Pharmaceutical compositions

Abstract

A pharmaceutical composition in the form of a solid dispersion comprising a macrolide, e.g. a rapamycin or an ascomycin, and a carrier medium.

Description

BACKGROUND AND SUMMARY [0001] This invention relates to oral pharmaceutical compositions comprising a macrolide, e.g. a rapamycin or an ascomycin, in a solid dispersion. [0002] Rapamycin is an immunosuppressive lactam macrolide produceable, for example by Streptomyces hygroscopicus. The structure of rapamycin is given in Kesseler, H., et al.; 1993; Helv. Chim. Acta; 76: 117. Rapamycin is an extremely potent immunosuppressant and has also been shown to have antitumor and antifungal activity. Its utility as a pharmaceutical, however, is restricted by its very low and variable bioavailability. Moreover, rapamycin is highly insoluble in aqueous media, e.g. water, making it difficult to formulate stable galenic compositions. Numerous derivatives of rapamycin are known. Certain 16-O-substituted rapamycins are disclosed in WO 94 / 02136, the contents of which are incorporated herein by reference. 40-O-substituted rapamycins are described in, e.g., in U.S. Pat. No. 5,258,389 and WO 94 / 09010 (...

AI Technical Summary

Benefits of technology

[0057] The rapamycin used in the compositions of this invention, e.g. 40-0-(2-hydroxy)ethyl rapamycin or rapamycin, may be in crystalline or amorphous form prior to formation of the solid dispersion. An advantage, therefore, of this invention is that the rapamycin need not be crystalline. Thus the rapamycin may be used directly in combination, for example with a solvent, and does not have to be isolated in advance. Another advantage of the invention is that dissolution rates of the solid dispersion are higher than dissolution rates found for a crystalline rapamycin or an amorphous rapamycin in a simple mixture.

[0058] In another aspect, this invention provides a pharmaceutical composition in the form of a solid dispersion comprising an ascomycin and a carrier medium.

[0059] Examples of suitable ascomycins for use in the solid dispersion compositions of this invention include ascomycin or a derivative thereof, e.g. 33epi-chloro-33-desoxy-ascomycin.

[0060] To date there is no conveniently administrable oral solid formulation available for 33-epi-chloro-33-desoxy-ascomycin. In another aspect, therefore, this invention provides a pharmaceutical composition in the form of a solid dispersion comprising 33-epi-chloro-33-desoxy-ascomycin and a carrier medium.

[0061] The compound 33-epi-chloro-33-desoxy-ascomycin is described in published European application EP 427 680 under Example 66a.

[0062] 33-epi-chloro-33-desoxy-ascomycin will be referred to hereinafter as Compound Y.

Problems solved by technology

Its utility as a pharmaceutical, however, is restricted by its very low and variable bioavailability.

Moreover, rapamycin is highly insoluble in aqueous media, e.g. water, making it difficult to formulate stable galenic compositions.

Simple mixtures are known for rapamycins, e.g. rapamycin, with conventional pharmaceutical excipients; however, disadvantages encountered with these compositions include unpredictable dissolution rates, irregular bioavailability profiles, and instability.

To date there is no conveniently administrable oral solid formulation available for rapamycin or a derivative thereof.

MDR is particularly problematic in cancer patients and AIDS patients who will not respond to conventional chemotherapy because the medication is pumped out of the cells by Pgp.

To date there is no conveniently administrable oral solid formulation available for 33-epi-chloro-33-desoxy-ascomycin.

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