Charged lipoprotein complexes and their uses
The present disclosure provides charged lipoprotein complexes that include as one component a negatively charged phospholipid that is expected to impart the complexes with improved therapeutic properties.
1. A lipoprotein complex comprising an ApoA-I apolipoprotein and a lipid fraction, wherein the lipid fraction consists essentially of sphingomyelin and about 3 wt% of a negatively charged phospholipid, wherein the molar ratio of the lipid fraction to the ApoA-I apolipoprotein is about 2:1 to 200:1, and wherein said lipoprotein complex is a small or large discoidal particle containing 2-4 ApoA-I equivalents.
2. The lipoprotein complex of claim 1 in which the negatively charged phospholipid is selected from a phosphatidylinositol, a phosphatidylserine, a phosphatidylglycerol, a phosphatidic acid, and mixtures thereof.
3. The lipoprotein complex of claim 1 in which the negatively charged phospholipid is a phosphatidylglycerol.
4. The lipoprotein complex of claim 1 in which the sphingomyelin comprises D-erythrose-sphingomyelin and/or D-erythrose dihydrosphingomyelin.
5. The lipoprotein complex of claim 1 in which the acyl chains of the sphingomyelin and/or negatively charged phospholipids are each, independently of one another, selected from a saturated, a mono-unsaturated and a polyunsaturated hydrocarbon containing from 6 to 24 carbon atoms.
6. The lipoprotein complex of claim 5 in which each acyl chain of the sphingomyelin and/or negatively charged phospholipid are the same.
7. The lipoprotein complex of claim 5 in which the acyl chains of the sphingomyelin and negatively charged phospholipid contain the same number of carbon atoms.
8. The lipoprotein complex of claim 5 in which the acyl chains of the sphingomyelin and negatively charged phospholipids have different degrees of saturation.
9. The lipoprotein complex of claim 1 in which the ApoA-I apolipoprotein is selected from mature human ApoA-I apolipoprotein, mature ApoA-I Milano , mature ApoA-l Paris , and mixtures thereof.
10. The lipoprotein complex of claim 1 in which the ApoA-I apolipoprotein is in the form of a monomer.
11. The lipoprotein complex of claim 1 in which the ApoA-I apolipoprotein is a mature human ApoA-I apolipoprotein and the negatively charged phospholipid is a phosphatidylglycerol.
12. The lipoprotein complex of claim 1 in which the molar ratio of the lipid fraction to the ApoA-I apolipoprotein is about 200:1 to 100:1.
13. The lipoprotein complex of claim 1 in which the molar ratio of the lipid fraction to the ApoA-I apolipoprotein is about 100:1 to 30:1.
14. The lipoprotein complex of claim 1 in which the ApoA-I apolipoprotein is a mature human ApoA-I apolipoprotein, the sphingomyelin is egg sphingomyelin, the negatively charged phospholipid is phosphatidylglycerol, and the molar ratio of the lipid fraction to the ApoA-I apolipoprotein is about 200:1 to 100:1.
15. The lipoprotein complex of claim 1 in which the ApoA-I apolipoprotein is a mature human ApoA-I apolipoprotein, the sphingomyelin is egg sphingomyelin, the negatively charged phospholipid is phosphatidylglycerol, and the molar ratio of the lipid fraction to the ApoA-I apolipoprotein about 100:1 to 30:1.
16. A pharmaceutical composition comprising a lipoprotein complex according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier, diluent and/or excipient.
17. A method of treating dyslipidemia or a disease associated with dyslipidemia in a subject, comprising administering to a subject in need thereof an effective amount of a lipoprotein complex according to any one of claims 1 to 15 .
18. The method of claim 17 in which the amount of the lipoprotein complex administered is effective to raise the subject's serum level of free or complexed apolipoprotein by about 10-300 mg/dL as compared to a baseline level.
19. The method of claim 17 in which the amount of the lipoprotein complex administered is sufficient to deliver about 1 to 100 mg/kg ApoA-I apolipoprotein.
20. The method of claim 17 in which the lipoprotein complex is administered intravenously.
21. The method of claim 17 which is practiced to treat dyslipidemia.
22. The method of claim 17 which is practiced to treat a disease associated with dyslipidemia.
23. The method of claim 17 in which the lipoprotein complex is adjunctively administered with a bile-acid resin, niacin, a statin, a fibrate and/or an inhibitor of cholesterol absorption.
24. The method of claim 17 in which the lipoprotein complex is administered in the form of a pharmaceutical composition comprising the lipoprotein complex and a pharmaceutically acceptable carrier, diluent and/or excipient.
25. The lipoprotein complex of claim 1 which is a large discoidal particle.
26. The lipoprotein complex of claim 25 in which the lipid:ApoA-I equivalent molar ratio (“R i ”) is about 200:1 to 100:1.
27. The lipoprotein complex of claim 25 which contains 1 molecule of charged phospholipid and 400 molecules of sphingomyelin.
28. The lipoprotein complex of claim 1 which is a small discoidal particle.
29. The lipoprotein complex of claim 28 in which R i is about 100:1 to 30:1.
30. The lipoprotein complex of claim 28 which contains 1 molecule of charged phospholipid and 400 molecules of sphingomyelin.
31. A pharmaceutical composition comprising a lipoprotein complex according to any one of claims 25 to 30 and a pharmaceutically acceptable carrier, diluent and/or excipient.
32. A method of treating dyslipidemia or a disease associated with dyslipidemia in a subject, comprising administering to a subject in need thereof an effective amount of a lipoprotein complex according to any one of claims 25 to 30 .
33. The method of claim 32 in which the amount of the lipoprotein complex administered is effective to raise the subject's serum level of free or complexed apolipoprotein by about 10-300 mg/dL as compared to a baseline level.
34. The method of claim 32 in which the amount of the lipoprotein complex administered is sufficient to deliver about 1 to 100 mg/kg ApoA-I apolipoprotein.
35. The method of claim 32 in which the lipoprotein complex is administered intravenously.
36. The method of claim 32 which is practiced to treat dyslipidemia.
37. The method of claim 32 which is practiced to treat a disease associated with dyslipidemia.
38. The method of claim 32 in which the lipoprotein complex is adjunctively administered with a bile-acid resin, niacin, a statin, a fibrate and/or an inhibitor of cholesterol absorption.
39. The method of claim 32 in which the lipoprotein complex is administered in the form of a pharmaceutical composition comprising the lipoprotein complex and a pharmaceutically acceptable carrier, diluent and/or excipient.
40. A lipoprotein complex of claim 1 , wherein said negatively charged phospholipid is phosphatidylglycerol, wherein said sphingomyelin and said phosphatidylglycerol have C16:0 acyl chains; wherein R i is about 2:1 to about 200:1.
41. The lipoprotein complex of claim 40 , wherein said C16:0 acyl chains correspond to the acyl chains of palmitic acid.
42. The lipoprotein complex of claim 41 , which is a large discoidal particle in which R i is about 200:1 to 100:1.
43. The lipoprotein complex of claim 41 , which is a large discoidal particle having an oblate diameter of about 10 to 14 nm.
44. The lipoprotein complex of claim 41 , which is a small discoidal particle in which R i is about 100:1 to 30:1.
45. The lipoprotein complex of claim 41 , which is a small discoidal particle having an oblate diameter of about 5 to 10 nm.
46. A pharmaceutical composition comprising a sterile suspension, solution or emulsion of the lipoprotein complex of any one of claims 40 to 45 in an aqueous medium.
47. The pharmaceutical composition of claim 46 which comprises one or more buffering agents, sugars or salts.
48. A pharmaceutical composition comprising the lipoprotein complex of any one of claims 40 to 45 in powder form.
49. The pharmaceutical composition of claim 48 in which the lipoprotein complex is lyophilized.
50. A method of treating acute coronary syndrome, comprising intravenously administering to a subject in need thereof an effective amount of a lipoprotein complex according to any one of claims 40 to 45 .
51. The method of claim 50 , in which the lipoprotein complex is adjunctively administered with a bile-acid resin, niacin, a statin, a fibrate and/or an inhibitor of cholesterol absorption
52. A method of treating acute coronary syndrome, comprising intravenously administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 46 .
53. The method of claim 52 , in which the pharmaceutical composition is adjunctively administered with a bile-acid resin, niacin, a statin, a fibrate and/or an inhibitor of cholesterol absorption.
54. A method of treating acute coronary syndrome, comprising intravenously administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 47 .
55. The method of claim 54 , in which the pharmaceutical composition is adjunctively administered with a bile-acid resin, niacin, a statin, a fibrate and/or an inhibitor of cholesterol absorption.