Liposome for incorporating large amounts of hydrophobic substances
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/07
A61K-031/045
A61K-031/135
A61K-031/165
A61K-031/21
A61K-031/215
A61K-031/235
A61K-031/24
A61K-031/335
A61K-031/40
A61K-031/44
A61K-031/66
A61K-031/685
A61K-031/683
출원번호
US-0624362
(2003-07-23)
등록번호
US-7485320
(2009-02-03)
우선권정보
TW-89119777 A(2000-09-25)
발명자
/ 주소
Kan,Pei
Wang,Ae June
Chen,Won Ko
Tsao,Chih Wan
출원인 / 주소
Industrial Technology Research Institute
대리인 / 주소
Rabin & Berdo, P.C.
인용정보
피인용 횟수 :
0인용 특허 :
5
초록▼
A liposome formulation 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 derivativ
A liposome formulation 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.
대표청구항▼
What is claimed is: 1. A formulated liposome for incorporating a high content of hydrophobic substances therein, comprising: a first phospholipid which is selected from the group consisting of a hydrogenated naturally-occurring phospholipid and a saturated phospholipid having long carbon chains (--
What is claimed is: 1. A formulated liposome for incorporating a high content of hydrophobic substances therein, comprising: a first phospholipid which is selected from the group consisting of a hydrogenated naturally-occurring phospholipid and a saturated phospholipid having long carbon chains (--(CH2)n--, in which n is at least 14), and which has a phase transition temperature Tg1 ranging between 40 and 74�� C.; a second phospholipid which is selected from the group consisting of an unsaturated phospholipid and a saturated phospholipid having short carbon chains (--(CH2)n--, in which n is at most 14), and which has a phase transition temperature Tg2 ranging between-30 and 10�� C.; liposome-forming materials effective to form a liposome in which the first phospholipid and the second phospholipid coexist in two immiscible phases and create several discontinuous regions, and in which a molar ratio of the first phospholipid to the second phospholipid is at least 3:16; and one or more hydrophobic substances incorporated in the liposome in an amount of at least 20 mole % to form the formulated liposome, wherein a drug delivery temperature T1 and a drug storage temperature T2 are chosen at specified ranges subject to an order of Tg1>T1>T2>Tg2, and wherein the formulated liposome has an incorporation efficiency which remains at least about 70% of incorporation efficiency for six months or more. 2. The formulated liposome according to claim 1, wherein the phase transition temperature of the first phospholipid ranges between 50 and 65�� C., and the phase transition temperature of the second phospholipid ranges between-20 and 4�� C. 3. The formulated liposome according to claim 1, wherein the first phospholipid is selected from the group consisting of phosphatidyl choline (PC), phosphatidyl glycerol (PG), phosphatidyl serine (PS), phosphatidyl acid (PA) and phosphatidyl ethanolamine (PE). 4. The formulated liposome according to claim 3, wherein the first phospholipid 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), diarachidoyl phosphatidyl choline, dimyristoyl phosphatidyl ethanolamine (DMPE), dipalmitoyl phosphatidyl ethanolamine (DPPE), distearoyl phosphatidyl ethanolamine (DSPE), dipalmitoyl phosphatidyl glycerol (DPPG), distearoyl phosphatidyl glycerol, dimyristoyl phosphatidyl acid (DMPA), dipalmitoyl phosphatidyl acid (DPPA), dipalmitoyl phosphatidyl serine (DPPS), and distearoyl phosphatidyl serine (DSPS). 5. The formulated liposome according to claim 1, wherein the second phospholipid is selected from the group consisting of phosphatidyl choline (PC), phosphatidyl glycerol (PG), phosphatidyl serine (PS), phosphatidyl acid (PA) and phosphatidyl ethanolamine (PE). 6. The formulated liposome according to claim 5, wherein the second phospholipid is selected from the group consisting of egg phosphatidyl choline (EPC), soy phosphatidyl choline (SPC), oleoyl palmitoyl phosphatidyl choline, dioleoyl phosphatidyl choline, dipetroselinoyl phosphatidyl choline, dipalmitelaidoyl phosphatidyl choline, dioleoyl phosphatidyl ethanolamine, dioleoyl phosphatidyl serine, dilauroyl phosphatidyl choline (DLPC), diundecanoyl phosphatidyl choline, didecanoyl phosphatidyl ethanolamine, and dinonanoyl phosphatidyl ethanolamine. 7. The formulated liposome according to claim 1, wherein the hydrophobic substances are one or more hydrophobic pharmaceutical compounds. 8. The formulated liposome according to claim 7, wherein the one or more hydrophobic pharmaceutical compound is paclitaxel. 9. The formulated liposome according to claim 8, wherein the paclitaxel is incorporated with a drug/lipid ratio ranging from at least 20 mole % to 25 mole %. 10. The formulated liposome according to claim 9, wherein the paclitaxel is incorporated with a drug/lipid ratio ranging from at least 20 mole % to 25 mole % when the first phospholipid is hydrogenated egg phosphatidyl choline (HEPC) and the second phospholipid is egg phosphatidyl choline (EPC). 11. The formulated liposome according to claim 9, wherein the paclitaxel is incorporated with a drug/lipid ratio ranging from at least 20 mole % to 25 mole % when the first phospholipid is hydrogenated soy phosphatidyl choline (HSPC) and the second phospholipid is egg phosphatidyl choline (EPC). 12. The formulated liposome according to 7, wherein the hydrophobic pharmaceutical compound is retinoic acid. 13. The formulated liposome according to claim 12, wherein the retinoic acid is incorporated with a drug/lipid ratio ranging from at least 20 mole % to 40 mole %. 14. The formulated liposome according to claim 13, wherein the retinoic acid is incorporated with a drug/lipid ratio ranging from at least 20 mole % to 40 mole % when the first phospholipid is hydrogenated soy phosphatidyl choline (HSPC) and the second phospholipid is egg phosphatidyl choline (EPC). 15. The formulated liposome according to claim 7, wherein the hydrophobic pharmaceutical compound is camptothecin. 16. The formulated liposome according to claim 15, wherein the camptothecin is incorporated with a drug/lipid ratio ranging from at least 20 mole % to 30 mole %. 17. The formulated liposome according to claim 16, wherein the camptothecin is incorporated with a drug/lipid ratio ranging from at least 20 mole % to 30 mole % when the first phospholipid is hydrogenated egg phosphatidyl choline (HEPC) and the second phospholipid is egg phosphatidyl choline (EPC). 18. The formulated liposome according to claim 7, wherein the hydrophobic pharmaceutical compound is selected from the group consisting of paclitaxel retinoic acid, and camptothecin. 19. The formulated liposome according to claim 1, wherein the liposome-forming materials are selected from the group consisting of hydrophilic polymer-modified lipids, cholesterol, antioxidant, and mixtures thereof. 20. The formulated liposome according to claim 19, wherein the hydrophilic polymer-modified lipid is methoxy polyethylene glycol-distearyloyl phosphatidyl ethanolamine (MPEG-DSPE). 21. The formulated liposome according to claim 1, wherein the one or more hydrophobic substances incorporated in the liposome is present in an amount of ranging from at least 20 mole % to about 25 mole %. 22. The formulated liposome according to claim 1, wherein the one or more hydrophobic substances incorporated in the liposome is present in an amount ranging from at least 20 mole % to about 25 mole. 23. The formulated liposome according to claim 1, wherein the first and second phospholipids are phosphatidyl cholines. 24. A formulated liposome for incorporating a high content of hydrophobic substances therein, comprising: a first phospholipid which is optionally a phosphatidyl choline, which is selected from the group consisting of a hydrogenated naturally-occurring phospholipid and a saturated phospholipid having long carbon chains (--(CH2)n--, in which n is at least 14), and which has a phase transition temperature Tg1 ranging between 40 and 74�� C.; a second phospholipid which is optionally a phosphatidyl choline, which is selected from the group consisting of an unsaturated phospholipid and a saturated phospholipid having short carbon chains (--(CH2)n--, in which n is at most 14, and which has a phase transition temperature Tg2 ranging between-30 and 10�� C.; liposome-forming materials effective to form a liposome in which the first phospholipid and the second phospholipid coexist in two immiscible phases and create several discontinuous regions; and one or more hydrophobic substances incorporated in the liposome in an amount of at least 20 mole % to form the formulated liposome, wherein a drug delivery temperature T1 and a drug storage temperature T2 are chosen at specified ranges subject to an order of Tg1>T1>T2>Tg2, and wherein the formulated liposome has an incorporation efficiency which remains at least about 70% of incorporation efficiency for six months or more. 25. The formulated liposome according to claim 24, wherein the phase transition temperature of the first phospholipid ranges from 50 to 65�� C., and the phase transition temperature of the second phospholipid ranges from-20 to 4�� C. 26. The formulated liposome according to claim 24, wherein the first phospholipid is a phosphatidyl choline (PC) and 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). 27. The liposome according to claim 24, wherein the second phospholipid is a phosphatidyl choline (PC) and is selected from the group consisting of egg phosphatidyl choline (EPC), soy phosphatidyl choline (SPC), synthetic or natural-occurring unsaturated phosphatidyl cholines and dilauroyl phosphatidyl choline (DLPC), oleoyl palmitoyl phosphatidyl choline, dioleoyl phosphatidyl choline, and dipetroselinoyl phosphatidyl choline, dipalmitelaidoyl phosphatidyl choline. 28. The formulated liposome according to claim 24, wherein the hydrophobic substances are one or more hydrophobic pharmaceutical compounds. 29. The formulated liposome according to claim 28, wherein the one or more hydrophobic pharmaceutical compound is paclitaxel. 30. The formulated liposome according to claim 29, wherein the paclitaxel is incorporated with a drug/lipid ratio ranging from at least 20 mole % to 25 mole %. 31. The formulated liposome according to claim 30, wherein the paclitaxel is incorporated with a drug/lipid ratio ranging from at least 20 mole % to 25 mole % when the first phospholipid is hydrogenated egg phosphatidyl choline (HEPC) and the second phospholipid is egg phosphatidyl choline (EPC). 32. The formulated liposome according to claim 30, wherein the paclitaxel is incorporated with a drug/lipid ratio ranging from at least 20 mole % to 25 mole % when the first phospholipid is hydrogenated soy phosphatidyl choline (HSPC) and the second phospholipid is egg phosphatidyl choline (EPC). 33. The formulated liposome according to claim 28, wherein the one or more hydrophobic pharmaceutical compound is retinoic acid. 34. The formulated liposome according to claim 33, wherein the retinoic acid is incorporated with a drug/lipid ratio ranging from at least 20 mole % to 40 mole %. 35. The formulated liposome according to claim 34, wherein the retinoic acid is incorporated with a drug/lipid ratio ranging from at least 20 mole % to 40 mole % when the first phospholipid is hydrogenated soy phosphatidyl choline (HSPC) and the second phospholipid is egg phosphatidyl choline (EPC). 36. The formulated liposome according to claim 28, wherein the one or more hydrophobic pharmaceutical compound is camptothecin. 37. The formulated liposome according to claim 36, wherein the camptothecin is incorporated with a drug/lipid ratio ranging from at least 20 mole % to 30 mole %. 38. The formulated liposome according to claim 37, wherein the camptothecin is incorporated with a drug/lipid ratio ranging from at least 20 mole % to 30 mole % when the first phospholipid is hydrogenated egg phosphatidyl choline (HEPC) and the second phospholipid is egg phosphatidyl choline (EPC). 39. The formulated liposome according to claim 28, wherein the one or more hydrophobic pharmaceutical compound is selected from the group consisting of paclitaxel, retinoic acid, and camptothecin. 40. The formulated liposome according to claim 24, wherein the liposome-forming materials are selected from the group consisting of hydrophilic polymer-modified lipids, cholesterol, antioxidant, and mixture thereof. 41. The formulated liposome according to claim 40, wherein the hydrophilic polymer-modified lipid is methoxy polyethylene glycol-distearyloyl phosphatidyl ethanolamine (MPEG-DSPE). 42. The formulated liposome according to claim 24, wherein the one or more hydrophobic substances incorporated in the liposome is present in an amount ranging from at least 20 mole % to about 25 mole %. 43. The formulated liposome according to claim 24, wherein the one or more hydrophobic substances incorporated in the liposome is present in an amount ranging from at least 20 mole % to about 25 mole %. 44. The formulated liposome according to claim 24, wherein the first phospholipid and the second phospholipid are present in a molar ratio of the first phospholipid to the second phospholipid is at least 3:16.
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