Liposome compositions and methods for the treatment of atherosclerosis

• US 7,101,570 B2
• Filed: 11/05/2001
• Issued: 09/05/2006
• Est. Priority Date: 03/04/1994
• Status: Expired due to Fees

• Current Assignee: Pfizer Inc.
• Original Assignee: University of British Columbia
• Inventors: Rodrigueza, Wendi, Hope, Michael J.
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US09/992,107
• Publication Number:
  US 20020110588A1
• Time in Patent Office: 1,765 Days
• Field of Search: 424/450, 424/1.21, 424/9.321, 424/9.51, 424/417, 424/400, 428/402.2, 514/824
• US Class Current: 424/450
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]

Abstract

The present invention provides compositions and methods for treating atherosclerosis. The compositions comprise unilamellar liposomes having an average diameter of 100-150 nanometers. Methods for treating atherosclerosis employing the compositions of the present invention are also provided.

Claims

1. A pharmaceutical composition for the treatment of a vascular disease or condition selected from the group consisting of atherosclerosis, hyperlipidemia, and hypoalphalipoproteinemia in a human, comprising a pharmaceutically acceptable and a therapeutically effective amount of unilamellar phospholipid liposomes consisting essentially of empty aqueous interiors and having a Gaussian distribution wherein at least 68% of the liposomes have a mean diameter of about 125±

30 nm, which liposomes mobilize more cholesterol than an equal amount of unilamellar phospholipid liposomes having a mean diameter of 30±

7 nm as measured in mice.

2. The pharmaceutical composition of claim 1 wherein 68% of the liposomes have a mean diameter between about 100-150 nm.

3. The pharmaceutical composition of claim 1 in which the therapeutically effective amount is about 7.0-105.0 grams.

4. The pharmaceutical composition of claim 1 in which the therapeutically effective amount is about 20.0-30.0 grams.

5. The pharmaceutical composition of claim 1 in which the therapeutically effective amount is about 21.0 grams.

6. The pharmaceutical composition of claim 1 comprising a pharmaceutically acceptable carrier selected from the group consisting of sterilized water, sterilized buffered water, sterilized saline solution, and a sterilized aqueous solution.

7. The pharmaceutical composition of claim 6 wherein the concentration of liposomes in the carrier is in the range of about 20-200 mg/ml.

8. The pharmaceutical composition of claim 6 wherein the concentration of liposomes in the carrier is about 200 mg/ml.

9. The pharmaceutical composition of claim 6 wherein the concentration of liposomes in the carrier is in the range of about 50-150 mg/ml.

10. The pharmaceutical composition of claim 6 wherein the concentration of liposomes in the carrier is about 100 mg/ml.

11. The pharmaceutical composition of claim 1 wherein the composition is lyophilized.

12. The pharmaceutical composition of claim 1, wherein the phospholipid is selected from the group consisting of egg phosphatidylcholine, egg phosphatidylglycerol, distearoylphosphatidylcholine, distearoylphosphatidylglycerol, phosphatidylcholine, phosphatidylglycerol, lecithin, β

,γ

-dipalmitoyl-α

-lecithin, sphingomyelin, phosphatidylserine, phosphatidic acid, phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine, phosphatidylinositol, cephalin, cardiolipin, oleoyl-palmitoyl-phosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, dioleoylphosphatidylglycerol, palmitoyl-oleoyl-phosphatidylcholine, di-stearoyl-phosphatidylcholine, stearoyl-palmitoyl-phosphatidylcholine, di-palmitoyl-phosphatidylethanolamine, di-stearoyl-phosphatidylethanolamine, di-myrstoyl-phosphatidylserine, and mixtures thereof.

13. The pharmaceutical composition of claim 1 wherein the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylglycerol, and mixtures thereof.

14. The pharmaceutical composition of claim 1, wherein the phospholipids are in a liquid crystalline phase at about 37°

C.

15. A pharmaceutical composition for the treatment of a vascular disease or condition selected from the group consisting of atherosclerosis, hyperlipidemia, and hypoalphalipoproteinemia in a human, comprising a pharmaceutically acceptable and a therapeutically effective amount of unilamellar phospholipid liposomes consisting essentially of empty aqueous interiors which liposomes are effective in promoting cholesterol efflux without causing a substantial increase in LDL or esterified cholesterol levels.

16. The pharmaceutical composition of claim 15 wherein the liposomes have a mean diameter between about 100-150 nm.

17. The pharmaceutical composition of claim 15 in which the therapeutically effective amount is about 7.0-105.0 grams.

18. The pharmaceutical composition of claim 15 in which the therapeutically effective amount is about 20.0-30.0 grams.

19. The pharmaceutical composition of claim 15 in which the therapeutically effective amount is about 21.0 grams.

20. The pharmaceutical composition of claim 15 comprising a pharmaceutically acceptable carrier selected from the group consisting of sterilized water, sterilized buffered water, sterilized saline solution, and a sterilized aqueous solution.

21. The pharmaceutical composition of claim 20 wherein the concentration of liposomes in the carrier is in the range of about 20-200 mg/ml.

22. The pharmaceutical composition of claim 20 wherein the concentration of liposomes in the carrier is about 200 mg/ml.

23. The pharmaceutical composition of claim 20 wherein the concentration of liposomes in the carrier is in the range of about 50-150 mg/ml.

24. The pharmaceutical composition of claim 20 wherein the concentration of liposomes in the carrier is about 100 mg/ml.

25. The pharmaceutical composition of claim 15 wherein the composition is lyophilized.

26. The pharmaceutical composition of claim 15, wherein the phospholipid is selected from the group consisting of egg phosphatidylcholine, egg phosphatidylglycerol, distearoylphosphatidylcholine, distearoylphosphatidylglycerol, phosphatidylcholine, phosphatidylglycerol, lecithin, β

,γ

-dipalmitoyl-α

-lecithin, sphingomyelin, phosphatidylserine, phosphatidic acid, phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine, phosphatidylinositol, cephalin, cardiolipin, oleoyl-palmitoyl-phosphatidylcholine, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, dioleoylphosphatidylglycerol, palmitoyl-oleoyl-phosphatidylcholine, di-stearoyl-phosphatidylcholine, stearoyl-palmitoyl-phosphatidylcholine, di-palmitoyl-phosphatidylethanolamine, di-stearoyl-phosphatidylethanolamine, di-myrstoyl-phosphatidylserine, and mixtures thereof.

27. The pharmaceutical composition of claim 15, wherein the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylglycerol, and mixtures thereof.

28. The pharmaceutical composition of claim 15, wherein the phospholipids are in a liquid crystalline phase at about 37°

C.