CA2346438C

CA2346438C - Utilisation of dialkylfumarates for treating host-versus-graft reactions and auto-immune diseases

Info

Publication number: CA2346438C
Application number: CA002346438A
Authority: CA
Inventors: Rajendra K. Joshi; Hans-Peter Strebel
Original assignee: Fumapharm AG
Current assignee: Biogen International GmbH
Priority date: 1998-11-19
Filing date: 1999-10-29
Publication date: 2006-10-03
Anticipated expiration: 2019-10-29
Also published as: EP1131065A2; HUP0103182A3; AU1157200A; CN1182844C; NO20011242L; EE04389B1; TR200101204T2; BG105396A; FR14C0051I2; US20090181085A1; HK1042242A1; JP2019123738A; PT1131065E; HU226689B1; CN1615839A; SK285601B6; PL348147A1; BE2014C040I2; US20140066505A1; HK1042242B

Abstract

The present invention relates to the use of certain dialkyl fumarates for the preparation of pharmaceutical preparations for use in transplantation medicine or for the therapy of autoimmune diseases and said compositions in the form of micro-tablets or pellets. For this purpose, the dialkyl fumarates may also be used in combination with conventional preparations used in transplantation medicine and immunosuppressive agents, especially cyclosporines.

Description

The Use of Dialkyl Fumarates Description The present invention relates to the use of dialkyl fu-marates for preparing pharmaceutical preparations for use in transplantation medicine or the therapy of auto-immune diseases and pharmaceutical preparations in the form of micro-tablets or micro-pellets containing dial-kyl fumarates.
On the one hand, therefore, it relates especially to the use of dialkyl fumarates for preparing pharmaceuti-cal preparations for the treatment, reduction or sup-pression of rejection reactions of the transplant by the recipient, i.e. host-versus graft reactions, or re-jection of the recipient by the transplant, i.e. graft-versus-host reactions. On the other hand, it relates to the use of dialkyl fumarates for preparing pharmaceuti-cal preparations for treating autoimmune diseases such as polyarthritis, multiple sclerosis, juvenile-onset diabetes, Hashimoto's thyroiditis, Grave's disease, systemic Lupus erythematodes (SLE), Sjogren's syndrome, pernicious anaemia and chronic active (= lupoid) hepa-titis.
Both graft rejection and autoimmune diseases are based on medically undesirable reactions or dysregulation of the immune system. Cytokins such as interleukins or tu-mour necrose factor a (TNF-a) are substantial mediators influencing the immune system. In general, both are treated by the administration of immunosuppressive agents such as cyclosporine.

2 In the overall result, autoimmune diseases may be de-fined as the failure of the tolerance of endogenic sub-stances or antigens. As a rule, this tolerance can be maintained only if the antigens keep coming into con-tact with immunological cells. When this tolerance is lost, autoantibodies are formed, i.e. a humoral immu-noresponse against endogenic tissue. The exact nature of the involvement of TNF-a is not known.
Transplantations are tissue or organ transplantations, i.e. the transfer of tissues such as cornea, skin, bones (bone chips), vessels or fasciae, of organs such as kidney, heart, liver, lung, pancreas or intestines, or of individual cells such as islet cells, a-cells and liver cells, the kidney having the greatest signifi-cance as a transplanted organ.
According to the degree of relationship between the do-nor and the recipient we differentiate between auto-transplantation (transfer to another part of the body of the same individual), iso-transplantation (transfer to another, genetically identical individual) and al-logenic transplantation (transfer to another individual of the same species). Depending on the site of origin and transplantation, we further differentiate between homotopic transplantation (transfer to the same site) and heterotopic transplantation (transfer to a differ-ent site). The above-mentioned trans;plantations play an important role in modern medicine.
A major problem in transplantation medicine is graft rejection after transplantation of the tissue, organ or cell by immunological defence reactions of the recipi-ent. Such a graft rejection is also called host-versus-graft reaction. The immunological defence reaction of the organism against the heteroprotein often results in rejection or dissolution of the grafts. In host-v~~'~sii~s-

3 graft reactions, different stages may be distinguished.
Depending on the degree of difference between the re-cipient and the donor, this reaction takes place at different speeds so that we speak of an acute, sub-acute or chronic reaction. The acute rejection process is accompanied by the irreversible loss of the trans-plant (necrotisation) as a result of arteriitis or ar-teriolitis within 48 hours and cannot be influenced by the administration of drugs. The sub-acute rejection reaction becomes manifest as a rejection crisis from day 12 to month 4 with reversible functional disorders as a result of a transplant vasculop~athy. Finally, the loss of function of the transplant as a result of vas-cular changes such as obliterating arteriopathy, which proceeds over weeks or years and can. practically not be influenced by drugs, is termed a chronic rejection re-action.
Vice-versa, rejection reactions of the transplant against the recipient, the so-called. graft-versus-host reactions, may occur when immunocomp~etent tissues are transplanted, i.e. primarily in bone marrow transplan-tation. Again, the severity of the reaction is graded, and substantially similar complications result as in host-versus-graft-reactions, namely arteriopathies and necroses.
To avoid such rejection reactions, i.e. the host-versus-graft reaction and the graft-versus-host reac-tion, transplantation medicine essentially makes use of immunosuppression, i.e. a weakening of the normal immu-noresponse. For this purpose, anti-lymphocyte sera are often used in combination with corticosteroids and so-called anti-metabolites, e.g. purine analogues such as 6-mercaptopurine and thioguanine which affect the nu-cleic acid and protein synthesis and thus prevent cell division and proliferation. This leads to suppression

4 of the production of antibodies and the cellular immune response. The immunosuppressive agents used for therapy are substances which suppress or weaken the immunoreac-tion in the body either specifically or non-specifical-ly. Non-specific immunosuppressive agents are cyto-static agents such as, for example, alkylating agents or antimetabolites.
In addition, active ingredients are known which cause at least partial specific immunosuppression, such as corticosteroids, antisera, antibodies FK-506, tacro-limus, mycophenolatemofetil and primarily cyclosporines such as cyclosporine A. As a result of using modern im-munosuppressive agents, the most important representa-tives of which are the cyclosporines, especially cyc-losporine A, it was possible to improve the results of transplantation considerably over the last few years.
At present, the survival rate after one year is about 60 o for liver transplantations, about 80 o for heart transplantations and over 90 % for kidney transplanta-tions.
Autoimmune diseases where the endogenic immune system attacks endogenic organs, tissues and cells are compa-rable to graft-versus-host reactions. These are also medically undesirable reactions of t:he immune system which may be treated with immunosuppressive agents, too.
The danger in using immunosuppressive agents lies in weakening the body's defence against. infectious dis-eases and the increased risk of malignant diseases.
Therefore, it is the object of the invention to provide a pharmaceutical preparation to be employed in trans-plantation medicine which may be used to treat, espe-cially to suppress, weaken and/or alleviate host-v~rx:-,.-

5 sus-graft reactions and graft-versus;-host reactions, but does not have the above disadvantage.
It is another object of the invention to provide a pharmaceutical preparation which may be employed for treating autoimmune diseases, particularly polyarthri-tis, multiple sclerosis, juvenile-onset diabetes, Hashimoto's thyroiditis, Grave's dig>ease, systemic Lu-pus erythematodes (SLE), Sjogren's ~>yndrome, pernicious anaemia and chronic active (= lupoid) hepatitis, with-out the disadvantages of immunosuppression.
The object of the invention is achieved by using cer-tain dialkyl fumarates for preparing pharmaceutical preparations for use in transplantation medicine and for the therapy of autoimmune diseases and pharmaceuti-cal preparations in the form of micro-tablets and mi-cro-pellets containing these dialkyl. fumarates. The in-dividual subject matters of the invention are charac-terised in detail in the claims. The preparations ac-cording to the invention do not contain any free fuma-ric acids per se.
It is known that pharmaceutical preparations which, upon biological degradation after administration, enter into the citric acid cycle or are part thereof gain in-creasing therapeutic significance - especially when given in high dosages - since they c:an alleviate or heal diseases caused cryptogenetical_ly.
Fumaric acid, for example, inhibits the growth of the Ehrlich ascites tumour in mice, reduces the toxic ef-fects of mitomycin C and aflatoxin and displays anti-psoriatic and anti-microbial activit:y. When adminis-tered parenterally, transdermally and especially per-orally, high dosages of fumaric acid or its derivatives known so far such as dihydroxyl fumaric acid, fumar-

6 amide and fumaronitrile have such unacceptably severe side effects and high toxicity that, in most cases, such a therapy had to be abandoned in the past.
Surprisingly, investigations carried out by the appli-cant have shown that methyl hydrogen fumarate, a meta-bolite of the dimethyl fumarate, initially increases the endotoxin-stimulated TNF-a secretion in human mono-nuclear cells of periphere blood (periphere blood mono-nuclear cells = PBMC cells) and in isolated monocytes.
In addition, the applicant was able to show that fuma-ric acid has an effect on in vitro and in vivo haemag-glutination which is comparable to that of cyclospo-rine.
Surprisingly, it has now been found that dialkyl fuma-rates are advantageous for preparing pharmaceutical compositions for use in transplantation medicine and for the therapy of autoimmune diseases. This is because compositions containing such dialkyl. fumarates surpris-ingly permit a positive modulation of the immune system in host-versus-graft reactions, graft-versus-host reac-tions and other autoimmune diseases.
European Patent Application 0 188 799 already describes fumaric acid derivatives and pharmaceutical composi-tions containing the same for the treatment of psoria-sis. Pharmaceutical compositions for the treatment of psoriasis containing a mixture of fumaric acid and other fumaric acid derivatives are ~;nown from DE-A-25 30 372. The content of free fumaric acid is obliga-tory for these medicaments.
DE-A-26 21 219 describes medicaments containing the fumaric acid monoethyl ester and its mineral salts as active ingredient for the treatment of psoriasis. The publication "Hautarzt (Dermatologist.) (1987) 279 -T

7 285" discusses the use of fumaric acid monoethyl ester salts. Pharmaceutical preparations containing a mix-ture of fumaric acid monoalkyl ester salts and a fuma-ric acid diester for the treatment of psoriasis, pso-riatic arthritis, neurodermatitis and enteritis re-gionalis Crohn are known from EP 0 ?.12 697 B,1.
Specifically, the object of the invention is achieved by the use of one or more dialkyl fumarates of the for-mula C = C

wherein R1 and R2, which may be the same or different, independently represent a linear, branched or cyclic, saturated or unsaturated Cl_2o alkyl radical which may be optionally substituted with halogen (C1, F, I, Br), hydroxy, C1_4 alkoxy, nitro or cyano for preparing a pharmaceutical preparation for use i.n transplantation medicine or for the therapy of autoi.mmune diseases.
The C1_2o alkyl radicals, preferably Cl_8 alkyl radi-cals, most preferably C1_5 alkyl radicals are, for ex-ample, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethyl hexyl, hexyl, cyclohexyl, heptyl, cyclohept:yl, octyl, vinyl, allyl, 2-hydroxy ethyl, 2 or 3-hydroxy propyl, 2-methoxy ethyl, methoxy methyl or 2- or 3-methoxy pro-pyl. Preferably at least one of the radicals R1 or R2 is C1_5 alkyl, especially methyl or Ethyl. More pref-erably, R1 and R2 are the same or different C1_~ alkyl radicals such as methyl, ethyl, n-propyl or t-buty.l.', methyl and ethyl being especially preferred. Most pre.f-

8 erably, R1 and R2 are identical and are methyl or ethyl. Especially preferred are the dimethyl fumarate, methyl ethyl fumarate and diethyl fumarate.
The dialkyl fumarates to be used according to the in-vention are prepared by processes known in the art (see, for example, EP 0 312 697).
Preferably, the active ingredients are used for prepar-ing oral preparations in the form of tablets, micro-tablets, pellets or granulates, optionally in capsules or sachets. Preparations in the form. of micro-tablets or pellets, optionally filled in capsules or sachets are preferred and are also a subject matter of the in-vention. The oral preparations may be provided with an enteric coating. Capsules may be soft or hard gelatine capsules.
The dialkyl fumarates used according to the invention may be used alone or as a mixture of several compounds, optionally in combination with the customary carriers and excipients. The amounts to be used are selected in such a manner that the preparations obtained contain the active ingredient in an amount corresponding to 10 to 300 mg of fumaric acid.
Preferred preparations according to the invention con-tain a total amount of 10 to 300 mg of dimethyl fuma-rate and/or diethyl fumarate.
According to a preferred embodiment, the size or the mean diameter, respectively, of the pellets or micro-tablets is in the range from 300 to 2,000 um, espe-cially in the range of 500 or 1,000 um.

9 In addition to graft-versus-host reactions (see above), the following autoimmune diseases to be treated may be named: polyarthritis, multiple sclerosis, graft-versus-host reactions, juvenile-onset diabetes, Hashimoto's thyroiditis, Grave's disease, systemic Lupus erythema-todes (SLE), Sjogren's syndrome, pernicious anaemia and chronic active (lupoid) hepatitis. Autoimmune diseases in a wider meaning also comprise psoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalis Crohn.
In addition to the preparations for peroral administra-tion in the form of micro-pellets, micro-tablets, cap-sules (such as soft and hard gelatine capsules), granu-lates and tablets cited above, suitable pharmaceutical preparations are preparations for cutaneous and trans-dermal administration in the form of ointments, plas-ters, lotions or shower preparations and for parenteral administration in the form of aqueous micro-disper-sions, oil-in-water emulsions or oily solutions for rectal administration of suppositories or micro-enemas.
Pharmaceutical preparations in the form of micro-tab-lets or micro-pellets are preferred for the therapy of all autoimmune diseases mentioned above, including pso-riasis, psoriatic arthritis, neurodermatitis and ente-ritis regionalis Crohn and are also a subject matter of the invention.
According to the invention, a therapy with dialkyl fu-marates may also be carried out in combination with one or more preparations of the triple drug therapy custom-arily used in organ transplantations or with cyclospo-rine A alone. For this purpose, the preparations admin-istered may contain a combination of the active ingre-dients in the known dosages or amounts, respectively.
Likewise, the combination therapy may consist of the parallel administration of separate preparations by t same or different routes. Optionally, the dosage of the active ingredient contained in addition to the dose of the fumaric acid derivative administered in accordance with the inventin may be reduced advantageously.
Another embodiment of the use according to the inven-tion is to alternate the drug therapy with immunosup-pressive agents such as cyclosporine in sequence with an application of the above-mentioned dialkyl fumarate.
This means that an application of fumaric acid deriva-tives as defined above over one or more weeks may fol-low a cyclosporine therapy of one or more weeks. This permits reduction of the Cyclosporine A dosage result-ing in a considerable decrease of th.e rate of side ef-fects in long-term therapy.
By administration of the dialkyl fumarates in the form of micro-tablets, which is preferred., gastrointestinal irritations and side effects, which are reduced already when conventional tablets are administered but is still observed, may be further reduced vis-a-vis fumaric acid derivatives and salts.
It is presumed that, upon administration of conven-tional tablets, the ingredients of the tablet are re-leased in the intestine in a concentration which is too high, causing local irritation of th.e intestinal mucous membrane. This local irritation results in a short-term release of very high TNF-a concentrations which may be responsible for the gastrointestinal side effects. In case of application of enteric-coated micro-tablets in capsules, on the other hand, very low local concentra-tions of the active ingredients in the intestinal epithelial cells are achieved. The micro-tablets are incrementally released by the stomach and passed into the small intestine by peristaltic movements so that distribution of the active ingredients is impr.dved.

This means that enteric-coated micro-tablets in the same dosage are distributed already in the stomach and passed to the intestine in portions, where the active ingredients are released in smaller dosages. This avoids local irritation of the intestinal epithelial cells and the release of TNF-a. It is assumed that this results in the improved tolerance of micro-tablets in the gastrointestinal tract vis-a-vis conventional tab-lets.
In addition, resorption is improved, because the dial-kyl fumarates to be used according to the invention are not the active ingredient per se, but a so-called pro-drug, which must be converted into the active ingredi-ent in the body.
In order to illustrate the use according to the inven-tion, different examples for preparing preferred drugs are given below.
Production examples In principle, the oral preparations according to the invention in the form of tablets or micro-tablets may be prepared by classical tabletting processes. Instead of such classical tabletting processes, other methods for the preparation of tablets may be used, such as di-rect tabletting and processes for preparing solid dis-persions in according with the melt method and the spray drying method.
The tablets may be provided with an enteric coating.
The enteric coating may be applied in a classical coat-ing pan or sprayed on or applied in a fluidised bed ap-paratus. The tablet may also be provided with a film coat.

. 12 Example 1 Preparation of enteric-coated micro-tablets in capsules containing 120.0 mg of dimethyl fumarate, which corre-s~onds to 96 mg of fumaric acid Taking the necessary precautions (breathing mask, gloves, protective clothing, etc.), 12.000 kg of di-methyl fumarate are crushed, mixed and homogenised by means of a sieve 800. Then an excipient mixture with the following composition is prepared: 17.50 kg of starch derivative (STA-RX~ 1500), 0.30 kg of micro-crystalline cellulose (Avicel~ PH 101), 0.75 kg of PVP
(Kollidon~ 120), 4.00 kg of Primogel0, 0.25 kg of col-loidal silicic acid (Aerosil~). The active ingredient is added to the entire powder mixture, mixed, homoge-nised by means of a sieve 200, processed in the usual manner with a 2 % aqueous solution of polyvidon pyr-rolidone (Kollidon~ K25) to obtain a binder granulate and then mixed in the dry state with the outer phase.
Said outer phase consists of 0.50 kg of Mg stearate and 1.50 kg of talcum.
Then the powder mixture is compressed in the usual man-ner to obtain convex tablets having a gross weight of

10.0 mg and a diameter of 2.0 mm.
One example to achieve resistance to gastric acid is to dissolve a solution of 2.250 kg of hydroxy propyl methyl cellulose phthalate (HPMCP, Pharmacoat~ HP 50) in portions in a mixture of the following solvents:
13.00 1 of acetone, 13.50 1 of ethanol (94 wt.-o, dena-tured with 2 0 of ketone) and 1.50 1 of demineralised water. As a plasticiser, castor oil (0.240 kg) is added to the finished solution and applied in portions onto the tablet cores in the customary manner.

After drying is completed, a suspension of the follow-ing composition is applied as a filrr~ coat in the same apparatus: 0.340 kg of talcum, 0.400 kg of titanium(VI) oxide Cronus RN 56, 0.324 kg of coloured lacquer L-Rot-lack 86837, 4.800 kg of Eudragit E 12.5 % and 0.120 kg of polyethylene glycol 6000, pH 11 XI in a solvent mix-ture of the following composition: 8.170 kg of 2-propa-nol, 0.200 kg of demineralised water and 0.600 kg of glycerine triacetate (Triacetin).
After that the enteric-coated micro-tablets are filled into hard gelatine capsules having a net weight of 400 mg and sealed.
Example 2 Preparation of enteric-coated micro-tablets in capsules containing 120.0 mg of dimethyl fumarate, which corre-sponds to 96 ma of fumaric acid 12.000 kg of dimethyl fumarate are crushed and homoge-nised as above. Then an excipient mixture composed as follows is prepared: 23.20 kg of microcrystalline cel-lulose (Avicel~ PH 200), 3.00 kg of Croscarmellose so-dium (AC-Di-SOL-SD-711), 2.50 kg of talcum, 0.10 kg of anhydrous silica (Aerosil~ 200) and 1.00 kg of Mg stearate. The active ingredient is then added to the entire powder mixture and mixed homogenously. By means of direct tabletting, the powder mixture is then pressed into convex tablets having a gross weight of 10.0 mg and a diameter of 2.00 mm.
After that, a solution of 0.94 Eudragit~ L in isopropa-nol is prepared which also contains 0.07 kg of dibutyl phthalate. This solution is sprayed onto the tablet cores. After that, a dispersion of 17.32 kg of Eudragit~ L D-55 and a mixture of 2.80 kg of m ,~;t~-~~~
. ~ L
J ci.:.: , talcum, 2.00 kg of Macrogol 6000 and 0.07 kg of dimeti-con in water is prepared and sprayed onto the cores.
Next, the enteric-coated micro-tablets are filled into hard gelatine capsules having a net weight of 650 mg and sealed.
Example 3 Preparation of micro-pellets in cap~~ules containing 50.0 mg of dimethyl fumarate, which corresponds to 40 mg of fumaric acid 5.000 kg of dimethyl fumarate are crushed and homoge-nised as above. In addition, 2 1 of a 20 0 (m/v) poly-vinyl pyrrolidone solution (Kollidon K-30) in ethanol are prepared. 7.250 kg of nonpareill.es pellets in a coating pan are sprayed with part of the Kollidon K-30 solution until slightly humid. Then the active ingredi-ent is added in portions until the pellets are dry.
This procedure of humidification/drying is continued until all of the active ingredient mixture has been added. Then the pellets are moved around until com-pletely dry.
After that, the pellets are filled into hard gelatine capsules (126.5 mg pellets/capsule).
Example 4 Preparation of enteric-coated capsules containing 110.0 mg of dimethyl fumarate, which corresponds to 88 mg of fumaric acid

11.000 kg of dimethyl fumarate are intensely mixed in a mixture consisting of 19.00 kg of starch, 5.65 kg of lactose, 2.00 kg of microcrystalline~ cellulose (Avi-cel~), 1.00 kg of polyvinyl pyrrolidone (Kollidon~ 25) and 2.443 kg of Primogel~ and, taking the necessary precautions (breathing mask, gloves, protective cloth-ing), homogenised by means of a sieve 800.
Using a 2 % aqueous solution of polyvinyl pyrrolidone (Kollidon~ K25), the entire powder mixture is processed into a binder granulate in the customary manner and mixed with the outer phase when dry. Said outer phase consists of 0.350 kg of colloidal silicic acid (Aero-sil~), 0.500 kg of Mg stearate and 1.500 kg of talcum.
The homogenous mixture is filled into suitable capsules in portions of 400 mg which are then provided with an enteric coating consisting of hydroxy propyl methyl cellulose stearate and castor oil as plasticiser in the customary manner. Instead of using hard gelatine cap-sules, the product may also be filled into suitable en-teric-coated capsules consisting of a mixture of cellu-lose acetate phthalate (CAP) and hydroxy propyl methyl cellulose phthalate (HPMCP).
In comparison with substances of the prior art such as cyclosporine, which may cause massive kidney disorders or diseases of the lymphoproliferative system, a ther-apy with fumaric acid derivatives according to the in-vention for the indications listed above rarely results in serious side effects.
Among other things, the immunosuppressive effect of cyclosporine is caused by the inhibition of Th-1 cell formation. As in vitro experiments of the applicant have shown, fumarates cause a shift of the cytokine pattern of the Thl type to the cytokine pattern of the Th2 type.
Especially in view of the long-term therapy and preven-tion which is always necessary in graft-versus-host re-actions and host-versus-graft reactions or other auto-immune diseases such as multiple sclerosis, the unex~ r-;, r, P J' .. T ...
r, pected effect of the use according t:o the invention is of the greatest interest. In a combination therapy of cyclosporine with the fumaric acid derivatives, the toxic side effects of the former compounds may be unex-pectedly reduced to a substantial degree. In addition, the use according to the invention i.s also significant in the substitution of the corticost:eroid therapy of autoimmune diseases which is known t:o be accompanied by severe side effects.

Claims

CLAIMS:

1. The use of one or more dialkyl fumarates for preparing a pharmaceutical preparation for treating host-versus-graft reactions or graft-versus-host reactions in organ and cell transplantation.

2. The use of one or more dialkyl fumarates for preparing a pharmaceutical preparation for the therapy of autoimmune diseases selected from the group consisting of juvenile-onset diabetes, Hashimoto's thyroiditis, Grave's disease, systemic Lupus erythematodes (SLE), Sjogren's syndrome, pernicious anaemia and chronic active (lupoid) hepatitis.

3. The use according to claim 1 or 2 of one or more dialkyl fumarates of the formula wherein R1 and R2, which may be the same or different, independently represent a linear, branched or cyclic, saturated or unsaturated C1-20 alkyl radical which may be optionally substituted with halogen (Cl, F, I, Br), hydroxy, C1-4 alkoxy, nitro or cyano for preparing a pharmaceutical preparation for use in transplantation medicine or for the therapy of autoimmune diseases selected from the group consisting of juvenile-onset diabetes, Hashimoto's thyroiditis, Grave's disease, systemic Lupus erythematodes (SLE), Sjogren's syndrome, pernicious anaemia and chronic active (lupoid) hepatitis.

4. The use according to claim 3, characterised in that the radicals R1 and R2 are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethyl hexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxy ethyl, 2-hydroxy propyl, 3-hydroxy propyl, 2-methoxy ethyl, methoxy ethyl, 2-methoxy propyl or 3-methoxy propyl.

5. The use according to claim 3 or 4, characterised in that R1 and R2 are identical and represent methyl or ethyl.

6. The use according to any one of the claims 1 to 5 where the dialkyl fumarates are formulated into an oral preparation in the form of tablets, microtablets, pellets or granulates, optionally in capsules or sachets.

7. The use according to claim 6, characterised in that the size or the mean diameter, respectively, of the pellets or micro-tablets is in the range of 300 to 2,000 um.

8. The use according to any one of claims 1 to 7, characterised in that the preparation is present in the form of soft or hard gelatine capsules.

9. The use according to any one of the claims 1 to 8 where the preparation contains an amount of the dialkyl fumarates corresponding to 10 to 300 mg of fumaric acid.

10. The use according to any one of claims 6 to 9, characterised in that the dosage units of the preparations are provided with an enteric coating.

11. The use according to any one of the claims 1 to 5, characterised in that the dialkyl fumarates are used in the form of preparations for cutaneous and transdermal administration, preparations for parenteral administration and preparations for rectal administration.

12. Pharmaceutical preparation in the form of microtablets or pellets comprising one or more dialkyl fumarates of the formula wherein R1 and R2, which may be the same or different, independently represent a linear, branched or cyclic, saturated or unsaturated C1-20 alkyl radical which may be optionally substituted with halogen (Cl, F, I, Br), hydroxy, C1-4 alkoxy, nitro or cyano, and suitable carriers and excipients for use in transplantation medicine or for the therapy of autoimmune diseases selected from the group consisting of polyarthritis, multiple sclerosis, juvenile-onset diabetes, Hashimoto's thyroiditis, Grave's disease, systemic Lupus erythematodes (SLE), Sjogren's syndrome, pernicious anaemia, chronic active (lupoid) hepatitis, psoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalis Crohn.

13. A preparation according to claim 12 comprising dimethyl fumarate, diethyl fumarate or methylethyl fumarate.

14. A preparation according to claim 12 or 13 comprising an amount of the dialkyl fumarates corresponding to 10 to 300 mg of fumaric acid.

15. The use of one or more dialkyl fumarates to prepare a pharmaceutical preparation in the form of micro-tablets or pellets for the therapy of autoimmune diseases selected from the group consisting of polyarthritis, multiple sclerosis, juvenile-onset diabetes, Hashimoto's thyroiditis, Grave's disease, systemic Lupus erythematodes (SLE), Sjogren's syndrome, pernicious anaemia and chronic active (lupoid) hepatitis.

16. The use according to claim 15 of one or more dialkyl fumarates of the formula wherein R1 and R2, which may be the same or different, independently represent a linear, branched or cyclic, saturated or unsaturated C1-20 alkyl radical which may be optionally substituted with halogen (Cl, F, I, Br), hydroxy, C1-4 alkoxy, nitro or cyano for preparing a pharmaceutical preparation for the therapy of autoimmune diseases selected from the group consisting of polyarthritis, multiple sclerosis, juvenile-onset diabetes, Hashimoto's thyroiditis, Grave's disease, systemic Lupus erythematodes (SLE), Sjogren's syndrome, pernicious anaemia and chronic active (lupoid) hepatitis.

17. The use according to claim 16, characterised in that the radicals R1 and R2 are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethyl hexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxy ethyl, 2-hydroxy propyl, 3-hydroxy propyl, 2-methoxy ethyl, methoxy ethyl, 2-methoxy propyl or 3-methoxy propyl.

18. The use according to claim 15 or 16, characterised in that R1 and R2 are identical and represent methyl or ethyl.

19. The use according to any one of the claims 15 to 18 where the dialkyl fumarates are formulated into an oral preparation in the form of tablets, microtablets, pellets in capsules or sachets.

20. The use according to any one of the claims 15 to 19, characterised in that the size or the mean diameter, respectively, of the pellets or micro-tablets is in the range of 300 to 2,000 µm.

21. The use according to claim 19, characterised in that the preparation is present in the form of soft or hard gelatine capsules.

22. The use according to any one of the claims 15 to 21 where the preparation contains an amount of the dialkyl fumarates corresponding to 10 to 300 mg of fumaric acid.

23. The use according to any one of claims 19 to 22, characterised in that the dosage units of the preparations are provided with an enteric coating.