Liposome composition and pharmaceutical composition
An object of the present invention is to provide a liposome composition and a pharmaceutical composition, which exhibit a high AUC. Provided are a liposome composition including a hydrophilic polymer-modified diacylphosphatidylethanolamine, a dihydrosphingomyelin, and cholesterols as components of a liposome membrane, in which the liposome composition encapsulates a drug, an inner water phase thereof contains ammonium sulfate, and a molar ratio of sulfate ions in the inner water phase to the drug in an entire water phase is 0.36 or more; and a pharmaceutical composition including the liposome composition.
1. A liposome composition comprising: liposomes each of which has an inner water phase and an aqueous solution which constitutes an outer water phase and in which the liposomes are dispersed,
wherein the liposomes comprise
a hydrophilic polymer-modified diacylphosphatidylethanolamine,
a dihydrosphingomyelin, and
cholesterols;
wherein each of the liposomes encapsulates a drug;
the drug is topotecan,
the inner water phase contains ammonium sulfate,
the molar ratio of sulfate ions in the inner water phase to the sum of the drug contained in the inner water phase and the outer water phase is 0.36 or more, and
the percentage of the hydrophilic polymer-modified diacylphosphatidylethanolamine in the liposome is 1 to 15 mol %.
2. The liposome composition according to claim 1 ,
wherein the molar ratio of the sulfate ions in the inner water phase to the sum of the drug contained in the inner water phase and the outer water phase is 0.6 or more and 1.8 or less.
3. The liposome composition according to claim 1 ,
wherein the hydrophilic polymer-modified diacylphosphatidylethanolamine is a polyethylene glycol- or methoxy polyethylene glycol-modified diacylphosphatidylethanolamine.
4. The liposome composition according to claim 1 ,
wherein the percentage of the hydrophilic polymer-modified diacylphosphatidylethanolamine in the liposome is 2 to 10 mol %.
5. The liposome composition according to claim 1 ,
wherein the percentage of cholesterols in the liposome is 35 to 43 mol %.
6. The liposome composition according to claim 1 , wherein the liposomes have a particle size of 30 nm to 150 nm.
7. The liposome composition according to claim 1 ,
wherein the outer water phase has a pH of 5.5 to 8.5.
8. The liposome composition according to claim 1 ,
wherein the dihydrosphingomyelin is a dihydrosphingomyelin containing a long-chain alkyl group having 16 carbon atoms and a long-chain alkyl group having 18 carbon atoms.
9. The liposome composition according to claim 1 ,
wherein the percentage of the sulfate ions contained in the inner water phase of the liposome to the sulfate ions in the entire liposome composition is at least 80%, and the percentage of the drug contained in the inner water phase of the liposome to the drug in the entire liposome composition is at least 80%.
10. The liposome composition according to claim 8 ,
wherein the drug release rate from the liposome in plasma having an ammonium concentration of 1 mmol/L or less is 20%/24 hours or less at 37° C., and the drug release rate from the liposome in plasma having an ammonium concentration of 4 to 6 mmol/L is 60%/24 hours or more at 37° C.
11. The liposome composition according to claim 1 ,
wherein the number of insoluble particles of more than 10 μm contained in 1 μmol of lipid of the liposome composition after storage for 1 month at 5° C. is 150 or less, and the number of insoluble particles of more than 25 μm contained in 1 μmol of lipid of the liposome composition is 15 or less.
12. A pharmaceutical composition comprising:
the liposome composition according to claim 1 .
13. A method for treating an anticancer disease, comprising administering the pharmaceutical composition according to claim 12 .
14. A liposome composition comprising: liposomes each of which has an inner water phase and an aqueous solution which constitutes an outer water phase and in which the liposomes are dispersed,
wherein the liposomes comprise
a hydrophilic polymer-modified diacylphosphatidylethanolamine,
a dihydrosphingomyelin, and
cholesterols;
wherein each of the liposomes encapsulates a drug;
the drug is topotecan,
the inner water phase contains ammonium sulfate,
the dihydrosphingomyelin is a dihydrosphingomyelin containing a long-chain alkyl group having 16 carbon atoms and a long-chain alkyl group having 18 carbon atoms, and
the percentage of the hydrophilic polymer-modified diacylphosphatidylethanolamine in the liposome is 1 to 15 mol %.
15. The liposome composition according to claim 1 ,
wherein the percentage of the dihydrosphingomyelin in the liposome is 40 to 70 mol %.
16. A pharmaceutical composition comprising:
the liposome composition according to claim 14 .