Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-05-28
2000-02-15
Krass, Frederick
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514 8, 514 11, 514570, 514576, 514960, 514962, 424457, 424458, 424459, 424461, 424462, 424463, 424468, 424474, 424475, 424479, 424480, 424482, 424490, 424493, 424494, 424495, 424497, A01N 4308, A61G 3134
Patent
active
060253916
DESCRIPTION:
BRIEF SUMMARY
This invention relates to mycophenolic acid.
Mycophenolic acid, also referred to herein as MPA, was first isolated in 1896, and has been extensively investigated as a pharmaceutical of potential commercial interest. It is known to have anti-tumor, anti-viral, immunosuppressive, anti-psoriatic, and anti-inflammatory activity [see e.g. W. A. Lee et al, Pharmaceutical Research (1990), 7, p. 161-166 and references cited therein]. Publications have appeared on MPA as an anti-cancer agent by Lilly scientists, see e.g. M. J. Sweeney et al., Cancer Research (1972), 32, 1795-1802, and by ICI scientists, see e.g. GB 1,157,099 and 1,203,328 and as an immunosuppressant agent see e.g. A. Mitsui et al. J. Antibiotics (1969) 22, p. 358-363. In the above-mentioned article by W. A. Lee et al it is stated that attempts have been made to increase the bio-availability or specificity of MPA by making derivatives. The poor bioavailability of the acid was thought to be caused by undetermined factors such as drug complexation in the gastro-intestinal lumen, a narrow absorption window, metabolism before absorption etc. The preparation of the morpholinoethyl ester, also known as mycophenolate mofetil (sometimes referred to herein as MMF), was described which had considerably higher bioavailability than MPA (100% for MMF and 43% for MPA). This derivative has been recently introduced commercially as an immunosuppressant for the treatment or prevention of organ or tissue transplant rejection, at daily dosages of from about 200 mg to about 3 grams p.o., e.g. about 2 g p.o. Patient compliance with MMF is not ideal, inter alia, because of side-effects e.g. gastro-intestinal side effects, the origin of which is not known.
We have now found, after exhaustive testing, that mycophenolate salts when enteric coated or adapted to be released in the upper part of the intestines, e.g. in the duodenum, jejeunum and/or ileum, are effective, well-tolerated, pharmaceuticals particularly for immunosuppressive indications especially for the treatment or prevention of organ, tissue or cellular allograft or xenograft rejection, e.g. after transplant, or the treatment or prevention of immune-mediated diseases (autoimmune diseases) and have interesting bioavailability and stability characteristics. Moreover fewer unit dosage forms are required to be administered than for MMF, leading to easier administration.
The present invention provides in one aspect a pharmaceutical composition comprising a myophenolate salt, the composition being adapted to release mycophenolate in the upper part of the intestinal tract (hereinafter referred to as a composition of the invention). The composition may be adapted in any conventional manner, preferably with means adapted to prevent release of the myocophenolate in the stomach and to ensure release in the upper part of the intestinal tract. In a further aspect the invention provides a pharmaceutical composition comprising a coated pharmaceutically acceptable mycophenolate salt.
Such salts are cationic salts, e.g. of alkali metals, especially the sodium salts. Sodium mycophenolate salts are known, e.g. in South African Patent 68/4959. We prefer to use the mono-sodium salt. This may be obtained in crystalline form by recrystallization from acetone/ethanol if necessary with water; Mpt. 189-191.degree. C.
The invention provides, more specifically, a solid enteric-coated composition in unit dose form for oral application, the core of the composition containing sodium mycophenolate in solid or liquid form.
The term "core" comprises sodium mycophenolate (or other cationic salt) if desired in admixture with further physiologically acceptable material, that can be surrounded by an enteric-coating. The term "core" comprises, in a wide sense, not only tablets, pellets or granules but also capsules, e.g. soft or hard capsules of gelatine or starch. Such cores may be produced in conventional manner. We have found that the mycophenolate salts, particularly the sodium salt, are particularly interesting for the production of tablets. When
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Haeberlin Barbara
Mak Ching-Pong
Meinzer Armin
Vonderscher Jacky
Kalinchak Stephen G.
Krass Frederick
Novartis AG
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