The use of fumaric acid derivatives

 

(57) Abstract:

The invention relates to containing certain monoalkyl esters of fumaric acid in the form of salts or the free acid individually or in combination with dialkylamino for the treatment of arthritis or multiple sclerosis, as well as reactions "graft versus host". The proposed tool is more effective and less toxic. 8 C.p. f-crystals, 1 table.

The invention relates to the application of certain monoalkyl esters of fumaric acid in the form of salts individually or in combination with dialkylamino to obtain pharmaceutical compositions for the treatment of arthritis or multiple sclerosis, as well as reactions "graft versus host". The invention relates to medicines for the treatment of arthritis, multiple sclerosis, reactions, graft versus host disease and other autoimmune diseases, which contain one or more monoalkyl esters of fumaric acid in the form of free acid, if necessary, together with dialkylamino, as biologically active substances. These compositions do not contain in itself fumaric acid. The use according to the invention rasprostrani graves ' disease), systemic lupus erythematosus (SLE), Sjogren syndrome (syndrome Segren), pernicious anaemia and chronic active (=lipoid) hepatitis. Objects according to the invention is characterized, in particular, in the claims.

Pharmaceutical compositions, which after the introduction of their biological decay into the citric acid cycle or part of it, often in high dosage, get more therapeutic value because they can be used to alleviate or treat cryptogenetic due to disease.

So, fumaric acid slows the growth of ascitic Ehrlich tumor in mice, reduces the toxic effects of mitomycin C and aflatoxin (K. Kuroda, M. Akao, Biochem.Pharmacol., 29, 2839-2844 [1980] / Gann, i2, 777-782 [1981] / Cancer Res., 36, 1900-1903 [1976] and has antipsoriatics, as well as antimicrobial activity (C. N. Huhtsnen, J. Food Sci., 48, 1574 [1983] / M. N. Islam, U.S. patent 4346118 from August 24, 1982 /S. A. 97, 161317b [1982]).

High input dose fumaric acid or its still known derivatives, as dihydroxyfumaric acid, fumarate or fumaronitrile, parenteral, dermal, in particular, however, oral administration have this kind of unacceptable side effects and high toxin most cases forced to withdraw from such therapy.

In European application 188749 already described derivatives of fumaric acid and containing pharmaceutical compositions for the treatment of psoriasis. From the application DE-a 2530372 known pharmaceutical compositions for the treatment of psoriasis, which contain a mixture of fumaric acid with other derivatives of fumaric acid. Share free fumaric acid in these medicines is required.

In the application DE-a 2621214 describes the medicinal product for the treatment of psoriasis, which contain monotropy ester of fumaric acid and its inorganic salts as biologically active substances. From the publication "Hautarzt, 279-285 [1987]" it is known the use of salts of monoethylene ester of fumaric acid (CA, Zn,Mg) and dimethyl ester of fumaric acid for the treatment of psoriasis. From European patent EP-0312697-B1-known pharmaceutical compositions for the treatment of psoriasis, psoriatic arthritis, neurodermatitis and regional enteritis Crohn's, which contain a mixture of salts monoalkyl esters of fumaric acid diesters of fumaric acid.

At present, in vitro studies and in animal experiments unexpectedly shown that the treatment of arthritis, multiple sclerosis, and Reese one or more compounds from the group consisting of salts of calcium, magnesium, zinc and iron monoalkyl esters of fumaric acid of General formula

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if necessary, mixed with dialkylamino formula

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if necessary, along with the usual pharmaceutical excipients and carriers, and a represents the divalent cation of a number of Sa, SB, Zn or Fe, respectively, monovalent cation of a number of potassium or sodium and n is 1 or 2 depending on the kind of cation.

Also found effective in the treatment of arthritis, multiple sclerosis or reactions "graft versus host" when using the pharmaceutical compositions in which envisages the use of one or more monoalkyl esters of fumaric acid formula

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if necessary, mixed with dialkylamino formula

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if necessary, along with the usual pharmaceutical excipients and carriers.

Preferred compositions according to the invention contain calcium salt nanometrology ester of fumaric acid, calcium salt nanometrology ester of fumaric acid in a mixture with dimethylfumarate or respectively with the corresponding salts RATM calcium salt monoalkyl ester of fumaric acid or, respectively alkilany ester of fumaric acid in the form of the free acid in the range from 10 to 300 mg, moreover, the total mass of biologically active compounds is from 10 to 300 mg.

Other preferred oral input forms contain from 10 to 290 wt.h. the calcium salt monoalkyl ester of fumaric acid and from 290 to 10 wt. including dimethylfumarate, and from 1 to 50 wt.h. zinc salts monoalkyl ester of fumaric acid or from 1 to 250 wt.h. the calcium salt monoalkyl ester of fumaric acid, from 250 to 10 wt.h. dimethylfumarate, from 1 to 50 wt.h. magnesium salts monoalkyl ester of fumaric acid and from 1 to 50 wt. including zinc salts monoalkyl ester of fumaric acid or, respectively nanometrology ether, and in each case the total mass of biologically active substances is from 30 to 300 mg.

Preferred compositions according to the invention also contain onomatology ester of fumaric acid in an amount of from 10 to 300 mg.

For the system "" in treatment, and also, conversely, to "exit" from treatment (gradually decreasing the dosage) preferred low dosage, which contains, for example, 30.0 mg of dimethylfumarate, 20.0 mg of the calcium salt of monoethylfumarate and 3.0 g of zinc salt of monoethylfumarate or respectively of monomethylfumarate.

For therapeutically salt of monoethylfumarate and 3.0 mg zinc salt of monoethylfumarate or respectively of monomethylfumarate.

Derivatives of fumaric acid contained in the proposed according to the invention compositions, receive, for example, the fact that the compound of the following formula

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a) in a known manner condensed with 2 moles of alkanol (ROH) to obtain the complex diapir and then controlled hydrolyzing to complex monoether;

or

b) in the usual manner condensed with 1 mol of the corresponding alkanol (ROH) and the resulting monochlorohydrin acid hydrolyzing to acid; or

in) famous image of fumaric acid directly condensed with 2 moles of alkanol (ROH) to obtain the corresponding complex diapir and then controlled hydrolyzing to complex monoether; or

g) maleic acid or maleic acid anhydride in a known manner directly condense with 1-2 moles of the corresponding alkanol (ROH) to obtain the complex mono - or diapir and then catalytically will isomerized to the corresponding derivative of fumaric acid.

Salt monoalkyl esters of fumaric acid can be obtained by the fact that the compound of General formula

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in which R means (C1-C5)-alkyl, enter into interaction with equivalent molar amounts of the hydroxide sludge is at.

In particularly preferred applications, in particular the use of the medicinal product with the following biologically active substances in specified dosages and in the indicated proportions:

in the form of a pharmaceutical composition for oral administration in the form of tablets or capsules of p. 1 claims, characterized in that they contain calcium salt nanometrology ester of fumaric acid in an amount of from 10 to 300 mg, and the total mass of biologically active compounds is from 10 to 300 mg; or

in the form of a pharmaceutical composition for oral administration in the form of tablets or capsules, characterized in that they contain from 10 to 290 wt.h. the calcium salt nanometrology ester of fumaric acid and from 290 to 10 wt.h. dimethylfumarate, and the total mass of biologically active substances is from 20 to 300 mg;

next, in the form of a pharmaceutical composition for oral administration in the form of tablets or capsules, characterized in that they contain, respectively, from 10 to 250 wt.h. the calcium salt nanometrology ester of fumaric acid of 1 to 50 wt.h. dimethylfumarate and from 1 to 50 wt.h. zinc salts nanometrology ester of fumaric acid, and the total mass biologico introduction in the form of tablets or capsules, characterized in that they contain from 10 to 250 wt.h. the calcium salt nanometrology ester of fumaric acid, from 250 to 10 wt.h. dimethylfumarate, from 1 to 50 wt.h. magnesium salts nanometrology ester of fumaric acid and from 1 to 50 wt.h. zinc salts nanometrology ester of fumaric acid, and the total mass of biologically active substances is from 30 to 300 mg; or

in the form of pharmaceutical compositions for oral administration, which can be equipped resistant to gastric juice coated;

in the form of a pharmaceutical composition for the treatment of arthritis, multiple sclerosis, or graft versus host for oral administration in the form of granules, microtablets, capsules, granules and tablets for skin and percutaneous introduction in the form of ointments, patches or lotions, for parenteral administration in the form of water microdisperse, emulsions of oil, water or oil solutions, for rectal injection in the form of suppositories or microenemas, and

in the form of a pharmaceutical composition for the treatment of arthritis, multiple sclerosis or reactions, graft versus host, characterized in that it contains one or more compounds from the group monoalkylated edilbertoneto formula

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and the media, and these compositions do not contain fumaric acid in free form; or

in the form of a pharmaceutical composition for oral administration in the form of tablets, capsules or microtablets, characterized in that they contain monoalkyl ester of fumaric acid in an amount of from 10 to 300 mg, and the total mass of biologically active compounds is from 10 to 300 mg; or

in the form of a pharmaceutical composition for oral administration in the form of tablets, capsules or, microtablets, characterized in that they contain from 10 to 290 wt.h. monoalkyl ester of fumaric acid and from 290 to 10 wt. hours of dialkylphosphate, and the total mass of biologically active substances is from 20 to 300 mg; or as pharmaceutical compositions that contain onomatology ester of fumaric acid (monomethylfumarate) in the form of the free acid; or

in the form of a pharmaceutical composition for oral administration in the form of tablets, capsules or microtablets, characterized in that they contain monomethylfumarate respectively in the range from 10 to 300 mg, and the total mass of biologically active compounds is from 10 to 300 mg;

or in the form of a pharmaceutical composition for oral introduced the speakers.h. dimethylfumarate, and the total mass of biologically active substances is from 20 to 300 mg, or, finally,

in the form of a pharmaceutical composition for the treatment of arthritis, multiple sclerosis or reactions "graft versus host" for oral administration in the form of microgranules, microtablets, capsules, granules and tablets for skin and percutaneous administration in the form of ointments, plasters, lotions and bath products, as well as for parenteral administration in the form of water microdisperse, emulsions, oil/water or oil solutions, for rectal administration in the form of suppositories or microenemas.

According to a preferred variant size or average diameter of the granules or microtablets is the largest in the area from 300 to 2000 μm, in particular in the range from 500 μm to 1500 μm, or 1000 μm.

Following a particularly preferred use according to the invention consists in the alternation of drug therapy with cyclosporine consistently using the above derivatives of fumaric acid. This means that after treatment with cyclosporine for from one to several weeks can be applied for from one to several weeks p is now known to reduce side effects due to long-term administration of cyclosporine.

To clarify the application according to the invention listed below are various examples retrieve the preferred drugs.

Examples of making

Example 1

Obtaining tablets with a film coating resistant to gastric juice, containing 100.0 mg of the calcium salt of monoethylfumarate, which corresponds to 71 mg of fumaric acid.

10,000 kg of the Calcium salt of monoethylfumarate crushed, intensively mixed and with appropriate precautions (breathing mask, gloves, protective clothing and so on) homogenized using a sieve 800. Then prepare a mixture of excipients the following composition: 21,000 kg derived starch (STA-RX 1500), 2,000 kg of microcrystalline cellulose (Avicel pH 101), 0,600 kg polyvinylpyrrolidone (PVP; Kollidon25), 4,000 kg Primogel, 0,300 kg of colloidal silicic acid (Aerosil).

The entire powder mixture is mixed with a biologically active substance are mixed, homogenized using sieves 200 and the usual way using a 2% aqueous solution of polyvinylpyrrolidone (PVP: Kollidon25) processed into granulate binder in the dry state of specilaty and 10% of magnesium stearate.

Then as usual pressed convex tablet weight of 400 mg and a diameter of 10.0 mm Instead of these classical methods tabletting you can also use other ways of getting tablets, as a direct tableting, as well as the preparation of solid dispersions by the methods of the melt and spray drying.

Resistance to gastric juice.

2,250 kg hydroxypropylmethylcellulose (NRSR, Pharmacoat HP50) dissolved in a mixture of solvents consisting of 2,50 l of demineralized water, 13,00 l of acetone (Ph.Helv. VII) and 13,00 l 94% ethanol, and the solution is mixed with 0,240 kg of castor oil (Ph.Eur.II). As usual in the boiler for drazhirovanija solution portions is applied or sprayed on the core tablets or applied in the apparatus of the fluidized bed to the design.

After appropriate drying then applied film coating. It consists of 4,800 kg of 12.5% solution of Eudragit E, 0,340 kg of talc (Ph. Eur. II) 0,520 kg of titanium oxide(VI) Cronus RN 56, 0,210 kg paramaka" ZLT-2 blue (Siegle) and 0.120 kg of polyethylene glycol 6000 (Ph.Helv.VII) in a solvent mixture consisting of 8,200 kg propan-2-ol (Ph.Heiv.VII) to 0.060 kg glyceryltrinitrate (Triacetin) and 0.200 kg dimissive and normally polished.

Example 2

Getting resistant to gastric juice capsules containing 86,5 mg of the calcium salt of monoethylfumarate and 110,0 mg dimethylfumarate, which corresponds to 150 mg of fumaric acid

8,650 kg Calcium salt of monoethylfumarate and 11,000 kg dimethylfumarate intensively stirred 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 polyvinylpyrrolidone (Kollidonand 4,000 kg Primogeland , with the appropriate precautions (breathing mask, gloves, protective clothing and so on) homogenized using a sieve 800.

The entire powder mixture using a 2% aqueous solution of polyvinylpyrrolidone (Kollidon25) in the usual way processed into granulate binder in the dried state is mixed with the external phase. It 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 filled capsules in portions of 500.0 mg, which then usual cause resistant to gastric juice coating consisting of hydroxypropylmethylcellulose and castor oil wtye to gastric juice capsules, consisting of a mixture of azettftalat cellulose (CAP) and hydroxypropylmethylcellulose (NRSR).

Example 3

Getting resistant to gastric juice capsules containing 203,0 mg of the calcium salt of monoethylfumarate, 5.0 mg of the magnesium salt of monoethylfumarate and 3.0 mg zinc salt of monoethylfumarate, which corresponds to 150 mg of fumaric acid

20,300 kg Calcium salt of monoethylfumarate and 0.500 kg magnesium salt of monoethylfumarate and 0.300 kg of zinc salts of monoethylfumarate crushed, intensively mixed and with appropriate precautions (breathing mask, gloves, protective clothing and so on) homogenized using a sieve 800. To this mixture of biologically active substances mixed with a homogeneous powder mixture of the following composition: 12,900 kg dried by spray drying of lactose, 1,000 kg of colloidal silicic acid, 2,000 kg of microcrystalline cellulose (Avicel), 1,000 kg of magnesium stearate (Ph.Helv.VII) and 2,000 kg of talc (Ph.Helv.VII). The entire powder mixture is again homogenized with 200 sieve and then bring in hard gelatin capsules servings net weight of 400 mg and close them. Coating resistant to gastric juice coating is carried out, as in PR is asih of 87.0 mg calcium salts, monoethylfumarate, 120,0 mg dimethylfumarate, 5.0 mg of the magnesium salt of monoethylfumarate and 3.0 mg zinc salt of monoethylfumarate, which corresponds in General, 164 mg of fumaric acid ("Forte - tablets).

8,700 kg Calcium salt of monoethylfumarate, 12,000 kg dimethylfumarate, 0.500 kg magnesium salt of monoethylfumarate and 0.30 kg of zinc salts of monoethylfumarate crushed, intensively mixed and with appropriate precautions (breathing mask, gloves, protective clothing and so on) homogenized using a sieve 800. Prepare a mixture of excipients the following composition: 18,00 kg derived starch (STA-RX 1500), 0.30 kg of microcrystalline cellulose (Avicel PH 101), 0.75 kg of polyvinylpyrrolidone (Kollidon 120), 4,00 kg primogel (Primogel), 0.25 kg of colloidal silicic acid (Aerosil). The entire powder mixture is mixed with a mixture of biologically active substances and homogenized with 200 sieve, using a 2% aqueous solution of polyvinylpyrrolidone (Kollidon K usual manner processed into granulate binder in the dried state is mixed with the external phase, which consists of 0.50 kg of magnesium stearate and 1.50 kg of talc. A powder mixture was then usual pressed into convex microtablets gross mA is their methods of making tablets, as a direct tableting, as well as to obtain a solid dispersion methods melt and spray drying.

Resistant to gastric juice, the coating can be applied or sprayed in a conventional boiler for drazhirovanija, as well as in the apparatus of the fluidized bed. To achieve resistance to gastric juice, 2,250 kg heritagepropertyrentals.com { WRMSR; Pharmacoat HP 50) portions dissolved in a mixture of the following solvents: 13,00 l of acetone, 13,50 l 94 wt. % ethanol, denatured with 2% ketone, and of 2.50 l of demineralized water. To a ready solution add 0,240 kg of castor oil as a plasticizer and as usual portions is applied to the core tablets.

Film coating: after drying then in the same apparatus is applied as a film coating suspension of the following composition: 0,340 kg of talc, 0,400 kg of titanium oxide (VI) (Cronus RN 56), 0,324 kg paramaka" (L-Rotlack 86837), 4,800 kg of 12.5% Eudragit E and 0.120 kg of polyethylene glycol 6000 (pH 11 (XI) in a solvent mixture of the following composition: 8,170 kg propan-2-ol, 0,200 kg of demineralised water and 0,600 kg glyceryltrinitrate (Triacetin).

Resistant to gastric juice by microtelecom portions of a net weight of 500.0 mg fill then t is coherent to gastric juice film coating, containing 67,0 mg of the calcium salt of monoethylfumarate, 30.0 mg of dimethylfumarate, 5.0 mg of the magnesium salt of monoethylfumarate and 3.0 mg zinc salt of monoethylfumarate, which corresponds to 75 mg of fumaric acid ("Mita" tablets).

3,000 kg of Dimethylfumarate, 6,700 kg of the calcium salt of monoethylfumarate, 0.500 kg magnesium salt of monoethylfumarate and 0.300 kg of zinc salts of monoethylfumarate crushed, intensively mixed and with appropriate precautions (breathing mask, gloves, protective clothing and so on) homogenized using a sieve 800. In a similar manner as described in example 4, to prepare a mixture of excipients the following composition, namely 30,000 kg derived starch (STA-RX 1500), 3,000 kg of microcrystalline cellulose (Avicel PH 101), 0,750 kg polyvinylpyrrolidone (PVP, Kollidon25), 4,000 kg of primogel (Primogel), 0,250 kg of colloidal silicic acid (Aerosil). Excipients and the mixture of biologically active substances intensively mixed and homogenized by means of a sieve 200. The entire mixture using a 2% aqueous solution of polyvinylpyrrolidone (PVP, Kollidon25) in the usual way processed into granulate binder. To the dried granulate as a researcher is ing (Ph.Eur.) and 0.800 to kg talc (Ph.Eur.II).

Homogeneous granulate mixture in the usual way pressed in the convex core tablets weighing 500.0 mg and a diameter of 11.5 mm, Along with ways to use binders can also find application in other ways tabletting, according to examples 1 and 4. Coating of core tablets resistant to gastric juice coating, and the coating film coating is carried out according to examples 1 and 4.

Preferably the compositions according to the invention is administered orally in the form of tablets or capsules, and these solid dosage forms in the form of a single dose preferably equipped resistant to gastric juice coating, which after passing through the stomach within a few minutes dissolves in the small intestine and from the dosage form is released active principle. For the system "input" "output" requires low dosage ("Mita"), for therapeutic dosage after phase "input" required a higher dosage ("Forte").

Along with oral injected drugs in the form of capsules, granules and tablets of the subject invention are preparations for cutaneous and percutaneous introduction in the form of ointments, plasters, lotions and bath products, drugs for parentela rectal administration in the form of suppositories or microenemas, as well as drugs for medical treatment of hair, nails, fingers and toes.

Example 6

Obtaining tablets resistant to gastric juice film coating containing 100.0 mg of the calcium salt of monomethylfumarate, which corresponds to 78 mg of fumaric acid.

10,000 kg of the Calcium salt of monomethylfumarate crushed, mix, and with appropriate precautions (breathing mask, gloves, protective clothing and so on) homogenized using a sieve 800. Then prepare a mixture of excipients the following composition: 21,000 kg derived starch(STA-RX 1500), 2,000 kg of microcrystalline cellulose (Avicel PH 101), 0,600 kg polyvinylpyrrolidone (PVP, Kollidon25), 4,000 kg of primogel (primogel), 0,300 kg of colloidal silicic acid (Aerosil). The entire powder mixture is mixed with a biologically active substance are mixed, homogenized with 200 sieve and using a 2% aqueous solution of polyvinylpyrrolidone (Kollidon30) in the usual way processed into granulate binder in the dried state is mixed with the external phase. External phase consists of 2,000 kg of the so-called FST-complex, containing 80% talc, 10% CR is m 10 mm Instead of these classical methods tabletting you can also use other ways of getting tablets, as a direct tableting, as well as to obtain a solid dispersion method melt and spray drying. Coating of core tablets resistant to gastric juice coating, and the coating film coating is carried out according to examples 1 and 4.

Example 7

Obtaining tablets with resistant to gastric juice film coating containing 50.0 mg of the calcium salt of monomethylfumarate, 50.0 mg of dimethylfumarate, 5.0 mg of the magnesium salt of monomethylfumarate and 3.0 mg zinc salt of monomethylfumarate, which corresponds to 85 mg of fumaric acid.

5,000 kg of Dimethylfumarate, 5,000 kg of the calcium salt of monomethylfumarate, 0.500 kg magnesium salt of monomethylfumarate and 0.300 kg of zinc salts of monomethylfumarate crushed, intensively mixed and with appropriate precautions (breathing mask, gloves, protective clothing and so on) homogenized using a sieve 800. In a similar manner as described in example 4, to prepare a mixture of excipients the following composition, namely: 19,000 kg derived starch (STA-RX 1500), 3,000 kg of microcrystalline cellulose (Avicel PH 101).

Excipients and the mixture of biologically active substances intensively mixed and homogenized by means of a sieve 200. The entire mixture using a 2% aqueous solution of polyvinylpyrrolidone (PVP, Kollidon25) in the usual way processed into granulate binder in the dried state is mixed with the external phase consisting of 0.500 kg of magnesium stearate (Ph.Eur.) and 1,500 kg of talc (Ph.Eur.II).

All the granulate then usual pressed into convex tablet weight of 400 mg and a diameter of 10 mm Instead of these classical methods tabletting you can also use other ways of getting tablets, as a direct tableting, as well as to obtain a solid dispersion method melt and spray drying.

Coating of core tablets resistant to gastric juice coating, and the coating film coating is carried out, as described in examples 1 and 4.

Example 8

Obtaining tablets with resistant to gastric juice film coating containing 50.0 mg of the calcium salt of mono-n-propylgallate, which corresponds to 32.8 mg of fumaric acid

5,000 kg of the Calcium salt of monopropionate crushed, mix, and when appropriate measures to provide the t of the mixture of excipients the following composition: 25,000 kg derived starch (STA-RX 1500), 3,000 kg of microcrystalline cellulose (Avicel PH 101), 0,600 kg polyvinylpyrrolidone (PVP, Kollidon25), 4,000 kg of primogel (Prirnogel), 0,300 kg of colloidal silicic acid (Aerosil). The entire powder mixture is mixed with a biologically active substance are mixed, homogenized with 200 sieve and using a 2% aqueous solution of polyvinylpyrrolidone (KollidonK30) in the usual way processed into granulate binder in the dried state is mixed with the external phase. External phase consists of 2,000 kg of the so-called FST-complex, containing 80% talc, 10% of the silicic acid and 10% of magnesium stearate. Then as usual pressed convex tablet weight of 400 mg and a diameter of 10 mm Instead of these classical methods tabletting you can also use other ways of getting tablets, as a direct tableting, as well as to obtain a solid dispersion method melt and spray drying. Coating of core tablets resistant to gastric juice coating, and the coating film coating is carried out, as described in examples 1 and 4.

Example 9

Getting resistant to gastric juice granules in capsules containing 50.0 mg calleta corresponds to 45 mg of fumaric acid.

5,000 kg of the Calcium salt of monomethylfumarate, 0,5000 kg magnesium salt of monomethylfumarate and 0.300 kg of zinc salts of monomethylfumarate crushed, intensively mixed and with appropriate precautions (breathing mask, gloves, protective clothing and so on ) homogenized using sieves 400. Along with this, prepare 2 l of 20% (weight/volume) solution of polyvinylpyrrolidone (KollidonK30) in ethanol. Boiler drazhirovanija put 7,250 kg unequal granules and sprinkle part of the solution kollidon K-30 until light moisture. Then added in several portions a mixture of biologically active substances to dry pellets. This cycle of wetting/ drying continues until the final addition of a mixture of biologically active substances. The remainder of the solution of polyvinylpyrrolidone is mixed with determined as 0.720 kg 12,5%-aqueous solution dragit E and this mixture is sprayed granules. The granules are then set in motion until it is fully dry. Instead of this technique, you can also use other methods of obtaining granules, as a coating in the fluidized layer, the extrusion method, spheroidal. Next, you can also get individual biologically active substances and after applying the protective film (see below) primeship lcom. After each cycle the spraying/drying determine the release of biologically active substances and add a 12.5% solution of Eudragit S/talc to ensure release according to the specification.

Resistant to gastric juice granules is then filled capsules (146 mg of granules in the capsule).

Example 10

Getting resistant to gastric juice capsules containing 50.0 mg of the calcium salt of monoisopropylamine, 50.0 mg of Diisopropylamine, 5.0 mg of the magnesium salt of monoisopropylamine and 3.0 mg zinc salt of monoisopropylamine, which corresponds to 67 mg of fumaric acid.

5,000 kg of the Calcium salt of monoisopropylamine, 5,000 kg of Diisopropylamine, 0.500 kg magnesium salt of monoisopropylamine and 0.300 kg of zinc salts of monoisopropylamine crushed, intensively mixed and with appropriate precautions (breathing mask, gloves, protective clothing and so on) homogenized using a sieve 800. To this mixture of biologically active substances mixed with a homogeneous powder mixture of the following composition: 32,200 kg dried by spray drying of lactose, 2,000 kg of microcrystalline cellulose (Avicel) and 1/000 kg of colloidal silicic acid (Aerosil), 1,000 kg is anaut it hard gelatin detachable capsule servings net weight of 500 mg and close them.

These capsules then you can apply resistant to gastric juice coating consisting of hydroxypropylmethylcellulose (NRSR) and castor oil as plasticizer. Instead of hard gelatin capsules powdery mixture can fill in the appropriate resistant to gastric juice capsules consisting of a mixture of azettftalat cellulose (CAP) and hydroxypropylmethylcellulose (NRSR).

Example 11

Getting micro granules in capsules containing 50.0 mg of monomethylfumarate, which corresponds to 44.6 mg of fumaric acid

5,000 kg of Monomethylfumarate crushed and when appropriate precautions vdyhatelnoy mask, gloves, protective clothing and so on) homogenized using sieves 400. Along with this, prepare 2 l of 20% (weight/volume) solution of polyvinylpyrrolidone (Kollidon K30) in ethanol. Boiler drazhirovanija put 7,250 kg unequal granules and sprinkle part of the solution kollidon K-30 until light moisture. Then added in several portions a mixture of biologically active substances to dry pellets. This cycle of wetting/drying continues until the final addition of a mixture of biologically active substances. The granules are then set in motion to full the fluidized layer, method of extrusion/spheroidal. Further, it is also possible to obtain granules with an individual biologically active substances and after applying the protective film to admix in the appropriate proportions.

The pellet is then filled capsules (126,5 mg of granules in the capsule).

Further, by inhibiting the formation of hemagglutinin in the experiment on animals, indicate the efficiency of use according to the invention and compared with the known from the prior art drug.

Investigation of the influence of the dosage form according to example 4 and the calcium salt of monomethylfumarate after oral administration to education hemagglutinin in mice.

By slowing down the formation of hemagglutinin in mice can prove immunosuppressive activity of substances. The test is based on direct haemagglutination, where due to specific antibodies directed against surface antigens of erythrocytes, is visible agglutination of erythrocytes.

Mice subjected to immunization with sheep red blood cells (day 0), then carry out a five-time introduction of the test substance (day 0-4) and on day 9 after immunization determine the level of hemagglutinin. Reduction OBS study of the effects of the dosage form according to example 4 and the calcium salt of monomethylfumarate - after the introduction of orally 150,300 and 600 mg/kg on education hemagglutinin in mice.

This experience was able to confirm dose-dependent suppressive activity of the dosage form based on the quantitative ratios of biologically active substances according to example 4 on the education of hemagglutinin in mice. The effect of total dose of 300 mg/kg of this medicinal forms (introduction combination of biologically active substances 0.8% suspension in an aqueous solution of hydroxypropylmethylcellulose gel-like consistency), respectively, is still in the normal range of variation, in contrast, after administration of 600 mg/kg of the above dosage forms reproducibly detect the inhibition of the formation of hemagglutinin of 29%.

Also for the calcium salt of monomethylfumarate can detect dose-dependent suppressive activity on the formation of hemagglutinin in mice. Dose of 300 mg/kg of the calcium salt of monomethylfumarate leads to a slight decrease in the formation of the ha, whereas after administration of 600 mg/kg of the calcium salt of monomethylfumarate reproducibly detected inhibition of education hemagglutinin 38%.

For comparison spend shooter. . Biological Ef-fets of Cyclosporin A: A New Antilyrophocytic Agent, Biological and Medical Research Division Sandoz Ltd., CH-4002 Basle, Switzerland; Agents and Actions, 6/4, 468-475 (1976)]). At the dose of 150 mg/kg of cyclosporine find a reduction in the formation of hemagglutinin by 37%. At the highest dose of 300 mg of cyclosporine per kg reach inhibiting the formation of hemagglutinin 59%.

The results of these studies allow us to conclude that as the dosage form according to example 4, and also calcium salt of monomethylfumarate show distinct immunosuppressive activity.

Immunosuppressive effects of cyclosporine, among other things, caused by slowing the formation of Th-1 cells. As shown by experiments in vitro, fumarate cause a shift pattern of cytokine of the Th1 type to type Th2 pattern of cytokine.

If you consider how the results of in vivo and experiments in vitro, it should be rational and above all unexpectedly improved using fumarate in transplantation medicine, especially with regard to long-term maintenance therapy.

The hemagglutinin: the name of the substances that cause hemagglutination, v. a. agglutinating antibodies, phytohemagglutinin from viral infections (e.g., surface antigens of viruses.

The hemagglutination: caused by hemagglutinin visible agglutination of red blood cells; as a direct (active) haemagglutination - such is caused by specific antibodies directed against surface antigens of red blood cells or an indirect (passive) haemagglutination - such, after loads of red blood cells with antigen (e.g. viral antigen by haemagglutination virus of typhus, globulin in antiglobulin test) caused by specific antibodies directed against the corresponding antigen. The intensity of haemagglutination (for example, when serological titration hemagglutinine antisera) point in a numeric value (the degree of dilution of the test serum, in which more directly visible to the hemagglutination).

About drug therapy in connection with the readings according to the invention in comparison with the processing of the substances known from the prior art, for example, cyclosporin, which can lead to kidney disorders in a large volume or diseases lymphoproliferative systems, in contrast, derivatives of fumaric acid lead only to temporary disturbances, and only rarely to the more serious side action is thinking always required long-term therapy and long-term prophylaxis in the case of reactions, graft-versus-host or multiple sclerosis, it is of great interest. When combined with cyclosporine derivatives of fumaric acid in an unexpected way can significantly reduce the toxic side effects of the above compounds. The use according to the invention moreover also of great importance when replacing corticoides therapy related, as is well known, with strong side effects.

1. For the treatment of arthritis, multiple sclerosis, reactions, graft versus host disease, juvenile diabetes, Hashimoto thyroiditis, graves disease (graves disease or graves ' disease), systemic lupus erythematosus (SLE), Sjogren syndrome (syndrome Segren), pernicious anaemia and chronic active (= lipoid) hepatitis, containing one or more compounds from the group of salts of sodium, potassium, calcium, magnesium, zinc and iron monoalkyl esters of fumaric acid of General formula

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if necessary, mixed with dialkylamino formula

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moreover, a represents the divalent cation of a number of Sa, SB, Zn or Fe, or a monovalent cation of a number of potassium or sodium and n is 1 or 2 depending on the kind of cation; or one or more compounds from a number of monoalkylamines General formula

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2. Means under item 1, characterized in that it contains calcium salt nanometrology ester of fumaric acid or of monoethylene ester of fumaric acid.

3. Means under item 1, characterized in that it contains one or more salts of calcium, magnesium and zinc monoecious ester of fumaric acid in a mixture with dimethylfumarate.

4. Means under item 1, characterized in that the calcium salt monoalkyl ester of fumaric acid is contained in an amount of from 10 to 300 mg, and the total mass of biologically active compounds is from 10 to 300 mg, while the tool is in the form of tablets or capsules for oral administration.

5. Means under item 1, characterized in that it contains 10-290 wt.h. the calcium salt monoalkyl ester of fumaric acid and 290-10 wt.h. dimethylfumarate, and the total mass of biologically active substances is from 20 to 300 mg, while the tool is in the form of tablets or capsules for oral administration.

6. Means under item 1, characterized in that it contains 10-250 wt.h. the calcium salt monoalkyl ester of fumaric acid, 1-50 wt.h. dimethylfumarate and 1-50 wt.h. zinc salts monoalkyl ester of fumaric acid, and the total mass of biological engineering is a high injection.

7. Means under item 1, characterized in that it contains 10-250 wt.h calcium salt monoalkyl ester of fumaric acid, 250-10 wt.h. dimethylfumarate, 1-50 wt.h. magnesium salts monoalkyl ester of fumaric acid and 1-50 wt.h. zinc salts monoalkyl ester of fumaric acid, and the total mass of biologically active substances is from 30 to 300 mg, while the tool is in the form of tablets or capsules for oral administration.

8. A tool according to any one of paragraphs.1-7, characterized in that it is in the form of granules or microtablets, size or average diameter is in the range from 300 to 2000 μm, in particular in the range from 500 to 1500 μm, or 1000 μm.

9. A tool according to any one of paragraphs.1-8, characterized in that the single dose funds are supplied resistant to gastric juice coating.

 

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