Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Patent
1995-12-21
1998-06-02
Kishore, Gollamudi S.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
436829, A61K 9127, A61K 9133
Patent
active
057595739
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US94/04,490 filed Apr. 22, 1994 and a Continuation-in-Part application of U.S. Ser. No. 08/051,135, filed Apr. 22, 1993, now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the field of liposome technology and pharmacotherapy. More specifically, the present invention relates to novel liposomes encapsulating pharmacologic compounds and cyclodextrins and to methods for their use.
2. Description of the Related Art
Liposomes are artificial lipid or phospholipid vesicles enclosing aqueous internal chambers into which molecules, e.g., drugs, can be encapsulated with the intention of achieving slow release of the drug after administration of the liposome to an individual. In recent years, several types of liposomes have been described (U.S. Pat. No. 4,552,803 to Lenk; U.S. Pat. No. 4,310,506 to Baldeschwieler; U.S. Pat. No. 4,235,871 to Papahadjopoulos; U.S. Pat. No. 4,224,179 to Schneider; U.S. Pat. No. 4,078,052 to Papahadjopoulos; U.S. Pat. No. 4,394,372 to Taylor; U.S. Pat. No. 4,308,166 to Marchetti; U.S. Pat. No. 4,485,054 to Mezei; and U.S. Pat. No. 4,508,703 to Redziniak; Szoka, et al., 1980, Ann. Rev. Biophys. Bioeng. 9:465-508; Liposomes, Marc J. Ostro, Ed., Marcel-Dekker, Inc., New York, 1983; Poznansky and Juliano, Pharmacol. Rev. 36:277-236, 1984: Kim, et al, Biochim. Biophys. Acta 728:339-348, 1983; Kim et al., Biochim. Biophys. Acta 646:1-10, 1981). Unilamellar liposomes have a single bilayer membrane enclosing an aqueous volume (Huang, 1969, Biochemistry 8:334-352) while multilamellar liposomes have numerous concentric membranes (Bangham et al, 1965, J. Mol. Biol. 13:238-252). Multivesicular liposomes are different from either unilamellar or multilamellar liposomes in that multivesicular liposomes have multiple non-concentric aqueous chambers (Kim et al., 1983, Biochim. Biophys. Acta 728:339-348).
Liposome delivery systems have been proposed for a variety of pharmacologically active compounds including antibiotics, hormones and anti-neoplastic agents (Liposomes, 1983, Marc J. Ostro, Ed., Marcel-Dekker, Inc., New York, 1983). The use of liposomes to encapsulate pharmacologic agents and the efficacy of liposomal delivery systems differs according to the water-and lipid-solubility of the drug. For example, hydrophilic substituted for encapsulation in multivesicular liposomes. In contrast, hydrophobic, water insoluble compounds tend to be incorporated into the lipid bilayer. These compounds, therefore, are not well suited for encapsulation into the aqueous internal chambers of a liposome delivery system. The cyclodextrin class of compounds, especially .beta.-cyclodextrin, has been used successfully to solubilize water-insoluble hydrophobic compounds (Strattan, January 1992, Pharm. Tech. 68-74; Strattan, February 1992, Pharm. Tech. 52-58; Stern, DN&P, 2:410-415, 1989; Pagington, Chem. Brit. 23:455-458, 1987).
Encapsulation of water-soluble pharmacologic compounds such as methotrexate into a variety of drug delivery systems has been previously reported. However, the release rates of methotrexate were found to be rapid and the previous encapsulations did not result in any major changes in pharmacokinetics. Kimelberg et al. reported the half-life of the liposomal methotrexate preparation in the cerebrospinal fluid to be extremely short (less than 1 hour) and not significantly different from the unencapsulated drug.
Many investigators have attempted to target pharmacologic agents, e.g., antineoplastic drugs such as methotrexate to a tumor with the intention of reducing systemic toxicity and increasing tumor kill. One approach is to instill the drug directly into a tumor-containing cavity such as peritoneal cavity or subarachnoid space. However, such intracavitary therapy is not always successful. One of the problems is that the intracavitary clearance is rapid, resulting in a short drug exposure. For a cell-cycle phase specific drug like methotrexate, prolonged exposure is necessary for optimal efficacy.
The pri
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patent: 4935407 (1990-06-01), Luider
patent: 5236907 (1993-08-01), Ueno
Takada BBA 802, 237, 1984.
Osrro Liposomes Marcel Dekker Inc p. 277, 1987.
Manosroi Drug Dev. & Ind. Pharmacy 16(5) p. 37 (1990).
DepoTech Corporation
Kishore Gollamudi S.
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