Liposomes Useful for Drug Delivery
The present invention provides liposome compositions containing substituted ammonium and/or polyanion, and optionally with a desired therapeutic or imaging entity. The present invention also provide methods of making the liposome compositions provided by the present invention.
1 . A pharmaceutical composition comprising a docetaxel prodrug liposome comprising sucrose octasulfate and an aminoacyl docetaxel pro-drug encapsulated within a unilamellar vesicle comprising sphingomyelin, cholesterol and a non-ionic PEG lipid derivative.
2 . The composition of claim 1 , wherein the docetaxel prodrug is 2′-(3-(N,N′-diethylamino)propionyl)-docetaxel.
3 . The composition of claim 1 , wherein the non-ionic PEG lipid derivative is PEG-DSG.
4 . The composition of claim 1 , wherein the unilamellar vesicle comprises sphingomyelin and PEG-DSG in a 3:2 molar ratio.
5 . The composition of claim 4 , wherein the docetaxel prodrug liposome comprises a vesicle consisting of a sphingomyelin, cholesterol and PEG-DSG encapsulating the sucrose octasulfate and the aminoacyl docetaxel pro-drug.
6 . The composition of claim 5 , wherein the vesicle consists of the sphingomyelin, cholesterol and PEG-DSG in a molar ratio of about 3:2:0.015.
7 . The composition of claim 6 , wherein the composition further comprises the docetaxel prodrug liposome in an aqueous carrier medium, and the sucrose octasulfate and the aminoacyl docetaxel prodrug are encapsulated in an encapsulated aqueous medium within the unilamellar vesicle.
8 . The composition of claim 7 , wherein the docetaxel prodrug liposome is further characterized by one or more of the following:
a. the pH of the aqueous carrier medium is about 4-7;
b. the liposome comprises about 0.05-0.65 mols of the aminoacyl docetaxel pro-drug compound per mol of total lipid in the liposome composition; and
c. the liposome comprises about 0.15 to about 1.5 mg of the encapsulated aminoacyl docetaxel pro-drug compound per mg of total lipid in the liposome composition.
9 . A composition of a liposome having an interior space, said composition comprising the liposome in an aqueous medium, wherein the interior space: 1) is aqueous, 2) is separated from the aqueous medium by a membrane comprised of one or more lipids, and 3) contains sucrose octasulfate polyanion in the form of an acid or a salt of a taxane selected from the group consisting of: docetaxel and 2′-(diethylamino)-ester aminoacyl docetaxel prodrug.
10 . The composition of claim 9 , wherein the interior space is essentially free of a solubilizing aid selected from a micelle-forming surfactant compound and a cyclodextrin compound and the taxane does not comprise a hydrophilic polymer moiety.
11 . The composition of claim 9 , wherein the liposome comprises sphingomyelin, cholesterol and PEG-DSG.
12 . The composition of claim 11 , wherein the liposome comprises sphingomyelin and cholesterol in a 3:2 molar ratio.
13 . The composition of claim 11 , wherein the liposome comprises sphingomyelin, cholesterol and PEG-DSG in a molar ratio of about 3:2:0.015.
14 . A docetaxel prodrug liposome composition comprising sucrose octasulfate and a 2′-(diethylamino)-ester aminoacyl docetaxel prodrug encapsulated within a liposome formed from one or more lipids, wherein at least about 90% of the docetaxel prodrug is encapsulated within the liposome.
15 . The composition of claim 14 , wherein about 0.2 moles of the docetaxel prodrug per mol of the total lipids is encapsulated within the liposome.
16 . The composition of claim 14 , wherein at least about 300 mg of the docetaxel prodrug is encapsulated in the liposome per g of the total lipids in the composition.
17 . The composition of claim 14 , wherein the lipids in the liposome comprise DSPC, cholesterol and PEG-DSPE in a molar ratio of about 3:2:0.015.
18 . The composition of claim 15 , wherein the lipids in the liposome are sphingomyelin, cholesterol and PEG-DSG in a molar ratio of about 3:2:0.015.
19 . The composition of claim 14 , wherein the pH of the docetaxel prodrug liposome composition is about 5.0-6.5 and wherein the composition has 300-500 mg of the docetaxel prodrug encapsulated in the liposome per g of the total lipids in the composition.
20 . A method of administering docetaxel to a patient in need thereof, the method comprising the step of parenterally administering to the patient a docetaxel prodrug liposome in a first aqueous medium at a pH of about 5.0-6.5, the docetaxel prodrug liposome comprising cholesterol and a phospholipid and encapsulating a 2′-(diethylamino)-ester aminoacyl docetaxel prodrug in a second aqueous medium encapsulated within the docetaxel prodrug liposome at a pH lower than the pH of the first aqueous medium, wherein at least a portion of the docetaxel pro-drug is converted to docetaxel outside the liposome after parenteral delivery of the docetaxel prodrug liposome to the patient.
21 . The method of claim 20 , wherein at least a portion of the docetaxel pro-drug is converted to docetaxel within the second aqueous medium encapsulated within the liposome after parenteral delivery of the docetaxel prodrug liposome.