MXPA00007089A - Utilization of alkyl hydrogen fumerates for treating psoriasis, psoriatic arthritis, neurodermatitis and regional enteritis - Google Patents
Utilization of alkyl hydrogen fumerates for treating psoriasis, psoriatic arthritis, neurodermatitis and regional enteritisInfo
- Publication number
- MXPA00007089A MXPA00007089A MXPA/A/2000/007089A MXPA00007089A MXPA00007089A MX PA00007089 A MXPA00007089 A MX PA00007089A MX PA00007089 A MXPA00007089 A MX PA00007089A MX PA00007089 A MXPA00007089 A MX PA00007089A
- Authority
- MX
- Mexico
- Prior art keywords
- fumarate
- microtablets
- alkyl
- use according
- microgranules
- Prior art date
Links
- 201000004681 psoriasis Diseases 0.000 title claims abstract description 13
- 206010011401 Crohn's disease Diseases 0.000 title claims abstract description 8
- 201000009053 neurodermatitis Diseases 0.000 title claims abstract description 7
- 206010037162 Psoriatic arthropathy Diseases 0.000 title claims abstract description 5
- 201000001263 psoriatic arthritis Diseases 0.000 title claims abstract description 5
- -1 alkyl hydrogen Chemical compound 0.000 title abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 title abstract 3
- 239000001257 hydrogen Substances 0.000 title abstract 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims description 18
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical class OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- LDCRTTXIJACKKU-ONEGZZNKSA-N Dimethyl fumarate Chemical compound COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 9
- 229960004419 dimethyl fumarate Drugs 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000002702 enteric coating Substances 0.000 claims 1
- 238000009505 enteric coating Methods 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 239000000969 carrier Substances 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 19
- 235000011087 fumaric acid Nutrition 0.000 description 10
- 239000001530 fumaric acid Substances 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 6
- XLYMOEINVGRTEX-ONEGZZNKSA-M (E)-4-ethoxy-4-oxobut-2-enoate Chemical compound CCOC(=O)\C=C\C([O-])=O XLYMOEINVGRTEX-ONEGZZNKSA-M 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 229940074369 monoethyl fumarate Drugs 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 150000002237 fumaric acid derivatives Chemical class 0.000 description 3
- 231100000486 side effect Toxicity 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 210000002784 Stomach Anatomy 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 230000000977 initiatory Effects 0.000 description 2
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- NKHAVTQWNUWKEO-NSCUHMNNSA-N (E)-4-methoxy-4-oxobut-2-enoic acid Chemical compound COC(=O)\C=C\C(O)=O NKHAVTQWNUWKEO-NSCUHMNNSA-N 0.000 description 1
- 206010003246 Arthritis Diseases 0.000 description 1
- 208000003468 Ehrlich Tumor Carcinoma Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 210000002615 Epidermis Anatomy 0.000 description 1
- 210000004211 Gastric Acid Anatomy 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 229960004857 Mitomycin Drugs 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- 229940071462 Oralone Drugs 0.000 description 1
- 102100010404 PLA2G4A Human genes 0.000 description 1
- 108010058864 Phospholipases A2 Proteins 0.000 description 1
- 241000048284 Potato virus P Species 0.000 description 1
- 206010068760 Ulcers Diseases 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000005409 aflatoxin Substances 0.000 description 1
- 230000000845 anti-microbial Effects 0.000 description 1
- 230000002682 anti-psoriatic Effects 0.000 description 1
- 230000002917 arthritic Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 230000004059 degradation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 150000002238 fumaric acids Chemical class 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229910052500 inorganic mineral Chemical class 0.000 description 1
- 230000003522 irritant Effects 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000011707 mineral Chemical class 0.000 description 1
- 229940005650 monomethyl fumarate Drugs 0.000 description 1
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 230000001185 psoriatic Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Abstract
The invention relates to the utilization of one or more alkyl hydrogen fumerates of general formula (I) in which R is a C1-5 alkyl, optionally mixed with a dialkyl fumerate of formula (II), and optional common pharmaceutical auxiliary agents and carriers for producing a pharmaceutical preparation in the form of microtablets or micropellets. The inventive hydrogen fumerates are used in order to treat psoriasis, psoriatic arthritis, neurodermatitis and regional enteritis.
Description
THE USE OF ACID SMOKES FROM WHOM YOU STOP. TREAT PSORIASIS, SORIATIC ARTHRITIS, NEURODERMATITIS AND REGIONAL ENTERITIS OF CROHN
The present invention relates to the use of the free acid form of certain monoalkyl esters of fumaric acid (alkyl acid fumarates) either alone or in combination with a dialkyl fumarate to prepare a pharmaceutical composition in the form of microtablets for treating psoriasis, psoriatic arthritis, neurodermatitis and regional Crohn's enteritis. *
Pharmaceutical preparations which, as a result of biological degradation after administration, lead to the cycle of citric acid or belong to this cycle are gaining more and more meaning in generally high doses, because it is possible to alleviate or cure cryptogenic diseases with their help. Thus, fumaric acid inhibits the growth of Ehrlich ascites tumors in mice, reduces the toxic effects of Mitomycin C and Aflatoxin [see K. Kuroda, M. Akao, Bioche. Pharmacol. 29, 2839-2844 (1980) / Gann. 72. 777-782 (1981) / Cancer Res. 36. 1900-1903 (1976)] and has both antipsoriatic and antimicrobial effect [C. N. Huhtsnen, J.
Food Sci. 4_8, 1574 (1983) / M.M. Islam, US-A-4, 346.118 / C.A. 97, 161317b (1982)]. When administered by the palenteral route, dermal route or particularly the oral one, the high doses of fumaric acid derivatives previously known for this purpose, such as fumaric acid dihydroxy, fumaramide and fumaronitrile have an unacceptable rate of side effects and high toxicity [P . Hollan, R.G. White, Brit. J. Dermatol. 85, 259-263 (19 * 71) / M. Hagedorn, K.W. Kalkoff, G. Kiefer, K. Baron, J. Hug, J.
Petres, Arch. Derm. Res 254, 67-73, (1975)] in such a way that a therapy has usually had to be indifferent. EP-A-0 188 749 already describes derivatives (salts) of fumaric acid and pharmaceutical compositions containing them for the treatment of psoriasis. Pharmaceutical compositions for treating psoriasis which include a mixture of fumaric acid and other fumaric acid derivatives are known from DE-A-25 30 372. A fumaric acid content is mandatory. DE-A-26 21 214 discloses drugs for treating psoriasis, which contain fumaric acid onoethyl esters and mineral salts thereof as the active ingredient. In addition, EP-A-0 312 697 describes the use of various monoalkyl acid ester salts
Fumárico for the therapy of psoriasis, psoriatic arthritis, neurodermatitis and regional enteritis
Crohn. The use of moonoethyl ester salts of fumaric acid (Ca, Zn, Mg) and dimethyl fumaric acid ester for the treatment of psoriasis is known from the publication "Hautarzt" (1987), 279-285. Since, in a psoriatic epidermis, the activity of phospholipase A2 changed, this enzyme may be stimulated by fumaric acid is a possible explanation of the mechanism of the compositions according to the invention. Surprisingly, we have now found that the treatment of psoriasis with alkyl fumarates even without salt formation can be achieved with a pharmaceutical composition which contains the free acid form of one or more fumarates-
C? -5 and, optionally, excipients and pharmaceutically acceptable carriers presented in the form of microtablets or microgranules. Optionally, those compositions may also contain one or more dialkyl fumarates. Compositions in the form of microtablets or microgranules allow the administration of the free acid in place of its salt without the side effects occurring.
known, especially the formation of ulcers. This is probably due to the fact that the microtablets or microgranules allow a uniform distribution in the stomach, thus avoiding the local irritant concentrations of the monoalkyl acid fumarate in the form of free acid. The compositions containing the free acid of the alkyl acid fumarate in an amount of 20 to 300 mg are particularly suitable for oral administration, the total weight of the active ingredients being
100 to 300 mg. For a systemic initiation of therapy or cessation thereof, respectively, a low dose containing 100 of 120 mg of active ingredient, for example 30.0 mg to 35.0 mg of dimethyl fumarate and
70 to 90 mg of methyl acid fumarate. From 190 to 210 mg of active ingredient, for example in the form of 120.0 mg of dimethyl fumarate and 90.0 mg of monoethyl fumarate, are an example of a therapeutic dose after the initial phase. The compositions according to the invention are administered orally in the form of microtablets or microtablets or encapsulated microgranules, the unique solid dosage dosage forms are dissolved in the stomach within a few
minutes and uniformly release the active ingredients of the pharmaceutical form. A lower dose is required for the initiation or cessation of systemic treatment and a higher dose for therapeutic treatment after the initial phase. The microtablets according to the invention are made by methods known in the art, such as granulation, sieving, extrusion / spheronization and the like. In addition to the active ingredient, they may contain the customary excipients and carriers such as lactose, PVP and the like. The microtablets or microgranules preferably have a size of 300-2000 μm, preferably of 500 to 1,500 μm and still preferably more preferably 1000 μm. To facilitate the administration of the single dose, the microtablets or microgranules can be encapsulated, for example in gelatin capsules. Optionally, microtablets or microgranules may be provided with a coating which is resistant to gastric acid. Such a coating can be applied with the known processes, for example by application or spraying in a fluidized bed apparatus or in the form of a film coating.
Example Production of encapsulated microgranules containing 50.0 mg of methyl fumarate acid (corresponding to a total of 44.6 mg of fumaric acid) Taking the necessary precautions (respirator mask, gloves, protective suit), 5,000 kg of acid fumarate are comminuted. methyl by means of a # 400 sieve and homogenized. In addition, 2 1 of a solution of 20% poivinylpyrrolidone (m / v) (Kollidon K30) in ethanol are prepared. 7.250 kg of Nonpareilles granules are introduced in a coating pan and sprayed with part of the Kollidon K-30 solution until slightly moistened. The active ingredient mixture is then added until the granules are dry. This humidification / drying process is continued until all the active ingredient mixture has been added. Finally, the granules move around until finally dried. After that, the granules are filled into a hard gelatin capsule (126.5 mg granule's / capsule). It was found that the preparations according to the invention have an effect similar to that of the preparations containing the known fumaric acid derivatives in salt form against various, clinical forms of psoriasis, psoriasis
arthritic, neurodermatitis and regional Crohn's enteritis (Crohn's disease), but are free from the known side effects of the administration of the free acid.
Acute toxicity test Prior to the clinical trial, the acute toxicity of methyl acid fumarate was tested by oral administration in rats. The results show a very low toxicity of the fumaric acids used (see Table 2). Table 1 Acute toxicity in rats (oral administration)
Pharmaceutical Equivalence Comparison of the pharmacokinetic data of Fumaderm forte (example 4 of European Patent 0 312 697 Bl) and monomethyl fumarate or monoethyl fumarate, respectively, as calcium salts.
Table 2 Equivalence
Fumaderm forte: This mixture contains 120 mg of dimethyl fumarate, 87 mg of monoethyl fumarate's calcium salt, 5 mg of magnesium salt of monoethyl fumarate, 3 mg of zinc salt of monoethyl fumarate. It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (7)
- CLAIMS Having described the invention as above, the content of the following claims is claimed as property. 1. The use of one or more alkyl acid fumarates of the general formula
- H COOH \ / C = C / \ ROOC H characterized in that R is C 5 alkyl, optionally in mixture with dialkyl fumarate of the formula
- H alkyl of COO-C -C. { \ / C = C \ OOC-C ^ C / H alkyl and optionally customary excipients and pharmaceutical carriers for preparing a pharmaceutical composition in the form of microtablets or microgranules to treat psoriasis, psoriatic arthritis, neurodermatitis and regional Crohn's enteritis. 2. The use according to claim 1, characterized in that methyl acid fumarate is used. 3. The use according to claim 1, characterized in that methyl acid fumarate mixed with dimethyl fumarate is used.
- 4. The use according to any of claims 1 to 3, for preparing a pharmaceutical composition for oral administration in the form of microtablets or microgranules, characterized in that the total weight of the active ingredients is from 20 to 300 mg. The use according to claims 1 to 4, characterized in that the preparation contains from 10 to 290 parts by weight of methyl fumarate and from 290 to 10 parts by weight of dimethyl fumarate. 6. The use according to any of the preceding claims for preparing a pharmaceutical composition for oral administration, characterized in that the microtablets or microgranules are provided with an enteric coating. The use according to any of the preceding claims, characterized in that the microtablets or microgranules have a size of 300 to 2,000 μm.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19814358.3 | 1998-03-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA00007089A true MXPA00007089A (en) | 2001-06-26 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU745281B2 (en) | Utilization of alkyl hydrogen fumerates for treating psoriasis, psoriatic arthritis, neurodermatitis and regional enteritis | |
AU696402B2 (en) | Oral 1alpha-hydroxyprevitamin D | |
DE19848260C2 (en) | Fumaric microtablets | |
US4959389A (en) | Pharmaceutical preparation for the treatment of psoriatic arthritis | |
DE602004010531T2 (en) | USE OF FUMIC ACID DERIVATIVES FOR THE TREATMENT OF HEART FAILURE AND ASTHMA | |
EP0804239B1 (en) | Anti-stress, anti-impairment and anti-aging drug and process for manufacturing thereof | |
EP0147741B1 (en) | Pharmaceutical composition with special 1,2-diacyl-glycero-3-phosphocholines for the treatment of diseases of the stomach and the intestines | |
DE3705549A1 (en) | USE OF PYRIDOXINE DERIVATIVES IN THE PROPHYLAXIS AND THERAPY OF HYPERLIPIDAEMIA AND ATHEROSCLEROSIS | |
LU86291A1 (en) | PHARMACEUTICAL PREPARATIONS WITH ANALGETIC EFFECTIVENESS, AND THEIR PRODUCTION AND USE | |
RU2152787C2 (en) | Drug against stress, activity level decrease and ageing and method of its preparing | |
JPS63152321A (en) | Lipid regulating composition | |
MXPA00007089A (en) | Utilization of alkyl hydrogen fumerates for treating psoriasis, psoriatic arthritis, neurodermatitis and regional enteritis | |
DE2806866A1 (en) | PHARMACEUTICAL PRODUCTS AND THEIR USE FOR PREVENTING HARMFUL SIDE EFFECTS OF ALKYLANTIC CYTOSTATICS | |
RU2084181C1 (en) | Method of preparing biologically active propolis food addition | |
JPH08208464A (en) | Agent for treatment and prevention of hyperlipemia | |
GB2234898A (en) | Oral pharmaceutical dosage form improving bioavailability | |
MXPA99010703A (en) | Use of fumaric acid derivatives | |
CS255226B1 (en) | Entrosolvent tablets containing sodium fluoride with its controlled releasing | |
IL88011A (en) | Pharmaceutical preparation for the treatment of psoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalis crohn comprising salts of monoalkyl esters of fumaric acid |