Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Patent
1989-11-14
1992-12-08
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
536 41, 536123, 536 11, 514 24, 514 25, A61K 9127, A61K 31715
Patent
active
051696363
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to liposomes and, more particularly, to liposomes which can remain in the blood at a high concentration level for a prolonged period of time while avoiding uptake thereof by reticuloendothelial system (RES) tissues.
BACKGROUND ART
Liposomes are closed vesicles composed of one or more lipid membranes mainly consisting of phospholipids and are used as models of biological membranes in physicochemical studies thereof. Furthermore, they can entrap various substances in the inside aqueous phase or in the membranes and therefore they have become a target of intensive investigations of their use as one of drug delivery systems containing various drugs entrapped therein. As regard the use thereof as such delivery system, there may be mentioned, among others, the report of B. E. Ryman et al. [Ann. N. Y. Acad. Sci., 308, 281 (1978)], the report of G. Gregoridias ("Liposome Technology", CRC Press Inc.) and the report of J. N. Weinstein [Science, 204, 188 (1979)]. In particular, they are effective in reducing the toxicity of highly toxic drugs, stabilizing drugs otherwise unstable in vivo and achieving sustained release of drugs in vivo. It is further known that they can be used as means of directing drugs to particular cells selectively by utilizing their property of fusing with cells or being taken up by cells. In a typical example of their application, liposomes are combined with, for example, enzymes (superoxide dismutase etc.), drugs (in particular antitumor agents, adriamycin), chelating agents, hormones (steroid compounds), radionuclides, interferons, interleukins, antigens and antibodies. It is also known that the duration of the efficacy of a drug showing a brief blood half-life, such as insulin, can be prolonged by entrapping it in liposomes. A therapy (missile therapy) has been developed as well which uses anticancer agent-containing liposomes combined with tumor surface-specific antigens bound thereto for selectively attacking cancer cells.
However, in their use in vivo, liposomes administered to the living body are captured by reticuloendothelial system tissues in a short time. This capture is a result of liposomes, which are macromolecules, being recognized as a foreign matter. Such characteristic is a great drawback when it is intended to direct liposomes to tissues other than RES tissues or to increase the duration of the efficacy of a drug in the blood circulation.
For removing such drawback, liposomes containing sialic acids in their lipid bilayer have been proposed (U.S. Pat. No.4,501,728). However, these liposomes cannot avoid capture by the RES to a sufficient extent, either, so that they cannot produce a satisfactory drug efficacy prolonging effect.
DISCLOSURE OF THE INVENTION
It is an object of the invention to provide liposomes which are hardly captured by the RES and can remain in the blood at a high concentration level over a prolonged period of time.
Other objects and features of the invention will become apparent from the description which follows.
Thus the invention provides liposomes characterized in that the liposome lipid membrane contains a glycolipid resulting from O-glycoside or S-glycoside bonding of a lipid and at least one carbohydrate selected from the group consisting of uronic acids, uronosyl-oligosaccharides, oligosaccharides composed of glucosamine and glucuronic acid, oligosaccharides composed of galactosamine and glucuronic acid, oligosaccharides composed of glucuronic acid and xylose, oligosaccharides composed of glucuronic acid and glucose, oligosaccharides composed of glucuronic acid and galactose, oligosaccharides composed of glucuronic acid and mannose, oligosaccharides composed of galacturonic acid and rhamnose, ketoaldonic acids, 2-acetamido-2-deoxyuronic acids, 2-acetamido-2-deoxyuronic acid-containing oligosaccharides, 6-O-carboxyethyl-.beta.-D-glucose, 6-O-carboxymethyl-.beta.-D-glucose, 6'-O-carboxymethyl-.beta.-D-maltose and 6'-O-carboxyethyl-.beta.-D-maltose.
As a result of their investigations, the present inventor
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Allen, T. M. and A. Chonn. "Large Unilamellar Liposomes with Low Uptake into the Reticuloendothelial System", FEBS Letters, vol. 223, No. 1, Oct. 1987) pp. 42-46.
Allen, Thersa M. et al. "Liposomes with Prolonged Circulation Times: Factors Affecting Uptake by Reticuloendothelial and Other Tissues", Biochimica et Biophysica Acta, vol. 981 (1989) pp. 27-35.
Gabizon, Alberto and Demetrios Papahadjopoulos. "Liposome Formulations with Prolonged Circulation Times in Blood and Enhanced Uptake by Tumors". Proc. Natl. Acad. Sci, vol. 85 Sep. 1988) pp. 6949-6953.
Nanba Yukihiro
Oku Naoto
Sakakibara Toshiyuki
Nippon Fine Chemical Co., Ltd.
Page Thurman K.
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