Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-09-27
2001-08-21
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
Reexamination Certificate
active
06277882
ABSTRACT:
The present invention relates to the use of the free acid form of certain fumaric acid monoalkyl esters (alkyl hydrogen fumarates) either alone or in combination with a dialkyl fumarate for preparing a pharmaceutical composition in the form of micro-tablets for treating psoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalis Crohn.
Pharmaceutical preparations which, as a result of biological degradation after administration, lead into the citric acid cycle or belong do that cycle are increasingly gaining significance in generally high dosages, since it is possible to relieve or cure cryptogenetic diseases with their aid.
Thus, fumaric acid inhibits the growth of the Ehrlich ascites tumour in mice, reduces the toxic effects of Mitomycin C and Aflatoxin [cf. K. Kuroda, M. Akao, Biochem. Pharmacol. 29, 2839-2844 (1980)/Gann. 72, 777-782 (1981)/Cancer Res. 36, 1900-1903 (1976)] and has a both anti-psoriatic and antimicrobial effect [C. N. Huhtsnen, J. Food Sci. 48, 1574 (1983)/M.N. Islam, U.S. Pat. No. 4,346,118/C.A. 97, 161317b (1982)].
When administered by the parenteral, dermal and particularly the oral route, high dosages of the fumaric acid derivatives previously known for this purpose such as dihydroxy fumaric acid, fumaramide and fumaronitrile have such an unacceptable rate of side effects and high toxicity [P. Holland, R. G. White, Brit. J. Dermatol. 85, 259-263 (1971)/M. Hagedorn, K. W. Kalkoff, G. Kiefer, D. Baron, J. Hug, J. Petres, Arch. Derm. Res. 254, 67-73, (1975)] that such a therapy usually had to be disregarded.
EP-A-0 188 749 already describes fumaric acid derivatives (salts) and pharmaceutical compositions containing the same for the treatment of psoriasis.
Pharmaceutical compositions for treating psoriasis which contain a mixture of fumaric acid and other fumaric acid derivatives are known from DE-A-25 30 372. A content of fumaric acid is obligatory.
DE-A-26 21 214 describes drugs for treating psoriasis which contain fumaric acid monoethyl ester and mineral salts thereof as the active ingredient. Moreover, EP-A-0 312 697 describes the use of various fumaric acid monoalkyl ester salts for the therapy of psoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalis Crohn.
The use of fumaric acid monoethyl ester salts (Ca, Zn, Mg) and fumaric acid dimethyl ester for the treatment of psoriasis is known from the publication “Hautarzt”(1987), 279-285.
Since, in a psoriatic epidermis, the activity of phosphoslipase A
2
is changed, the fact that this enzyme is stimulated by fumaric acid is one possible explanation of the mechanism of the compositions according to the invention.
Surprisingly, we have now found that the treatment of psoriasis with alkyl hydrogen fumarates even without salt formation can be achieved with a pharmaceutical composition which contains the free acid form of one or several C-
1-5
-alkyl hydrogen fumarates and, optionally, pharmaceutically acceptable excipients and carriers and is presented in the form of micro-tablets or micro-pellets. Optionally, these compositions may also contain one or several dialkyl fumarates.
The compositions in the form of micro-tablets or micro-pellets permit the administration of the free acid instead of its salt without the occurrence of the known side effects, especially the formation of ulcers. This is probably due to the fact that micro-tablets or micro-pellets permit a uniform distribution in the stomach, thus avoiding irritating local concentrations of the monoalkyl hydrogen fumarate in the form of the free acid.
Compositions containing the free acid of the alkyl hydrogen fumarate in an amount of 20 to 300 mg are particularly suitable for oral administration, the total weight of the active ingredients being 100 to 300 mg.
For the systemic start of a therapy or the cessation thereof, respectively, a low dosage containing 100 of 120 mg of active ingredient, e.g. 30.0 mg to 35.0 mg of dimethyl fumarate and 70 to 90 mg of methyl hydrogen fumarate, is advantageous.
190 to 210 mg of active ingredient, e.g. in the form of 120.0 mg of dimethyl fumarate and 90.0 mg of monoethyl fumarate, are an example of a therapeutic dosage after the initial phase.
The compositions according to the invention are administered orally in the form of micro-tablets or encapsulated micro-tablets or micro-pellets, the solid single dosage drug forms dissolving in the stomach within a few minutes and uniformly releasing the active ingredients from the drug form. A lower dosage is required for the start or cessation of systemic treatment and a higher dosage for therapeutic treatment after the initial phase.
The micro-tablets according to the invention are made by methods known in the prior art, such as granulation, screening, extrusion/spheronisation and such like. In addition to the active ingredient, they may contain customary excipients and carriers such as lactose, PVP and such like. The micro-tablets or micro-pellets preferably have a size of 300-2,000 &mgr;m, preferably 500 to 1,500 &mgr;m and even more preferably 1,000 &mgr;m.
To facilitate administration of the single dosage, the micro-tablets or micro-pellets may be encapsulated, for example in gelatinous capsules. Optionally, the micro-tablets or micro-pellets may be provided with a coating which is resistant to gastric acid. Such a coating may be applied with known processes, e.g. by application or spraying in a fluidised bed apparatus or in the form of a film coating.
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Sebök, Bela et al., “Antiproliferative and Cytotoxic profiles of Antipsoriatic Fumaric Acid Derivatives in Keratinocyte Cultures”, European Journal of Pharm., Environ. Toxicol. Pharmacol. Sect., 1994, vol. 270, pp. 79-87.
Nibbering, P.H. et al., “Intracellular Signalling by Binding Sites for the Antipsoratic Agent Monomethylfumarate on Human Granulocytes”, British J. Dermatol., 1997, vol. 137, pp. 65-75.
Altmeyer, P. et al., “Systemische Therapie der Psoriasis”, T & E Dermatologie Jg., 1997, vol. 27, pp. 380-382, & 384.
Nibbering, Peter H., “Effects of Monomethylfumarate on Human Granulocytes”, Journal of Investigative Dermatology, 1993, pp. 37-42.
Joshi Rajendra K.
Strebel Hans-Peter
Fumapharm AG
Jarvis William R. A.
Kim Vickie
Siebarth & Patty, L.L.C.
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