US006509376B1
`(10) Patent No.:
`a2) United States Patent
`US 6,509,376 B1
`Joshi et al.
`(45) Date of Patent:
`Jan. 21, 2003
`
`
`(54) UTILIZATION OF DIALKYFUMARATES
`(75)
`Inventors: Rajendra KumarJoshi, Ziirich (CH);
`Hans-Peter Strebel, Muri (CH)
`
`(73) Assignee: Fumapharm AG, Muri (CH)
`
`(*) Notice:
`
`(21) Appl. No.:
`(22)
`PCTFiled:
`(86) PCT No.:
`
`§ 371 (CQ),
`(2),
`(4) Date: May 10, 2001
`>
`.
`>
`(87) PCT Pub. No.: WO00/30622
`
`PCIPub. Date: Jun. 2, 2000
`Foreign Application Priority Data
`(30)
`.
`Nov. 19, 1998
`(DE) waccee eee ceeereeeeeceeeneeeeeeene 198 53 487
`
`(SL)
`
`Tint. C7 oie eeeneeeeneereeeeeeeenneee A61K 31/225
`
`(52) U.S. Che ve eecesetesenenseeenees 514/547, 514/960
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`09/831,620
`Oct. 29, 1999
`PCT/EP99/08215
`
`OTHER PUBLICATIONS
`Altmeyer, P. et al., “Systemische Therapie der Psoriasis”, T
`& E Dermatologie Jg., 1997, vol. 27, ppg. 380-382, 384—
`not translated.
`Gasser, et al., “Host Vs Graft and Graft Vs Host Reactions
`After Allogeneic Heterotopic Small Bowel ‘lransplantation
`in the Rat”, Transplantation Proceedings, vol. 24, No. 3,
`Jun., 1992, ppg.
`Nathens,et al., “The Glutathione Depleting Agent Diethyl-
`maleate Prolongs Renal Allograft Survival’, Journal of
`Surgical Research, vol. 77, 1998, ppg 75-79.
`Nibbering, P.H.et al., “Intracellular Signalling by Binding
`Sites for the Antipsoratic Agent Monomethylfumarate on
`Human Granulocytes”, British J. Dermatol., 1997, vol. 137,
`ppg. 65-75.
`Nibbering, Peter H., “Effects of Monomethylfumarate on
`Human Granulocytes”, Journal of Investigative Dermatol-
`ogy, 1993, vol. 101, ppg. 37-42.
`Sebok, Bela et al., “Antiproliferative and Cytotoxic profiles
`of Antipsoriatic Fumaric Acid Derivatives in Keratinocyte
`Cultures”, European Journal of Pharm., Environ. Toxicol.
`Pharmacol.
`Schwinghammer et al., “Pharmacologic prophylaxis of
`acute graft-versus—host disease after allogeneic marrow
`transplantation”, Therapy Reviews, Clinical Pharmacy,vol.
`12, Oct. 1993, ppg 736-761.
`Medline Abstract of Bayard et al., “Peroral longterm treat-
`ment of psoriasis using fumaric acid derivatives”, Hautarzt,
`May 1987, 38(5), ppg 279-85.
`:
`Hunziker T. et al; “Is Psoriasis an Autoimmune Disease”,
`(58) Field of Search ..0....eee 514/547, 960
`Excerpt from “Therapeutische Umschau”, Determatological
`:
`Clinic of the University of Berne; 1993, vol. 50; 2”? edition;
`(56)
`References Cited
`pp. 110-113. (Translated version 5 pages).
`U.S. PATENT DOCUMENTS
`M. Bacharach—Buhlesetal., “Fumaric Acid Esters (FAEs)
`Suppress CD 15- and ODP 4—positive Cells in Psoriasis”,
`teens A
`2,jose cecher i. al.
`Acta Derm Venerol (Stockh), 1994; Suppl. 186: 79-82.
`514/547
`#7068 Nees Satoet a a
`H. M. Ockenfels, et al.,
`“The antipsoricatic agent dimeth-
`4959,380 A
`9/1990 Speiser at al sreeeereneens 5L44o4
`5149.695 ‘A *
`9/1992 Speiseret1 “sta5 ylfumarate immunomodulates T-cell cytokine secretionand
`5914196 A
`5/1993 Plank
`T
`teteesenseeeness
`inhibits cytokines of the psoriatic cytokine network”, British
`
`5,242,905 A * 9/1903 Blank seesssesssssesseeeene si4ji9_-:Journal of Dermatology, 1998, vol. 139, 390-395.
`5,359.128 A
`10/1994 Blank
`“Merck Manual’, 1987, Merck XP-002141006, p. 327,
`5,424,332 A
`6/1995. Speiser et ale assesses 514/547
`Paragraph 2—paragraph 6.
`5,451,667 A
`9/1995 Speiser et al. eee 536/41
`Immunodulation durch Fumaderm, Das richtungsweisende
`5,538,968 A
`7/1996 Chiesietal.
`Konzept, Charité—Berlin, Hautklinik, Symposium, Nov.
`5,548,059 A
`8/1996 Bayley etal.
`1-3, 1996, 28 pages, 4 page english translation of pp.
`5,972,363 A
`10/1999 Clikemanetal.
`23-24.
`:
`6,277,882 B1 *
`8/2001 Joshi et al. 514/547
`eo
`6,355,676 B1
`3/2002.
`Joshiet al.
`cited by examiner
`6,359,003 B1
`3/2002 Joshi et al.
`Primary Examiner—Kevin E. Weddington
`FOREIGN PATENT DOCUMENTS
`(74) Attorney, Agent, or Firm—Sieberth & Patty, L.L.C.
`2248955
`§/1997
`(67)
`ABSTRACT
`25 30 372 Al
`1/197
`The present invention relates to the use of certain dialkyl
`eesarod \ ‘hoog
`fumarates for the preparation ofpharmaceutical preparations
`0188749
`7/1986
`for use in transplantation medicine or for the therapy of
`0312697
`4/1989
`autoimmune diseases and said compositions inthe form of
`WO 95/25102
`9/1995
`micro-tablets or pellets. For this purpose, the dialkyl fuma-
`WO 96/27369
`9/1996
`rates may also be used in combination with conventional
`WoO 98/04290
`2/1998
`preparations used in transplantation medicine and immuno-
`WO 98/27970
`7/1998
`suppressive agents, especially cyclosporines.
`WO 98/52549
`11/1998
`WO 99/21565
`5/1999
`
`CA
`DE
`be
`EP
`EP
`WO
`WO
`wo
`wo
`WO
`WO
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`16 Claims, No Drawings
`
`Sawai (IPR2019-00789), Ex. 1025, p. 001
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`Sawai (IPR2019-00789), Ex. 1025, p. 001
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`US 6,509,376 B1
`
`1
`UTILIZATION OF DIALKYFUMARATES
`
`REFERENCE TO RELATED APPLICATIONS
`
`This application 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
`
`The present invention relates to the use of dialkyl fuma-
`rates 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.
`Onthe one hand,therefore, it relates especially to the use
`of dialkyl fumarates for preparing pharmaceutical prepara-
`tions 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,
`Le. graft-versus-host reactions. On the other hand,it relates
`to the use of dialkyl fumarates for preparing pharmaceutical
`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) hepatitis.
`Both graft rejection and autoimmunediseases are based
`on medically undesirable reactions or dysregulation of the
`immune system. Cytokins such as interleukins or tumour
`necrose factor a (TNF-a) 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 defined
`as the failure of the tolerance of endogenic substances or
`antigens. As a rule, this tolerance can be maintained only if
`the antigens keep coming into contact with immunological
`cells. Whenthis toleranceis lost, autoantibodies are formed,
`ie. a humoral immunoresponse against endogenic tissue.
`The exact nature of the involvement of TNF-a is not known.
`
`Transplantations are tissue or organ transplantations,Le.
`the transfer of tissues such as cornea, skin, bones (bone
`chips), vessels or fasciae, of organs such as kidney,heart,
`liver, lung, pancreasor intestines, or of individual cells such
`as islet cells, a-cells and liver cells, the kidney having the
`greatest significance as a transplanted organ.
`According to the degree of relationship between the donor
`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 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 differentsite). The above-mentioned transplan-
`tations 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 recipient. 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-versus-graft reactions, different stages may be
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`distinguished. Depending on the degree of difference
`between the recipientand the donor, this reaction takes place
`at different speeds so that we speak of an acute, subacute 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 resull of a transplant vasculopathy. Finally, the loss of
`function of the transplant as a result of vascular changes
`such as oblitcrating artcriopathy, which proceeds over wecks
`or years and can practically not be influenced by drugs,is
`ermed a chronic rejection reaction.
`Vice-versa, rejection reactions of the transplant against
`he recipient, the so-called graft-versus-host reactions, may
`occur when immunocompetent tissues are transplanted, i.e.
`primarily in bone marrowtransplantation. Again, the sever-
`ity of the reaction is graded, and substantially similar
`complications result as in host-versus-graft-reactions,
`namely arteriopathies and necroses.
`the host-versus-
`To avoid such rejection reactions, i.e.
`graft reaction and the graft-versus-host reaction, transplan-
`ation medicine essentially makes use of
`immunosuppression, i.e. a weakening of the normal immu-
`noresponse. Forthis 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 or the production of antibodies and
`he 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 suchas, 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,
`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.
`Autoimmunediseases where the endogenic immune sys-
`tem attacks endogenic organs, tissues and cells are compa-
`rable to graft-versus-host reactions. These are also medically
`undesirable reactions of the 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 diseases
`and the increased risk of malignant diseases. Therefore, it is
`the object of the invention to provide a pharmaceutical
`preparation to be employed in transplantation medicine
`which maybe usedtotreat, especially to suppress, weaken
`and/oralleviate 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 pharma-
`ceutical preparation which may be employed for treating
`autoimmune diseases, particularly polyarthritis, multiple
`sclerosis, juvenile-onset diabetes, Hashimoto’s thyroiditis,
`
`Sawai (IPR2019-00789), Ex. 1025, p. 002
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`Sawai (IPR2019-00789), Ex. 1025, p. 002
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`US 6,509,376 B1
`
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`Grave’s disease, systemic Lupus erythematodes (SLE),
`Sjogren’s syndrome, pernicious anaemia and chronic active
`(=lupoid) hepatitis, without the disadvantages of immuno-
`suppression.
`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
`autoimmunediseases and pharmaceutical preparationsin the
`form of micro-tablets and micro-pellets containing these
`dialkyl fumarates. The individual subject matters of the
`invention are characterised in detail
`in the claims. The
`preparations according to the invention do not contain any
`free fumaric acidsperse.
`It is known that pharmaceutical preparations which, upon
`biological degradation after administration, enter into the
`citric acid cycle or are part thereof gain increasing thera-
`peutic significance—especially when given in high
`dosages—since they can alleviate or heal diseases caused
`cryptogenetically.
`inhibits the growth of the
`Fumaric acid, for example,
`Ehrlich ascites tumour in mice, reduces the toxic effects of
`mitomycin C and aflatoxin and displays anti-psoriatic 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.
`
`Surprisingly, investigations carried out by the applicant
`have shown that methyl hydrogen fumarate, a metabolite of
`the dimethyl fumarate,
`initially increases the endotoxin-
`stimulated TNF-c secretion in human mono-nuclearcells of
`periphere blood (periphere blood mono-nuclear cells=
`PBMCcells) and in isolated monocytes. In addition, the
`applicant was able to show that fumaric acid has an cffect on
`10 vitro and in vivo haemag-glutination which is comparable
`to that of cyclosporine.
`
`Surprisingly, it has now been found that dialkyl fumarates
`are advantageous for preparing pharmaceutical composi-
`tions for use in transplantation medicine and for the therapy
`of autoimmunediseases. This is because compositions con-
`taining such dialkyl fumarates surprisingly permit a positive
`modulation of the immune system in host-versus-graft
`reactions, graft-versus-host reactions and other autoimmune
`diseases.
`
`European Patent Application 0 188 749 already describes
`fumaric acid derivatives and pharmaceutical compositions
`containing the same for the treatment of psoriasis. Pharma-
`ceutical compositions for the treatment of psoriasis contain-
`ing a mixture of fumaric acid and other
`fumaric acid
`derivatives are known from DE-A-25 30 372. The content of
`
`free fumaric acid is obligatory for these medicaments.
`
`DE-A-26 21 214 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) 279-285” discusses the
`use of fumaric acid monoethyl ester salts. Pharmaceutical
`preparations containing a mixture of fumaric acid monoalkyl
`ester salts and a fumaric acid diester for the treatment of
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`psoriasis, psoriatic arthritis, neurodermatitis and enteritis
`regionalis Crohn are known from EP 0 312 697 B1.
`
`65
`
`Specifically, the object of the invention is achieved by the
`use of one or more dialkyl fumarates of the formula
`
`H
`
`COO—R,
`
`C=C
`
`Ry—00C
`
`H
`
`wherein R, and R,, which may be the sameor different,
`independently represent a linear, branched or cyclic, satu-
`rated or unsaturated C,_5, alkyl radical which may be
`optionally substituted with halogen (Cl, F, L, Br), hydroxy,
`C,.4 alkoxy, nitro or cyano for preparing a pharmaceutical
`preparation for usc in transplantation medicine or for the
`therapy of autoimmune diseases.
`The C,_59 alkyl radicals, preferably C,_, alkyl radicals,
`most preferably C,_; alkyl radicals are, for example, 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 or
`3-hydroxy propyl, 2-methoxy ethyl, methoxy methylor 2- or
`3-methoxy propyl. Preferably at least one of the radicals R,
`or R,
`is C,_; alkyl, especially methyl or ethyl. More
`preferably, R, and R, are the same or different C,_; alkyl
`radicals such as methyl, ethyl, n-propyl or t-butyl, methyl
`and ethyl being especially preferred. Most preferably, R,
`and R, 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 inven-
`tion are prepared by processes knownin the art (see, for
`example, EP 0 312 697).
`Preferably, the active ingredients are used for preparing
`oral preparationsin 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 invention. 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 contain
`a total amount of 10 to 300 mg of dimethyl fumarate 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 ym, especially in the range
`of 500 or 1,000 um.
`In addition to graft-versus-host reactions (see above), the
`following autoimmunediseasesto be treated may be named:
`polyarthritis, multiple sclerosis, graft-versus-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, neurodermatitis and
`enteritis regionalis Crohn.
`In addition to the preparations for peroral administration
`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 preparations and for
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`Sawai (IPR2019-00789), Ex. 1025, p. 003
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`Sawai (IPR2019-00789), Ex. 1025, p. 003
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`US 6,509,376 B1
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`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 autormmune
`diseases mentioned above,
`including psoriasis, psoriatic
`arthritis, neurodermatitis and enteritis regionalis Crohn and
`are also a subject matter of the invention.
`According to the invention, a therapy with dialkyl fuma-
`rales may also be carried oul in combination with one or
`more preparations of the triple drug therapy customarily
`used in organ transplantations or with cyclosporine A alonc.
`Forthis 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 parallel administration of separate
`preparation sameor 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 maybe reduced advantageously.
`Another embodimentof the use accordingto the invention
`is to alternate the drug therapy with immunosuporessive
`agents such as cyclosporine in sequence with an application
`of the above-mentioned dialkyl fumarate. This meansthat an
`application of fumaric acid derivatives as defined above over
`one or more weeks may followa cyclosporine therapy of one
`or more weeks. This permits reduction of the Cyclosporine
`A dosage resulling in a considerable decrease of the rate of
`side effects in long-term therapy.
`By administration of the dialkyl fumarates in the form of 3
`micro-tablets, which is preferred, gastrointestinal irritations
`and side effects, which are reduced already when conven-
`tional 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 conventional
`tablets,
`the ingredients of the tablet are released in the
`intestine in a concentration whichis too high, causing local
`irritation of the intestinal mucous membrane. This local
`irritation results in a short-term release of very high TNF-a
`concentrations which maybe responsible for the gastrointes-
`tinal 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 sothatdistribution of the
`active ingredients is improved.
`This means that enteric-coated micro-tablets in the same
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`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 conven-
`tional tablets.
`
`In addition, resorption is improved, because the dialkyl
`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 ingredient in the body.
`In order to illustrate the use according to the invention,
`different examples for preparing preferred drugs are given
`below.
`
`PRODUCTION EXAMPLES
`
`In principle, the oral preparations according to the inven-
`tion in the form of tablets or micro-tablets may be prepared
`by classical tabletting processes. Instead of such classical
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`tabletting processes, other methods for the preparation 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.
`The tablets may be provided with an enteric coating. 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.
`EXAMPLE1
`
`Preparation of Enteric-coated Micro-tablets in Capsules
`Containing 120.0 mg of Dimethyl Fumarate, which Corre-
`sponds to 96 mg of Fumaric Acid
`Taking the necessary precautions (breathing mask,
`gloves, protective clothing, etc.), 12.000 kg of dimethyl
`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 Primogel®, 0.25 kg of colloidal silicic acid (Acrosil®).
`The active ingredient is added to the entire powder mixture,
`mixed, homogenised by meansof a sicve 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 Mgstearate and 1.50 kg
`of talcum.
`
`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.
`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 | 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.
`
`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-Rotlack 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 deminera-
`lised water and 0.600 kg of glycerinetriacetate (Triacetin).
`After that the enteric-coated micro-tablets are filled into
`
`hard gelatine capsules having a net weight of 400 mg and
`sealed.
`
`EXAMPLE2
`
`Preparation of Enteric-coated Micro-tablets in Capsules
`Containing 120.0 mg of Dimethyl Fumarate, which Corre-
`sponds to 96 mg 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 cellulose
`(Avicelo® PH 200), 3.00 kg of Croscarmellose sodium
`(AC-Di-SOL-SD-711), 2.50 kg of talcum, 0.10 kg of anhy-
`droussilica (Acrosil® 200) and 1.00 kg of Mgstearate. The
`active ingredientis then addedto the entire powder mixture
`and mixed homogenously. By meansof 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.
`
`Sawai (IPR2019-00789), Ex. 1025, p. 004
`
`Sawai (IPR2019-00789), Ex. 1025, p. 004
`
`

`

`US 6,509,376 B1
`
`7
`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 micro-talcum, 2.00 kg of Macrogol 6000 and
`0.07 kg of dimeticon 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.
`EXAMPLE3
`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 homoge-
`nised as above. In addition, 2 1 of a 20% (m/v) polyvinyl
`pyrrolidone solution (Kollidon K-30) in ethanol are pre-
`pared. 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 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).
`EXAMPLE4
`
`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 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), homogenised by means
`of a sieve 800.
`Using a 2% aqueoussolution 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 colloidalsilicic acid (Aerosil®), 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
`capsules, the product mayalso be filled into suitable enteric-
`coated capsules consisting of a mixture of cellulose acetate
`phthalate (CAP) and hydroxy propyl! methyl cellulose phtha-
`late (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 therapy with
`fumaric acid derivatives according to the invention 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 forma-
`tion. 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 lh2 type.
`Especially in view of the long-term therapy and preven-
`tion whichis always necessary in graft-versus-host reactions
`and host-versus-graft reactions or other immune 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
`
`wn
`
`10
`
`15
`
`25
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`derivatives, the toxic side effects of the former compounds
`may be unexpectedly reduces to a substantial degree. In
`addition, the use according to the invention is also signifi-
`cant
`in the substitution of the corticosteroid therapy of
`autoimmune diseases which is known to be accompanied by
`severe side effects.
`Whatis claimed is:
`1. Pharmaceutical preparation in the form of microtablets
`or micropellets comprising one or more dialkyl fumarates of
`the formula
`
`H
`
`COO—R,
`
`C=C
`
`Ry—OOC
`
`H
`
`wherein R, and R,, which may be the sameor different,
`independently represent a linear, branched or cyclic, satu-
`rated or unsaturated C,_5. alkyl radical which may be
`optionally substituted with halogen (Cl, F, I, Br), hydroxy,
`C,., alkoxy, nitro or cyano, and optionally suitable carriers
`and excipients for use in transplantation medicineor for the
`therapy of autoimmune diseases such as polyarthritis, mul-
`tiple 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, neuro-
`dermatitis and enteritis regionalis Crohn.
`2. A preparation according to claim 1 comprising dim-
`ethyl fumarate, diethyl fumarate or methylethyl fumarate.
`3. A preparation according to claim 1 or 2 comprising an
`amountof the active ingredient corresponding to 10 to 300
`mg of fumaric acid.
`4. A preparation according to claim 1 wherein the one or
`more dialkylfumarates is diethylfumarate.
`5. A preparation according to claim 1 wherein the one or
`more dialkylfumarates is dimethylfumarate.
`6. A preparation according to claims 4 or 5 wherein the
`amountof dialkylfumarate in said preparation corresponds
`o 10 to 300 mg of fumaric acid.
`7. A preparation according to any of claims 1, 2, 4 or 5
`wherein the preparation is formulated into an oral prepara-
`ion in which the microtablets or micropellets are in capsules
`or sachets.
`8. A preparation according to any of claims 1, 2, 4 or 5
`wherein the preparation is formulated into an oral prepara-
`ion in which the microtablets or micropellets are in soft or
`hard gelatine capsules.
`9. A preparation according to any of claims 1, 2, 4 or 5
`wherein the microtablets or micropellets are provided with
`an enteric coating.
`10. A preparation according to claim 1 wherein the
`preparation is formulated into an oral preparation in which
`he microtablets or micropellets are in capsules or sachets
`and wherein the amount of dialkylfumarate in said prepa-
`ation corresponds to 10 to 300 mg of fumaric acid.
`11. A preparation according to claim 1 wherein the
`preparation is formulated into an oral preparation in which
`he microtablets or micropellets are in soft or hard gelatine
`capsules and wherein the amountof dialkylfumarate in said
`preparation corresponds to 10 to 300 mg of fumaric acid.
`12. A preparation according to claim 1 wherein the
`microtablets or micropellets are provided with an enteric
`coating and wherein the amount of dialkylfumarate in said
`preparation corresponds to 10 to 300 mg of fumaric acid.
`13. A p