(12) United States Patent
`Joshi et al.
`
`(10) Patent N0.:
`
`(45) Date of Patent:
`
`US 6,436,992 B1
`Aug. 20, 2002
`
`US006436992B1
`
`(54) USE OF FUMARIC ACID DERIVATIVES
`
`(75)
`
`Inventors: Rajendra Kumar Joshi, Zurich; Hans
`Peter Strebel, Muri, both of (CH)
`
`(73) Assignee: Fumapharm AG, Muri (CH)
`
`ot1ce:
`* N’
`
`1sc a1mer, t e term o t is
`u ect to an
`yd'l'
`Sbj
`h
`fh'
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.:
`
`09/194,862
`
`(22) PCT Filed:
`
`Apr. 1, 1998
`
`(86) PCT No.:
`
`PCT/EP98/01894
`
`§ 371 (C)(1),
`(2), (4) Date:
`
`Jul. 8, 1999
`
`(87) PCT Pub. No.: WO98/52549
`
`PCT Pub. Date: Nov. 26, 1998
`
`(30)
`
`Foreign Application Priority Data
`
`May 20, 1997
`
`(DE)
`
`....................................... .. 197 21 099
`
`(51)
`
`Int. Cl.7 ..................... .. A61K 31/225; A61K 31/22
`
`(52) U.S. Cl.
`
`...................... .. 514/547; 514/546; 514/549
`
`(58) Field of Search ............................... .. 514/547, 546,
`514/549
`
`(56)
`
`CN
`DE
`DE
`EP
`EP
`EP
`GB
`WO
`WO
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`............ .. 514/494
`9/1990 Speiser et al.
`4,959,389 A *
`FOREIGN PATENT DOCUMENTS
`
`941 191 48
`26 21 214
`35 31 597
`312 697
`0 312 692
`793 966
`2 291 422
`W096/01122
`WO960890 A1
`
`*
`
`6/1996
`11/1977
`3/1987
`4/1989
`4/1993
`9/1997
`1/1996
`1/1996
`3/1996
`
`........ .. A61K/38/13
`....... .. A61K/31/215
`........ .. A61K/45/02
`....... .. A61K/31/225
`....... .. A61K/31/225
`........ .. A61K/38/13
`....... .. C07N/471/04
`........ .. A61K/38/20
`........ .. A01N/13/00
`
`OTHER PUBLICATIONS
`
`“Immunmodulation durch Fumaderm”, Symposium, with
`partial
`translation, Chanite—Berlene Haulkluli Nov.
`1,
`1996-Nov. 3, 1996.
`Article entitled “A Defective Purine Nucleotide Synthesis
`Pathway in Psoriatic Patients” by R. Kiehl, et al., dated Aug.
`1992 taken from Acta Derm. Venerol, No. XP-002088945,
`pp. 253-255.
`Article entitled “Effect of Fumaric Acid, Its Dimethylester,
`and Topical Antipsoriatic Drugs on Epidermal Differentia-
`tion in the Mouse Tail Model”, by B. Seok, et al., taken from
`Skin Pharmacology, dated Mar. 1996, No. XP-002088946,
`pp 99-103.
`Article entitled “Contact urticaria from Diethyl fumarate” by
`Arto Lahti, et al., taken from Contact Dermatitis, dated Mar.
`1985, No. XP-002088947, pp. 139-140.
`
`Page 1 of11
`
`Article entitled “Osteomalazie als offenbar seltene Neben-
`
`Wirkung der oralen Fumarsauretherapie” by Lothar Filegner,
`et
`al.,
`taken from Hautarzt, dated Sep.
`1992, No.
`XP002088948, pp. 554-560.
`
`Article entitled “Nephrotoxische Wirkung von Fumarsaure-
`derivaten” by A. Sadjak, et al., taken from Deutsch Med.
`Wochenschr, No. XP-002088949, dated Mar. 22, 1991, p.
`478.
`
`Article entitled “Acetysalicylic acid inhibits non-immuno-
`logic Contact urticaria” by Arto Lahti, et al., taken from
`Contact Dermatitis,
`dated Mar.
`3,
`1987,
`No.
`XP—002088950, pp 133-135.
`
`Article entitled “ZWei Falle von Nebenwirkungen einer
`Fumarsareester-Lokaltherapie”, by P. Diicker, et al., taken
`from H+G Zeischrift fiir Haukrankheiten, dated Aug. 1990,
`No. XP-002088951, pp 734-736.
`
`Article entitled “Fumaric acid therapy in psoriasis: Results
`and side effect of 2 years of treatment” by Dinanda N.
`Kolbach, et al., dated Nov. 1992, taken from J. American
`Acady of Dermatology, No. XP-002089560, pp 769-771.
`
`Article entitled “Dimethylfumarate Is an Inhibitor of Cytoki-
`ne-Induced E-Selectin, VCAM-1, and ICAM-1 Expression
`in Human Endothelial Cells” by Marc Vandermeeren, et al.,
`dated Mar 8, 1997, taken from Biochemical and Biophysical
`Research Communication, No. XP-002089561, pp 19-23.
`
`Article entitled Systemic therapy with fumaric acid deri-
`vates: New possibilites in the treatment of psoriasis, by C.
`Nieboer, et al., dated Apr. 8, 1990, No. XP-002089562, pp.
`601-608.
`
`Article entitled “Fumaric Acid Esters (FAEs) Suppress CD
`15-and ODP 4-positive Cells in Psoriasis” by M. Bacharac-
`h-Buhles, et al., taken Acta Derm Venereol (Stockh), 1994,
`pp 79-82 No. XP-002088940.
`
`Article entitled “Psoriasis, eine Autoimmunkranl<heit?” by
`Th. Hunziker, et al., taken from Therapeutisch Umscham,
`No. XP-002088941, p 110-113.
`
`Article entitled “The antipsoriatic agent dimethylfumarate
`immunomodulates T-cell cytokine secretion and inhibits
`cytokines of the psoriate cytokine networ ” by H.M. Ock-
`enfels, et al., taken from British Journal of Dermotology,
`dated 1998, No. XP-002089713, pp 390-395.
`
`Article entitled “Perorale Langzeitbehandlung der Psoriasis
`mit Fumarsaurederivaten” by Walter Bayard, et al., taken
`from Her Hautrtz, dated 1997, pp 279-285.
`
`(List continued on next page.)
`
`Primary Examiner—Russell Travers
`(74) Attorney, Agent, or Firm—Cohen, Pontani, Lieberman
`& Pavane
`
`(57)
`
`ABSTRACT
`
`Disclosed is a method of treating auto-immune diseases by
`the administration of certain fumaric acid monoalkyl esters
`as salts or free acids thereof either alone or in combination
`
`with a dialkyl fumarate.
`
`23 Claims, No Drawing
`
`sCoalition Exhibit 1
`
`Coalition v. Bioge
`
`IPR Unassigned
`
`Page 1 of 11
`
`

`

`US 6,436,992 B1
`Page 2
`
`OTHER PUBLICATIONS
`
`Article entitled “Elevation of Gluthathione Levels by Phase
`II Enzyme Inducers: Lack of Inhibition of Human Immu-
`nodeficiency Virus Type 1 Replication in Chronically
`Infected Monocytoid Cells”, by Hans J. Prochaska, et al.,
`taken from Mol. Pharmacol, No. XP002088942, pp
`916-921.
`
`Article entitled “Antiproliferative and cytotoxic profiles of
`antipsoriatic fumaric acid derivatives in keratinocyte cul-
`tures” by Béla Sebok, et al., taken from Eur. J. Pharmacol.
`Article entitled “Fumaric acid derivatives evoke a transient
`increase in intracellular free calcium concentration and
`
`inhibit the proliferation of human keratinocytes” by H.B.
`Thio, et al., taken from British Journal of Dermatology,
`dated Dec. 1994, No. XP-002088944, pp 856-861.
`
`Article taken from “Der Hautarzi” published by Spring-
`er-Verlag 1987 entitled “Perorale Langzeitbehandllung der
`Psoriasis mit Fumarsaurederivarten” Written by Walter Bay-
`nard,, pp 279-285.
`Mar. Index 10”“ Ed 1983 Abstract 2748.*
`
`Hunziku et al Acta Derm Venenol (Stockl.) 1994 Suppl
`1868—79—82.*
`
`Therapeutische Umcschan, Bend 50, Heltz pp 110-113,
`1993.*
`
`Sebok et al, European J of Pharmacology vol. 270 pp 79-87,
`1994.*
`
`* cited by examiner
`
`Page2of11
`
`Page 2 of 11
`
`

`

`US 6,436,992 B1
`
`1
`USE OF FUMARIC ACID DERIVATIVES
`
`This Application is a 371 of PCT/EP98/01894 filed Apr.
`1, 1998 which claims priority from German Patent Appli-
`cation no. 197,21,099.5 filed May 20, 1997.
`BACKGROUND OF THE INVENTION
`
`The present invention relates to the use of certain fumaric
`acid monoalkyl esters as salt either alone or in combination
`with a dialkyl fumarate for preparing pharmaceutical com-
`positions for the treatment of poly-arthritis, multiple scle-
`rosis and graft-versus-host reactions. The invention also
`relates to medicaments containing one or several fumaric
`acid monoalkyl esters in the form of free acids, optionally in
`combination with dialkyl fumarate, as active ingredient for
`the treatment of polyarthritis, multiple sclerosis, graft-
`versus-host reactions and other auto-immune diseases.
`
`These compositions do not contain fumaric acid per se. The
`use according to the invention also extends to the treatment
`of juvenile diabetes, Hashimoto’s thyroiditis, Grave’s
`disease, systemic Lupus erythematosus (SLE), Sjogren’s
`syndrome, pernicious anaemia and chronically active
`(=lupoid) hepatitis.
`Pharmaceutical compositions which end in the citric acid
`cycle when decomposed after administration or which
`belong to the citric acid cycle are increasingly gaining
`therapeutic value, especially when given in high dosages,
`because they help relieve or heal diseases with cryptogenetic
`causes.
`
`inhibits the growth of the
`Fumaric acid, for example,
`Ehrlich ascites tumour in mice, reduces the toxic effects of
`mitomycin C and aflatoxin
`Kuroda, M. Akao, Biochem.
`Pharmacol. 29, 2839-2844 (1980)/Gann. 72, 777-782
`(1981)/Cancer Res. 36, 1900-1903, (1976)] and displays a
`anti-psoriatic and anti-microbial activity [C. N. Huhtsnen, J.
`Food Sci. 48, 1574 (1983)/M. N. Islam, U.S. Pat. No.
`4,346,118 dated Aug. 24, 1982/C. A. 97, 161317b (1982)].
`When administered parenterally, dermally and especially
`perorally, high dosages of fumaric acids or its derivatives
`known so far such as dihydroxy fumaric acid, fumaramide
`and fumaronitrile have such unacceptably severe side effects
`and high toxicity [P. Holland, R. G. White, Brit. Dermatol.
`85, 259-263 (1971)/M. Hagedorn, K. W. Kalkoff, G. Kiefer,
`D. Baron. J. Hug, J. Petres, Arch. Derm. Res. 254, 67-73
`(1975)] that,
`in most cases, such a therapy had to be
`abandoned in the past.
`European Patent Application 18 87 49 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 (Ca, Zn, Mg) and
`of the fumaric acid dimethyl ester for the treatment of
`psoriasis. Pharmaceutical compositions containing a mix-
`ture of fumaric acid monoalkyl ester salts and a fumaric acid
`diester for the treatment of psoriasis, psoriatic arthritis,
`neurodermitis and enteritis regionalis Crohn are known from
`EP 0 312 697 B1.
`
`Surprisingly, we have now found in in vitro tests and in
`animal experiments that it is possible to treat polyarthritis,
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`multiple sclerosis and graft-versus-host reactions with phar-
`maceutical compositions using one or several compounds
`from the group consisting of calcium, magnesium, zinc and
`iron salts of fumaric acid monoalkyl esters of the general
`formula
`
`H
`
`C1-C5—Alkyl—OOC
`
`coo
`c—-c/\
`H
`
`optionally in admixture with dialkyl fumarate of the
`formula
`
`H
`
`/c=c
`
`coo—c1—c5—A1ky1
`
`C1-C5—Alkyl—OOC
`
`H
`
`whereinAis a bivalent cation from the series consisting
`of Ca, Mg, Zn or Fe or a monovalent cation from the
`series consisting of potassium or sodium, respectively,
`and n denotes the numeral 1 or 2 depending on the type
`of cation,
`optionally together with commonly used pharmaceutical
`excipients.
`We also found an effect when polyarthritis, multiple
`sclerosis and graft-versus-host reactions were treated with
`pharmaceutical compositions containing one or several
`compounds of alkyl hydrogen fumaric acid of the general
`formula
`
`H
`
`ROOC
`
`COOH
`
`/C=C
`H
`
`optionally in admixture with dialkyl fumarate of the
`formula
`
`H
`
`COOR
`
`F
`
`/
`
`2
`
`R1OOC
`
`H
`
`wherein R, R1, R2 may be the same or different and
`each of R, R1 and R2 is an alkyl group having 1 to 5
`carbon atoms (C1-C5 alkyl);
`and, optionally, commonly used pharmaceutical excipi-
`ents and carriers.
`
`Preferred compositions according to the invention contain
`the calcium salt of the fumaric acid monomethyl ester, the
`calcium salt of the fumaric acid monomethyl ester in admix-
`ture with dimethyl fumarate or the relevant salts of the
`fumaric acid monoethyl ester.
`Preparations containing the calcium salt of the fumaric
`acid monoalkyl ester or the fumaric acid alkyl ester in the
`form of the free acid in an amount of 10 to 300 mg are
`especially suitable for administration, the total weight of the
`active ingredients being 10 to 300 mg.
`Other preferred oral forms of administration contain 10 to
`290 parts by weight of the calcium salt of the fumaric acid
`monoalkyl ester and 290 to 10 parts by weight of dimethyl
`fumarate as well as 1 to 50 parts by weight of the zinc salt
`of the fumaric acid monoalkyl ester or 1 to 250 parts by
`weight of the calcium salt of the fumaric acid monoalkyl
`
`Page3of11
`
`Page 3 of 11
`
`

`

`US 6,436,992 B1
`
`3
`ester, 250 to 10 parts by weight of dimethyl fumarate, 1 to
`50 parts by weight of the magnesium salt of the fumaric acid
`monoalkyl ester and 1 to 50 parts by weight of the zinc salt
`of the fumaric acid monoalkyl ester or the monomethyl ester,
`respectively, the total weight of the active ingredients being
`30 to 300 mg.
`Preferred compositions according to the invention also
`contain the methyl hydrogen fumarate in an amount of 10 to
`300 mg.
`For commencement of a systemic therapy and, vice versa,
`termination of the treatment by gradual reduction of the
`dosage,
`low doses containing, for example, 30.0 mg of
`dimethyl fumarate, 20.0 mg of the calcium salt of monoethyl
`fumarate and 3.0 mg of the zinc salt of monoethyl fumarate
`or monomethyl fumarate, respectively, are advantageous.
`For therapeutic dosing after an initial phase, for example,
`a dosage of 120.0 mg of dimethyl fumarate, 87.0 mg of the
`calcium salt of the monoethyl fumarate and 3.0 mg of the
`zinc salt of the mono ethyl fumarate or the monomethyl
`fumarate may be used.
`The fumaric acid derivatives contained in the composi-
`tions according to the invention, are obtained by
`a) condensation of a compound of the formula
`
`0
`
`Ck——C——CH O
`
`HC——C——Cl
`
`with 2 moles of alkyl alcohol (ROH) by a known
`method to obtain a diester, followed by controlled
`hydrolysation to obtain a monoester, or
`b) condensation of 1 mole of the relevant alkyl alcohol
`(ROH) in the usual manner followed by hydrolysis of
`the monoacid chloride thus obtained to obtain an acid,
`or
`
`c) direct condensation of the fumaric acid with 2 moles of
`alkyl alcohol (ROH) by a known method to obtain the
`relevant diester followed by controlled hydrolysation to
`obtain the monoester, or
`d) direct condensation of maleic acid or maleic anhydride
`with 1-2 moles of the relevant alkyl alcohol (ROH) by
`a known method to obtain a mono- or diester followed
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`by catalytic isomerisation to obtain the respective
`fumaric acid derivative.
`
`45
`
`The salts of the fumaric acid monoalkyl esters may also
`be obtained by reacting a compound of the general formula
`
`0
`
`R——O——C——CH O
`
`Hc——c——oH
`
`wherein R is a C1-C5 alkyl group with equivalent mole
`amounts of Na, K, Fe, Ca, Mg or Zn hydroxide or oxide in
`toluene and removing the water generated during the reac-
`tion.
`
`For particularly preferred applications, preparations con-
`taining the following active ingredients in the stated dosages
`and proportions are used:
`as a pharmaceutical composition for oral administration in
`the form of tablets or capsules, characterised in that
`they contain the calcium salt of the fumaric acid
`monomethyl ester in an amount of 10 to 300 mg, the
`total weight of the active ingredients being 10 to 300
`mg; or
`
`50
`
`55
`
`60
`
`65
`
`4
`as a pharmaceutical composition for oral administration in
`the form of tablets or capsules, characterised in that
`they contain 10 to 290 parts by weight of the calcium
`salt of the fumaric acid monomethyl ester and 290 to 10
`parts by weight of dimethyl fumarate, the total weight
`of the active ingredients being 20 to 300 mg; or
`additionally, as a pharmaceutical composition for oral
`administration in the form of tablets or capsules char-
`acterised in that they contain 10 to 250 parts by weight
`of the calcium salt of the fumaric acid monomethyl
`ester, 1 to 50 parts by weight of dimethyl fumarate and
`1 to 50 parts by weight of the zinc salt of the fumaric
`acid monomethyl ester, the total weight of the active
`ingredients being 20 to 300 mg, or as a pharmaceutical
`composition for oral administration in the form of
`tablets or capsules, characterised in that they contain 10
`to 250 parts by weight of the calcium salt of the fumaric
`acid mono methyl ester, 250 to 10 parts by weight of
`dimethyl fumarate, 1 to 50 parts by weight of the
`magnesium salt of the fumaric acid monomethyl ester
`and 1 to 50 parts by weight of the zinc salt of the
`fumaric acid monomethyl ester, the total weight of the
`active ingredients being 30 to 300 mg, or, alternatively,
`as a pharmaceutical composition for oral administration
`which may be provided with a coating resistant to
`gastric acid,
`as a pharmaceutical preparation for the treatment of
`polyarthritis, multiple sclerosis or graft-versus-host
`reactions for peroral administration in the form of
`pellets, micro-tablets, capsules, granules and tablets, in
`the form of ointments, plasters or lotions for cutaneous
`and transdermal administration, in the form of aqueous
`micro-dispersions, oil-in-water emulsions or oily solu-
`tions for parenteral administration, or suppositories or
`micro-enemas for rectal administration, and
`as a pharmaceutical composition for the treatment of
`polyarthritis, multiple sclerosis or graft-versus-host
`reactions, characterised in that it contains one or several
`compounds selected from the group consisting of free
`acids of fumaric acid monoalkyl esters of the general
`formula
`
`H
`
`ROOC
`
`COOH
`
`/C=C
`H
`
`optionally in combination with dialkyl fumarate of the
`formula
`
`H
`
`COOR
`
`C:
`
`/
`
`2
`
`RIOOC
`
`H
`
`and R, R1 and R2 are as defined above.
`and carriers, said composition not containing fumaric acid
`in its free form, or
`as a pharmaceutical composition for oral administration in
`the form of tablets, capsules or micro-tablets, charac-
`terised in that they contain alkyl hydrogen fumarate in
`an amount of 10 to 300 mg, the total weight of the
`active ingredients being 10 to 300 mg, or
`as a pharmaceutical composition for oral administration in
`the form of tablets, capsules or micro-tablets, charac-
`terised in that they contain 10 to 290 parts by weight of
`
`Page4of11
`
`Page 4 of 11
`
`

`

`US 6,436,992 B1
`
`5
`alkyl hydrogen fumarate and 290 to 10 parts by weight
`of dialkyl fumarate,
`the total weight of the active
`ingredients being 20 to 300 mg, or as pharmaceutical
`compositions containing the free acid of the fumaric
`acid monomethyl ester (methyl hydrogen fumarate), or
`as a pharmaceutical composition for oral administration in
`the form of tablets, capsules or micro-tablets, charac-
`terised in that they each contain the methyl hydrogen
`fumarate in an amount of 10 to 300 mg, the total weight
`of the active ingredients being 10 to 300 mg,
`or as a pharmaceutical composition for oral administra-
`tion in the form of tablets, capsules or micro-tablets
`containing 10 to 290 parts by weight of methyl hydro-
`gen fumarate and 290 to 10 parts by weight of dimethyl
`fumarate,
`the total weight of the active ingredients
`being 20 to 300 mg, or,
`as a pharmaceutical composition for the treatment of
`polyarthritis, multiple sclerosis or graft-versus-host
`reactions for peroral administration in the form of
`micro-pellets, micro-tablets, capsules, granulates and
`tablets, in the form of ointments, plasters, lotions or
`shower preparations for cutaneous and transdermal
`administration,
`in the form of aqueous micro-
`dispersions, oil-in-water emulsion or oily solutions for
`parenteral administration, or suppositories or micro-
`enemas for rectal administration.
`
`According to a preferred form of administration, the size
`or mean diameter of the pellets or micro-tablets is in the
`range of 300 to 2,000 ym, especially in the range of 500 pm
`to 1,500 pm or 1,000 ym.
`Another special benefit of the use according to the inven-
`tion is to alternate a treatment regimen with cyclosporin
`sequentially with administration of the fumaric acid deriva-
`tives described above. In other words, an application of
`fumaric acid derivatives according to the above definitions
`for a period of one or several weeks could follow a
`cyclosporin therapy extending over one or several weeks. As
`a result, the well-known severe side effects of a long-term
`cyclosporin therapy can be reduced dramatically and unex-
`pectedly.
`In order to illustrate the use according to the invention,
`various examples for the preparation of preferred medica-
`ments are given below:
`
`PRODUCTION EXAMPLES
`
`Example 1
`
`Production of enteric-coated film tablets containing
`100.0 mg of monoethyl fumarate-Ca salt, which
`corresponds to 71 mg of fumaric acid
`
`Taking the necessary precautions (breathing mask,
`gloves, protective clothing, etc.), 10.000 kg of monoethyl
`fumarate-Ca salt are crushed, mixed intensely and homoge-
`nised by means of an 800 sieve. Then an excipient mixture
`of the following composition is prepared: 21.000 kg of
`starch derivative (STA-RX 1500®), 2.000 kg of micro-
`crystalline cellulose (Avicel PH 101®), 0.600 kg of poly-
`vinyl pyrrolidone (PVP, Kollidon® 25), 4.000 kg of
`Primogel®, 0.300 kg of colloidal silicic acid (Aerosil®).
`The active ingredient
`is added to the entire powder
`mixture, mixed, homogenised by means of a 200 sieve and
`processed with a 2% aqueous solution of polyvinyl pyrroli-
`done (PVP, Kollidon® 25) in the usual manner into binder
`granules, and then mixed with the outer phase in a dry state.
`The latter consists of 2.000 kg of a so-called FST complex
`
`6
`containing 80% of talcum, 10% of silicic acid and 10% of
`magnesium stearate.
`Afterwards the mixture is pressed into convex tablets with
`a weight of 400 mg and a diameter of 10.0 mm by the usual
`method. Instead of these classic compaction methods, other
`methods such as direct compaction or solid dispersions
`according to the melting and spray drying method may also
`be used for preparing tablets.
`Enteric Coating
`Asolution of 2.250 kg of hydroxy propyl methyl cellulose
`phthalate (HPMCP, Pharmacoat HP® 50) is dissolved in a
`solvent mixture consisting of 2.50 liters of demineralised
`water, 13.00 liters of acetone (Ph. Helv. VII) and 13.00 liters
`of ethanol (94% by weight) and then 0.240 kg of castor oil
`(Ph. Eur. II) added to the solution. The solution is poured or
`sprayed in portions onto the tablet cores in a coating pan in
`a conventional manner or applied by means of a fluidised
`bed apparatus of the appropriate structure.
`After drying,
`the film coating is applied. Said coating
`consists of a solution of Eudragit E 12.5%® 4.800 kg,
`talcum (Ph. Eur. II) 0.340 kg, titanium(VI) oxide Cronus RN
`56® 0.520 kg, coloured lacquer ZLT-2 blue (Siegle) 0.210
`kg, and polyethylene glycol 6000 (Ph. Helv. VII) 0.120 kg
`in a solvent mixture of 8.200 kg of 2-propanol (Ph. Helv.
`VII), 0.060 kg of glycerine triacetate (Triacetin®) and 0.200
`kg of demineralised water. After homogenous distribution in
`the coating pan or the fluidised bed, the mixture is dried and
`polished in the usual manner.
`
`Example 2
`
`Preparation of enteric coated capsules containing
`86.5 mg of monoethyl fumarate-Ca salt and 110.0
`mg of dimethyl fumarate, which corresponds to a
`total of 150 mg of fumaric acid
`
`Taking the necessary precautions (breathing mask,
`gloves, protective clothing, etc.), 8.650 kg of monoethyl
`fumarate-Ca salt and 11.000 kg of dimethyl fumarate are
`intensely mixed with a mixture consisting of 15.000 kg of
`starch, 6.000 kg of lactose (Ph. Helv. VII), 2.000 kg of
`micro-crystalline cellulose (Avicel®), 1.000 kg of polyvinyl
`pyrrolidone (Kollidon® 25) and 4.000 kg of Primogel® and
`homogenised by means of a 800 sieve.
`Together with a 2% aqueous solution of polyvinyl pyr-
`rolidone (Kollidon® 25) the entire powder mixture is pro-
`cessed in the usual manner into a binder granulate and mixed
`with the outer phase in the dried state. 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 (Ph. Helv.
`VII). The homogeneous mixture is then filled in portions of
`500.0 mg into appropriate capsules which are then provided
`with a enteric-coated coating consisting of hydroxy propyl
`methyl cellulose stearate and castor oil as softening agent by
`a known method. Instead of hard gelatine capsules,
`the
`mixture may also be filled into appropriate gastric acid-
`resistant capsules, which consist of a mixture of cellulose
`acetate phthalate (CAP) and hydroxy propyl ethyl cellulose
`phthalate (HPMCP).
`
`Example 3
`
`Preparation of enteric-coated capsules containing
`203.0 mg of monoethyl fumarate-Ca salt, 5.0 mg of
`monoethyl fumarate-Mg salt and 3.0 mg of
`monoethyl fumarate-Zn salt, which corresponds to
`a total of 150 mg of fumaric acid
`
`Taking the necessary precautions (breathing mask,
`gloves, protective clothing, etc.), 20.300 kg of mono ethyl
`
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`US 6,436,992 B1
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`7
`fumarate-Ca salt, 0.500 kg of monoethyl fumarate-Mg salt
`and 0.300 kg of monoethyl fumarate-Zn salt are crushed,
`mixed intensely and homogenised using an 800 sieve. A
`homogenous powder mixture of the following composition
`is mixed into this active ingredient mixture: spray-dried
`lactose 12.900 kg, colloidal silicic acid 1.000 kg, micro-
`crystalline cellulose (Avicel®) 2.000 kg, magnesium stear-
`ate (Ph. Helv. VII) 1.000 kg and talcum (Ph. Helv. VII) 2.000
`kg. The entire powder mixture is homogenised once again
`by means of a 200 sieve, filled into hard gelatine capsules
`with a net weight of 400 mg and sealed. The application of
`a gastric acid-resistant coating is carried out in accordance
`with example 2.
`
`Example 4
`
`Preparation of enteric-coated micro-tablets in
`capsules containing 87.0 mg of monoethyl
`fumarate-Ca salt, 120.0 mg of dimethyl fumarate,
`5.0 mg of monoethyl fumarate-Mg salt and 3.0 mg
`of monoethyl fumarate-Zn salt, which corresponds
`to a total of 164 mg of fumaric acid (“forte”
`tablets)
`
`Taking the necessary precautions (breathing mask,
`gloves, protective clothing, etc.), 8.700 kg of monoethyl
`fumarate-Ca salt, 12.000 kg of dimethyl fumarate, 0.500 kg
`of monoethyl fumarate-Mg salt and 0.30 kg of monoethyl
`fumarate-Zn salt are crushed, intensely mixed and homoge-
`nised by means of an 800 sieve. Then an excipient mixture
`of the following composition is prepared: 18.00 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
`(Aerosil). The entire powder mixture is added to the active
`ingredient mixture, homogenised by means of a 200 sieve,
`processed in the usual manner with a 2% aqueous solution
`of polyvinyl pyrrolidone (Kollidon K25) to obtain a binder
`granulate and mixed in a dry state with the outer phase
`consisting of 0.50 kg of Mg stearate and 1.50 kg of talcum.
`Then the powder mixture is pressed by the conventional
`method into convex micro-tablets with a gross mass of 10.0
`mg and a diameter of 2.0 mm. Instead of this classic
`tabletting method other methods for making tablets such as
`direct tabletting or solid dispersions by the melt method and
`the spray drying method may also be used.
`The gastric acid-resistant coating may be poured or
`sprayed on in a classic coating pan or applied in a fluidised-
`bed apparatus. In order to achieve resistance to gastric acid,
`portions of a solution of 2.250 kg of hydroxy propyl methyl
`cellulose phthalate (HPMCP, Pharmacoat HP 50) are dis-
`solved in a mixture of the following solvents: acetone 13.00
`1, ethanol 94% weight denatured with 2% ketone 13.50 1 and
`demineralised water 2.50 1. 0.240 kg of castor oil are added
`as softening agent to the finished solution and applied in
`portions to the tablet cores in the usual manner.
`Film-coat: After drying is completed, a suspension of the
`following composition is applied as a film-coat in the same
`apparatus: talcum 0.340 kg, titanium (VI) oxide Cronus RN
`56 0.400 kg, coloured lacquer L red lacquer 86837 0.324 kg,
`Eudragit E 12.5% 4.800 kg and polyethylene glycol 6000
`pH 11 XI 0.120 kg in a solvent mixture of the following
`composition: 2-propanol 8.170 kg, aqua demineralisata
`0.200 kg and glycerine triacetate (Triacetin) 0.600 kg.
`The gastric acid-resistant micro-tablets are then filled into
`hard gelatine capsules at a net weight of 500.0 mg and
`sealed.
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`10
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`Example 5
`
`Preparation of enteric-coated film tablets containing
`67.0 mg of monoethyl fumarate-Ca salt, 30.0 mg of
`dimethyl fumarate, 5.0 mg of monoethyl fumarate-
`Mg salt and 3.0 mg of monoethyl fumarate-Zn salt,
`which corresponds to 75 mg of fumaric acids
`(“mite” tablets)
`
`Taking the necessary precautions (breathing mask,
`gloves, protective clothing, etc.), 3.000 kg of dimethyl
`fumarate, 6.700 kg of monoethyl fumarate-Ca salt, 0.500 kg
`of monoethyl fumarate-Mg salt and 0,300 kg of monoethyl
`fumarate-Zn salt are homogenised by means of an 800 sieve.
`An excipient mixture of the following composition is pre-
`pared in a similar manner to example 4, namely 30.000 kg
`of starch derivative (STA-RX 1500®), 3.000 kg of micro-
`crystalline cellulose (Avicel PH 101), 0.750 kg of polyvinyl
`pyrrolidone (PVP, Kollidon® 25), 4.000 kg of Primogel,
`0.250 kg of colloidal silicic acid (Aerosil®). The excipients
`and the mixture of active ingredients are mixed intimately
`and homogenised by means of a 200 sieve. With the aid of
`a 2% aqueous solution of polyvinyl pyrrolidone (PVP,
`Kollidon® 25), the mass is processed in the usual manner to
`obtain a binder granulate. Apowder mixture of the following
`excipients is added to the dried granulate as an outer phase:
`0.500 kg of Mg stearate (Ph. Eur.) and 0.800 kg of talcum
`(Ph. Eur. II).
`The homogenous granulate mixture is pressed in the usual
`manner to obtain convex tablet cores having a weight of
`500.0 mg and a diameter of 11.5 mm. In addition to binder
`methods other tabletting methods according to examples 1
`and 4 may also be used. The application of a gastric
`acid-resistant coating and a film-coat to the tablet cores is
`described analogously in examples 1 and 4.
`The compositions according to the invention are prefer-
`ably administered perorally in the form of tablets or cap-
`sules. These solid single-dosage medicaments are preferably
`provided with a gastric acid-resistant coating which, once
`having passed the stomach, is dissolved within a few min-
`utes by the juice present in the small intestine and releases
`the active ingredient from the medicament. At the beginning
`and at the end of systemic treatment a lower dosage (mite)
`is required, whereas higher dosages (forte) are suitable for a
`regimen after the initial phase.
`In addition to compositions given orally in the form of
`capsules, granulates and tablets, preparations for cutaneous
`and transdermal administration in the form of ointments,
`plasters, lotions and shower compositions, preparations for
`parenteral administration in the form of aqueous micro-
`dispersions, oil-in-water emulsions or oily solutions, prepa-
`rations for rectal administration in the form of suppositories
`or micro-enemas and preparations for a therapy of hair,
`finger-nails and toe-nails by medication are also the subject
`matter of the invention.
`
`Example 6
`
`Preparation of enteric-coated film-tablets containing
`100.0 mg of monomethyl fumarate-Ca salt, which
`corresponds to 78 mg of fumaric acid
`
`Taking the necessary precautions (breathing mask,
`gloves, protective clothing, etc.), 10.000 kg of monomethyl
`fumarate calcium salt are crushed, mixed and homogenised
`by means of an 800 sieve. Then an excipient mixture with
`the following composition is prepared: 21.000 kg of starch
`derivative (STA-RX 1500®), 2.000 kg of micro-crystalline
`
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`US 6,436,992 B1
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`cellulose (Avicel PH 101®), 0.600 kg of polyvinyl pyrroli-
`done (PVP, Kollidon® 25) 4.000 kg of Primogel, 0.300 kg
`of colloidal silicic acid (Aerosil®). The active ingredient is
`added to the mixture, mixed, homogenised by means of a
`200 sieve, processed in the usual manner with a 2% aqueous
`solution of polyvidon pyrrolidone (Kollidon® K30)
`to
`obtain a binder granulate and then mixed in the dry state
`with the outer phase. Said outer phase consists of 2.000 kg
`of a so-called FST-complex containing 80% of talcum, 10%
`of silicic acid and 10% of magnesium stearate. Then the
`mixture is pressed in the usual manner to obtain convex
`tablets having a weight of 400 mg and a diameter of 10 mm.
`Instead of these classic tabletting methods other methods for
`preparing tablets such as direct tabletting and solid disper-
`sions according to the melting and spray-drying method may
`also be used. The application of a gastric acid-resistant
`coating and a film-coat to the tablet cores is carried out
`analogously to examples 1 and 4.
`
`Example 7
`
`Preparation of enteric-coated film-tablets containing
`50.0 mg of monomethyl fumarate-Ca salt, 50.0 mg
`of dimethyl fumarate, 5 .0 mg of monomethyl
`fumarate-Mg salt and 3.0 mg of monomethyl
`fumarate-Zn salt, which corresponds to 85 mg of
`fumaric acid
`
`Taking the necessary precautions (breathing mask,
`gloves, protective clothing, etc.), 5.000 kg of dimethyl
`fumarate, 5.000 kg of monomethyl fumarate-Ca salt, 0.500
`kg of monomethyl fumarate-Mg salt and 0.300 kg of
`monomethyl fumarate-Zn salt are crushed, mixed and
`homogenised by means of an 800 sieve. Then an excipient
`mixture with the following composition is prepared as
`described in example 4: 19.000 kg of starch derivative
`(STA-RX 1500®), 3.000 kg of m