Liposome preparation

Details Liposome preparation Liposome preparation

1996-09-10

1998-07-07

Kishore, Gollamudi S.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

A61K 9127, A61K 9133

Patent

active

057764883

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/J895/00383 filed Mar. 8, 1995.
1. Technical Field
The present invention relates to a liposome preparation which suppresses migration, to bone marrow, of a water-soluble 2'-deoxycytidine compound having an anti-malignant tumor activity, and which enhances migration thereof to tumor tissues.
2Background Art
Of the therapies of malignant tumors, chemical treatment is among the effective treatments along with surgical treatment and radiation treatment. However, an anti-malignant tumor agent which selectively eradicates tumor tissue cells has not been developed to date, and reduction of side effects such as myelotoxicity has been the problem to be solved during use. An attempt has been made to reduce side effects and enhance antitumor effects by modification, by pharmaceutical methods, of an anti-malignant tumor agent into a targeted preparation which targets malignant tumor tissues. Clinical tests have proved superior anti-malignant tumor effects achieved by a local administration of an anti-malignant tumor agent containing neocarzinostatin combined with a styrene-maleic acid anhydride copolymer, which have been suspended in an oily contrast medium, to malignant tumor tissue sites in the liver for the treatment of the malignant tumor by virtue of accumulation of the 44, pp. 2115-2121 (1984)!. However, this method is associated with difficulties in that a special administration skill is needed and the number of applicable malignant tumors is limited. A method has been sought, therefore, which enables reduction of side effects and enhancement of anti-malignant tumor effects by systemic administration.
Of such studies, a method comprising encapsulating an anti-malignant tumor agent in liposomes has been known, which utilizes the tendency, when compared to normal tissues, of malignant tumor tissues toward easy uptake of microparticles, such as liposomes, which are fine and closed vesicles having a lipid bilayer structure formed upon dispersion of phospholipids or glycolipids in aqueous solutions. Encapsulation of an anti-malignant tumor agent in liposomes has revealed high anti-malignant tumor effects resulting from the suppression of adverse influences on normal cells and possible consecutive administration of the agent in large doses. Yet, mere formulation into liposomes does not suppress migration of an anti-malignant tumor agent to myeloid tissues, nor does it allow sufficient accumulation of the agent in malignant tumor tissues. Thus, an attempt has been made to prolong residence of the agent in blood by various modifications of liposomes, whereby to ultimately accumulate the anti-malignant tumor agent in malignant tumor tissues. Such attempt vol 36, pp. 2949-2957 (1976)!, (2) using a liposome membrane structure-reinforcing factor such as phosphatidylcholine having long chain (1985)!, (3) adding a synthetic lipid of a water-soluble polymer (e.g., polyethylene glycol), a natural polysaccharide or a sugar which has been vol. 1113, pp. 171-199 (1992), and Oyo Saibo Seibutsugaku Kenkyu, vol. 9 (3-4), pp. 53-61 (1992)! and other methods, and the third method in fact has achieved accumulation in malignant tumor tissues. However, no report has documented a successful suppression of migration of an anti-malignant tumor agent to myeloid tissues, the site of expression of side effects caused by the anti-malignant tumor agent, and the problem regarding the expression of myelotoxicity has not been resolved.
In the meantime, it has been reported that migration to myeloid tissues was enhanced by applying a negative charge to the membrane surface of This literature only reports incorporation of ethylenediaminetetraacetic acid into myeloid tissues. Although application of positive charge to the membrane surface of liposomes has been known, there are only reports of a liposome preparation aiming at increasing the concentration of calcium in serum (Japanese Patent Application under PCT laid-open under Kohyo No. 500378/1988), a liposome preparation aiming at supply of magnesium to patients with

REFERENCES:
patent: 5246708 (1993-09-01), Borstel
Allen et al., Biochemica et Biophysica Acta., vol. 643 (1981), pp. 346-362.
Kobayashi, Kobunshi (1980) vol. 29 (2), p. 117.
Kataoka et al., Annals New York Academy of sciences (1978) vol. 308, pp. 387-394.
Rustum et al., Cancer Research, vol. 39(4), pp. 1390-1395 (1979).
Kobayashi et al., Int. J. Cancer, vol. 20, pp. 581-587 (1977).

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