Liposome and method for producing liposome

Abstract

It is intended to provide a liposome preparation which is a liposome, has a lipid bilayer membrane composed of an inner membrane constituted by a lipid including one or more types of functional lipids (a lipid capable of chemically interacting with another compound such as a charged lipid, a polarizable lipid, a lipid-soluble lipid or a water-soluble lipid) and an outer membrane constituted by a lipid with or without including one or more types of functional lipids, and is characterized in that at least a condition that the amount of any one type of functional lipid contained in the inner membrane is larger than in the outer membrane is satisfied. The liposome preparation is suitable as a liposome for encapsulating a contrast agent (a neutral substance having a hydroxy group), siRNA (an anionic substance) having an anticancer activity or the like. Its encapsulation ratio of drug agents, dispersion stability, control release and the like have been improved.

1 . A liposome comprising a lipid bimolecular membrane composed of:
 an inner membrane constituted with a lipid which contains one or more functional lipids; and   an outer membrane constituted with a lipid which contains or does not contain one or more functional lipids,   wherein an amount of one of the functional lipids contained in the inner membrane is larger than an amount of the one of the functional lipids contained in the outer membrane.   
   
   
       2 . The liposome as described in  claim 1 ,
 wherein at least one of the functional lipids is a compound which chemically interacts with other compound.   
   
   
       3 . The liposome as described in  claim 1 ,
 wherein the one or more functional lipids are selected from the group consisting of a charged lipid, a polarized lipid, a lipo-soluble lipid and a water-soluble lipid.   
   
   
       4 . The liposome as described in  claim 1 ,
 encapsulating a compound other than a solvent and constituting components of the membranes of the liposome.   
   
   
       5 . The liposome as described in  claim 4 ,
 wherein the compound is an anionic compound which has a sequence of bases.   
   
   
       6 . The liposome as described in  claim 5 ,
 wherein the anionic compound is a siRNA which has an anticancer activity.   
   
   
       7 . The liposome as described in  claim 4 ,
 wherein the compound is a neutral compound having a hydroxyl group.   
   
   
       8 . The liposome as described in  claim 7 ,
 wherein the neutral compound having a hydroxyl group is a contrast medium.   
   
   
       9 . A method for producing a liposome comprising the steps of:
 (1) mixing supercritical or semi-supercritical carbon dioxide, a water-soluble solvent (W 1 ) and a mixed lipid component (F 1 ) which forms an inner membrane of the liposome so as to prepare a W 1 /CO 2  emulsion (a first emulsion preparation step);   (2) adding the W 1 /CO 2  emulsion prepared in the step (1) to a mixture of a water-soluble solvent (W 2 ) and a mixed lipid component (F 2 ) which forms an outer membrane of the liposome with stirring so as to prepare a W/CO 2 /W 2  emulsion (a second emulsion preparation step);   (3) eliminating the solvents contained in the W 1 /CO 2 /W 2  emulsion prepared in the step (2) so as to prepare a suspension of the liposome comprising the inner membrane composed of F 1  and the outer membrane composed of F 2 ; and   (4) adding a compound to be encapsulated in the liposome to the suspension of the liposome prepared in the step (3), or to a water-soluble solvent in which a freeze-dried material of the suspension of the liposome prepared in the step (3) is re-dispersed,   wherein an amount of one of the functional lipids contained in F 1  of the step (1) is larger than an amount of the one of the functional lipids contained in F 2  of the step (2).   
   
   
       10 . A method for producing a liposome comprising the steps of:
 (1) mixing supercritical or semi-supercritical carbon dioxide, a water-soluble solvent (W 1 ), a compound to be encapsulated in the liposome and a mixed lipid component (F 1 ) which forms an inner membrane of the liposome so as to prepare a W 1 /CO 2  emulsion (a first emulsion preparation step);   (2) adding the W 1 /CO 2  emulsion prepared in the step (1) to a mixture of a water-soluble solvent (W 2 ) and a mixed lipid component (F 2 ) which forms an outer membrane of the liposome with stirring so as to prepare a W/CO 2 /W 2  emulsion (a second emulsion preparation step); and   (3) eliminating the solvents contained in the W 1 /CO 2 /W 2  emulsion prepared in the step (2) so as to prepare a suspension of the liposome comprising the inner membrane composed of F 1  and the outer membrane composed of F 2 ,
 wherein an amount of one of the functional lipids contained in F 1  of the step (1) is larger than an amount of the one of the functional lipids contained in F 2  of the step (2).