Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Patent
1989-08-25
1991-09-17
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
264 43, 264 46, 514 6, A61K 3722, A61K 3714
Patent
active
050493914
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel method for preparing liposomes. More particularly, the invention is concerned with a method for preparing liposomes with an aqueous solution innerly incorporated.
Furthermore, the invention relates to novel hemoglobin-containing liposomes (called hemosomes herein below) with a highly concentrated aqueous solution of hemoglobin innerly contained.
Liposomes are closed vesicles consisting of lipid bilayers with aqueous spaces innerly contained. Biological membranes are believed to be of lipid bimolecular structure. In this respect, liposomes are widely used in the study on physicochemical properties of the biomembrane as a model membrane. Various substances can be incorporated in aqueous spaces or in phospholipid bilayers of liposomes. The liposomes are fused with or incorporated in the cells so that they are also used as a carrier for delivering a substance into the living body. Studies using liposomes cover a wide variety of fields including biology, medical science and pharmaceutical science. Studies have been made on its application as a carrier for delivering oxygen or an anticancer drug, immunological application, cell interaction or application as a drug delivery system, etc.
Moreover, hemosomes are expected to be useful as artificial erythrocytes having high oxygen carrying capacity and safety and being stable to oxidation.
BACKGROUND TECHNOLOGY
As described above, liposomes are utilized in a wide variety of fields. However, it was impossible by the prior-art methods for preparing liposomes to produce liposomes with a high-viscosity aqueous solution innerly incorporated. Prior methods for preparing liposomes include so-called film methods, detergent-removal methods and reverse-phase evaporation methods. The film methods comprises forming a dried thin film of liposome-forming lipids on the inner surface of a vessel, to which an aqueous solution of a substance to be incorporated is added and subjecting the resulting mass to shaking or ultrasonication. The detergent-removal method depends upon removing detergents by dialysis from an aqueous solution which contains detergents and phospholipids to form mixed micelles, which results in the formation of liposomes. The reverse-phase evaporation method is a method in which liposomes are prepared by adding to an organic solvent solution of liposome-forming lipids an aqueous solution of a substance to be incorporated to form a water-in-oil emulsion and then removing the organic solvent by evaporation. According to these prior art methods, whereas liposomes are formed in cases where the aqueous solution to be innerly incorporated is of a low viscosity, the yield will be extremely low if it is of a high viscosity over 10 cP (20.degree. C.), and desirable liposomes will not be produced in some cases. This has restricted uses of liposomes. For example, liposomes containing an aqueous hemoglobin solution are known as artificial erythrocytes, but, because of the viscosity restriction, the hemoglobin concentration cannot be so high as that of natural hemoglobin (which is 35% (w/v)), being as low as approximately 15%, so that the oxygen-carrying capacity is low.
On the other hand, Miller et al. reported a hemoglobin-containing liposome prepared by the so-called film method (U.S. Pat. No. 4,133,874). According to the method, the liposome is produced by dissolving liposome-forming lipids in an appropriate solvent such as chloroform, distilling off the solvent from the resulting solution to form a film of the lipids, to which an aqueous solution of hemoglobin is added and then subjecting the liposome to ultrasonication. The method is advantageous in that the hemoglobin can be kept with relatively little degradation due to contact with oxygen only for a short period. However, the oxygen-carrying function is likely to be lost due to slow oxidation of the heme iron of hemoglobin in the liposome during storage. Although hemoglobin in the blood cell is provided with a mechanism wherein the hemoglobin oxidized to the m
REFERENCES:
patent: 4133874 (1979-01-01), Miller et al.
patent: 4681582 (1987-07-01), Yamamoto
patent: 4776991 (1988-10-01), Farmer et al.
patent: 4818537 (1989-04-01), Guo
Sakaguchi Keisuke
Suzuki Kazuhiko
Kishore G. S.
Page Thurman K.
Terumo Kabushiki Kaisha
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