MXPA00007089A - Utilization of alkyl hydrogen fumerates for treating psoriasis, psoriatic arthritis, neurodermatitis and regional enteritis - Google Patents

Abstract

The invention relates to the utilization of one or more alkyl hydrogen fumerates of general formula (I) in which R is a C1-5 alkyl, optionally mixed with a dialkyl fumerate of formula (II), and optional common pharmaceutical auxiliary agents and carriers for producing a pharmaceutical preparation in the form of microtablets or micropellets. The inventive hydrogen fumerates are used in order to treat psoriasis, psoriatic arthritis, neurodermatitis and regional enteritis.

Description

THE USE OF ACID SMOKES FROM WHOM YOU STOP. TREAT PSORIASIS, SORIATIC ARTHRITIS, NEURODERMATITIS AND REGIONAL ENTERITIS OF CROHN The present invention relates to the use of the free acid form of certain monoalkyl esters of fumaric acid (alkyl acid fumarates) either alone or in combination with a dialkyl fumarate to prepare a pharmaceutical composition in the form of microtablets for treating psoriasis, psoriatic arthritis, neurodermatitis and regional Crohn's enteritis. * Pharmaceutical preparations which, as a result of biological degradation after administration, lead to the cycle of citric acid or belong to this cycle are gaining more and more meaning in generally high doses, because it is possible to alleviate or cure cryptogenic diseases with their help. Thus, fumaric acid inhibits the growth of Ehrlich ascites tumors in mice, reduces the toxic effects of Mitomycin C and Aflatoxin [see K. Kuroda, M. Akao, Bioche. Pharmacol. 29, 2839-2844 (1980) / Gann. 72. 777-782 (1981) / Cancer Res. 36. 1900-1903 (1976)] and has both antipsoriatic and antimicrobial effect [C. N. Huhtsnen, J.

Food Sci. 4_8, 1574 (1983) / M.M. Islam, US-A-4, 346.118 / C.A. 97, 161317b (1982)]. When administered by the palenteral route, dermal route or particularly the oral one, the high doses of fumaric acid derivatives previously known for this purpose, such as fumaric acid dihydroxy, fumaramide and fumaronitrile have an unacceptable rate of side effects and high toxicity [P . Hollan, R.G. White, Brit. J. Dermatol. 85, 259-263 (19 * 71) / M. Hagedorn, K.W. Kalkoff, G. Kiefer, K. Baron, J. Hug, J.

Petres, Arch. Derm. Res 254, 67-73, (1975)] in such a way that a therapy has usually had to be indifferent. EP-A-0 188 749 already describes derivatives (salts) of fumaric acid and pharmaceutical compositions containing them for the treatment of psoriasis. Pharmaceutical compositions for treating psoriasis which include a mixture of fumaric acid and other fumaric acid derivatives are known from DE-A-25 30 372. A fumaric acid content is mandatory. DE-A-26 21 214 discloses drugs for treating psoriasis, which contain fumaric acid onoethyl esters and mineral salts thereof as the active ingredient. In addition, EP-A-0 312 697 describes the use of various monoalkyl acid ester salts Fumárico for the therapy of psoriasis, psoriatic arthritis, neurodermatitis and regional enteritis Crohn. The use of moonoethyl ester salts of fumaric acid (Ca, Zn, Mg) and dimethyl fumaric acid ester for the treatment of psoriasis is known from the publication "Hautarzt" (1987), 279-285. Since, in a psoriatic epidermis, the activity of phospholipase A2 changed, this enzyme may be stimulated by fumaric acid is a possible explanation of the mechanism of the compositions according to the invention. Surprisingly, we have now found that the treatment of psoriasis with alkyl fumarates even without salt formation can be achieved with a pharmaceutical composition which contains the free acid form of one or more fumarates- C? -5 and, optionally, excipients and pharmaceutically acceptable carriers presented in the form of microtablets or microgranules. Optionally, those compositions may also contain one or more dialkyl fumarates. Compositions in the form of microtablets or microgranules allow the administration of the free acid in place of its salt without the side effects occurring. known, especially the formation of ulcers. This is probably due to the fact that the microtablets or microgranules allow a uniform distribution in the stomach, thus avoiding the local irritant concentrations of the monoalkyl acid fumarate in the form of free acid. The compositions containing the free acid of the alkyl acid 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 a systemic initiation of therapy or cessation thereof, respectively, a low dose containing 100 of 120 mg of active ingredient, for example 30.0 mg to 35.0 mg of dimethyl fumarate and 70 to 90 mg of methyl acid fumarate. From 190 to 210 mg of active ingredient, for example in the form of 120.0 mg of dimethyl fumarate and 90.0 mg of monoethyl fumarate, are an example of a therapeutic dose after the initial phase. The compositions according to the invention are administered orally in the form of microtablets or microtablets or encapsulated microgranules, the unique solid dosage dosage forms are dissolved in the stomach within a few minutes and uniformly release the active ingredients of the pharmaceutical form. A lower dose is required for the initiation or cessation of systemic treatment and a higher dose for therapeutic treatment after the initial phase. The microtablets according to the invention are made by methods known in the art, such as granulation, sieving, extrusion / spheronization and the like. In addition to the active ingredient, they may contain the customary excipients and carriers such as lactose, PVP and the like. The microtablets or microgranules preferably have a size of 300-2000 μm, preferably of 500 to 1,500 μm and still preferably more preferably 1000 μm. To facilitate the administration of the single dose, the microtablets or microgranules can be encapsulated, for example in gelatin capsules. Optionally, microtablets or microgranules may be provided with a coating which is resistant to gastric acid. Such a coating can be applied with the known processes, for example by application or spraying in a fluidized bed apparatus or in the form of a film coating.

Example Production of encapsulated microgranules containing 50.0 mg of methyl fumarate acid (corresponding to a total of 44.6 mg of fumaric acid) Taking the necessary precautions (respirator mask, gloves, protective suit), 5,000 kg of acid fumarate are comminuted. methyl by means of a # 400 sieve and homogenized. In addition, 2 1 of a solution of 20% poivinylpyrrolidone (m / v) (Kollidon K30) in ethanol are prepared. 7.250 kg of Nonpareilles granules are introduced in a coating pan and sprayed with part of the Kollidon K-30 solution until slightly moistened. The active ingredient mixture is then added until the granules are dry. This humidification / drying process is continued until all the active ingredient mixture has been added. Finally, the granules move around until finally dried. After that, the granules are filled into a hard gelatin capsule (126.5 mg granule's / capsule). It was found that the preparations according to the invention have an effect similar to that of the preparations containing the known fumaric acid derivatives in salt form against various, clinical forms of psoriasis, psoriasis arthritic, neurodermatitis and regional Crohn's enteritis (Crohn's disease), but are free from the known side effects of the administration of the free acid.

Acute toxicity test Prior to the clinical trial, the acute toxicity of methyl acid fumarate was tested by oral administration in rats. The results show a very low toxicity of the fumaric acids used (see Table 2). Table 1 Acute toxicity in rats (oral administration) Pharmaceutical Equivalence Comparison of the pharmacokinetic data of Fumaderm forte (example 4 of European Patent 0 312 697 Bl) and monomethyl fumarate or monoethyl fumarate, respectively, as calcium salts.

Table 2 Equivalence Fumaderm forte: This mixture contains 120 mg of dimethyl fumarate, 87 mg of monoethyl fumarate's calcium salt, 5 mg of magnesium salt of monoethyl fumarate, 3 mg of zinc salt of monoethyl fumarate. It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (7)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property. 1. The use of one or more alkyl acid fumarates of the general formula
2. H COOH \ / C = C / \ ROOC H characterized in that R is C 5 alkyl, optionally in mixture with dialkyl fumarate of the formula
3. H alkyl of COO-C -C. { \ / C = C \ OOC-C ^ C / H alkyl and optionally customary excipients and pharmaceutical carriers for preparing a pharmaceutical composition in the form of microtablets or microgranules to treat psoriasis, psoriatic arthritis, neurodermatitis and regional Crohn's enteritis. 2. The use according to claim 1, characterized in that methyl acid fumarate is used. 3. The use according to claim 1, characterized in that methyl acid fumarate mixed with dimethyl fumarate is used.
4. 4. The use according to any of claims 1 to 3, for preparing a pharmaceutical composition for oral administration in the form of microtablets or microgranules, characterized in that the total weight of the active ingredients is from 20 to 300 mg. The use according to claims 1 to 4, characterized in that the preparation contains from 10 to 290 parts by weight of methyl fumarate and from 290 to 10 parts by weight of dimethyl fumarate. 6. The use according to any of the preceding claims for preparing a pharmaceutical composition for oral administration, characterized in that the microtablets or microgranules are provided with an enteric coating. The use according to any of the preceding claims, characterized in that the microtablets or microgranules have a size of 300 to 2,000 μm.