(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2003/0018072 A1
`Joshi et al.
`(43) Pub. Date:
`Jan. 23, 2003
`
`US 20030018072A1
`
`(54) UTILIZATION OF DIALKYLFUMARATES
`
`(30)
`
`Foreign Application Priority Data
`
`(76)
`
`Inventors: Rajendra Kumar Joshi, Zurich (CH);
`Hans-Peter Strebel, Muri (CH)
`
`Nov. 19, 1998
`
`(DE) ................................... .. 198 53 487.6
`
`Publication Classification
`
`Correspondence Address:
`SIEBERTH & PATTY
`2924 BRAKLEY DRIVE SUITE A 1
`
`BATON ROUGE, LA 70816
`
`(21) Appl. No.:
`
`10/197,077
`
`(22)
`
`Filed:
`
`Jul. 17, 2002
`
`Related U.S. Application Data
`
`(62) Division of application No. 09/831,620, filed on May
`10, 2001, filed as 371 of international application No.
`PCT/EP99/08215, filed on Oct. 29, 1999.
`
`Int. Cl.7 .................... .. A61K 31/275; A61K 31/225
`(51)
`(52) U.S.Cl.
`.......................................... .. 514/527; 514/547
`
`(57)
`
`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 fuma-
`rates may also be used in combination with conventional
`preparations used in transplantation medicine and immuno-
`suppressive agents, especially cyclosporines.
`
`Page 1 of 6
`
`Coalition Exhibit 10
`
`Coalition V. Biogen
`
`IPR Unassigned
`
`Page 1 of 6
`
`

`
`US 2003/0018072 A1
`
`Jan. 23, 2003
`
`UTILIZATION OF DIALKYLFUMARATES
`
`REFERENCE TO RELATED APPLICATIONS
`
`[0001] This is a Division of commonly-owned application
`Ser. No. 09/831,620, filed May 10, 2001, which is a 371
`continuation of PCT Application PCT/EP99/08215, filed
`Oct. 29, 1999, the text of which is not in English, which PCT
`Application claims priority on German Application No. 198
`53 487.6, filed Nov. 19, 1998, the text of which is not in
`English.
`
`DESCRIPTION
`
`[0002] The present invention relates to the use of dialkyl
`fumarates for preparing pharmaceutical preparations for use
`in transplantation medicine or the therapy of autoimmune
`diseases and pharmaceutical preparations in the form of
`micro-tablets or micro-pellets containing dialkyl fumarates.
`
`[0003] On the one hand, therefore, it relates especially to
`the use of dialkyl fumarates for preparing pharmaceutical
`preparations for the treatment, reduction or suppression of
`rejection reactions of the transplant by the recipient,
`i.e.
`host-versus graft reactions, or rejection 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
`pharmaceutical preparations for treating autoimmune dis-
`eases such as polyarthritis, multiple sclerosis, juvenile-onset
`diabetes, Hashimoto’s thyroiditis, Grave’s disease, systemic
`Lupus erythematodes (SLE), Sjogren’s syndrome, perni-
`cious anaemia and chronic active (=lupoid) hepatitis.
`
`[0004] Both graft rejection and autoimmune diseases are
`based on medically undesirable reactions or dysregulation of
`the immune system. Cytokins such as interleukins or tumour
`necrose factor a (TNF-(X) are substantial mediators influ-
`encing the immune system. In general, both are treated by
`the administration of immunosuppressive agents such as
`cyclosporine.
`
`In the overall result, autoimmune diseases may be
`[0005]
`defined as the failure of the tolerance of endogenic sub-
`stances or antigens. As a rule, this tolerance can be main-
`tained only if the antigens keep coming into contact with
`immunological cells. When this tolerance is lost, autoanti-
`bodies are formed, i.e. a humoral immunoresponse against
`endogenic tissue. The exact nature of the involvement of
`TNF-(X is not known.
`
`[0006] Transplantations are tissue or organ transplanta-
`tions, 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, ot-cells and liver cells, the kidney
`having the greatest significance as a transplanted organ.
`
`[0007] According to the degree of relationship between
`the donor and the recipient we differentiate between
`autotransplantation (transfer to another part of the body of
`the same individual), iso-transplantation (transfer to another,
`genetically identical individual) and allogenic transplanta-
`tion (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 different site). The above-mentioned transplan-
`tations play an important role in modern medicine.
`
`[0008] A major problem in transplantation medicine is
`graft rejection after transplantation of the tissue, organ or
`cell by immunological defense reactions of the recipient.
`Such a graft rejection is also called host-versus-graft reac-
`tion. The immunological defense reaction of the organism
`against the heteroprotein often results in rejection or disso-
`lution of the grafts. In host-verses-graft reactions, different
`stages may be distinguished. Depending on the degree of
`difference between the recipient 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 transplant
`(necrotisation) as a result of arteriitis or arteriolitis 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 vasculopathy.
`Finally, the loss of function of the transplant as a result of
`vascular changes such as obliterating arteriopathy, which
`proceeds over weeks or years and can practically not be
`influenced by drugs, is termed a chronic rejection reaction.
`
`[0009] Vice-versa, rejection reactions of the transplant
`against the recipient, the so-called graft-versus-host reac-
`tions, may occur when immunocompetent tissues are trans-
`planted,
`i.e. primarily in bone marrow transplantation.
`Again, the severity of the reaction is graded, and substan-
`tially similar complications result as in host-versus-graft-
`reactions, namely arteriopathies and necroses.
`
`the host-
`i.e.
`To avoid such rejection reactions,
`[0010]
`versus-graft
`reaction and the graft-versus-host reaction,
`transplantation medicine essentially makes use of immuno-
`suppression,
`i.e. a weakening of the normal
`immunore-
`sponse. 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 nucleic acid and protein
`synthesis and thus prevent cell division and proliferation.
`This leads to suppression of the production of antibodies and
`the cellular
`immune response. The immunosuppressive
`agents used for therapy are substances which suppress or
`weaken the immunoreaction in the body either specifically
`or non-specifically. Non-specific immunosuppressive agents
`are cytostatic agents such as, for example, alkylating agents
`or antimetabolites.
`
`In addition, active ingredients are known which
`[0011]
`cause at least partial specific immunosuppression, such as
`corticosteroids, antisera, antibodies FK-506,
`tacrolimus,
`mycophenolatemofetil and primarily cyclosporines such as
`cyclosporine A. As a result of using modern immunosup-
`pressive agents, the most important representatives of which
`are the cyclosporines, especially cyclosporine A,
`it was
`possible to improve the results of transplantation consider-
`ably over the last few years. At present, the survival rate
`after one year is about 60% for liver transplantations, about
`80% for heart transplantations and over 90% for kidney
`transplantations.
`endogenic
`the
`diseases where
`[0012] Autoimmune
`immune system attacks endogenic organs, tissues and cells
`are comparable to graft-versus-host reactions. These are also
`medically undesirable reactions of the immune system
`which may be treated with immunosuppressive agents, too.
`[0013] The danger in using immunosuppressive agents
`lies in weakening the body’s defense against
`infectious
`
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`US 2003/0018072 A1
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`
`diseases and the increased risk of malignant diseases. There-
`fore, it is the object of the invention to provide a pharma-
`ceutical preparation to be employed in transplantation medi-
`cine which may be used to treat, especially to suppress
`weaken and/or alleviate host-versus-graft
`reactions and
`graft-versus-host reactions, but does not have the above
`disadvantage.
`
`It is another object of the invention to provide a
`[0014]
`pharmaceutical preparation which may be employed for
`treating autoimmune diseases, particularly polyarthritis,
`multiple sclerosis, juvenile-onset diabetes, Hashimoto’s thy-
`roiditis, Grave’s disease, systemic Lupus erythematodes
`(SLE), Sjogren’s syndrome, pernicious anaemia and chronic
`active (=lupoid) hepatitis, without
`the disadvantages of
`immunosuppression.
`
`[0015] The object of the invention is achieved by using
`certain dialkyl
`fumarates for preparing pharmaceutical
`preparations for use in transplantation medicine and for the
`therapy of autoimmune diseases and pharmaceutical prepa-
`rations in the form of micro-tablets and micro-pellets con-
`taining these dialkyl fumarates. The individual subject mat-
`ters of the invention are characterized in detail in the claims.
`
`The preparations according to the invention do not contain
`any free fumaric acids per se.
`
`is known that pharmaceutical preparations
`It
`[0016]
`which, upon biological degradation after administration,
`enter into the citric acid cycle or are part thereof gain
`increasing therapeutic significance—especially when given
`in high dosages—since they can alleviate or heal diseases
`caused cryptogenetically.
`
`[0017] Fumaric acid, for example, inhibits the growth of
`the Ehrlich ascites tumour in mice, reduces the toxic effects
`of mitomycin C and aflatoxin and displays antipsoriatic and
`anti-microbial activity. When administered parenterally,
`transdermally and especially perorally, high dosages of
`fumaric acid or its derivatives known so far such as dihy-
`droxyl fumaric acid, fumaramide 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.
`
`investigations carried out by the
`[0018] Surprisingly,
`applicant have shown that methyl hydrogen fumarate, a
`metabolite of the dimethyl fumarate, initially increases the
`endotoxin-stimulated TNF-(X 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 fumaric acid
`has an effect on in vitro and in vivo haemagglutination
`which is comparable to that of cyclosporine.
`
`[0019] Surprisingly, it has now been found that dialkyl
`fumarates are advantageous for preparing pharmaceutical
`compositions for use in transplantation medicine and for the
`therapy of autoimmune diseases. This is because composi-
`tions containing such dialkyl fumarates surprisingly permit
`a positive modulation of the immune system in host-versus-
`graft reactions, graft-versus-host reactions and other autoim-
`mune diseases.
`
`[0020] European Patent Application 0188 749 already
`describes fumaric acid derivatives and pharmaceutical com-
`positions containing the same for the treatment of psoriasis.
`Pharmaceutical compositions for the treatment of psoriasis
`
`containing a mixture of fumaric acid and other fumaric acid
`derivatives are known from DE-A-25 30 372. The content of
`
`free fumaric acid is obligatory for these medicaments.
`
`[0021] DE-A-26 21 214 describes medicaments contain-
`ing the fumaric acid monoethyl ester and its mineral salts as
`active ingredient for the treatment of psoriasis. The publi-
`cation “Hautarzt (Dermatologist) (1987) 279-285” discusses
`the use of fumaric acid monoethyl ester salts. Pharmaceu-
`tical preparations containing a mixture of fumaric acid
`monoalkyl ester salts and a fumaric acid diester for the
`treatment of psoriasis, psoriatic arthritis, neurodermatitis
`and enteritis regionalis Crohn are known from EP 0 312 697
`B 1.
`
`[0022] Specifically, the object of the invention is achieved
`by the use of one or more dialkyl fumarates of the formula
`
`H
`
`COO—R1
`
`c=(:
`
`R2— ooc
`
`H
`
`[0023] 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 phar-
`maceutical preparation for use in transplantation medicine or
`for the therapy of autoimmune diseases.
`
`[0024] The C1_20 alkyl radicals, preferably C1_8 alkyl radi-
`cals, most preferably C1_5 alkyl radicals are, for example,
`methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-bu-
`tyl, pentyl, cyclopentyl, 2-ethyl hexyl, hexyl, cyclohexyl,
`heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2 or
`3-hydroxy propyl, 2-methoxy ethyl, methoxy methyl or 2- or
`3-methoxy propyl. 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_5 alkyl radicals
`such as methyl, ethyl, n-propyl or t-butyl, methyl and ethyl
`being especially preferred. Most preferably, R1 and R2 are
`identical and are methyl or ethyl. Especially preferred are
`the dimethyl fumarate, methyl ethyl fumarate and diethyl
`fumarate.
`
`[0025] The dialkyl fumarates to be used according to the
`invention are prepared by processes known in the art (see,
`for example, EP 0 312 697).
`
`[0026] Preferably, the active ingredients are used for pre-
`paring 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, option-
`ally filled in capsules or sachets are preferred and are also a
`subject matter of the invention. The oral preparations may be
`provided with an enteric coating. Capsules may be soft or
`hard gelatine capsules.
`
`[0027] The dialkyl fumarates used according to the inven-
`tion may be used alone or as a mixture of several com-
`pounds, optionally in combination with the customary car-
`riers 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.
`
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`Jan. 23, 2003
`
`[0028] Preferred preparations according to the invention
`contain a total amount of 10 to 300 mg of dimethyl fumarate
`and/or diethyl fumarate.
`
`[0029] 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 ym, especially in the
`range of 500 or 1,000 ym.
`
`reactions (see
`In addition to graft-versus-host
`[0030]
`above), the following autoimmune diseases to be treated
`may be named: polyarthritis, multiple sclerosis, graft-ver-
`sus-host
`reactions,
`juvenile-onset diabetes, Hashimoto’s
`thyroiditis, Grave’s disease, systemic Lupus erythematodes
`(SLE), Sjogren’s syndrome, pernicious anaemia and chronic
`active (lupoid) hepatitis. Autoimmune diseases in a wider
`meaning also comprise psoriasis, psoriatic arthritis, neuro-
`dermatitis and enteritis regionalis Crohn.
`
`In addition to the preparations for peroral admin-
`[0031]
`istration in the form of micro-pellets, micro-tablets, capsules
`(such as soft and hard gelatine capsules), granulates and
`tablets cited above, suitable pharmaceutical preparations are
`preparations for cutaneous and transdermal administration
`in the form of ointments, plasters, lotions or shower prepa-
`rations and for parenteral administration in the form of
`aqueous micro-dispersions, oil-in-water emulsions or oily
`solutions for rectal administration of suppositories or micro-
`enemas. Pharmaceutical preparations in the form of micro-
`tablets or micro-pellets are preferred for the therapy of all
`autoimmune diseases mentioned above, including psoriasis,
`psoriatic arthritis, neurodermatitis and enteritis regionalis
`Crohn and are also a subject matter of the invention.
`
`[0032] According to the invention, a therapy with dialkyl
`fumarates may also be carried out in combination with one
`or more preparations of the triple drug therapy customarily
`used in organ transplantations or with cyclosporine A alone.
`For this purpose, the preparations administered may contain
`a combination of the active ingredients in the known dos-
`ages or amounts, respectively. Likewise, the combination
`therapy may consist of the parallel administration of sepa-
`rate preparations, by the 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 invention may be reduced advanta-
`geously.
`
`[0033] Another embodiment of the use according to the
`invention 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 derivatives as
`defined above over one or more weeks may follow a
`cyclosporine therapy of one or more weeks. This permits
`reduction of the Cyclosporine A dosage resulting in a
`considerable decrease of the rate of side effects in long-term
`therapy.
`
`[0034] 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 con-
`[0035]
`ventional tablets, the ingredients of the tablet are released in
`
`the intestine in a concentration which is too high, causing
`local irritation of the intestinal mucous membrane. This
`
`local irritation results in a short-term release of very high
`TNF-(X 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 concentrations of the active ingredients in the intestinal
`epithelial cells are achieved. The micro-tablets are incre-
`mentally released by the stomach and passed into the small
`intestine by peristaltic movements so that distribution of the
`active ingredients is improved.
`
`[0036] 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 ingre-
`dients are released in smaller dosages. This avoids local
`irritation of the intestinal epithelial cells and the release of
`TNF-(X.
`It
`is assumed that
`this results in the improved
`tolerance of micro-tablets in the gastrointestinal tract vis-a-
`vis conventional tablets.
`
`In addition, resorption is improved, because the
`[0037]
`dialkyl fumarates to be used according to the invention are
`not the active ingredient per se, but a so-called prodrug,
`which must be converted into the active ingredient in the
`body.
`
`In order to illustrate the use according to the
`[0038]
`invention, different examples for preparing preferred drugs
`are given below.
`
`Production Examples
`
`In principle, the oral preparations according to the
`[0039]
`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 prepa-
`ration of tablets may be used, such as direct tabletting and
`processes for preparing solid dispersions in according with
`the melt method and the spray drying method.
`
`[0040] The tablets may be provided with an enteric coat-
`ing. The enteric coating may be applied in a classical coating
`pan or sprayed on or applied in a fluidised bed apparatus.
`The tablet may also be provided with a film coat.
`
`EXAMPLE 1
`
`Preparation of Enteric-coated Micro-tablets in
`Capsules Containing 120.0 mg of Dimethyl
`Fumarate, which Corresponds to 96 mg of Fumaric
`Acid
`
`[0041] Taking the necessary precautions (breathing mask,
`gloves, protective clothing, etc.), 12.000 kg of dimethyl
`fumarate are crushed, mixed and homogenized 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 microcrystalline cellulose
`(Avicel® PH 101), 0.75 kg of PVP (Kollidon® 120), 4.00 kg
`of Primogel®, 0.25 kg of colloidal silicic acid (Aerosil®).
`The active ingredient is added to the entire powder mixture,
`mixed, homogenized by means of a sieve 200, processed in
`the usual manner with a 2% aqueous solution of polyvidon
`pyrrolidone (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.
`
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`US 2003/0018072 A1
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`
`[0042] Then the powder mixture is compressed in the
`usual manner to obtain convex tablets having a gross weight
`of 10.0 mg and a diameter of 2.0 mm.
`
`[0043] 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 por-
`tions in a mixture of the following solvents: 13.00 1 of
`acetone, 13.50 1 of ethanol (94 wt.-%, denatured with 2% 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.
`
`[0044] After drying is completed, a suspension of the
`following composition is applied as a film 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 mixture of
`the following composition: 8.170 kg of 2-propanol, 0.200 kg
`of demineralised water and 0.600 kg of glycerine triacetate
`(Triacetin).
`
`[0045] 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 Corresponds to 96 mg Offumaric
`Acid
`
`12.000 kg of dimethyl fumarate are crushed and
`[0046]
`homogenized as above. Then an excipient mixture com-
`posed as follows is prepared: 23.20 kg of microcrystalline
`cellulose (Avicel® PH 200), 3.00 kg of Croscarmellose
`sodium (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.
`
`[0047] After that, a solution of 0.94 Eudragit® L in
`isopropanol
`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 microtalcum, 2.00 kg of
`Macrogol 6000 and 0.07 kg of dimeticon in water is pre-
`pared and sprayed onto the cores.
`
`the enteric-coated micro-tablets are filled
`[0048] Next,
`into hard gelatine capsules having a net weight of 650 mg
`and sealed.
`
`EXAMPLE 3
`
`Preparation of Micro-pellets in Capsules Containing
`50.0 mg of Dimethyl Fumarate, which Corresponds
`to 40 mg of Fumaric Acid
`
`5.000 kg of dimethyl fumarate are crushed and
`[0049]
`homogenized as above. In addition, 2 1 of a 20% (m/v)
`polyvinyl pyrrolidone solution (Kollidon K-30) in ethanol
`
`are prepared. 7.250 kg of nonpareilles pellets in a coating
`pan are sprayed with part of the Kollidon K-30 solution until
`slightly humid. Then the active ingredient
`is added in
`portions until the pellets are dry. This procedure of humidi-
`fication/drying is continued until all of the active ingredient
`mixture has been added. Then the pellets are moved around
`until completely dry.
`
`[0050] 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 Dimethylfumarate, which Corresponds
`to 88 mg of Fumaric Acid
`
`fumarate are intensely
`11.000 kg of dimethyl
`[0051]
`mixed in a mixture consisting of 14.00 kg of starch, 5.65 kg
`of lactose, 2.00 kg of microcrystalline cellulose (Avicel®),
`1.00 kg of polyvinyl pyrrolidone (Kollidon®25) and 2.443
`kg of Primogel® and,
`taking the necessary precautions
`(breathing mask, gloves, protective clothing), homogenized
`by means of a sieve 800.
`
`[0052] Using a 2% aqueous solution of polyvinyl pyrroli-
`done (Kollidon® K25), the entire powder mixture is pro-
`cessed 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 (Aerosil®),
`0.500 kg of Mg stearate and 1.500 kg of talcum. The
`homogenous mixture is filled into suitable capsules in por-
`tions of 400 mg which are then provided with an enteric
`coating consisting of hydroxy propyl methyl cellulose stear-
`ate and castor oil as plasticiser in the customary manner.
`Instead of using hard gelatine capsules, the product may also
`be filled into suitable enteric-coated capsules consisting of a
`mixture of cellulose acetate phthalate (CAP) and hydroxy
`propyl methyl cellulose phthalate (HPMCP).
`
`In comparison with substances of the prior art such
`[0053]
`as cyclosporine, which may cause massive kidney disorders
`or diseases of the lymphoproliferative system, a therapy
`with fumaric acid derivatives according to the invention for
`the indications listed above rarely results in serious side
`effects.
`
`[0054] 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
`Th1 type to the cytokine pattern of the Th2 type.
`
`[0055] Especially in view of the long-term therapy and
`prevention which is always necessary in graft-versus-host
`reactions and host-versus-graft reactions or other autoim-
`mune diseases such as multiple sclerosis, the unexpected
`effect of the use according to 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 unexpectedly reduced to a substantial
`degree. In addition, the use according to the invention is also
`significant in the substitution of the corticosteroid therapy of
`autoimmune diseases which is known to be accompanied by
`severe side effects.
`
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`Page 5 of 6
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`

`
`US 2003/0018072 A1
`
`Jan. 23, 2003
`
`That which is claimed is:
`
`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 of 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, perni-
`cious anaemia and chronic active (lupoid) hepatitis.
`3. The use according to claims 1 or 2 of one or more
`dialkyl fumarates of the formula
`
`preparations for cutaneous and transdermal administration,
`preparations for parenteral administration and preparations
`for rectal administration.
`
`12. The use of one or more dialkyl fumarates for preparing
`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.
`13. The use according to claim 12 of one or more dialkyl
`fumarates of the formula
`
`H
`
`coo—R1
`
`c=(:
`
`H
`
`coo—R1
`
`c=(:
`
`R2— ooc
`
`H
`
`R2— ooc
`
`H
`
`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, sys-
`temic Lupus erythematodes (SLE), Sjogren’s syn-
`drome, pernicious anaemia and chronic active (lupoid)
`hapatitis.
`4. The use according to claim 3, characterized 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 and/or 3-hydroxy propyl, 2-meth-
`oxy ethyl, methoxy ethyl or 2- or 3-methoxy propyl.
`5. The use according to claims 3 or 4, characterized in that
`R1 and R2 are identical and represent methyl or ethyl.
`6. The use according to any of the claims 1 to 5 Where the
`active ingredients are formulated into an oral preparation in
`the form of tablets, micro-tablets, pellets or granulates,
`optionally in capsules or sachets.
`7. The use according to claim 6, characterized in that the
`size or the mean diameter, respectively, of the pellets or
`micro-tablets is in the range of 300 to 2,000 gm.
`8. The use according to any of claims 1 to 7, characterized
`in that the preparation is present in the form of soft or hard
`gelatine capsules.
`9. The use according to any of the claims 1 to 8 Where the
`preparation contains an amount of the active ingredient
`corresponding to 10 to 300 mg of fumaric acid.
`10. The use according to any of claims 6 to 9, character-
`ized in that the dosage units of the drugs are provided with
`an enteric coating.
`11. The use according to any of the claims 1 to 5,
`characterized in that the drugs are used in the form of
`
`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 autoim-
`mune 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, per-
`nicious anaemia, and chronic active (lupoid) hepatitis.
`14. The use according to claim 13, characterized 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 and/or 3-hydroxy propyl, 2-meth-
`oxy ethyl, methoxy ethyl or 2- or 3-methoxy propyl.
`15. The use according to claims 12 or 13, characterized in
`that R1 and R2 are identical and represent methyl or ethyl.
`16. The use according to any of claims 12 to 15 Where the
`active ingredients are formulated into an oral preparation in
`the form of tablets, micro-tablets, pellets in capsules or
`sachets.
`
`17. The use according to any of claims 12 to 16, charac-
`terized in that the size or the mean diameter, respectively, of
`the pellets or micro-tablets is in the range of 300 to 2,000
`pm.
`18. The use according to claim 16, characterized in that
`the preparation is present in the form of soft or hard gelatine
`capsules.
`19. The use according to any of claims 12 to 18 Where the
`preparation contains an amount of the active ingredient
`corresponding to 10 to 300 mg of fumaric acid.
`20. The use according to any of claims 16 to 19, charac-
`terized in that the dosage units of the drugs are provided with
`an enteric coating.
`
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