MXPA99010703A - Use of fumaric acid derivatives - Google Patents

Abstract

The invention relates to the use of given fumaric acid monoalkyl esters as salts or free acids either alone or combined with a dyakyl fumarate in the production of pharmaceutical preparations for the treatment of polyarthritis or multiple sclerosis, in addition to graft-versus-host reaction.

Description

USE OF DERIVATIVES OF THE FUMARIC ACID FIELD OF THE INVENTION The present invention relates to the use of certain monoalkyl esters of fumaric acid as salts either alone or in combination with a dialkyl fumarate to prepare pharmaceutical compositions for the treatment of polyarthritis, multiple sclerosis, graft rejection reactions. The invention also relates to medicaments containing one or several monoalkyl esters of fumaric acid in the form of free acids, optionally combined with dialkyl fumarate, as an active ingredient for the treatment of polyarthritis, multiple sclerosis, graft rejection reactions and other autoimmune diseases. These compositions do not contain fumaric acid itself. The use according to the invention also extends to the treatment of juvenile diabetes, Hashimoto's thyroiditis, Grave's disease, systemic Lupus erythema tosus (SLE), Sjogren's syndrome, pernicious anemia and chronically active hepatitis (= lupoid). The materials according to the invention are characterized in detail in the claims.

BACKGROUND OF THE INVENTION Pharmaceutical compositions that terminate P1578 / 99MX in the citric acid cycle when they decompose after administration or that belong to the citric acid cycle are acquiring therapeutic value in an increasing way, especially when they occur in high doses, because they help to alleviate or cure diseases with cryptogenic causes . For example, fumaric acid inhibits Ehrilc ascites tumor growth in mice, decreases the toxic effects of mitoin C and aflatoxin [K. Kuroda, M. Akao, Biochem. Pharmacol. 29, 2839-2844 (1980) / Gann. 72_, 777-782 (1981) / Cancer Res. 3_6, 1900-1903 (1976)] and shows an antipsoriatic and antimicrobial activity [C.N. Huhtsnen, J. Food Sci. 48_, 1574 (1983) / M.N. Islam, US-A-4, 346, 118 dated August 24, 1982 / C.A. 97, 161317b (1982)]. When administered parenterally, dermally and especially orally, the high doses of fumaric acids or their derivatives hitherto known as fumaric acid, fumaramide and fumaronitrile have such unacceptably severe side effects and high toxicity [P. Holland, R.G. White, Brit. Dermatoi. 8_5, 259-263 (1971) / M. Hagedorn, K.W. Kalkoff, G. Kiefer, D. Baron. J. Hug, J. Petres, Arch. Derm. Res. 254, 67-73 (1975)] that in the past, in most cases, the therapy had to be abandoned.

P1578 / 99MX European Patent Application 18 87 49 already describes fumaric acid derivatives and pharmaceutical compositions containing them for the treatment of psoriasis. Pharmaceutical compositions for the treatment of psoriasis containing a mixture of fumaric acid and other fumaric acid derivatives are known from DE-A-25 30 372. The content of free fumaric acid is obligatory for these medicaments. DE-A-26 21 214 discloses medicaments containing the monoethyl ester of fumaric acid and its mineral salts as an active ingredient for the treatment of psoriasis. The publication "Hautarzt (Dermatologist) (1987) 279-285" discusses the use of the salts of (Ca, Zn, Mg) of the fumaric acid monoethyl ester and the fumaric acid dimethyl ester for the treatment of psoriasis. Pharmaceutical compositions containing a mixture of fumaric acid monoalkyl ester salts and a fumaric acid diester for the treatment of psoriasis, psoriatic arthritis, neurodermatitis and regional Crohn's enteritis are known from EP 0 312 697 Bl.

DETAILED DESCRIPTION OF THE INVENTION Surprisingly, we have found in the in vi tro tests and in animal experiments that it is possible to treat polyarthritis, multiple sclerosis and P1578 / 99MX rejection reactions of grafts with pharmaceutical compositions using one or more compounds from the group consisting of calcium, magnesium, zinc and iron salts of monoalkyl esters of fumaric acid of the general formula H COO C = C A Ci-C5-AlquiIo-? OC "H optionally in a mixture with dialkyl fumarate of the formula H COO-C-i-Cs-Alkyl C = C C -? - C5-Alkyl-OOC H wherein A is a bivalent cation of the series consisting of Ca, Mg, Zn or Fe or a monovalent cation of the series consisting of potassium or sodium, respectively and n indicates the number 1 or 2 depending on the type of cation, optionally together with commonly used pharmaceutical excipients. We also found an effect when polyarthritis, multiple sclerosis, and rejection reactions were treated with grafts that contained one or P1578 / 99MX various alkyl hydrofumaric acid compounds of the general formula H COOH C = C Cl-C5-Alkyl-Q0C 'H optionally in mixture with dialkyl fumarate of the formula H COO -C1-C5-Alkyl C = C C-l-Co-Alkyl-OOC H and optionally, excipients and pharmaceutical vehicles commonly used. Preferred compositions according to the invention contain the calcium salt of the fumaric acid monomethyl ester, the calcium salt of the fumaric acid monomethyl ester in xture with dimethyl fumarate or the relevant salts of the fumaric acid monoethyl ester. The preparations containing the calcium salt of the fumaric acid monoalkyl ester or the fumaric acid alkyl ester in the free acid form in an amount between 10 and 300 mg are especially suitable for nistration, the total weight of the active ingredient being between 10 and 300 P1578 / 99MX mg. Other preferred oral nistration forms contain between 10 and 290 parts by weight of the calcium salt of the monoalkyl ester of fumaric acid and between 290 and 10 parts by weight of dimethyl fumarate and between 1 and 50 parts by weight of the salt of zinc of the monoalkyl ester of fumaric acid or between 1 and 250 parts by weight of the calcium salt of the fumaric acid monoalkyl ester, between 250 and 10 parts by weight of dimethyl fumarate, between 1 and 50 parts by weight of the salt of magnesium of the monoalkyl ester of fumaric acid and between 1 and 50 parts by weight of the zinc salt of the monoalkyl ester or monomethyl ester of fumaric acid, respectively, the total weight of active ingredients is between 30 and 300 mg. The preferred compositions according to the invention also contain the methyl hydrofumarate in an amount between 10 and 300 mg. For the initiation of a systemic therapy and vice versa, low doses contain, for example, 30.0 mg of dimethyl fumarate, 20.0 mg of the monoethyl fumarate calcium salt, and are advantageous for the termination of the treatment by gradually decreasing the dose. 3.0 mg of the zinc salt of monoethyl fumarate or monomethyl fumarate, respectively. For therapeutic dosing after a P1578 / 99MX initial phase, for example, a dose of 120.0 mg of dimethyl fumarate, 87.0 mg of the calcium salt of monoethyl fumarate and 3.0 mg of the zinc salt of monoethyl fumarate or monomethyl fumarate can be used. . The fumaric acid derivatives contained in the compositions according to the invention are obtained by a) condensation of a compound of the formula O Cl C - CH O HC Cl with 2 moles of alkyl alcohol (ROH) by a known method to obtain a diester, followed by controlled hydrolysis to obtain a monoester, or b) condensation of 1 mole of the relevant alkyl alcohol (ROH) in the usual way followed by hydrolysis of the monoacid chloride thus obtained to obtain an acid, or c) direct condensation of fumaric acid with two moles of alkyl alcohol (ROH) by a known method to obtain the relevant diester. Followed by controlled hydrolysis to obtain the monoester, or d) direct condensation of maleic acid or P1578 / 99MX maleic anhydride with one to two moles of the relevant alkyl alcohol (ROH) by a known method to obtain a mono- or diester, followed by catalytic isomerization to obtain the respective fumaric acid derivative. The salts of the fumaric acid monoalkyl esters can also be obtained by reacting a compound of the general formula 0 R - O C- CH O HC C - OH wherein R is a C1-C5 alkyl group with equivalent molar amounts of Na, K, Fe, Ca, Mg hydroxide or oxide, in toluene and removing the water generated during the reaction. For particularly preferred applications, the preparations containing the following active ingredients are used in the established doses and proportions: - as a pharmaceutical composition for oral administration in the form of tablets or capsules according to claim 1, characterized in that they contain the calcium salt of the monomethyl ester of fumaric acid in an amount between 10 and 300 mg, the total weight of the active ingredients is between 10 and 300 mg; or P1578 / 99MX - as a pharmaceutical composition for oral administration in the form of tablets or capsules, characterized in that they contain between 10 and 290 parts by weight of the calcium salt of the fumaric acid monomethyl ester and between 290 and 10 parts by weight of the fumarate of dimethyl, the total weight of the active ingredients is between 20 and 300 mg; or - in addition, as a pharmaceutical composition for oral administration in the form of tablets or capsules characterized in that they contain between 10 and 250 parts by weight of the calcium salt of the fumaric acid monomethyl ester, between 1 and 50 parts by weight of the fumarate of dimethyl and between 1 and 50 parts by weight of the zinc salt of the fumaric acid monomethyl ester, the total weight of the active ingredients is between 20 and 300 g, or as a pharmaceutical composition for oral administration in the form of tablets or capsules , characterized in that they contain between 10 and 250 parts by weight of the calcium salt of the monomethyl ester of fumaric acid, between 250 and 10 parts by weight of dimethyl fumarate, between 1 and 50 parts by weight of the magnesium salt of the monomethyl ester of fumaric acid and between 1 and 50 parts by weight of the zinc salt of the fumaric acid monomethyl ester, the total weight of the active ingredients is between 30 and 300 mg or alternatively, or a pharmaceutical composition for P1578 / 99MX oral administration which may be provided with a gastric acid resistant coating, such as a pharmaceutical preparation for the treatment of polyarthritis, multiple sclerosis or graft rejection reactions for oral administration in the form of granules, microtablets, capsules, granules and tablets , in the form of ointments, patches or lotions for cutaneous and transdermal administration, in the form of aqueous microdispersions, oil-in-water emulsions or oily solutions for parenteral administration or suppositories or microenemas for rectal administration, and as a pharmaceutical composition for the treatment of polyarthritis, multiple sclerosis or graft rejection reactions, characterized in that it contains one or several compounds selected from the group consisting of free acids of fumaric acid monoalkyl esters of the general formula H COOH C = C Cl-C5-AIqullo-Q0C 'H optionally in combination with dialkyl fumarate of the formula 578 / 99MX H COO-Cl-Cs-Alkyl C = C. C -! - C5-Alkyl-OOC H and vehicles, the composition does not contain fumaric acid in its free form, or - as a pharmaceutical composition for oral administration in the form of tablets, capsules or microtablets, characterized in that they contain alkyl acid fumarate in an amount between 10 and 300 mg, the weight total of the active ingredient is between 10 and 300 mg, or - as a pharmaceutical composition for oral administration in the form of tablets, capsules or microtablets, characterized in that they contain between 10 and 290 parts by weight of alkyl fumarate and between 290 and 10 parts. by weight of dialkyl fumarate, the total weight of the active ingredients is between 20 and 300 mg, or as pharmaceutical compositions containing the free acid of the fumaric acid monomethyl ester (methyl acid fumarate), or - as a pharmaceutical composition for oral administration in the form of tablets, capsules or microtablets, characterized in that each contains the acid fumarate of methyl in an amount between 10 and 300 mg, the total weight of the active ingredients is between 10 and 300 mg, P1578 / 99MX or as a pharmaceutical composition for oral administration in the form of tablets, capsules or microtablets containing between 10 and 290 parts by weight of methyl fumarate and between 290 and 10 parts by weight of dimethyl fumarate, the total weight of the active ingredients is between 20 and 300 mg, or finally - as a pharmaceutical composition for the treatment of polyarthritis, multiple sclerosis or rejection reactions of grafts for oral administration in the form of micro-granules, microtablets, capsules, granules and tablets, in the form of ointments, patches, lotions or bath preparations for cutaneous and transdermal administration, in the form of aqueous icrodispersions, oil-in-water emulsions or oily solutions for parenteral administration or suppositories or microenemas for rectal administration. According to a preferred form of administration, the average size or diameter of the granules or microtablets is in the range between 300 and 2,000 μm, especially in the range between 500 μm and 1,500 μm or 1,000 μm. Another special advantage of the use according to the present invention is to alternate a treatment regimen with cyclosporin sequentially with the administration of the fumaric acid derivatives described above. That is, to an application of P1578 / 99MX derivatives of fumaric acid according to the above definitions for a period of one or several weeks could follow a ciclosporin therapy that extends for one or several weeks. As a consequence, the well-known severe side effects of long-term therapy with cyclosporine can be dramatically and unexpectedly reduced. To illustrate the use according to the invention, various examples are given below for the preparation of the preferred medicaments: Production examples Example 1 Production of enteric-coated tablets which are 100.0 mg of monoethyl fumarate calcium salt, corresponding to 7-1 mg of fumaric acid Taking the necessary precautions (mask, gloves, protective clothing, etc.), 10,000 kg of salt of monoethyl fumarate calcium are ground, mixed vigorously and homogenized by a 800 sieve. An excipient mixture is then prepared with the following composition: 21,000 kg of starch derivative (STA-RX 1500®), 2,000 kg of microcrystalline cellulose (Avicel PH101®), 0.600 kg of polyvinyl pyrrolidone (PVP Kollidon® 25), 4,000 kg of Primogel®, 0.300 kg of colloidal silicic acid (Aerosil®).

P1578 / 99MX The active ingredient is added to the whole powder mixture, mixed, homogenized by a 200 sieve and processed with 2% aqueous solution of polyvinyl pyrrolidone (PVP, Kollidon® 25) in the usual way to form granules compacted and then mixed with the external dry phase. The latter consists of 2,000 kg of a complex called FST containing 80% talc, 10% silicic acid and 10% magnesium stearate. The mixture is then pressed by the usual method to form convex tablets with a weight of 400 mg and a diameter of 10.0 mm. Instead of this conventional compaction method, other methods can also be used to prepare the tablets as direct compaction or solid dispersions according to the melt-drying and atomization method.

Enteric coating A 2,250 kg solution of hydroxy propyl methyl cellulose phthalate (HPMCP, Pharmacoat HP® 50) is dissolved in a solvent mixture consisting of 2.50 liters of demineralised water, 13.00 liters of acetone (Ph. Helv. VII) and 13.00 liters of ethanol (94% by weight) and then 0.240 kg of castor oil (Ph. Eur. II) are added to the solution. The solution is poured or atomized in portions onto the tablet cores in a coating tray in a conventional manner or applied by P1578 / 99MX medium of a fluidized bed apparatus with adequate structure. After drying, the film coating is applied. The coating consists of a solution of Eudragit E 12.5% ® 4,800 kg, talc 0.340 kg (Ph. Eur. II), titanium oxide (VI) Cronus RN 56® 0. 520 kg, colorful lacquer ZLT-2 blue (Siegle) 0.210 kg and polyethylene glycol 6000 (Ph. Helv VII) 0.120 kg in a solvent mixture of 8,200 kg of 2-propanol (Ph. Helv. VII), 0.060 kg of triacetate of glycerin (Triacetin®) and 0.200 kg of demineralized water.

After homogenous distribution in the coating tray or in the fluidized bed, the mixture is dried and polished in the usual manner.

Example 2_ Preparation of enteric coated capsules containing 86.5 mg of monoethyl fumarate calcium salt and 110.0 mg of dimethyl fumarate, corresponding to a total of 150 mg of fumaric acid Taking the necessary precautions (mask, gloves, protective clothing , etc.), 8,650 kg of calcium salt of monoethyl fumarate and 11,000 kg of dimethyl fumarate are mixed vigorously with a mixture consisting of 15,000 kg of starch, 6,000 kg of lactose (Ph. Helv, VII), 2,000 kg of microcrystalline cellulose (Avicel®), 1,000 kg of polyvinyl pyrrolidone (Kollidon® 25) and 4,000 kg of P1578 / 99MX Primogel® and homogenized by means of an 800 sieve. Together with a 2% aqueous solution of polyvinyl pyrrolidone (Kollidon® 25) the whole powder mixture is processed in the usual way to form a compacted granulate and mixed with the external phase in dry. The external phase consists of 0.350 kg of colloidal silicic acid (Aerosil®), 0.500 kg of magnesium stearate and 1,500 kg of talc (Ph. Helv. VII). The homogeneous mixture is then poured into portions of 500.0 mg in appropriate capsules which are then provided with an enteric layer coating consisting of hydroxy propyl methyl cellulose, stearate and castor oil as a softening agent by a known method. Instead of hard gelatin capsules, the mixture can also be emptied into suitable gastric acid resistant capsules, which consist of a mixture of cellulose acetate phthalate (CAP) and hydroxy propyl ethyl cellulose phthalate (HPMCP).

Use 3_ Preparation of enteric coated capsules containing 203.0 mg of calcium salt of monoethyl fumarate, 5.0 mg of magnesium salt of monoethyl fumarate and 3.0 zinc salt of monoethyl fumarate, corresponding to a total of 150 mg of fumaric acid P1578 / 99MX Taking the necessary precautions (mask, gloves, protective clothing, etc.), 20,300 kg of calcium salt of monoethyl fumarate, 0.500 kg of magnesium salt of monoethyl fumarate and 0.300 kg of zinc salt were crushed. monoethyl fumarate, are vigorously mixed and homogenized using an 800 sieve. A homogeneous powder mixture of the following composition is combined with this active ingredient mixture: spray dried lactose 12,900 kg, colloidal silicic acid 1,000 kg, microcrystalline cellulose (Avicel ®) 2,000 kg, magnesium stearate (Ph. Helv VII) 1,000 kg and talc (H. Helv VII) 2,000 kg. The whole powder mixture is homogenized again by a 200 mesh, emptied into hard gelatin capsules with a net weight of 400 mg and sealed. The application of a gastric acid resistant coating is carried out according to example 2.

Example ^ Preparation of enteric coated microtablets in capsules containing 87.0 mg of calcium salt of monoethyl fumarate, 120.0 mg of dimethyl fumarate, 5.0 mg of magnesium salt of monoethyl fumarate and 3.0 mg of zinc salt of fumarate of monoethyl, corresponding to a total of 164 mg of fumaric acid (tablets "for e") Taking the necessary precautions P1578 / 99MX (mask, gloves, protective clothing, etc.), 8,700 kg of calcium salt of monoethyl fumarate, 12,000 kg of dimethyl fumarate, 0.500 kg of magnesium salt of monoethyl fumarate and 0.30 kg of zinc salt of monoethyl fumarate are comminuted, vigorously mixed and homogenized by means of an 800 sieve. An excipient mixture is then prepared with the following composition: 18.00 kg of starch derivative (STA-RX 1500), 0.30 kg of microcrystalline cellulose ( Avicel PH - 101), 0.75 kg of PVP (Kollidon 120), 4.00 kg of Primogel, 0.25 kg colloidal silicic acid (Aerosil). The whole powder mixture is added to the mixture of active ingredients, homogenized by means of a 200 sieve, processed in the usual way with a 2% aqueous solution of polyvinyl pyrrolidone (Kollidon K25) to obtain a compacted granulate and dry mix with the external phase consisting of 0.50 kg of magnesium stearate and 1.50 kg of talc. Then the powder mixture is compressed by the conventional method to form convex microtablets with a gross mass of 10.0 mg and a diameter of 2.0 mm. Instead of this conventional tabletting method, other methods can also be used to make tablets such as direct tableting or solid dispersions by the melting and spray drying method. The gastric acid resistant coating can be poured or atomized into a tray of P1578 / 99MX classic coating or applied in a fluidized bed apparatus. To achieve resistance to gastric acid, portions of a 2,250 kg solution of hydroxypropyl methyl cellulose phthalate (HPMCP, Pharmacoat HP 50) are dissolved in a mixture of the following solvents: acetone 13.00 1, ethanol 94% by weight denatured with 2% Ketone 13.50 1 and demineralized water 2.50 1. To the finished solution 0.240 kg of castor oil is added as a softening agent and applied in portions to the tablet cores in the usual manner. Film coating: After drying, a suspension of the following composition is applied as a film coating in the same apparatus: talc 0.340 kg of titanium oxide (VI) Cronus RN 56 0.400 kg, colorful lacquer L red 86837 0.324 kg , Eudragit E 12.5% 4.800 kg and polyethylene glycol 6000 pH 11 XI 0.120 kg in a solvent mixture with the following composition: 2-propanol 8,170 kg, demineralised water 0.200 kg and glycerin triacetate (Triacetin) 0.600 kg. The microtablets resistant to gastric acid are then emptied into hard gelatin capsules at a net weight of 500.0 mg and sealed.

Example 5_ Preparation of enteric-coated tablets containing 67.0 mg of calcium fumarate salt P1578 / 99MX monoethyl, 30.0 mg of dimethyl fumarate, 5.0 mg of magnesium salt of monoethyl fumarate and 3.0 mg of zinc salt of monoethyl fumarate, corresponding to 7_5 mg of fumaric acid (tablets "mite") Taking the necessary precautions (mask, gloves, protective clothing, etc.), 3,000 kg of dimethyl fumarate, 6,700 kg of calcium salt of monoethyl fumarate, 0.500 kg of magnesium salt of monoethyl fumarate and 0.300 kg of zinc salt of fumarate of monoethyl are homogenized by means of an 800 sieve. In the same manner as in Example 4, a carrier mixture is prepared with the following composition, ie 30,000 kg of starch derivative (STA-RX 1500®), 3,000 kg of microcrystalline cellulose (Avicel PH 101®), 0.750 kg of polyvinyl pyrrolidone (PVP, Kollidon® 25), 4000 kg of Primogel, 0.250 kg of colloidal silicic acid (Aerosil®). The excipients and the mixture of active ingredients are intimately mixed and homogenized by a 200 sieve. With the aid of a 2% aqueous solution of polyvinyl pyrrolidone (PVP, Kollidon® 25), the dough is processed in the usual way to obtain a compacted granulate. A powder mixture of the following excipients is added to the dried granulate as external phase: 0.500 kg of magnesium stearate (Ph. Eur.) And 0.800 kg of talc (Ph. Eur. II).

P1578 / 99MX The homogenous mixture of granules is pressed in the usual way to obtain convex tablet cores having a weight of 500.0 mg and a diameter of 11.5 mm. In addition to the compaction methods, other tabletting methods according to examples 1 and 4 can be used. The coating application resistant to gastric acid and a coating on film the tablet cores is analogously described in examples 1 and 4. The compositions according to The invention is preferably administered orally in the form of tablets or capsules. These single-dose drugs are preferably provided with a coating resistant to gastric acid, once they have passed through the stomach, dissolve in a few minutes by the juice present in the small intestine and release the active ingredient of the drug. At the beginning and at the end of the systemic treatment, a lower dose (limit) is required, while high doses (forte) are adequate for a regimen after the initial phase. In addition to compositions orally administered in the form of tablets or capsules, preparations for cutaneous or transdermal administration in the form of ointments, patches, lotions and bath compositions, preparations for parenteral administration in the form of aqueous microdispersions, oil-in-water emulsions.

P1578.99MX or oil solutions, preparations for rectal administration in the form of suppositories or microenemas or preparations for therapy of the hair, fingernails and feet by medication, are also matters of the invention.

Example 6_ Preparation of enteric coated tablets containing 100 mg of calcium salt of monomethyl fumarate, corresponding to 7_8 mg of fumaric acid Taking the necessary precautions (mask, gloves, protective clothing, etc.), 10,000 kg of calcium salt of monomethyl fumarate are crushed, mixed and homogenized by a sieve 800. An excipient mixture is then prepared with the following composition: 21,000 kg of derivative of starch (STA-RX 1500®), 2,000 kg of microcrystalline cellulose (Avicel PH101®), 0.600 kg of polyvinyl pyrrolidone (PVP, Kollidon® 25), 4,000 kg of Primogel, 0.300 kg of colloidal silicic acid (Aerosil®). The active ingredient is added to the mixture, mixed, homogenized by a sieve 200, is processed in the usual manner with a 2% aqueous solution of polyvinyl pyrrolidone (Kollidon® K30) to obtain a compacted granulate and then dry-blended with the external phase. The external phase consists of 2,000 kg of the complex called FST that P1578 / 99MX contains 80% talc, 10% silicic acid and 10% magnesium stearate. The mixture is then pressed in the usual manner to obtain convex tablets having a weight of 400 mg and a diameter of 10 mm. Instead of these conventional tabletting methods, other methods can be used to prepare tablets such as direct tableting and solid dispersion according to the melt-drying and spray-drying method. The application of a gastric acid resistant coating and a film coating to the tablet cores is carried out analogously to Examples 1 and 4.

Example 7_ Preparation of enteric coated tablets containing 50.0 mg of calcium salt of monomethyl fumarate, 50.0 mg of dimethyl fumarate, 5.0 mg of magnesium salt of monomethyl fumarate and 3.0 mg of zinc salt of monomethyl fumarate , which correspond to 8_5 g of fumaric acid Taking the necessary precautions (mask, gloves, protective clothing, etc.), 5,000 kg of dimethyl fumarate, 5,000 kg of calcium salt of monomethyl fumarate, 0.500 kg of magnesium salt of monomethyl fumarate and 0.300 kg of zinc salt of monomethyl fumarate are ground, mixed and homogenized by means of an 800 sieve. An excipient mixture is then prepared with the P1578 / 99MX following composition in the manner described in Example 4: 19,000 kg of starch derivative (STA-RX 1500®), 3,000 kg of microcrystalline cellulose (Avicel PH101®), 0.750 kg of polyvinyl pyrrolidone (PVP, Kollidon ® 120), 4000 kg of Pri ogel, 0.250 kg of colloidal silicic acid (Aerosil®). The excipients and the active ingredient are mixed vigorously, homogenized by means of a 200 sieve, processed in the usual manner with a 2% aqueous solution of polyvinyl pyrrolidone (PVP, Kollidon® 25) to obtain a compacted granulate and then dry mix with the external phase. The external phase consists of 0.500 kg of magnesium stearate (P. Eur.) And 1500 kg of talc (Ph. Eur. II). Then the whole granulate is pressed in the usual way to obtain convex tablets having a weight of 400 mg and a diameter of 10 mm. In place of the conventional tabletting methods, other methods can also be used to prepare tablets such as direct tableting and solid dispersions according to the melt-drying method. The application of a gastric acid resistant coating and a film coating to the tablet cores is carried out analogously to examples 1 and 4.

P1578 / 99MX Example 8 ^ Preparation of enteric coated tablets containing 50.0 mg of mono-n-propyl fumarate calcium salt, corresponding to 32.8 mg of fumaric acid Taking the necessary precautions (mask, gloves, protective clothing, etc.), 5,000 kg of calcium salt of mono-propyl fumarate, are ground, mixed and homogenized by means of an 800 sieve. An excipient mixture is then prepared with the following composition : 25,000 kg of starch derivative (STA-RX 1500®), 3,000 kg of microcrystalline cellulose (Avicel PH101®), 0.600 kg of polyvinyl pyrrolidone (PVP, Kollidon® 25), 4,000 kg of Primogel, 0.300 kg of colloidal silicic acid (Aerosil®). The active ingredient is added to the powder mixture, homogenized by means of a 200 sieve, processed in the usual way with a 2% aqueous solution of polyvinyl pyrrolidone (Kollidon® K30) to obtain a compacted granulate and then mixed dry with the external phase. The external phase consists of 2,000 kg of the complex called FST containing 80% talc, 10% silicic acid and 10% magnesium stearate. Then the whole granulate is pressed in the usual way to obtain convex tablets having a weight of 400 mg and a diameter of 10 mm. In P1578 / 99MX instead of the classic tableting methods too. other methods can be used to prepare tablets such as direct tableting and solid dispersions according to the melt-drying method. The application of a gastric acid resistant coating and a film coating to the tablet cores is carried out analogously to examples 1 and 4.

EXAMPLE 9 Preparation of gastric acid-resistant granules in capsules containing 50.0 mg of calcium salt of monomethyl fumarate, 5.0 mg of magnesium salt of monomethyl fumarate and 3.0 mg of zinc salt of monomethyl fumarate, corresponding to 4_5 mg of fumaric acid Taking the necessary precautions (mask, gloves, protective clothing, etc.), 5,000 kg of calcium salt of monomethyl fumarate, 0.500 kg of magnesium salt of monomethyl fumarate and 0.300 kg of zinc salt of monomethyl fumarate are comminuted, vigorously mixed and homogenized by means of a 400 sieve. At the same time, 2 1 of a solution in 20% ethanol (m / V) of polyvinyl pyrrolidone (Kollidon K30) are prepared. 7.250 kg of these unmatched granules are placed in a tray to be coated and sprayed with a part of the P1578 / 99MX Kollidon K30 solution until lightly moistened. Then the active ingredient mixture is added in portions until the granules are dry. This moistening / drying process is continued until all the active ingredient mixture has been added. The rest of the PVP solution is mixed with 0.720 kg of Eudragit E 12.5% solution and is atomized in its entirety on the granules. Finally the granules are stirred until they are completely dry. Instead of this method other methods can be used to prepare granules, such as fluidized bed coating or the spherosing method. In addition, granules containing individual active ingredients can be prepared and then added in suitable proportions after they have been provided with a film coating (see below). The granules are atomized with Eudragit S 12.5% solution and dried with talc. After each atomization / drying cycle the release of the active ingredient is measured and the addition of Eudragit S 12.5% / talc solution continues until the release values meet the specification. Then the enteric coated granules are emptied into capsules (146 mg granules / capsule).

Example 10 Preparation of acid resistant capsules Gastric P1578 / 99MX containing 50.0 mg of calcium salt of mono isopropyl fumarate, 50.0 mg of diisopropyl fumarate, 5.0 mg of magnesium salt of mono isopropyl fumarate and 3.0 mg of zinc salt of mono isopropyl fumarate, corresponding to 67 mg of fumaric acid Taking the necessary precautions (mask, gloves, protective clothing, etc.), 5,000 kg of calcium salt of mono isopropyl fumarate, 5,000 kg of diisopropyl fumarate, 0.500 kg of magnesium salt of mono-isopropyl fumarate, 0.300 kg of zinc salt of mono-isopropyl fumarate, are comminuted, mixed vigorously and homogenized by means of an 800 sieve. Then a powder mixture with the following composition is mixed with this ingredient mixture active: 32,200 kg of lactose dried by atomization, 2,000 kg of microcrystalline cellulose (Avicel) and 1,000 kg colloidal silicic acid (Aerosil®), 1,000 kg of magnesium stearate and 2,000 kg of talc. The complete mixture of powders is once again homogenized by means of a sieve 200, emptied into hard gelatine capsules to a net weight of 500 mg and sealed. These capsules are then normally provided with an enteric coating consisting of hydroxy propyl methyl cellulose phthalate (HPMCP) and castor oil as a softener. Instead of hard gelatin capsules, the active ingredient P1578 / 99MX can also be emptied into other gastric acid-resistant capsules consisting of a mixture of cellulose acetate phthalate (CAP) and hydroxy propyl ethyl cellulose acetate phthalate (HPMCP).

Example 11 Preparation of micro-granules in capsules containing 50.0 mg of methyl fumarate, corresponding to a total of 44.6 mg of fumaric acid Taking the necessary precautions (mask, gloves, protective clothing, etc.), 5,000 kg of methyl acid fumarate are crushed and homogenized by means of a 400 sieve. In addition, 2 1 of a 20% solution (m / V) of polyvinyl are prepared pyrrolidone (Kollidon K30) in ethanol. 7.250 kg of unpaired granules are placed in a coating pan and sprayed with part of the Kollidon K30 solution until they are slightly moistened. Then the active ingredient mixture is added in portions until the granules are dry. This moistening / drying process is continued until all the active ingredient mixture has been added. Finally, the granules are stirred until they are completely dry. Instead of this method other methods can be used to prepare granules, such as the fluidized bed coating and the extrusion / spherosing method. In addition, granules can also be prepared with ingredients P1578 / 99MX individual assets that are added in the proper ratio after coating with film. Then the granules are emptied into capsules (126.5 mg granules / capsule). Next, the efficacy of the use according to the invention in the example of the inhibition of haemagglutinin formation in an animal experiment is shown and compared with a recognized medicine of the prior art: Investigation of the influence of a formulation according to example 4_ and of calcium salt of methyl fumarate on the formation of haemagglutinin in mice after oral administration. By inhibiting the formation of haemagglutinin in mice, the immunosuppressive effects of certain drugs can be demonstrated. substances. This test is based on direct hemagglutination in which visible agglutination of erythrocytes occurs due to specific antibodies directed against the surface antigens of erythrocytes. The mice are immunized with sheep erythrocytes (day 0). Then the substance to be tested is applied five times (days 0-4). On the ninth day after immunization, the hemagglutinin levels are determined. A reduction in the formation of hemagglutinin demonstrates an immunosuppressive effect.

P1578 / 99MX The objective of these tests was to test the effect of a formulation according to Example 4 and the calcium salt of methyl fumarate in the formation of hemagglutinin in mice after oral administration of 150, 300 and 600 mg / kg, respectively. In this experiment, it was possible to demonstrate the dose-dependent immunosuppressive effect of the formulation, based on the proportions of the active ingredients according to Example 4 in the formation of haemagglutinin in mice. The effect of a total dose of 300 mg / kg of the formulation (application of the combination of active ingredients in a suspension of 0.8% in aqueous HPMC of gel consistency) was still in the normal range of deviation, while it could be demonstrated an inhibition in the formation of hemagglutinin of 29% reproducible after the administration of 600 mg / kg of the previous formulation. A dose-dependent suppressive effect on hemagglutinin formation in mice could also be demonstrated for the calcium salt of methyl acid fumarate. A dose of 300 mg / kg of the calcium salt of methyl acid fumarate caused a slight reduction in the formation of haemagglutinin, while an inhibition in the formation of hemagglutinin of 38% reproducible could be demonstrated, after the administration of 600 P1578 / 99MX mg / kg of calcium salt of fumarate methyl acid. For comparison, an analogous experiment was carried out in a dose range of 150, 200 and 300 mg / kg of cyclosporin A (dose range selected according to Borel et al., 19761). For ciclosporin, a 37% reduction in hemagglutinin formation at a dose of 150 mg / kg could be demonstrated. At a maximum dose of 300 mg / kg of ciclosporin, an inhibition of hemagglutinin formation of 59% was achieved. The results of these investigations allow the conclusion that both a formulation according to Example 4 and the calcium salt of methyl acid fumarate exert a significant immunosuppressive effect. Among other things, the immunosuppressive effect. of cyclosporin is caused by an inhibition of Th-1 cell formation. As the in vitro experiments have shown, fumarates cause a change in the pattern of the Th2-type cytokine to Th2. In the findings of both the experiments vi vi and in vi tro is seen at the same time, a significant and unexpected improved use of the 1 J.B. Borel et al., Biological Effects of Cyclosporin A: A New Antilymp otic Agent, Biological and Medical Research Division, Sandoz, Ltd., CH-4002 Basle, Switzerland; Agents and Actions, 6/4, 468-475 (1975) P1578 / 99MX fumarates in transplant medicine, especially with respect to long-term maintenance therapy results.

Investigation of the influence of a formulation according to example 4 and of the calcium salt of methyl fumarate acid after oral administration in the formation of hemagglutinin in mice Reduction of the formation of serum hemagglutinin in mice p.o. = administered orally Hemagglutinins: Designation for substances that cause haemagglutination, especially agglutinating antibodies, phytohemagglutinins, in general haemagglutinins formed by viral infection P1578 / 99MX (measles, mumps, rubella, influenza, arbovirosis) and surface antigens of certain types of viruses.

Hemagglutination; Visible agglutination of erythrocytes caused by haemagglutinins; as direct hemagglutination (active) caused by antibodies specifically directed against erythrocyte surface antigens or as indirect haemagglutination (passive) after loading the erythrocytes with an antigen (for example, Vi-antigen in typhim-Vi-haemagglutination, globulin in an antigen test). globulin) caused by antibodies specifically directed against the relevant antigen. The intensity of a hemagglutination (for example in a serological evaluation of a haemagglutinating antiserum) is reported by a number (dilution step of the tested serum in which a haemagglutination can be detected). Compared with a therapy with prior art substances such as cyclosporin which can cause severe disorders in the kidney or diseases of the lymphoproliferative system, treatment with fumaric acid derivatives according to the indications of the invention will only cause temporary disturbances and will rarely have side effects. severe [cf. DMW (German Weekly Medical Magazine), 121 (1996) pages 1605-1607].

P1578 / 99MX Especially, considering the necessary long-term therapy and the prevention of graft rejection reactions or multiple sclerosis, this unexpected effect of the use according to the invention is of great interest. Cyclosporin combination therapy with fumaric acid derivatives will dramatically and unexpectedly reduce the toxic effects of the former. In addition, the use according to the invention is also of greater importance in the substitution of a corticosteroid therapy, which as is generally known, has severe side effects.

P1578 / 99MX

Claims (10)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property; 1. The use of one of several compounds selected from the group consisting of sodium, potassium, calcium, magnesium, zinc and iron salts of the monoalkyl esters of fumaric acid of the general formula
2. H COO C = C A C -] - C5-Alkyl-OOC 'H optionally in combination with dialkyl fumarate of the formula
3. H COO -C1-C5-Alkyl C = C C -! - C5-Alkyl-OOC ^ H wherein A is a bivalent cation of the series consisting of Ca, Mg, Zn or Fe or a monovalent cation of the series consisting of potassium or sodium, respectively and n indicates the number 1. or 2
4. P1578 / 99MX depending on the type of cation, or one or more compounds of the series consisting of fumarate alkyl acids of the general formula
5. OH optionally in combination with dialkyl fumarate of the formula
6. H COO - Cl-C5-Alkyl C = c C-J-Co-Alkyl-OOC 'H and optionally, excipients and pharmaceutical carriers commonly used for the treatment of polyarthritis, multiple sclerosis or graft rejection reactions, juvenile diabetes, Hashimoto's thyroiditis, Grave's disease, systemic Lupus erythema todes (SLE), Sjogren's syndrome, pernicious anemia or hepatitis active chronicle (lupoid). 2. The use according to claim 1, characterized in that the calcium salt of the fumaric acid monomethyl ester or the fumaric acid monoethyl ester is used.
7. P1578 / 99MX 3. The use according to claim 1, characterized in that one or more compounds selected from the calcium, magnesium and zinc salts of the fumaric acid monomethyl ester are used in mixture with dimethyl fumarate. The use according to claim 1, for oral administration in the form of tablets or capsules, characterized in that the calcium salt of the monoalkyl ester of fumaric acid is used in an amount between 10 and 300 mg, the total weight of the active ingredients is between 10 and 300 mg. The use according to claim 1, for oral administration in the form of tablets or capsules, characterized in that between 10 and 290 parts by weight of the calcium salt of the fumaric acid monoalkyl ester and between 290 and 10 parts by weight of dimethyl fumarate, the total weight of the active ingredients is between 20 and 300 mg. The use according to claim 1, for oral administration in the form of tablets or capsules, characterized in that between 10 and 250 parts by weight of the calcium salt of the fumaric acid monoalkyl ester are used, between 1 and 50 parts by weight of dimethyl fumarate and between 1 and 50 parts by weight of the zinc salt of the fumaric acid monoalkyl ester, the total weight of the active ingredients is between 20 and 300 mg. 7. The use according to claim 1, for
8. P1578 / 99MX prepare a pharmaceutical composition for oral administration in the form of tablets or capsules, characterized in that between 10 and 250 parts by weight of the calcium salt of the monoalkyl ester of fumaric acid are used, between 250 and 10 parts by weight of fumarate of dimethyl, between 1 and 50 parts by weight of the magnesium salt of the monoalkyl ester of fumaric acid and between 1 and 50 parts by weight of the zinc salt of the fumaric acid monoalkyl ester, the total weight of the active ingredients is between 30 and 50 parts by weight. and 300 mg. The use according to any of claims 1 to 7, characterized in that an application of cyclosporin is carried out in sequence or alternatively together with the application of fumaric acid ester compounds of the definition according to claim 1.
9. 9. The Use according to any of claims 1 to 8, characterized in that the size of the average diameter, respectively, of granules or microtablets is in the range between 300 and 2,000 μm, especially in the range between 500 μm and 1,500 μm or 1,000 μm.
10. 10. The use according to claims 1 to 9, characterized in that the dosage units of the medicaments are provided with an enteric layer. P1578 / 99MX