Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-01-26
1999-12-21
Krass, Frederick
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514330, 514331, 514885, 514950, 514964, 514970, 424489, 424501, A61K 31445
Patent
active
060049731
DESCRIPTION:
BRIEF SUMMARY
This invention relates to oral pharmaceutical compositions comprising a macrolide, e.g. a rapamycin or an ascomycin, in a solid dispersion.
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 rapamycin 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 (O-aryl and O-alkyl rapamycins); WO 92/05179 (carboxylic acid esters), U.S. Pat. No. 5,118,677 (amide esters), U.S. Pat. No. 5,118,678 (carbamates), U.S. Pat. No. 5,100,883 (fluorinated esters), U.S. Pat. No. 5,151,413 (acetals), U.S. Pat. No. 5,120,842 (silyl ethers), WO 93/11130 (methylene rapamycin and derivatives), WO 94/02136 (methoxy derivatives), WO 94/02385 and WO 95/14023 (alkenyl derivatives) all of which are incorporated herein by reference. 32-O-dihydro or substituted rapamycin are described, e.g., in U.S. Pat. No. 5,256,790, incorporated herein by reference.
Further rapamycin derivatives are described in PCT application number EP96/02441, for example 32-deoxorapamycin as described in Example 1, and 16-pent-2-ynyloxy-32(S)-dihydrorapamycin as described in Examples 2 and 3. The contents of PCT application number EP96/02441 are incorporated herein by reference.
Rapamycin and its structurally similar analogues and derivatives are termed collectively herein as "rapamycins".
On oral administration to humans, solid rapamycins, e.g. rapamycin, may not be absorbed to any significant extent into the bloodstream. 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.
Accordingly, in one aspect, this invention provides a pharmaceutical composition in the form of a solid dispersion comprising a rapamycin and a carrier medium.
The compositions of this invention provide a high bioavailability of drug substance, are convenient to administer, and are stable.
The rapamycin used in the compositions of this invention may be any rapamycin or derivative thereof, for example as disclosed above or in the above-mentioned patent applications.
Thus the rapamycin used in the solid dispersion compositions of this invention may be rapamycin or an O-substituted derivative in which the hydroxyl group on the cyclohexyl ring of rapamycin is replaced by --OR.sub.1 in which R.sub.1 is hydroxyalkyl, hydroxyalkoxyalkyl, acylaminoalkyl and aminoalkyl; e.g. as described in WO94/09010, for example 40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin and 40-O-(2-acetaminoethyl)-rapamycin. The rapamycin derivative may be a 26- or 28-substituted derivative.
Preferred rapamycins for use in the solid dispersion compositions of this invention include rapamycin, 40-O-(2-hydroxy)ethyl rapamycin, 32-deoxorapamycin and 16-pent-2-ynyloxy-32(S)-dihydrorapamycin. A more preferred rapamycin is 40-O-(2-hydroxy)ethyl rapamycin (hereinafter referred to as compound X).
Numbering of rapamycin derivatives as used herein refers to the structure disclosed as Formula A at page 4 of published PCT application WO 96/13273, the contents of which are incorporated herein by reference.
The term solid dispersion as used herein is understood to mean a co-pr
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patent: 5387589 (1995-02-01), Kulkarni
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Guitard Patrice
Haeberlin Barbara
Link Rainer
Richter Friedrich
Hoxie Thomas
Krass Frederick
Novartis AG
Wissing William K.
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