percent plaque area.

53. The method of claim 44, wherein said method provides for an increase mean coronary luminal diameter in an affected vessel.

54. The method of claim 44, wherein said method provides for decreased angiographic lesions as compared to a subject not receiving said treatment.

55. The method of claim 44, wherein said method provides for achieving patency of an occluded vessel or of maintaining patency of an occluded vessel.