Liposome for incorporating large amounts of hydrophobic substances

• US 20020058060A1
• Filed: 05/30/2001
• Published: 05/16/2002
• Est. Priority Date: 09/25/2000
• Status: Abandoned Application

• Current Assignee: Industrial Technology Research Institute
• Original Assignee: Industrial Technology Research Institute
• Inventors: Wang, Ae-June, Kan, Pei, Chen, Won-Ko, Tsao, Chih-Wan
• Application Number:
  US09/866,584
• Publication Number:
  US 20020058060A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911

Abstract

A liposome for stably incorporating high content of hydrophobic substance is disclosed. The liposome includes two phospholipids with different phase transition temperatures such as saturated and unsaturated phosphatidyl cholines, hydrophobic substances, cholesterol, cholesterol derivatives, antioxidant and hydrophilic polymer-modified lipids such as MPEG-DSPE.

Claims

1. A liposome for incorporating high content of hydrophobic substances comprising:

a first phospholipid;

a second phospholipid;

one or more hydrophobic substances; and

liposome-forming materials, wherein the first and the second phospholipid coexist in the liposome in a separated-phase form.

2. The liposome according to claim 1, wherein a phase transition temperature of the first phospholipid is higher than the specified temperatures of drug delivery and storage, while a phase transition temperature of the second phospholipid is lower than the specified temperatures of drug delivery and storage.

3. The liposome according to claim 2, wherein the first phospholipid is a hydrogenated naturally-occurring phospholipid or a saturated phospholipid with long carbon chains.

4. The liposome according to claim 3, wherein the first phospholipid is selected from the group consisting of phosphatidyl choline (PC), phosphatidyl glycerol (PG), phosphatidyl serine (PS), phosphatidyl ethanolamine (PE), phospatidyl inositol (PI), phosphaphatic acid (PA), and sphingomyelin (SM).

5. The liposome according to claim 4, wherein phosphatidyl choline (PC) is selected from the group consisting of hydrogenated egg phosphatidyl choline (HEPC), hydrogenated soy phosphatidyl choline (HSPC), dipalmitoyl phosphatidyl choline (DPPC) and distearyloyl phosphatidyl choline (DSPC),

6. The liposome according to claim 2, wherein the second phospholipid is an unsaturated phospholipid or a saturated phospholipid with short carbon chains.

7. The liposome according to claim 6, wherein the second phospholipid is selected from the group consisting of phosphatidyl choline (PC), phosphatidyl glycerol (PG), phosphatidyl serine (PS), phosphatidyl ethanolamine (PE), phospatidyl inositol (PI), phosphaphatic acid (PA), and sphingomyelin (SM).

8. The liposome according to claim 7, wherein phosphatidyl choline (PC) is selected from the group consisting of egg phosphatidyl choline (EPC), soy phosphatidyl choline (SPC), synthetic or naturally-occurring unsaturated phosphatidyl cholines, dimyristoyl phosphatidyl choline (DMPC) and dilauroyl phosphatidyl choline (DLPC).

9. The liposome according to claim 1, wherein the hydrophobic substances are one or more hydrophobic compounds.

10. The liposome according to claim 9, wherein the hydrophobic compound is paclitaxel and/or a derivative thereof.

11. The liposome according to claim 10, wherein paclitaxel and/or the derivative thereof are/is incorporated with a drug/lipid ratio ranging from about 0.5 mole % to 25 mole %.

12. The liposome according to claim 9, wherein the hydrophobic compound is retinoic acid and/or a derivative thereof.

13. The liposome according to claim 12, wherein the retinoic acid and/or the derivative thereof are/is incorporated with a drug/lipid ratio ranging from about 0.5 mole % to 40 mole %.

14. The liposome according to claim 9, wherein the hydrophobic compound is camptothecin and/or a derivative thereof.

15. The liposome according to claim 14, wherein the camptothecin and/or the derivative thereof are/is incorporated with a drug/lipid ratio ranging from about 0.5 mole % to 30 mole %.

16. The liposome according to claim 9, wherein the hydrophobic compound is polythiophene and/or a derivative thereof.

17. The liposome according to claim 16, wherein the polythiophene and/or the derivative thereof are/is incorporated with a drug/lipid ratio ranging from about 0.5 mole % to 100 mole %.

18. The liposome according to claim 9, wherein the hydrophobic drug is selected from the group consisting of paclitaxel and/or a derivatives thereof, retinoic acid and/or the derivatives thereof, camptothecin and/or the derivatives thereof, and polythiophene and/or derivatives thereof.

19. The liposome according to claim 1, wherein the liposome-forming materials are selected from the group consisting of hydrophilic polymer-modified lipids, cholesterol, cholesterol derivative, antioxidant, and mixtures thereof.

20. A liposome for incorporating high content of hydrophobic substances comprising:

a first phosphatidyl choline;

a second phosphatidyl choline;

one or more hydrophobic substances; and

liposome-forming materials, wherein the first and the second phosphatidyl cholines coexist in the liposome in a separated-phase form.

21. The liposome according to claim 20, wherein a phase transition temperature of the first phosphatidyl choline is higher than the specified temperatures of drug delivery and storage, while a phase transition temperature of the second phosphatidyl choline is lower than the specified temperatures of drug delivery and storage.

22. The liposome according to claim 21, wherein the first phosphatidyl choline is a hydrogenated naturally-occurring phosphatidyl choline or a saturated phosphatidyl choline with long carbon chains.

23. The liposome according to claim 22, wherein the phosphatidyl choline (PC) is selected from the group consisting of hydrogenated egg phosphatidyl choline (HBEPC), hydrogenated soy phosphatidyl choline (HSPC), dipalmitoyl phosphatidyl choline (DPPC) and distearyloyl phosphatidyl choline (DSPC),

24. The liposome according to claim 21, wherein the second phosphatidyl choline is an unsaturated phosphatidyl choline or a saturated phosphatidyl choline with short carbon chains.

25. The liposome according to claim 24, wherein phosphatidyl choline (PC) is selected from the group consisting of egg phosphatidyl choline (EPC), soy phosphatidyl choline (SPC), synthetic or natural-occurring unsaturated phosphatidyl cholines, dimyristoyl phosphatidyl choline (DMPC) and dilauroyl phosphatidyl choline (DLPC).

26. The liposome according to claim 20, wherein the hydrophobic substances are one or more hydrophobic drugs.

27. The liposome according to claim 26, wherein the hydrophobic drug is paclitaxel and/or a derivative thereof.

28. The liposome according to claim 27, wherein the paclitaxel and/or its derivative is incorporated with a drug/lipid ratio ranging from about 0.5 mole % to 25 mole %.

29. The liposome according to claim 26, wherein the hydrophobic drug is retinoic acid and/or a derivative thereof.

30. The liposome according to claim 29, wherein the retinoic acid and/or the derivative thereof are/is incorporated with a drug/lipid ratio ranging from about 0.5 mole % to 40 mole %.

31. The liposome according to claim 26, wherein the hydrophobic drug is camptothecin and/or a derivative.

32. The liposome according to claim 31, wherein the camptothecin and/or the derivative thereof are/is incorporated with a drug/lipid ratio ranging from about 0.5 mole % to 30 mole %.

33. The liposome according to claim 26, wherein the hydrophobic drug is polythiophene and/or a derivative thereof.

34. The liposome according to claim 33, wherein the polythiophene and/or the derivative thereof are/is incorporated with a drug/lipid ratio ranging from about 0.5 mole % to 100 mole %.

35. The liposome according to claim 26, wherein the hydrophobic drug is selected from the group consisting of paclitaxel, retinoic acid, camptothecin, polythiophene and their derivatives.

36. The liposome according to claim 20, wherein the liposome-forming materials are selected from the group consisting of hydrophilic polymer-modified lipids, cholesterol, cholesterol derivative, antioxidant, and mixture thereof.