Liposomal camptothecins and uses thereof

Abstract

This invention relates to improved liposomal camptothecin compositions and methods of manufacturing and using such compositions for treating neoplasia and for inhibiting angiogenesis.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application claims priority to U.S. Provisional Patent Application Nos. 60 / 215,556, filed Jun. 30, 2000, and 60 / 264,616, filed Jan. 26, 2001, both of which are hereby incorporated by reference in their entireties for all purposes. U.S. patent application Ser. No. ______, bearing Attorney Document No. 016303-008030, filed Jun. 29, 2001, entitled “Liposomal Antineoplastic Drugs and Uses Thereof,” is hereby incorporated by reference for all purposes.BACKGROUND OF THE INVENTION [0002] This invention relates to improved liposomal camptothecin compositions and methods of manufacturing and using such compositions for treating neoplasia and for inhibiting angiogenesis. [0003] Therapeutic camptothecins, such as Topotecan (9-dimethylaminomethyl-10-hydroxy-camptothecin; Hycamtin™), and Irinotecan, are a semi-synthetic, water soluble derivative of camptothecin, an alkaloid extracted from the stem wood of the Chinese tree Camptotheca acu...

AI Technical Summary

Benefits of technology

"The present invention provides improved liposomal camptothecin compositions with increased clinical efficacy and decreased collateral toxicity. These compositions have a drug:lipid ratio of about 0.005 to about 0.1. The invention also provides methods of using these compositions to treat neoplasia and inhibit angiogenesis. The liposomal camptothecin compositions retain greater than 50% of the camptothecin as the active lactone species after 12 hours in blood circulation. The invention also provides a lipid formulation of a camptothecin with sphingomyelin, cholesterol, and a divalent ionophore. The invention further provides a method of treating a solid tumor in a human with the liposomal camptothecin compositions. The camptothecin dosage in the liposomal unit dosage form ranges from 0.015 mg / M2 / dose to about 0.5 mg / M2 / dose. The liposomal unit dosage form comprises a mixture of sphingomyelin and cholesterol, preferably at a ratio of about (30:70 to about (60:40."

Problems solved by technology

All these treatments are associated with dose-limiting toxicity such as non-cumulative myelosuppression leading to anaemia, neutropenia and thrombocytopenia, and gastrointestinal-related toxicity, including mucositis and diarrhea.

However, not all lipid formulations are equal for drug delivery purposes and extensive research continues into formulations which demonstrate preferred characteristics for drug loading and storage, drug administration, pharmacokinetics, biodistribution, leakage rates, tumor accumulation, toxicity profile, and the like.

With camptothecins, the field is further complicated because dose limiting toxicities in humans may be 10-fold lower than in mice (Erickson-Miller, et al., Cancer Chemother. Pharmacol. 39:467-472 (1997)).

However, to date, lipid formulations have not provided sufficiently remarkable activity to warrant clinical advancement.

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