(12) United States Patent
`J oshi et a].
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 7,320,999 B2
`Jan. 22, 2008
`
`US007320999B2
`
`(54) DIMETHYL FUMARATE FOR THE
`TREATMENT OF MULTIPLE SCLEROSIS
`
`(75) Inventors: Rajendra Kumar J oshi, Zurich (CH);
`Hans-Peter Strebel, Muri (CH)
`
`(73) Assignee: Fumapharm AG, LuZern (CH)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 202 days.
`
`(21) Appl. N0.: 10/197,077
`
`(22) Filed:
`
`Jul. 17, 2002
`
`(65)
`
`Prior Publication Data
`
`US 2003/0018072 A1
`
`Jan. 23, 2003
`
`Related US. Application Data
`
`(62) Division of application No. 09/831,620, ?led as appli
`cation No. PCT/EP99/08215 on Oct. 29, 1999, noW
`Pat. No. 6,509,376.
`
`(30)
`
`Foreign Application Priority Data
`
`Nov. 19, 1998 (DE) .............................. .. 198 53 487
`
`(51) Int. Cl.
`(2006.01)
`A61K 31/22
`(52) US. Cl. .................................................... .. 514/549
`(58) Field of Classi?cation Search ................... .. None
`See application ?le for complete search history.
`
`(56)
`
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`W0
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`W0
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`(Continued)
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`
`(Continued)
`Primary ExamineriRaymond J. Henley, III
`(74) Attorney, Agent, or FirmiFinnegan, Henderson,
`FaraboW, Garrett & Dunner, L.L.P.
`
`(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.
`
`18 Claims, No Drawings
`
`Sawai (IPR2019-00789), Ex. 1009, p. 001
`
`

`

`US 7,320,999 B2
`Page 2
`
`FOREIGN PATENT DOCUMENTS
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`
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`

`

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`Page 3
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`
`Sawai (IPR2019-00789), Ex. 1009, p. 003
`
`

`

`US 7,320,999 B2
`
`1
`DIMETHYL FUMARATE FOR THE
`TREATMENT OF MULTIPLE SCLEROSIS
`
`REFERENCE TO RELATED APPLICATIONS
`
`This is a Division of commonly-oWned application Ser.
`No. 09/831,620, ?led May 10, 2001, now US. Pat. No.
`6,509,376, Which is a 371 continuation of PCT Application
`PCT/EP99/08215, ?led Oct. 29, 1999, the text of Which is
`not in English, Which PCT Application claims priority on
`German Application No. 198 53 487.6, ?led 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.
`On the one hand, therefore, it relates especially to the use
`of dialkyl fumarates for preparing pharmaceutical prepara
`tions for the treatment, reduction or suppression of rej ection
`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 diseases such as pol
`yarthritis, multiple sclerosis, juvenile-onset diabetes, Hash
`imoto’s thyroiditis, Grave’s disease, systemic Lupus erythe
`matodes (SLE), Sjogren’s syndrome, pernicious anaemia
`and chronic active (:lupoid) hepatitis.
`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-ot) are substantial mediators in?u
`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 de?ned
`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. When this tolerance is lost, autoantibodies are formed,
`i.e. a humoral immunoresponse against endogenic tissue.
`The exact nature of the involvement of TNF -0t 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, ot-cells and liver cells, the kidney having the
`greatest signi?cance as a transplanted organ.
`According to the degree of relationship betWeen the donor
`and the recipient We differentiate betWeen autotransplanta
`tion (transfer to another part of the body of the same
`individual), iso-transplantation (transfer to another, geneti
`cally identical individual) and allogenic transplantation
`(transfer to another individual of the same species). Depend
`ing 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 transplantations 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 defense reactions of the recipient. Such a
`graft rejection is also called host-versus-graft reaction. The
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`60
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`2
`immunological defense reaction of the organism against the
`heteroprotein often results in rejection or dissolution 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 in?uenced 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 in?uenced by drugs, is
`termed a chronic rejection reaction.
`Vice-versa, rejection reactions of the transplant against
`the recipient, the so-called graft-versus-host reactions, may
`occur When immunocompetent tissues are transplanted, i.e.
`primarily in bone marroW transplantation. Again, the sever
`ity 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 reaction, transplan
`tation medicine essentially makes use of immunosuppres
`sion, i.e. a Weakening of the normal immunoresponse. For
`this purpose, anti-lymphocyte sera are often used in com
`bination With corticosteroids and so-called anti-metabolites,
`e.g. purine analogues such as 6-mercaptopurine and thiogua
`nine 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 immu
`noreaction in the body either speci?cally or non-speci?cally.
`Non-speci?c immunosuppressive agents are cytostatic
`agents such as, for example, alkylating agents or antime
`tabolites.
`In addition, active ingredients are knoWn Which cause at
`least partial speci?c immunosuppression, such as corticos
`teroids, antisera, antibodies FK-506, tacrolimus, mycophe
`nolatemofetil and primarily cyclosporines such as cyclospo
`rine A. As a result of using modern immunosuppressive
`agents, the most important representatives of Which are the
`cyclosporines, especially cyclosporine 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% for liver transplantations, about 80% for heart
`transplantations and over 90% for kidney transplantations.
`Autoimmune diseases 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 defense 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 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 pharma
`ceutical preparation Which may be employed for treating
`autoimmune diseases, particularly polyarthritis, multiple
`
`Sawai (IPR2019-00789), Ex. 1009, p. 004
`
`

`

`US 7,320,999 B2
`
`3
`sclerosis, juvenile-onset diabetes, Hashimoto’s thyroiditis,
`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
`autoimmune diseases and pharmaceutical preparations in the
`form of micro-tablets and micro-pellets containing these
`dialkyl fumarates. The individual subject matters 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.
`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 signi?cance4especially When given in high dos
`agesisince they can alleviate or heal diseases caused
`cryptogenetically.
`Fumaric acid, for example, inhibits the groWth of the
`Ehrlich ascites tumour in mice, reduces the toxic effects of
`mitomycin C and a?atoxin 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.
`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-ot secretion in human mononuclear cells of
`periphere blood (periphere blood mononuclear 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.
`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 autoimmune diseases. This is because compositions con
`taining such dialkyl fumarates surprisingly permit a positive
`modulation of the immune system in host-versus-graft reac
`tions, graft-versus-host reactions and other autoimmune
`diseases.
`European Patent Application 0188 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
`psoriasis, psoriatic arthritis, neurodermatitis and enteritis
`regionalis Crohn are knoWn from EP 0 312 697 B1.
`Speci?cally, the object of the invention is achieved by the
`use of one or more dialkyl fumarates of the formula
`
`H
`
`coo —Rl
`
`wherein R1 and R2, Which may be the same or different,
`independently represent a linear, branched or cyclic, satu
`rated or unsaturated Cl_2O alkyl radical Which may be
`optionally substituted With halogen (Cl, F, I, Br), hydroxy,
`Cl4 alkoxy, nitro or cyano for preparing a pharmaceutical
`preparation for use in transplantation medicine or for the
`therapy of autoimmune diseases.
`The Cl_2O alkyl radicals, preferably C1_8 alkyl radicals,
`most preferably C l_5 alkyl radicals are, for example, methyl,
`ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl,
`cyclopentyl, 2-ethyl hexyl, hexyl, cyclohexyl, heptyl, cyclo
`heptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2 or 3-hydroxy
`propyl, 2-methoxy ethyl, methoxy methyl or 2- or 3-meth
`oxy propyl. Preferably at least one of the radicals R1 or R2
`is C l_5 alkyl, especially methyl or ethyl. More preferably, 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 dim
`ethyl fumarate, methyl ethyl fumarate and diethyl fumarate.
`The dialkyl fumarates to be used according to the inven
`tion are prepared by processes knoWn in the art (see, for
`example, EP 0 312 697).
`Preferably, the active ingredients are used for preparing
`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 ?lled 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 um, especially in the range
`of 500 or 1,000 pm.
`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 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
`parenteral administration in the form of aqueous micro
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Sawai (IPR2019-00789), Ex. 1009, p. 005
`
`

`

`US 7,320,999 B2
`
`5
`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.
`According to the invention, a therapy With dialkyl fuma
`rates 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.
`Another embodiment of the use according to the invention
`is to alternate the drug therapy With immunosuppressive
`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 de?ned above over
`one or more Weeks may folloW a cyclosporine therapy of one
`or more Weeks. This permits reduction of the Cyclosporine
`A dosage resulti