Method of manufacture of liposome composition
The present invention provides a method of manufacture of a liposome composition including a step in which: a liposome dispersion liquid containing a liposome, and further containing cyclodextrin in the liposome internal phase is provided and a step in which an active compound is introduced into said liposome internal phase, and the liposome composition.
1. A method for preparing a liposome composition, comprising:
(a) preparing a liposome dispersion liquid comprising liposome and further comprising cyclodextrin in both the liposome internal phase and the liposome external phase;
(b) preparing a solution comprising an active compound and/or pharmaceutically acceptable salt thereof;
(c) mixing the liposome dispersion liquid prepared in (a) with the solution prepared in (b), thus preparing a mixed solution that has a higher concentration of cyclodextrin in the liposome internal phase than in the liposome external phase;
(d) heating the mixed solution prepared in (c) to a temperature equal to or higher than the liposome's lipid bilayer phase transition temperature; and
(e) obtaining, from the mixed solution of (d), a liposome composition that comprises the active compound complexed with the cyclodextrin in the liposome internal phase,
wherein the liposome in (a) is formed in a cyclodextrin-containing solution;
wherein the cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, 6-O-maltosyl-β-cyclodextrin and sufobutylether-β-cyclodextrin; and
wherein the liposome's membrane comprises phospholipids that comprise saturated or unsaturated fatty-acid residues with a carbon number of 12 to 20.
2. The method according to claim 1 , wherein (a) preparing the liposome dispersion liquid further comprises: substituting or diluting the liposome external phase of the liposome dispersion liquid prepared in (a) with a liposome external phase that is cyclodextrin-free or that results in a liposome dispersion liquid that has a higher concentration of cyclodextrin the liposome internal phase than in the liposome external phase.
3. The method according to claim 1 , wherein the temperature equal to or higher than the liposome's lipid bilayer phase transition tempera u is from 20 to 100° C.
4. The method according to claim 1 , wherein the temperature equal to or higher than the liposome's lipid bilayer phase transition temperature is from 40 to 80° C.