IL88011A - Pharmaceutical preparation for the treatment of psoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalis crohn comprising salts of monoalkyl esters of fumaric acid - Google Patents

Description

88011 /3 ,η>ΌΝ>ΊΊΌ) 0>ρΊ£) Tip1?! , Πη«3Ό-1 Ί3 > ? ΠΊΠ ΐ Ί>ΐηη ΓΡ"ΊΝ»1£) η^ΏΊΓΐ D > >?p^N 1 J Ί Q D ' ΊΌΌΝ !?y PHARMACEUTICAL PREPARATION FOR THE TREATMENT OF PSORIASIS, PSORIATIC ARTHRITIS, NEURODERMATITIS AND ENTERITIS REGIONALIS CROHN COMPRISING SALTS OF MONOALKYL ESTERS OF FUMARIC ACID PHARMACEUTICAL PREPARATION FOR THE TREATMENT OF PSORIASIS, PSORIATIC ARTHRITIS, NEURODERMATITIS AND ENTERITIS REGIONALIS CROHN COMPRISING SALTS OF MONOALKYL ESTERS OF FUMARIC ACID Field of the Invention The present invention relates to pharmaceutical preparations for the treatment of psoriasis, psoriatic arthritis, neurodermatitis and. Enteritis regional is Crohn (Morbus Crohn)- BACKGROUND ART Pharmaceutical preparations which after administration enter, upon their biological degradation, into the citric acid cycle or belong to it are acquiring greater and greater therapeutic value, generally in high doses, since it is possible to mitigate or cure cryptogenically induced diseases with them.

Thus, fu aric acid impedes the growth of the Ehrlich ascites tumor in mice, reduces the toxic effects of mitomycin C and aflatoxin (K. Kuroda, M. AJao, Biochem, Pharmacol. 2_£, 2839-2844 (1980)/Gann. 72, 77-782 ( 1981) /Cancer Res. 3 6 . 1900-1903 (1976)) and has an anti-psoriatic as well as antimicrobial action (C.N. Huhtsnen, J. Food Sci. 48, 1574 (1983)/M.N. Islam, U.S. Patent 4,346,118 issued August 24, 1982/C.A. 97, 161317b (1982) ) .

High doses of fumaric acid or its presently known derivatives such as dihydroxy fumaric acid, fumaramide and fumaronitrile have such an unacceptable rate of adverse effects and high toxicity upon parenteral, dermal and, in particular, peroral adminstration (P. Holland, R.G. White, Brit. J. Dermatol. 85/ 259-263 (1971J/M. Hadedorn, K.W. Kalkoff, G. Kiefer, D.

Baron, J. Hug, J. Petres, Arch. Derm. Res. 254, 67-73 (1975)), that up to now it has been necessary in most cases to refrain from such therapy.

In European Patent Application No. 188749, which corresponds to Israel Application No. 77537, fumaric acid derivatives and pharmaceutical preparations containing them have already been described for the treatment of psoriasis.

R in the general formula of these derivatives is a Cr to C~. ÷ 6 24 hydrocarbon group which is different from the Cn_5 alkyl group according to the invention.

In German Patent Application No. 2840498 published on August 2, 1979, a fumarate-based composition containing ascorbic acid, cysteine and methionine has been described for internal use in the treatment of psoriasis.

German Patent Application No. 2530372 ( Schweckendiek ) discloses pharmaceutical preparations for the treatment of psoriasis, which preparations must contain as an essential component pure fumaric acid (see examples 1 to 7 , claim 1 ) . This is contrary to the preparations according to the present application, which do not contain fumaric acid per se .

German Patent Application No. 2621214 (Koronis) discloses pharmaceutical preparations containing fumaric acid monoethylester and the mineral salts thereof for the treatment of psoriasis.

The- article "Perorale Langzeitbehandlung der Psoriasis mit Fumarsaurederivaten" by Walter Bayard, et al, published in Der Hautarzt (1987] 38:279-285, relates to the treatment of psoriasis using fumaric acid monoethylester (Ca, Zn, Mg) salt in combination with dimethyl fumaric acid ester.

These preparations are specifically excluded from the present application. 88011/2 SUMMARY F THE INVENTION The present invention relates to pharmaceutical compositions for the treatment of psoriasis, psoriatic arthritis, neurodermatitis and Enteritis regionalis Crohn comprising one or more compounds selected from the group of calcium, magnesium, zinc and iron salts of fumaric acid monoalkylesters of the general formula optionally admixed with a dialkylfumarate of the formula OO-Ci-Cs-Alkyl and ordinary pharmaceutically acceptable adjuvants and vehicles, with the proviso that the pharmaceutical composition for treating psoriasis does not contain fumaric acid per se or mineral salts of fumaric acid monoethylester.

PRESENTLY PREFERRED EMBODIMENTS Preferred combination preparations in accordance with the invention contain the calcium salt of fumaric acid monoethylester , the calcium salt of fumaric acid monoethylester combined with dimethylfumarate, the calcium and zinc salts of fumaric acid monoethylester combined with dimethylfumarate, or the calcium, magnesium and zinc salts of fumaric acid monoethylester in combination with dimethylfumarate.

For oral adminstration, combination preparations which contain the calcium salt of fumaric acid monoalkylester in an amount of 100 to 300 mg are particularly suitable, the total weight of the active substances being 100 to 300 mg.

Other preferred oral forms of adminstration contain 10 to 290 parts by weight of the calcium salt of fumaric acid monoalkylester and 290 to 10 parts by weight of dimethylfumarate or 10 to 250 parts by weight of the calcium salt of fumaric acid monoalkylester, together with 1 to 50 parts by weight of dimethylfumarate and 1 to 50 parts by weight of the zinc salt of fumaric acid monoalkylester or 10 to 250 parts by weight of the calcium salt of fumaric acid monoalkylester, together with 250 to 10 parts by weight of dimethylfumarate, 1 to 50 parts by weight of the magnesium salt of fumaric acid monoalkylester and 1 to 50. parts by weight of the zinc salt of fumaric acid monoalkylester, the total weight of the active substances being 100 to 300 mg in each case.

For systemic initiation of the treatment or conclusion thereof a low dose is advantageous, containing, for instance, 30.0 mg dimethylfumarate, 67.0 mg of the calcium salt of monoethylfumarate, 5.0 mg of the magnesium salt of monoethylfumarate and 3.0 mg of the zinc salt of monoethylfumarate. , For the therapeutic dose after the initiating phase there can be used, for instance, a dose of 120.0 mg dimethylfumarate, 87.0 mg of the calcium salt of monoethylfumarate, 5.0 mg of the magnesium salt of monoethylfumarate and 3.0 mg of the zinc salt of monoethylfumarate .

The fumaric acid derivatives contained in the preparations of the invention are obtained, for instance, in the manner that a compound of the formula 0 II CI - C - CH 0 II II H - C - C - CI a) is condensed with 2 mols of alkyl alcohol (ROH) to form the diester and then hydrolyzed in controlled fashion to form the monoester, or b) condensed with 1 mol of a corresponding alkyl alcohol (ROH) whereupon the monoacid chloride obtained is hydrolyzed to the acid, or c) fumaric acid is condensed directly with 2 mols of alkyl alcohol (ROH) ; to form .a diester and then hydrolyzed under controlled conditions to the monoester, or d) maleic acid or maleic anhydride is condensed directly with 1 to 2 mols of the corresponding alkyl alcohol (ROH) to form a mono- or diester and then catalytically ■ isomerized to form the corresponding fumaric acid derivative.

The salts of the fumaric acid monoalkylesters can be obtained by reacting a compound of the general formula in which R is a Ci~C5 alkyl group, with one-half mol of Ca, Mg or Zn hydroxide or oxide in toluene and azeotropically removing the water which has formed during the reaction.

Example 1 Preparation of enteric-coated film tablets containing 210 ma of monoethylfumarate Ca salt corresponding to 150 mg of fumaric acid; 21.000 kg of monoethylfumarate calcium salt are crushed, mixed and homogenized by means of an 800 screen applying suitable precautionary measures (breathing mask, gloves, protective clothing, etc.). A mixture of adjuvants having the following composition is then prepared: 20.000 kg of starch derivative (STA-RX 150 000 kg of microcrystalline cellulose (Avicel PH Ιθϋ , 0.600 kg of polyvinyl pyrrolidone (PVP, Kollidoi® 25) , 4.000 kg Primoge.®, 0.300 kg of colloidal silicic acid (Aeros i l ^ ) . The total powder mixture is treated with the active substance, homogenized by means of a 200 screen and worked with a 2% aqueous solution of polyvinyl pyrrolidone (Kollidoi® K 30) in customary manner to form a binder granulate and then mixed in dry state with the outer phase. The latter consists of 2.000 kg of a so-called FST complex, containing 80% " talc, 10% silicic acid and 10% magnesium stearate. It is then pressed in customary manner to form barreled tablets of a weight of 500 mg and a diameter of 11.5 mm. Instead of these conventional methods of tabletting, other methods for the production of tablets can also be used, such as direct tabletting drying method.

Enteric Coating; A solution of 2.250 kg of hydroxy propylmethyl cellulose phthalate (HPMCP, Pharmacoat HP 50¾ is dissolved in a solvent mixture of 2.50 liters of demineralized water, 13.00 liters of acetone Ph. Helv. VII and 13.00 liters of ethanol 94 wt % and the solution is treated with 2.40 kg of castor oil (European Pharmacopoeia II) . The solution is gelled in a coating kettle in conventional manner individually ..*·.: on the tablet cores or sprayed thereon or applied in a fluidized bed-like apparatus .

After suitable drying, the film coating is then applied. It consists of a solution of Eudragi1®E 12.5%, 4.800 kg, colored lacquer ZLT 2 blue (Siegle) 0.210 kg, titanium (VI)- oxide Kronos RN 56, 0.520 kg, talc (European Pharmacopoeia) 0.340 kg and polyethylene glycol 6000 Ph. Helv. VII 0.120 kg, in a solvent mixture of 8.200 kg 2-propanol, Ph. Helv. VII, 0.060 kg glycerine triacetate and 0.200 kg demineralized water.

After homogeneous distribution in the coating kettle or fluidized bed, drying is effected, followed by polishing in the customary manner.

Example 2 Production of enteric-coated capsules containing 86.5 g of monoethylfumarate Ca salt and 110.0 g of dimethylfumarate corresponding to a total of 150 mg of furoaric acid: 8.650 kg of monoethylfumarate Ca salt and 11.000 kg of dimethylfumarate are mixed intensively with a mixture consisting of 15.000 kg starch, 6.000 kg lactose Ph. Helv. VII, 2.000 kg microcrystalline cellulose (Avicei¾ , 1.000 kg polyvinyl pyrrolidone (Kollidor® 25) and 4.000 kg Primoge homogenized by- means of an 800 screen, applying suitable precautionary The entire powder mixture is worked with a 2% aqueous solution of polyvinylpyrrolidone (Kollidoi® 25) in customary manner to form a binder granulate and mixed in dry state with the outer phase. The latter consists of 0.350 kg of colloidal silicic acid (Aeros 0.500 kg of Mg stearate and 1.500 kg of talc Ph.

Helv. VII. The homogeneous mixture is then filled into suitable capsules in portions of 500.0 mg which are finally provided in customary manner with an enteric coating consisting of hydroxypropyl methylcellulose stearate and castor oil as softener. Instead of effecting the filling into hard gelatine capsules it can be effected into corresponding enteric-coated capsules consisting of a mixture of cellulose acetate phthalate (CAP) and hydroxypropyl methyl cellulose phthalate (HP CP).

Example 3 Production of enteric-coated capsules containing 203.0 mq of monoethylfumarate Ca salt as well as 5.0 mg of monoethylfumarate Mg salt and 3.0 mg of monoethylfumarate Zn salt corresponding to a total of 150 mg of fumaric acid; .300 kg of monoethylfumarate Ca salt as well as 0.500 kg of monoethylfumarate Mg salt and 0.300 kg of monoethylfumarate Zn salt are crushed, mixed intensively and homogenized by means of an 800 screen taking suitable precautionary measures (breathing mask, gloves, protective clothing, etc.) To this mixture of active substances, there is added a homogeneous powder mixture of the following composition: spray-dried lactose 12.900 kg, colloidal silicic acid 1.000 kg, microcrystalline cellulose (Avicei¾ 2.000 kg, magnesium stearate (Ph. Helv. VII) 1.000 kg and talc (PH. Helv. VII) 2.000 kg. The entire powder mixture is homogenized again by means of a 200 screen and then filled into two-piece hard gelatine capsules of a net weight of 400 mg enclosed. The coating with an enteric coating is effected in the same way as in Example 2.

Example 4 Production of enteric-coated tablets containing 87.0 ma monoethylfu arate Ca salt. 120.0 ma dimethylfumarate. 5.0 ma monoethylfumarate Ma salt and 3.0 mg onoethy fumarate Zn salt corresponding to 164 ma fumaric acid ("Forte" tablets) : 12.000 kg fumaric acid dimethylester, 8.700 'kg monoethylfumarate Ca salt, 0.500 kg monoethylfumarate Mg salt and 0.300 kg monoethyl fumarate Zn salt are crushed, mixed intensively and homogenized by means of an 800 screen, observing suitable precautionary measures (breathing mask, gloves, protective clothing, etc.). An adjuvant mixture of the following composition is prepared in a manner similar to that described under Example 1, namely starch derivative (STA-RX 1500^ 18.000 kg, microcrystalline cellulose (Avicel H 1θί¾ 0.300 kg, polyvinyl pyrrolidone (PVP, Kollidoi 120) 0.750 kg, Primoge^S) 4.000 kg, and colloidal silicic acid (Aerosii¾ 0.250 kg.

Adjuvants and the combination of active substances are vigorously mixed and homogenized by means of a 200 screen. The entire mixture is worked together with a 2% aqueous solution of polyvinyl pyrrolidone (Kollidoi® K25) in the customary manner to form a binder granulate and mixed in dried state with the outer phase. The latter consists of 0.500 kg Mg stearate (Ph. Eur.) and 1.500 kg talc (Ph. Eur. II). The entire granulate' is then compacted in customary manner to form barreled tablets of 500 mg gross weight and 11.5 mm in diameter. Instead of this conventional tabletting method other methods for the production of tablets can also be used, such as direct tabletting and solid dispersions by the melting and spray-drying method.

The enteric coating can be applied in a conventional coating kettle or sprayed on or be applied in a fluidized bed apparatus. For resistance to the gastric juice a solution of 2.250 kg hydroxypropyl methyl cellulose phthalate (HPMCP, Pharmacoat HP 50 is dissolved in portions in a mixture of the following solvents: acetone 13.00 liters, ethanol 94 weight % denatured with 2% ketone 13.50 liters, and demineralized water 2.50 liters. Castor oil Ph Eur. 0.240 kg is added as softener to the final solution and the solution is applied in customar manner in separate portions to the barreled tablet cores.

Film coating: After the drying a suspension of the following composition is then applied as film coating in the same apparatus: talc Ph Eur II 0.340 kg, titanium (VI) oxide Cronus Rn 56® 0.400 kg, colored lacquer L-red lacquer 85237 N 0.324 kg, Eudragit E. 12.5®4.800 kg and polyethylene glycol 6000 pH 11 XI 0.120 kg in a solvent mixture of the following composition: 2- propanol DAB 8.170 kg, demineralized water 0.200 kg and glycerine triacetate (Triacetin¾ 0.060 kg.

Example 5 Preparation of enteric-coated film tablets containing 67.0 ma monoethylfumarate Ca salt, 30.0 q dimethylfu arate , 5.0 mg monoethylfu arate Mq salt and 3.0 q monoethylfu arate Zn salt corresponding to 75 mq fumaric acid ("Mite" tablets) : 3.000 kg fumaric acid di ethylester , 6.700 kg monoethylfumarate Ca salt, 0.500 kg monoethylfumarate Mg salt as well as 0.300 kg monoethylfumarate Zn salt are crushed, mixed intensively and homogenized by means of an 800 screen. In this connection suitable protective measures should be taken such as breathing mask, gloves, protective clothing, etc. It is then added to a mixture consisting of 30.000 kg starch derivative (STA-RX 150<®, 3.000 kg macrocrystalline cellulose (Avicel pH loi¾ , 0.750 kg polyvinyl pyrrolidone (PVP Kollidoi® 25) , 4.000 kg Primogei¾ 0.250 kg colloidal silica (Aerosii¾ . The mixture of active substances is mixed until homogeneous, passed through a 200 screen and worked up with a 2% aqueous solution of polyvinyl pyrrolidone (K 25) in customary manner to form a binder granulate. A powder mixture consisting of the following . . . . . - The homogeneous granulate mixture is compacted in customary manner to form barreled tablet cores' of a weight of 500.00 g and a diameter of 11.5 mm. In addition to the binder, methods other tabletting methods can also be used, in accordance with Examples 1 and 4.

The coating of the tablet cores with an enteric coating and with a film coating is effected in a manner similar to that described under Examples 1 and .

Example 6 Preparation of enteric-coated film tablets containing 100 mg of monomethylfumarate Ca salt corresponding to 78 mg of fumaric ac d .000 kg of monomethylfumarate calcium salt are. crushed, mixed and homogenized by means of an 800 screen applying suitable precautionary measures (breathing mask, gloves, protective clothing, etc.) . A mixture of adjuvants having the following composition is then prepared: 21.000 kg of starch derivative (STA-RX 1500), 2.000 kg of microcrystalline cellulose (Avicel PH 101), 0.600 kg of polyvinyl pyrrolidone (PVP Kollidon 25), 4.000 kg Primogel, 0.300 kg of colloidal silicic acid (Aerosil) . The total powder mixture is treated with the active substance, homogenized by means of a 200 , screen and worked with a 2 % aqueous solution of polyvinyl pyrrolidone (Kollidon K 30) in customary manner to form a binder granulate and then mixed in dry state with the outer · phase. The latter consists of 2.000 kg of a so-called FST complex, containing 80 % talcum, 10 % colloidal silicic acid and 10 % magnesium stearate. It is then pressed in customary manner to form barreled' tablets of a weight of 400 mg and a diameter of 10 mm. Instead of these conventional methods of tabletting, other methods for the production of tablets can also be used, such as direct tabletting as well as solid dispersions by the melt method and the spray-drying method.

The coating of the tablet cores with an enteric coating and ' with a film coating is effected in a manner similar- to that described under Examples 1 and 4. - 11a - Example 7 Production of enteric-coated tablets containing 50 mg monomethylfumarate Ca salt, 50 mg dimethylfumarate, ' 5 mg monomethylfumarate Mg salt and 3 mg monomethylfumarate Zn salt corresponding to 85 mg fumaric acid .000. kg fumaric acid dimethylester, 5.000 kg monomethylfumarate Ca salt, 0.500 kg monomethylfumarate Mg salt and 0.300 kg monomethylfumarate Zn salt are crushed, mixed intensively and homogenized by means of an 800 screen, observing suitable precautionary measures (breathing mask, gloves, protective clothing,' etc.). An adjuvant mixture of the following composition is prepared in a manner similar to that described under Example 4, namely starch derivative (STA-RX 1500) 19.000 kg, microcrystalline cellulose (Avicel pH 101) 3.000 kg, polyvinyl' pyrrolidone (PVP, Kollidon 120) 0.750 kg, Primogel 4.000 kg, and colloidal silicic acid (Aerosil) 0.250 kg.

Adjuvants and the combination of active substances are vigorously mixed and homogenized by means of a 200 screen. The entire mixture is worked together with a 2 % aqueous solution of polyvinyl pyrrolidone (Kollidon K 25) in the customary manner to form a binder granulate and mixed in dried state with the outer phase. The latter consists of 0.500 kg Mg stearate (Ph. Eur.) and 1.500 kg talcum (Ph. Eur. II). The entire granulate is then compacted in customary manner to form barreled tablets of 400 mg gross weight and 10 mm in diameter. Instead of this conventional tabletting method other methods for the production of tablets can also be used, such as direct tabletting and solid dispersions by the melting and spray-drying method.

The coating of the tablet cores with an enteric coating and with a film coating is effected in a manner similar to that described under Examples 1 and . - lib - Example 8 Preparation of enteric-coated film tablets containing -100 mg of monopropylfumarate Ca salt corresponding to 65 mg of fumaric acid .000 kg of monopropyl fumarate calcium salt are crushed, mixed and homogenized by means of an 800 screen applying suitable precautionary measures (breathing mask, gloves, protective clothing, etc.). A mixture of adjuvants having the following composition is then prepared: 21.000 kg of starch derivative (STA-RX 1500), 2.000 kg of microcrystalline cellulose (Avicel PH 101), 0.600 kg of polyvinyl pyrrolidone (PVP, Kollidon 25), 4.000 kg Primogel, 0.300 kg of colloidal silicic acid (Aerosil) . The total powder mixture is treated with the active substance, homogenized by means of a 200 screen and worked with a 2 % aqueous solution of polyvinyl pyrrolidone (Kollidon K 30) in customary manner to form a binder granulate and then mixed in dry state with the outer phase. The latter consists of 2.000 kg of a so-called FST complex, containing 80 % talcum, 10 % colloidal silicic acid and 10 % magnesium stearate. It is then pressed in customary manner to form barreled tablets of a weight of 400 mg and a diameter of 10 mm. Instead of these conventional methods of tabletting, other methods for the production of tablets can also be used, such as direct tabletting as well as solid dispersions by the melt method and the spray-drying method.

The coating of the tablet cores with an enteric coating and with a film coating is effected in a manner similar to that described under Examples 1 and . - 11c - Example 9 Production of enteric-coated tablets containing 50 mg mono-propylfumarate Ca salt/ 50 mg dimethylfumarate, 5 mg monomethylfumarate Mg salt and 3 mg monomethylf marate Zn salt corresponding to 79 mg fumaric acid .000 kg fumaric acid dimethylester, 5.000 kg monomethylfumarate, 0.500 kg monomethylfumarate Mg salt and 0.300 kg monomethylfumarate Zn salt are crushed, mixed intensively and homogenized by means of an 800 screen, observing suitable precautionary measures (breathing mask, gloves, protective clothing, etc.) . An adjuvant mixture of the following composition is prepared in a manner similar to that described under Example 4, namely starch derivative (STA-RX 1500) 19.000 kg, microcrystalline cellulose (Avicel pH 101) 3.000 kg, polyvinyl pyrrolidone (PVP, Kollidon 120) 0.750 kg, rimoyel 4.000 ky, and colloidal silicic acid (Aerosil) 0.250 kg.

Adjuvants and the combination of active substances are vigorously mixed and homogenized by means of a 200 screen. The entire mixture is worked together with a 2 % aqueous solution of polyvinyl pyrrolidone (Kollidon K 25) in the customary manner to form a binder granulate and mixed in dried state with the outer phase. The latter consists of 0.500 kg Mg stearate (Ph. Eur.) and 1.500 kg talcum (Ph. Eur. II). The entire granulate is then compacted in customary manner to form barreled tablets of 400 mg gross weight and 10 mm in diameter. Instead of this conventional tabletting method other methods for the production of tablets can also be used, such as direct tabletting and. solid dispersions by the melting and · spray-drying method.

The coating of the tablet cores with an enteric coating and with a film coating is effected in a manner similar to that described under Examples 1 and 4. - lid - Example 10 Preparation of enteric-coated film tablets containing 50 mg monopropylfumarate Ca salt, 50 mg dipropylfumarate/ 5 mg monopropylfumarate Mg salt and 3 mg monopropylfumarate Zn salt corresponding to 67 mg fumaric acid .000 kg fumaric acid dipropylester, 5.000 kg monopropylfumarate Ca salt, 0.500 kg monopropylfumarate Mg salt as well as 0.300 kg monopropylfumarate Zn salt are crushed, mixed intensively and homogenized by means of an 800 screen. In this connection suitable protective measures should be taken such as breathing mask, gloves, protective clothing, etc.. It is then added to a mixture consisting of 19.000 kg starch derivative (STA-RX 1500), 3.000 kg microcrystalline cellulose (Avicel pH 101), 0.750 kg polyvinyl pyrrolidone (PVP Kollidon 25), 4.000 kg Primogel, 0.250 kg colloidal silicic (Aerosil) . The mixture of active substances is mixed until homogeneous, passed through a 200 screen and worked up with a 2 % aqueous solution of polyvinyl pyrrolidone (K 25) in customary manner to form a binder granulate. A powder mixture consisting of the following adjuvants is added as outer phase to the dried granulate: 0.500 kg Mg stearate (Ph. Eur. II) and 1.500 kg talcum (Ph. Helv. VII) .

The homogeneous granulate mixture is compacted in customary manner to form barreled tablet cores of a weight of 400 mg and a diameter of 10 mm. In addition to the binder methods other tabletting methods can also be used, in accordance with Example 1 and 4.

The coating of the tablet cores with an enteric coating and with a film coating is effected in a manner similar to that described under Example 1 and 1. - lie - Example 11 Production of enteric-coated tablets containing 100 mg mono-methylfumarate Ca salt, 5 mg monomethylfumarate Mg salt and 3 mg monomethylfumarate Zn salt corresponding to 84 mg fumaric acid .000 kg monomethylfumarate Ca salt, 0.500 kg monomethylfumarate Mg salt and 0.300 kg monomethylfumarate Zn salt are crushed, mixed intensively and homogenized by means of an 800 screen, observing suitable precautionary measures (breathing mask, gloves, protective clothing, etc.). An adjuvant mixture of the following composition is prepared in a manner similar to that described under Example 4, namely starch derivative (STA-RX 1500) 19.000 kg, microcrystalline cellulose (Avicel pH 101) 3.000 kg, polyvinyl pyrrolidone (PVP, Kollidon 120) 0.750 kg, Primogel 4.000 kg, and colloidal silicic acid (Aerosil) 0.250 kg.

Adjuvants and the combination of active substances are vigorously mixed and homogenized by means of a 200 screen. The entire mixture is worked together with a 2 % aqueous solution of polyvinyl pyrrolidone (Kollidon K 25) in the customary manner to form a binder granulate and mixed in dried state with the outer phase. The latter consists of 0.500 kg Mg stearate (Ph. Eur.) and 1.500. kg talcum (Ph. Eur. II). The entire granulate is then compacted in customary manner to form barreled tablets of 400 mg gross weight and 10 mm in diameter. Instead of this conventional tabletting method other methods for the production of tablets can also be used, such as direct tabletting and solid dispersions by the melting and spray-drying method.

The coating of the tablet cores with an enteric coating and with a film coating is effected in a manner similar to that described under Examples 1 and . - llf - The preparations in accordance with the invention are preferably administered orally in the form of tablets or capsules. These solid single-dose forms being preferably provided with an enteric coating which, after passage through the stomach, dissolves in the juice of the small-intestine within a few minutes and liberates the active principle from the preparation. For the systemic initiation or termination a low dose ("mite") is necessary; for the therapeutic dose after the initiation phase a higher dose ("forte") is necessary.

It has been found that the mixed .preparations of the invention exhibit upon oral adminstration a considerably bette action against the different clinical forms of psoriasis) psoriatic arthritis, neurodermatiti.s and Enteritis regionalis Crohn (Morbus Crohn).

Since the activity of phospholipase A2 is changed in a psoriatic epidermis, a possible explanation of the mechanism of action of the combination preparations of the invention lies in this enzyme being stimulated by calcium monoethyl fumarate , whereas Mg and Zn cations are of great importance for the skin metabolism of psoriasis atients.

An object of the invention, in addition to orally administrable preparations in the form of capsules, granulates and tablets, are preparations for cutaneous and transdermal adminstration in the form of ointments, plasters, lotions and douche agents, for parenteral adminstration in the form of aqueous microdispersions , O/W emulsions or oily solutions, for rectal administration as suppositories or micro-enemas and for the medicinal treatment of hair, fingernails and toenails.

Therapeutic treatment of psoriasis with the compositions according to Example 4 and the results thereof In an intra-individual case-control study over a period of a year the ambulent peroral treatment of psoriasis was observed on a total of 24 patients (see Table 1) . All patients had previously responded poorly to conventional medicines and forms of therapy, so that it can be termed a negative selection.

Half of all the ambulant perorally treated patients showed substantial improvement objectively, this improvement generally taking place only after treatment for several weeks.

No severe objective adverse effects were noted, in particular disturbances of kidney or liver function or changes in blood count.

The acute toxicity was studied orally on mice and rats before the clinical trial. The results showed very low toxicity of the fumaric acid derivatives used (see Table 2) .

Table 1: Clinical Results of the Psoriasis Treatment" Study I Study II n = 13 patients n «* 11 patients formulation formulation according to according to Example 4 Example 4 1. Duration of the treatment 3 months 1 year 2. Results: -very good 4 patients 5 patients -good 3 patients 1 patient -unsatisfactory 4 patients 3 patients 3. Discontinuation of therapy because of adverse effects 2 patients 2 patients Table 2: Acute Toxicity Study (peroral) Composition Sex of according Animals to Example 4 Mice Rats LD50 (24 hours) in mg/kg male 5750 4700 female 8200 4600 LD50 (14 days) in mg/kg male 5600 4700 female 6950 3900 Lowest Toxic . Dose in mg/kg male .3160 3160 female 3160 3160 Lowest Lethal Dose in mg/kg 5620 4640 · Stomach & Intestinal Wall Haemorrhagic in mg/kg 5600 none Spleen Inflammatory none none Oedema Epithelial none none In the following the treatment of patients suffering from neurodermatitis and Enteritis regionalis Crohn (Morbus Crohn) and the results of the treatment are shown: HM - female - 1951 - disease: Enteritis regionalis Crohn - dose: 3 tablets/day (formulation of Example 5) - treatment period: May 7, 1986 to November 27, 1986 - result: intestinal tract calm since then without medication EL - female - 1919 - disease: Enteritis regionalis Crohn - begin of therapy: March 24, 1984 - dose: 3 tablets/day (formulation of Example 5) - result: intestinal bleeding and ulcer activity subsides WCh - female - 1945 - disease: Enteritis regionalis Crohn - begin of therapy: April 9, 1988 - dose: 3 tablets/day (formulation of Example 5) - result: everything more calm but yet too early for an assessment NK - male - 1971 - disease: Neurodermatitis - disease period: 16 years - begin of therapy: December 16, 1987 - dose: 3 tablets/day (formulation of Example 4) - result: very good - - - female - 1926 disease: Neurodermatitis disease period: 40 years begin of therapy September 4, 1986 dose: 2 tablets/day (formulation of Example result: good AS - female - 1941 - disease: Neurodermatitis - disease period: 20 years - begin of therapy: December 16, 1987 - dose: 6 tablets/day (formulation of Example 5) - result: very good D.E. - female - 1960 - disease: Ichthyosis - begin of therapy: March 15, 1988 - dose: 6 tablets/day (formulation of Example 5) - result: good It is understood that the scope of the invention is only as defined in the claims.

Claims (11)

-17- 88011/3 What is claimed is:

1. A pharmaceutical composition for the treatment of psoriasis, psori atic arthritis, neurodermatitis and Enteritis regionalis Crohn comprising one or more compounds selected from the group of calcium, magnesium, zinc and iron salts of fumaric acid monoalkylesters of the general formula H c1-c5-Alkyl-ooc optionally admixed with a dialkylfumarate of the formula H COO-C!-Cs-Alkyl C!-Cs-Alkyl-OOC H and ordinary pharmaceutically acceptable adjuvants and vehicles^ with the proviso that the pharmaceutical composition for treating psoriasis does not contain fumaric acid per se or mineral salts of fumaric acid monoethylester.

2. The pharmaceutical composition according to Claim 1, whereby the compound is .comprised of the calcium salt of fumaric acid monoethylester.

3. The pharmaceutical composition according to Claim 1, whereby the compound is comprised of the calcium salt of fumaric acid monoethylester in admixture with dimethylfumarate.

4. The pharmaceutical composition according to Claim 1, whereby the composition is comprised of the calcium and zinc salts of fumaric acid monoethylester in admixture with dimethylfumarate.

5. The pharmaceutical composition according to Claim 1, wherein the composition is comprised of the calcium, magnesium and zinc salts of fumaric acid onoethy les ter in admixture with dimethyl fumarate .

6. Λ pharmaceutical composition as in Claim 1 for oral, administration in the form of tablets or capsules according to Claim 1, wherein the compound is comprised of the calcium salt of fumaric acid monoalkylester in an amount of 100 to 300 g, the total weight of the active substances being 100 to 300 mg.

7. A pharmaceutical composition as in Claim 1 for oral administration in the form of tablets or capsules according to Claim 1, comprising 10 to 290 parts by weight of the calcium salt of fumaric acid monoalkylester and 290 to 10 parts by weight of di ethylfumarate, the total weight of the active substances being 100 to 300 mg.

8. A pharmaceutical composition .as in Claim 1 for oral administration in the form of tablets or capsules according to Claim 1, comprising 10 to 250 parts by weight of the calcium salt of fumaric acid monoalkylester, 1 to 50 parts by weight of dimethylfumarate and 1 to 50 parts by weight of the zinc salt of fumaric acid monoalkylester, the total weight of the active substances being 100 to 300 mg.

9. A ■ pharmaceutical composition as in Claim 1 for oral administration in the form of tablets or capsules according to Claim 1, comprising 10 to 250 parts by weight of the calcium salt of fumaric acid monoalkylester, 250 to 10 parts by weight of dimethylfumarate, 1 to 50 parts by weight of the magnesium salt of fumaric acid monoalkylester, and 1 to 50 parts by weight of the zinc salt of fumaric acid monoalkylester, the total weight of the active substances being 100 to 300 mg .

10. The pharmaceutical composition for oral administration according to Claims 1 to 9, additionally comprising an enteric coating.

11. Pharmaceutical composition for the treatment of psoriasis, psoriatic arthritis, neurodermatitis and Enteritis regional is Crohn according to Claims 1 to 9 for peroral administration in form of capsules, granula and tablets, for the cutaneous and transdermal administration in form of ointments, plasters, lotions and douche agents, for parenteral administration in form of aqueous micro-dispersions, o/w emulsions or oily solutions, for the rectal administration in form of suppositories or micro-enemas and for the medicinal treatment of hair, finger and toe nails.