EP1408947A2 - Fumaric acid derivatives as nf-kappab inhibitors - Google Patents

Fumaric acid derivatives as nf-kappab inhibitors

Info

Publication number
EP1408947A2
EP1408947A2 EP02712806A EP02712806A EP1408947A2 EP 1408947 A2 EP1408947 A2 EP 1408947A2 EP 02712806 A EP02712806 A EP 02712806A EP 02712806 A EP02712806 A EP 02712806A EP 1408947 A2 EP1408947 A2 EP 1408947A2
Authority
EP
European Patent Office
Prior art keywords
fumarate
fumaric acid
use according
ethyl
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02712806A
Other languages
German (de)
French (fr)
Inventor
Rajendra Kumar Joshi
Hans-Peter Strebel
Peter Petzelbauer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biogen International GmbH
Original Assignee
Fumapharm AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fumapharm AG filed Critical Fumapharm AG
Publication of EP1408947A2 publication Critical patent/EP1408947A2/en
Withdrawn legal-status Critical Current

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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
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    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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Definitions

  • the present invention relates to the use of one or more fumaric acid derivatives as NF-kappaB inhibitor. At the same time, the present invention relates to the use of the fumaric acid derivatives for the production of a pharmaceutical preparation for the treatment of NF-kappaB-controllable diseases.
  • NF-kappaB is a transcription factor of eukaryotic cells.
  • NF-kappaB belongs to the family of Rel proteins, a class of transcription factors that are characterized by a so-called Rel domain.
  • the Rel domain is named after the first member found as an oncogene in an avian virus.
  • Specific sites in this homologous Rel domain (RHD), which consists of 300 amino acids, are for the DNA binding to the kappaB sites, the dimerization with other proteins of the Rel family and the interaction with I-responsible.
  • NF-kappa-Bl pl05 / p50
  • NF-kappaB2 pl00 / p52
  • RelA ⁇ 65
  • RelB RelB
  • these five members of the Rel protein family can combine to form homo- and heterodimers in any form, although only a few specific combinations have been observed in vivo.
  • the classic and best characterized NF-kappaB molecule is a heterodimer of the p50 / p65 subunits NF-kappaB 1 / RelA. This heterodimer is the most common complex and can be found in practically all cell types.
  • the NF-kappaB heterodimer p50 / p65 migrates into the cell nucleus and binds there to the consensus sequence 5'-GGGRNNYYCC-3 '.
  • the p50 subunit mainly serves as a DNA-binding subunit, while the p65 subunit provides the transactivation function.
  • each of the heterodimers exhibits unique properties in terms of cell type specificity, DNA binding preferences, differential interactions with I-kappaB isoforms, differential activation requirements and the kinetics of activation.
  • the rapid inducibility of NF-kappaB is attributed to the fact that the factor is present in an inactive form in the cytoplasm of the cell, specifically in the complex bound to the NF-kappaB inhibitor I-kappaB. No new protein synthesis is therefore required for the activation, but only the solution of the complex with I-kappaB or the breakdown of this inhibitor and the subsequent translocation of the then active NF-kappaB dimer into the nucleus.
  • NF-kappaB can be activated by a wide variety of physiological and non-physiological stimuli. These include cytokines, mitogens, viruses, viral products, cross-linking of antigen receptors on T and B lymphocytes, calcium ionophores, phorbol esters, UV rays, oxidation stress, phosphatase inhibitors and others. Equally broad is the large number of genes regulated or activated by NF-kappaB, the transcription of which is activated, induced or enhanced by binding of the heterodimer to the consensus sequence as described above. TNF-Alpha, IL-1, IL-2 and lipopolysaccharides are particularly important stimulants.
  • the regulated genes generally comprise genes which are involved in the immune function, in the inflammation responses, in cell adhesion, cell growth and also cell death.
  • genes of cell adhesion molecules, cytokines, cytokine receptors, acute phase proteins, growth factors and also viral genes are to be mentioned here.
  • the genes which are induced by NF-kappaB include in particular the genes for interferon-beta, for the light chain of immunoglobulin, for the T cell receptor, for TNF-alpha and TNF-beta and for the tissue factor (CD 142) , formerly known as tissue thromboplastin or factor III.
  • NF-kappaB Due to its central position in the regulation of immune reactions and inflammatory responses, as well as its participation in the regulation of tissue factors, cytokines, etc., it has been assumed that the development of selective inhibitors for the transcription factor NF-kappaB expect similar advantages leaves, as they are already known from anti-inflammatory agents. Examples include steroidal anti-inflammatories, interferons, or cyclosporin.
  • NF-kappaB inhibiting activity.
  • This effect can preferably be used for the production of a pharmaceutical preparation which contains these fumaric acid derivatives individually or in a mixture for the therapy of NF-kappaB-mediated or influenceable diseases.
  • the diseases that can be influenced by NF-kappaB are progressive systemic scleroderma, osteochondritis syphilitica (Wegener's Disease), cutis marmorata, (Livedo Reticularis), Behcet disease, panarteritis, ulcerative colitis, vasculitis, etc.
  • one or more fumaric acid derivatives selected from the group consisting of fumaric acid dialkyl esters and fumaric acid monoalkyl esters in the form of the free acid or in salt form and mixtures thereof are preferably used according to the invention for NF-kappaB inhibition and for the preparation of the pharmaceutical preparation.
  • the fumaric acid dialkyl esters preferably correspond to the formula
  • Ri and R ⁇ which can each be the same or different, independently of one another represent a linear, branched, saturated or unsaturated C 24 alkyl radical or a C5-50 aryl radical and these radicals optionally with halogen (F, Cl, Br , I), hydroxy, -C 4 alkoxy, nitro or cyano are substituted.
  • the radicals Ri and R ⁇ are preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, Octyl, vinyl, allyl, 2-hydroxyethyl, 2-ode.f 3-hydroxypropyl, 2,3-dihydroxypropyl, methoxymethyl, 2-methoxyethyl or 2- or 3-methoxypropyl.
  • the fumaric acid monoalkyl esters preferably correspond to the formula
  • R 1 is a radical as defined above;
  • the fumaric acid derivatives for producing the pharmaceutical preparation according to the invention are preferably used in such an amount that this pharmaceutical preparation contains, per dose unit, an amount of one or more fumaric acid derivative (s) in an amount of 1-500 mg, preferably 10-300 mg and most preferably corresponds to 10-200 mg of fumaric acid.
  • the pharmaceutical preparation is administered orally, parenterally, rectally, transdermally, dermally, nasally, pulmonally (inhalation) or ophthalmically (in the form of eye drops) are preferred, with oral administration being preferred.
  • the preparation is then in a form suitable for the particular administration.
  • a pharmaceutical preparation according to the invention is preferably in the form of single-unit-dose tablets, microtablets (multiple-unit-dose tablets) or mini-tablets, micropellets or granules, the microtablets, pellets or that Granules are possibly encapsulated or filled in sachets, capsules or drinking solutions.
  • these are provided with an enteric coating.
  • the coating can also be provided on the encapsulated or filled dosage forms.
  • parenteral administration via injection IV, IMSC, IP
  • the preparation is in a suitable form. All common liquid carriers suitable for injection can be used.
  • the pharmaceutical preparation according to the invention can preferably contain 10-500 mg of dialkyl fumarate, in particular dimethyl fumarate and / or diethyl fumarate, 10-500 mg of calcium alkyl fumarate, in particular calcium methyl fumarate and / or calcium ethyl fumarate, 0-250 mg of zinc alkyl fumarate, in particular zinc methyl fumarate and / or Zinc ethyl fumarate, 0-250 mg alkyl hydrogen fumarate, in particular methyl hydrogen fumarate and / or ethyl hydrogen fumarate and 0-250 mg magnesium alkyl fumarate, in particular magnesium methyl mmarat and / or magnesium ethyl fumarate, the sum of the stated amounts being an equivalent of 10 to 500 mg, preferably 10 to 300 mg and most preferably corresponds to 100 mg of fumaric acid.
  • Preferred preparations according to the invention contain only dimethyl fumarate in an amount of 10 to 300 mg.
  • the pharmaceutical preparation is in the form of microtablets or micropellets. These preferably have a size or an average diameter of ⁇ 5000 micrometers, preferably 300 to 2500 micrometers, in particular 300 to 1000 micrometers for pellets and 1000 to 2500 micrometers for micro-tablets.
  • microtablets preferably enteric-coated microtablets
  • enteric-coated microtablets are already distributed in the stomach and thus enter the intestine in portions, where the active ingredients are released in locally smaller doses at the same total dose.
  • This prevents local irritation of the intestinal epithelial cells, which results in the better gastrointestinal tolerance of the microtablets compared to conventional tablets.
  • the fumaric acid derivatives contained in the preparations according to the invention are produced, for example, in accordance with the process described in EP 0 312 679.
  • the oral preparations according to the invention can be produced in the form of tablets or microtablets using conventional tableting methods.
  • other methods for producing tablets can also be used, such as direct tableting, and processes for producing solid dispersions using the melting method and the spray drying method.
  • the tablets can be provided with enteric coatings.
  • the enteric coating can be poured on or sprayed on in a classic coating pan. However, the coating can also be carried out in a layered layer apparatus.
  • the tablet can also be provided with a film coat.
  • the entire powder mixture is mixed with the active ingredient, mixed, homogenised by means of a sieve 200 and processed with a 2% aqueous solution of polyvinyl pyrrolidone (PVP, Kollidon ® 25) in the usual manner into a binder granulate and mixed in a dry state with the outer phase ,
  • PVP polyvinyl pyrrolidone
  • This consists of 2 kg of a so-called FST complex, containing 80% talc, 10% silica and 10% magnesium stearate.
  • the film coating is then applied.
  • This consists of a solution of Eudragit E ® 12.5% 4.8 kg, Talcum Ph.Eur.II 0.34 kg, titanium (V ⁇ ) oxide Cronus RN 56 ® 0.52 kg, color varnish ZLT-2 blue (Siegle) 0.21 kg and polyethylene glycol 6000 Ph. Helv. VII 0.12 kg in a solvent mixture of 8.2 kg 2-propanol Ph.Helv. VII, 0.06 kg glycerol triacetate (Triacetin ® ) and 0.2 kg Aqua demineralisata. After homogeneous distribution in the coating pan or fluidized bed, the mixture is dried and polished in the customary manner.
  • Triacetin ® Triacetin ®
  • the entire powder mixture is processed with a 2% aqueous solution of polyvinylpyrrolidone (Kollidon ® 25) in the usual manner into a binder granulate and mixed in the dry state with the outer phase.
  • This consists of 0.35 kg of colloidal silica (Aerosil ® ), 0.5 kg of magnesium stearate and 1.5 kg of talc Ph. Helv. VII.
  • the homogeneous mixture is then filled into appropriate capsules in 500.0 mg portions, which finally in the usual way with an enteric coating consisting of hydroxypropylethyl cellulose phatalate and castor oil as a plasticizer.
  • the filling can also take place in corresponding gastro-resistant capsules, consisting of a mixture of cellulose acetate phthalate (CAP) and hydroxypropylethyl cellulose phthalate (HPMCP).
  • CAP cellulose acetate phthalate
  • HPMCP hydroxypropylethyl cellulose phthalate
  • the entire powder mixture is mixed with the active ingredient mixture and homogenized by means of a sieve 200 and processed with a 2% aqueous solution of polyvinylpyrrolidone (Kollidon K25) in the usual way to a binder granulate and mixed in a dry state with the outer phase. This consists of 0.5 kg magnesium stearate and 1.5 kg talc.
  • the powder mixture is then pressed in the usual way to curved micro-tablets of 10.0 mg gross mass and 2.0 mm in diameter.
  • other methods for producing tablets can also be used, such as direct tableting and solid dispersions using the melting method and the spray drying method.
  • the enteric coating can be poured on or sprayed on in a classic coating pan and applied in a fluidized bed apparatus.
  • a solution of 2.250 kg of hydroxypropylmethyl cellulose phthalate (HPMCP, Pharmacoat HP 50) is dissolved in portions in a mixture of the following solvents: acetone 13 1, ethanol 94% by weight denatured with 2% ketone 13.5 1 and aqua demineralisata 2, 5 1. 0.240 kg of castor oil is added to the finished solution as a plasticizer and applied in portions to the tablet cores in the usual way.
  • Film coat After drying is complete, a suspension of the following composition is then applied as a film coat in the same apparatus: talc 0.340 kg, titanium (VI) oxide Cronus RN 56 0.4 kg, color varnish L-red varnish 86837 0.324 kg, Eudragit E 12.5 % 4.8 kg and polyethylene glycol 6000 pH 11 XI 0.12 kg in a solvent mixture of the following composition: 2-propanol 8.17 kg, aqua demineralisata 0.2 kg and glycerol tracetate (triacetine) 0.6 kg.
  • the enteric-coated micro-tablets are then filled into hard gelatin capsules of 500.0 mg net weight and sealed.
  • Example 4 The enteric-coated micro-tablets are then filled into hard gelatin capsules of 500.0 mg net weight and sealed.
  • the powder mixture is then pressed in the usual way into curved tablets of 10.0 mg gross mass and 2.0 mm in diameter.
  • HPMCP hydroxypropylmethylcellulose phthalate
  • Pharmacoat® HP 50 hydroxypropylmethylcellulose phthalate
  • acetone 13 1 ethanol (94% by weight denatured with 2% ketone) 13
  • 5 1 and Aqua demineralisata 1.5 1.
  • Castor oil (0.24 kg) is added to the finished solution as a plasticizer and applied in portions to the tablet cores in the usual way.
  • a suspension of the following composition is then applied as a film coat in the same apparatus: talc 0.34 kg, titanium (VI) oxide Cronus RN 56 0.4 kg, color varnish L-red varnish 86837 0.324 kg, Eudragit E 12, 5% 4.8 kg and polyethylene glycol 6000 pH 11 XI 0.12 kg in a solvent mixture of the following composition: 2-propanol 8.17 kg, aqua demineralisata 0.2 kg and glycerol triacetate (triacetin) 0.6 kg.
  • the enteric-coated micro-tablets are then filled into hard gelatin capsules with a net weight of 400 mg and sealed.
  • a solution of 0.94 Eudragit® L in isopropanol is then prepared, which also contains 0.07 kg of dibutyl phthalate. This solution is sprayed onto the tablet cores.
  • a dispersion of 17.32 kg of Eudragit® L D-55 and a mixture of 2.8 kg of microtalkum, 2 kg of Macrogol 6000 and 0.07 kg of Dimeticon is then prepared in water and sprayed onto the cores.
  • enteric-coated micro-tablets are then filled into hard gelatin capsules with a net weight of 650 mg and sealed.
  • NF-kappa-B (p65) was inserted into the vector pEGFP-Cl, which contained EGFP (green fluorescent protein) linked to a cytomegalovirus promoter (Clontech). This leads to the expression of a fluorescent NF-kappaB.
  • HUNEC cells were seeded between the third and fifth passages in 12-well gelatin-coated culture plates (Costar) and grown to 80 and 90% confluency, respectively. The cells were finally transfected using the calcium phosphate precipitation method. More specifically, the cells were conditioned with Dulbecco's modified Eagles medium (DMEM), the precipitate containing 1 ⁇ g DNA per well was added after 2 hours and the cells were incubated for a further 4 hours. After washing with HBSS (Hanks balanced salt solution), culture medium was added and the cells were allowed to grow for a further 18 hours before being stimulated.
  • DMEM Dulbecco's modified Eagles medium
  • the cells were conditioned with 40 ⁇ M / 1 dimethyl fumarate, whereby parallel batches without DNA served as a control. 2 hours after the start of conditioning, the cells were stimulated with 10 ng / ml TNF-alpha for the times given in Table 1.
  • the cells were then lysed, the supernatant discarded and the cell nuclei were collected in donut buffer with protease inhibitors (10 mM Tris-HCl pH 7.6, 0.5 mM MgCl, 10 ⁇ g / ml leupeptin, 10 ⁇ g / ml aprotinin , 1 mM phenylmethylsulfonyl fluoride, 1.8 mg / ml iodoacetamide). After centrifugation for 10 min. at 1200 g, 4 ° C, the cell nuclei were analyzed on a FACscanflow cytometer (Becton Dickinson).
  • protease inhibitors 10 mM Tris-HCl pH 7.6, 0.5 mM MgCl, 10 ⁇ g / ml leupeptin, 10 ⁇ g / ml aprotinin , 1 mM phenylmethylsulfonyl fluoride, 1.8 mg
  • a triple repeat of the AP-1 consensus site (binding site) 48 bp, 3 x TGTGATGACTCAGGTT) and a triple repeat of the NF-kappa_B consensus site (60 bp, 3 x AATCGTGGAATTTCCTCTGA), flanked by Spel binding sites (not shown), were inserted into the Spel site of the pTK-UBT-luc vector (de Martin, Gene 124, 137-38, 1993).
  • HUVEC cells were transfected with the constructs thus obtained as described in Example 6. For the transfection, 2.5 ⁇ g of the respective promoter construct were added per well. In order to check the transfection efficiency, cotransfections with 500 ng of a pSV-beta galactosidase control vector (Promega Corp., Madison, WI, USA) were carried out in each experiment as a control. 2 days after transfection, the cells were stimulated for 2 hours with 10 ng / ml TNF-alpha with and without the addition of 6 ⁇ g / ml dimethyl fumarate (DMF). The cells were then harvested by trypsinization, pelletized, washed and in 200 ⁇ l "reporter lysis buffer" (Promega) for 15 min. resuspended according to the manufacturer's instructions.
  • a pSV-beta galactosidase control vector Promega Corp., Madison, WI, USA
  • Luciferase activity was measured on a Berthold AutoLumat LB9507 luminometer using the Luciferase test system (Promega). Beta-galactosidase activity was determined using the Promega beta-galactosidase enzyme assay system. The luciferase activities obtained with the respective promoter constructs were normalized to the beta-galactosidase activity. The range of variation in beta-galactosidase activity within the individual experiments was below 10%. Table 2 shows the respective results as x times compared to the baseline. Table 2: Increase in transcription

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Abstract

The invention relates to the use of at least one fumaric acid derivative as an NF-kappaB inhibitor for the treatment of diseases such as progressive systemic sclerodermia, mottled skin, Behçet's disease, ulcerative colitis, vasculitis, osteoarthritis, gout, arteriosclerosis, Reiter's syndrome, types of encephelitis, endotoxin shock, pneumonia, encephalomyelitis, anorexia nervosa, hepatitis, mesangial nephritis, reperfusion syndrome, cytomegalovirus retinopathy, adenoviral diseases such as adenoviral catarrhal fever, AIDS, neuralgia, inflammatory demyelination polyneuropathy, multiplex type of mononeuropathy, mucoviscidosis, Bechterew's disease, endobrachyoesophagus, EBV (Epstein Barr virus) infection, interstitial cystitis, pancreatic diabetes type II, the radiation sensitisation of malignant tumours, and the multiple resistance of malignant cells in cancers.

Description

Fumarsaurederivate als NF-kappaB-Inhibitor Fumaric acid derivatives as NF kappaB inhibitor
Die vorliegende Erfindung betrifft die Verwendung eines oder mehrerer Fumarsaurederivate als NF-kappaB-Inhibitor. Gleichzeitig betrifft die vorliegende Erfindung die Verwendung der Fumarsaurederivate zur Herstellung einer pharmazeutischen Zubereitung zur Behandlung von NF-kappaB beeinflussbaren Erkrankungen.The present invention relates to the use of one or more fumaric acid derivatives as NF-kappaB inhibitor. At the same time, the present invention relates to the use of the fumaric acid derivatives for the production of a pharmaceutical preparation for the treatment of NF-kappaB-controllable diseases.
Bekannt ist, dass pharmazeutische Zubereitungen, die nach Verabreichung bei ihrem biologischen Abbau in den Zitronensäurezyklus einmünden oder diesem angehören, wie die Fu- marsäure, zumeist in hoher Dosierung immer mehr an therapeutischem Wert gewinnen, da man mit ihrer Hilfe kryptogenetisch bedingte Krankheiten zu lindern oder zu heilen vermag. Weiterhin hemmt Fumarsäure das Wachstum des Ehrlich-Ascites-Tumors bei Mäusen, vermindert die toxischen Effekte von Mitomycin C und Aflatoxin und besitzt eine antipsoriati- sche sowie antimikrobielle Wirkung.It is known that pharmaceutical preparations which, after administration, when they biodegrade or belong to the citric acid cycle, like fumaric acid, usually gain more and more therapeutic value in high doses, since they help to alleviate or reduce cryptogenetically caused diseases is able to heal. Fumaric acid also inhibits the growth of the Ehrlich ascites tumor in mice, reduces the toxic effects of mitomycin C and aflatoxin and has an antipsoriatic and antimicrobial effect.
Wichtigste praktische Anwendung ist die Behandlung von Psoriasis mit verschiedenen Fu- marsäurederivaten. Diese ist bereits in einer Anzahl von Patenten beschrieben worden, siehe z. B. EP 188 749, DE 25 30 372, DE 26 21 214 oder EP 312 697.The most important practical application is the treatment of psoriasis with various fumaric acid derivatives. This has already been described in a number of patents, see e.g. B. EP 188 749, DE 25 30 372, DE 26 21 214 or EP 312 697.
Eine weitere Verwendung bestimmter Fumarsaurederivate, nämlich der Alkylhydrogen- fumarate, offenbaren die DE 197 21 099.6 sowie die DE 198 53 487.6, gemäß denen diese bestimmten Fumarsaurederivate zur Behandlung von Autoimmunerkrankungen wie insbesondere der Polyarthritis, der Multiplen Sklerose und von Graft-versus-Host-Reaktionen beschrieben werden. Weiterhin lehren die DE 198 53 487.6 sowie die DE 198 39 566.3 die Verwendung von Alkylhydrogenfumaraten und Dialkylfumaraten in der Transplantationsmedizin. Obwohl einzelne Untersuchungen zum Wirkmechanismus der Fumarsaurederivate in der in der Psoriasisbehandlung vorliegen, ist genaueres hierzu bisher nicht bekannt. Der NF-kappaB (nuklearer Faktor kappaB) ist ein Transkriptionsfaktor eukaryontischer Zellen. NF-kappaB gehört zur Familie der Rel-Proteine, einer Klasse von Transkriptionsfaktoren, die durch eine sog. Rel-Domäne gekennzeichnet sind. Die Rel-Domäne ist nach dem ersten Mitglied benannt, das als ein Onkogen in einem Vogelvirus gefunden wurde. Spezifische Sites in dieser homologen Rel-Domäne (Rel-homology domain = RHD), die aus 300 Aminosäuren besteht, sind für die DNA-Bindung an die kappaB-Sites, die Dimeri- sierung mit anderen Proteinen der Rel-Familie und die Wechselwirkung mit I-kappaB verantwortlich.Another use of certain fumaric acid derivatives, namely the alkyl hydrogen fumarates, is disclosed in DE 197 21 099.6 and DE 198 53 487.6, according to which these specific fumaric acid derivatives are used to treat autoimmune diseases such as, in particular, polyarthritis, multiple sclerosis and graft-versus-host Reactions are described. Furthermore, DE 198 53 487.6 and DE 198 39 566.3 teach the use of alkyl hydrogen fumarates and dialkyl fumarates in transplantation medicine. Although individual studies on the mechanism of action of fumaric acid derivatives in psoriasis treatment are available, more details are not yet known. The NF-kappaB (nuclear factor kappaB) is a transcription factor of eukaryotic cells. NF-kappaB belongs to the family of Rel proteins, a class of transcription factors that are characterized by a so-called Rel domain. The Rel domain is named after the first member found as an oncogene in an avian virus. Specific sites in this homologous Rel domain (RHD), which consists of 300 amino acids, are for the DNA binding to the kappaB sites, the dimerization with other proteins of the Rel family and the interaction with I-responsible.
Bislang sind bei Säugern fünf Mitglieder der Rel-Familie bekannt. Diese sind c-Rel, NF- kappa-Bl (pl05/p50), NF-kappaB2 (pl00/p52), RelA (ρ65) und RelB. Theoretisch können diese fünf Mitglieder der Rel-Proteinfamilie in jeder Form zu Homo- und Heterodimere kombinieren, obwohl nur einige bestimmte Kombinationen in vivo beobachtet worden sind. Bei dem klassischen und am besten charakterisierten NF-kappaB Molekül handelt es sich um ein Heterodimer der p50/p65 Untereinheiten NF-kappaB 1 /RelA. Dieses Heterodimer stellt den häufigsten Komplex dar und findet sich in praktisch allen Zelltypen.So far, five members of the Rel family are known in mammals. These are c-Rel, NF-kappa-Bl (pl05 / p50), NF-kappaB2 (pl00 / p52), RelA (ρ65) and RelB. Theoretically, these five members of the Rel protein family can combine to form homo- and heterodimers in any form, although only a few specific combinations have been observed in vivo. The classic and best characterized NF-kappaB molecule is a heterodimer of the p50 / p65 subunits NF-kappaB 1 / RelA. This heterodimer is the most common complex and can be found in practically all cell types.
Nach der zellulären Aktivierung und der Dissoziation von I-kappaB wandert das NF-kappaB Heterodimer p50/p65 in den Zellkern und bindet dort an die Konsensussequenz 5'- GGGRNNYYCC-3'. Dabei dient die p50 Untereinheit vorwiegend als DNA-bindende Untereinheit, während die p65 Untereinheit die Transaktivierungsfunktion liefert.After cellular activation and the dissociation of I-kappaB, the NF-kappaB heterodimer p50 / p65 migrates into the cell nucleus and binds there to the consensus sequence 5'-GGGRNNYYCC-3 '. The p50 subunit mainly serves as a DNA-binding subunit, while the p65 subunit provides the transactivation function.
Jedes der Heterodimere zeigt durch die unterschiedlichen Kombinationen einzigartige Eigenschaften, was die Zelltyp-Spezifität, Präferenzen bezüglich der DNA-Bindung stellen, differentielle Wechselwirkungen mit I-kappaB-Isoformen, differentielle Aktivierungserfordernisse und die Kinetik der Aktivierung angeht. Die schnelle Induzierbarkeit von NF-kappaB wird der Tatsache zugeschrieben, dass der Faktor im Zytoplasma der Zelle in einer inaktiven Form vorliegt, und zwar im Komplex an den NF-kappaB-Inhibitor I-kappaB gebunden. Für die Aktivierung ist daher keine neue Proteinsynthese erforderlich, sondern lediglich die Lösung des Komplexes mit I-kappaB bzw. der Abbau dieses Inhibitors und die anschließende Translokation des dann aktiven NF- kappaB-Dimeren in den Kern.Due to the different combinations, each of the heterodimers exhibits unique properties in terms of cell type specificity, DNA binding preferences, differential interactions with I-kappaB isoforms, differential activation requirements and the kinetics of activation. The rapid inducibility of NF-kappaB is attributed to the fact that the factor is present in an inactive form in the cytoplasm of the cell, specifically in the complex bound to the NF-kappaB inhibitor I-kappaB. No new protein synthesis is therefore required for the activation, but only the solution of the complex with I-kappaB or the breakdown of this inhibitor and the subsequent translocation of the then active NF-kappaB dimer into the nucleus.
NF-kappaB kann durch eine breite Vielzahl von physiologischen und nichtphysiologischen Stimuli aktiviert werden. Diese schließen Zytokine, Mitogene, Viren, virale Produkte, die Quervernetzung von Antigenrezeptoren auf T- und B-Lymphozyten, Kalzium-ionophoren, Phorbolester, UV-Strahlen, Oxidationsstress, Phosphatasehemmer und anderes ein. Gleichermaßen breit ist die Vielzahl der von NF-kappaB regulierten bzw. aktivierten Gene, deren Transkription durch Bindung des Heterodimere an die Konsensussequenz wie oben beschreiben aktiviert, induziert oder verstärkt wird. Als wichtige Stimulantien sind insbesondere TNF- Alpha, IL-1, IL-2, und Lipopolysacharide zu nennen.NF-kappaB can be activated by a wide variety of physiological and non-physiological stimuli. These include cytokines, mitogens, viruses, viral products, cross-linking of antigen receptors on T and B lymphocytes, calcium ionophores, phorbol esters, UV rays, oxidation stress, phosphatase inhibitors and others. Equally broad is the large number of genes regulated or activated by NF-kappaB, the transcription of which is activated, induced or enhanced by binding of the heterodimer to the consensus sequence as described above. TNF-Alpha, IL-1, IL-2 and lipopolysaccharides are particularly important stimulants.
Die regulierten Gene umfassen allgemein Gene, die an der Jjrrmunfunktion, an der Entzün- dungsrespons, an der Zelladhäsion, dem Zellwachstum aber auch dem Zelltod beteiligt sind. Insbesondere sind hier zu nennen Gene von Zell-Adhäsionsmolekülen, Zytokinen, Zytokin- Rezeptoren, Akutphasenproteinen, Wachstumsfaktoren und auch virale Gene. Zu den Genen, die durch NF-kappaB induziert werden, gehören insbesondere die Gene für Interferon- Beta, für die leichte Kette des Immunglobulins, für den T-Zellrezeptor, für TNF-alpha und TNF-beta sowie für den Gewebsfaktor (CD 142), früher als Gewebstromboplastin oder Faktor III bezeichnet.The regulated genes generally comprise genes which are involved in the immune function, in the inflammation responses, in cell adhesion, cell growth and also cell death. In particular, genes of cell adhesion molecules, cytokines, cytokine receptors, acute phase proteins, growth factors and also viral genes are to be mentioned here. The genes which are induced by NF-kappaB include in particular the genes for interferon-beta, for the light chain of immunoglobulin, for the T cell receptor, for TNF-alpha and TNF-beta and for the tissue factor (CD 142) , formerly known as tissue thromboplastin or factor III.
Aufgrund seiner aus dem obigen ersichtlichen zentralen Stellung in der Regulation von Immunreaktionen und Entzündungsantworten sowie aufgrund der Beteiligung an der Regulation von Gewebsfaktoren, Zytokinen usw. ist vermutet worden, dass die Entwicklung von selektiven Inhibitoren für den Transkriptionsfaktor NF-kappaB ähnüche Vorteile erwarten lässt, wie sie bereits von entzündungshemmenden Wirkstoffen bekannt sind. Zu nennen sind hier bspw. die steroidalen Entzündungshemmer, Interferone, oder das Cyclosporin.Due to its central position in the regulation of immune reactions and inflammatory responses, as well as its participation in the regulation of tissue factors, cytokines, etc., it has been assumed that the development of selective inhibitors for the transcription factor NF-kappaB expect similar advantages leaves, as they are already known from anti-inflammatory agents. Examples include steroidal anti-inflammatories, interferons, or cyclosporin.
Es wurde nun überraschend gefunden, dass einzelne Fumarsaurederivate oder deren Mischungen NF-kappaB inhibierende Wirkung haben. Diese Wirkung lässt sich bevorzugt für die Herstellung einer pharmazeutischen Zubereitung, welche diese Fumarsaurederivate einzeln oder im Gemisch enthält, zur Therapie NF-kappaB vermittelter bzw. beinflußbarer Erkrankungen nutzen. Insbesondere handelt es sich bei den NF-kappaB beeinflussbaren Erkrankungen um die progressive systemische Sklerodermie, die Osteochondritis syphilitica (Wegener's Disease), die Cutis marmorata, (Livedo Reticularis), die Behcet-Disease, die Panarteritis, die Colitis ulcerosa, die Vasculitis, die Osteoarthritis, die Gicht, die Ateri- osklerosis, die Reiter's Erkrankung, die bronchozentische Granulomatose, Encephalitis- Typen, den Endotoxin-Schock (septisch-toxischer Schock), die Sepsis, die Pneumonie, die Encephalomyelitis, die Anorexia nervosa, die Hepatitis (die akute Hepatitis, die chronische Hepatitis, die toxische Hepatitis, die Alkoholhepatitis, die virale Hepatitis, die Gelbsucht, die Leberinsuffizienz und die cytomegalovirale Hepatitis), die Rennert T Lymphomatosis, die mesangiale Nephritis, die Postangioplastie-Restenose, das Reperfusionssyndrom, die cytomegalovirale Retinopathie, Adeno virale Erkrankungen wie adenovirale Erkältungserkrankungen, adenovirales Pharyngocoηjunctivalfieber und adenovirale Ophthalmie, AIDS, das Guillain-Barre-Syndrom, die postherpetische oder postzoster Neuralgie (engl. : posther- petic neuralgia), die inflammatorische demyelinisierende Polyneuropathie, die Mononeuro- pathia multiplex, die Mukoviszidose, Morbus Bechterew, Barett-Ösophagus, EBV-(Epstein- Barr-Virus)-Infektion, das kardiale Remodeling (engl. : cardiac remodeling), interstitielle Zystitis, Diabetes mellitus Typ II, die Strahlensensibilisierung maligner Tumore (engl. : human tumor radiosensitization), die Mehrfachresistenz maligner Zellen auf Chemotherapeuti- ka (engl. : multidrug resistance in chemotherapy), Granuloma annulare und Krebserkrankungen wie Mamma Karzinom, Kolonkarzinom, Melanom, primäres Leberzellkarzinom, Adenokarzinom, Kaposi Sarkom, Prostatakarzinom, Leukämie wie die akute myeloische Leukämie, das multiple Myelom (Plasmozytom), Burkitt-Lymphom, und den Castleman- Tumor. Vorzugsweise verwendet man erfindungsgemäß zur NF-kappaB-Inhibition sowie zur Herstellung der pharmazeutischen Zubereitung ein oder mehrere Fumarsaurederivate, ausgewählt aus der Gruppe, bestehend aus Fumarsäuredialkylestern und Fumarsäuremono- alkylestern in Form der freien Säure oder in Salzform und Mischungen derselben.It has now surprisingly been found that individual fumaric acid derivatives or their mixtures have NF-kappaB inhibiting activity. This effect can preferably be used for the production of a pharmaceutical preparation which contains these fumaric acid derivatives individually or in a mixture for the therapy of NF-kappaB-mediated or influenceable diseases. In particular, the diseases that can be influenced by NF-kappaB are progressive systemic scleroderma, osteochondritis syphilitica (Wegener's Disease), cutis marmorata, (Livedo Reticularis), Behcet disease, panarteritis, ulcerative colitis, vasculitis, etc. Osteoarthritis, gout, atherosclerosis, Reiter's disease, bronchocentic granulomatosis, types of encephalitis, endotoxin shock (septic-toxic shock), sepsis, pneumonia, encephalomyelitis, anorexia nervosa, hepatitis (the acute hepatitis, chronic hepatitis, toxic hepatitis, alcoholic hepatitis, viral hepatitis, jaundice, hepatic insufficiency and cytomegaloviral hepatitis), Rennert T lymphomatosis, mesangial nephritis, postangioplasty restenosis, reperfusion syndrome, retperfyt syndrome, retina Adeno viral diseases such as adenoviral colds, adenoviral pharyngocoηjuncti valfieber and adenoviral ophthalmia, AIDS, Guillain-Barre syndrome, post-herpetic or post-zoster neuralgia : postherpetic neuralgia), inflammatory demyelinating polyneuropathy, mononeuropathy multiplex, cystic fibrosis, ankylosing spondylitis, beret esophagus, EBV (Epstein-Barr virus) infection, cardiac remodeling (English: cardiac remodeling) , interstitial cystitis, type II diabetes, the radiation sensitization of malignant tumors (English: human tumor radiosensitization), the multiple resistance of malignant cells to chemotherapy (English: multidrug resistance in chemotherapy), granuloma annular and cancers such as breast cancer, colon cancer, Melanoma, primary liver cell carcinoma, adenocarcinoma, Kaposi's sarcoma, prostate carcinoma, leukemia such as acute myeloid leukemia, multiple myeloma (plasmacytoma), Burkitt's lymphoma, and the Castleman tumor. According to the invention, one or more fumaric acid derivatives selected from the group consisting of fumaric acid dialkyl esters and fumaric acid monoalkyl esters in the form of the free acid or in salt form and mixtures thereof are preferably used according to the invention for NF-kappaB inhibition and for the preparation of the pharmaceutical preparation.
Die Fumarsäuredialkylester entsprechen vorzugsweise der FormelThe fumaric acid dialkyl esters preferably correspond to the formula
in der Ri und R∑, die jeweils gleich oder verschieden sein können, unabhängig voneinander einen linearen, verzweigten, gesättigten oder ungesättigten Cι-24-Alkylrest oder einen C5-50- Arylrest bedeuten und diese Reste gegebenenfalls mit Halogen (F, Cl, Br, I), Hydroxy, Cι-4-Alkoxy, Nitro oder Cyano substituiert sind.in the Ri and R∑, which can each be the same or different, independently of one another represent a linear, branched, saturated or unsaturated C 24 alkyl radical or a C5-50 aryl radical and these radicals optionally with halogen (F, Cl, Br , I), hydroxy, -C 4 alkoxy, nitro or cyano are substituted.
Bevorzugt handelt es sich bei den Resten Ri und R∑ um Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, sec-Butyl, t-Butyl, Pentyl, Cyclopentyl, 2-Ethylhexyl, Hexyl, Cyclohexyl, Heptyl, Cycloheptyl, Octyl, Vinyl, Allyl, 2-Hydroxy ethyl, 2- ode.f 3-Hydroxypropyl, 2,3- Dihydroxypropyl, Methoxymethyl, 2-Methoxyethyl oder 2- oder 3-Methoxypropyl.The radicals Ri and R∑ are preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, Octyl, vinyl, allyl, 2-hydroxyethyl, 2-ode.f 3-hydroxypropyl, 2,3-dihydroxypropyl, methoxymethyl, 2-methoxyethyl or 2- or 3-methoxypropyl.
Die Fumarsäuremonoalkylester entsprechen bevorzugt der FormelThe fumaric acid monoalkyl esters preferably correspond to the formula
in der Ri einen wie oben definierten Rest bedeutet; A Wasserstoff, ein Alkali- oder Erdalkalimetallkation oder ein physiologisch verträgliches Übergangsmetallkation, vorzugsweise ausgewählt unter Li+, Na+, K+, Mg2+, Ca2+, Zn2+, Fe2+ und Mn2+, ist und n gleich 1 oder 2 ist und der Valenz von A entspricht.in which R 1 is a radical as defined above; A hydrogen, an alkali or alkaline earth metal cation or a physiologically acceptable transition metal cation, preferably selected from Li + , Na + , K + , Mg 2+ , Ca 2+ , Zn 2+ , Fe 2+ and Mn 2+ , and n is 1 or 2 and corresponds to the valence of A.
Bevorzugt verwendet werden gemäß der Erfmdung ein oder mehrere Fumarsäurederivat(e), die aus der Gruppe, umfassend Fumarsäuredimethylester, Fumarsäurediethylester, Fumar- säuremethylethylester, Methylhydrogenfumarat, Ethylhydrogenmmarat, Magnesiummethyl- fumarat, Magnesiumethylfumarat, Zinkmethylmmarat, Zinkethylmmarat, Eisenmethylfuma- rat, Eisenethylfumarat, Calciummethylmmarat und Calciumethylnimarat, ausgewählt sind.According to the invention, preference is given to using one or more fumaric acid derivative (s) from the group comprising dimethyl fumarate, diethyl fumarate, methyl fumarate, methyl hydrogen fumarate, ethyl hydrogen fumarate, magnesium methyl fumarate, magnesium ethyl fumarate, zinc methyl fumarate, iron methyl fumarate, zinc methyl fumarate, zinc methyl fumarate, zinc methyl fumarate, zinc methyl fumarate, zinc methyl fumarate, zinc methyl fumarate, zinc methyl fumarate, zinc methyl fumarate, zinc methyl fumarate, zinc methyl fumarate, zinc methyl fumarate, zinc ethyl fumarate Calcium ethyl nimate are selected.
Bevorzugt werden die Fumarsaurederivate zur Herstellung der pharmazeutischen Zubereitung gemäß der Erfindung in einer solchen Menge eingesetzt, dass diese pharmazeutische Zubereitung pro Dosiseinheit eine Menge von einem oder mehreren Fumarsäurederivat(en) enthält, die einer Menge von 1-500 mg, vorzugsweise 10-300 mg und am meisten bevorzugt 10-200 mg Fumar säure entspricht bzw. äquivalent ist.The fumaric acid derivatives for producing the pharmaceutical preparation according to the invention are preferably used in such an amount that this pharmaceutical preparation contains, per dose unit, an amount of one or more fumaric acid derivative (s) in an amount of 1-500 mg, preferably 10-300 mg and most preferably corresponds to 10-200 mg of fumaric acid.
Bevorzugt sind Anwendungen, bei denen die pharmazeutische Zubereitung oral, parenteral, rektal, transdermal, dermal, nasal, pulmonal (Inhalation) oder ophthal (in Form von Augentropfen) verabreicht wird, wobei die orale Verabreichung bevorzugt ist. Die Zubereitung liegt dann in für die jeweilige Verabreichung geeigneter Form vor.Applications in which the pharmaceutical preparation is administered orally, parenterally, rectally, transdermally, dermally, nasally, pulmonally (inhalation) or ophthalmically (in the form of eye drops) are preferred, with oral administration being preferred. The preparation is then in a form suitable for the particular administration.
Erfolgt eine orale Verabreichung, so liegt eine pharmazeutische Zubereitung gemäß der Erfmdung bevorzugt in Form von Single-Unit-Dose-Tabletten, Mikrotabletten (Multiple- Unit-Dose-Tabletten) oder Minitabletten, Mikropellets bzw. Granulat, wobei die Mikrotabletten, Pellets oder das Granulat gegebenenfalls verkapselt oder in Sachets abgefüllt sind, Kapseln oder Trinklösungen vor. Wenn es sich um feste Dosisformen bzw. Verabreichungsformen handelt, werden diese in einer bevorzugten Ausführungsform mit einem magensaft- resistenten Überzug versehen. Der Überzug kann auch auf den verkapselten bzw. abgefüllten Dosisformen vorgesehen sein. Bei parenteraler Verabreichung über Injektion (i.V. , i.m. s.c , i.p.) liegt die Zubereitung in hierfür geeigneter Form vor. Es können alle üblichen flüssigen, für die Injektion geeigneten Träger verwendet werden.If oral administration takes place, a pharmaceutical preparation according to the invention is preferably in the form of single-unit-dose tablets, microtablets (multiple-unit-dose tablets) or mini-tablets, micropellets or granules, the microtablets, pellets or that Granules are possibly encapsulated or filled in sachets, capsules or drinking solutions. In the case of solid dosage forms or administration forms, in a preferred embodiment these are provided with an enteric coating. The coating can also be provided on the encapsulated or filled dosage forms. In the case of parenteral administration via injection (IV, IMSC, IP), the preparation is in a suitable form. All common liquid carriers suitable for injection can be used.
Die erfmdungsgemäße pharmazeutische Zubereitung kann bevorzugt einzeln oder im Gemisch enthalten 10-500 mg Dialkylfumarat, insbesondere Dimethylfumarat und/oder Diethylfumarat, 10-500 mg Calciumalkylfumarat, insbesondere Calciummethylfumarat und/oder Calciumethylfumarat, 0-250 mg Zinkalkylfumarat, insbesondere Zinkmethylfuma- rat und/oder Zinkethylfumarat, 0-250 mg Alkylhydrogenfumarat, insbesondere Methyl- hydrogenfumarat und/oder Ethylhydrogenfumarat und 0-250 mg Magnesiumalkylfumarat, insbesondere Magnesiummethylmmarat und/oder Magnesiumethylfumarat, wobei die Summe der genannten Mengen einem Äquivalent von 10 bis 500 mg, vorzugsweise 10 bis 300 mg und am meisten bevorzugt 100 mg Fumar säure entspricht.The pharmaceutical preparation according to the invention can preferably contain 10-500 mg of dialkyl fumarate, in particular dimethyl fumarate and / or diethyl fumarate, 10-500 mg of calcium alkyl fumarate, in particular calcium methyl fumarate and / or calcium ethyl fumarate, 0-250 mg of zinc alkyl fumarate, in particular zinc methyl fumarate and / or Zinc ethyl fumarate, 0-250 mg alkyl hydrogen fumarate, in particular methyl hydrogen fumarate and / or ethyl hydrogen fumarate and 0-250 mg magnesium alkyl fumarate, in particular magnesium methyl mmarat and / or magnesium ethyl fumarate, the sum of the stated amounts being an equivalent of 10 to 500 mg, preferably 10 to 300 mg and most preferably corresponds to 100 mg of fumaric acid.
Bevorzugte Zubereitungen gemäß der Erfindung enthalten ausschließlich Dimethylfumarat in einer Menge von 10 bis 300 mg.Preferred preparations according to the invention contain only dimethyl fumarate in an amount of 10 to 300 mg.
Nach einer besonders bevorzugten Ausführungsform liegt die pharmazeutische Zubereitung in Form von Mikrotabletten oder Mikropellets vor. Diese weisen vorzugsweise eine Größe bzw. einen mittleren Durchmesser von < 5000 Mikrometer, bevorzugt 300 bis 2500 Mikrometer, insbesondere 300 bis 1000 Mikrometer für Pellets und 1000 bis 2500 Mikrometer für Mikrotabletten auf. Durch Verabreichung der Fumarsaurederivate in Form von Mikrotabletten, die erfindungsgemäß bevorzugt ist, lassen sich die bei der Verabreichung von herkömmlichen Single-Unit-Dose-Tabletten nicht auszuschliessenden gastrointestinalen Reizungen bzw. Nebenwirkungen weiter verringern. Dies beruht vermutlich darauf, dass sich die Mikrotabletten, vorzugsweise magensaftresistente Mikrotabletten, im Magen bereits verteilen und somit portionsweise in den Darm gelangen, wo die Wirkstoffe bei insgesamt gleicher Dosierung in lokal kleineren Dosen freigesetzt werden. Dadurch lässt sich wiederum die lokale Reizung der Darmepitelzellen vermeiden, woraus die bessere Magen- Darmverträglichkeit der Mikrotabletten gegenüber herkömmlichen Tabletten resultiert. Die in den erfmdungsgemäßen Zubereitungen enthaltenen Fumarsaurederivate werden beispielsweise gemäß dem in der EP 0 312 679 beschriebenen Verfahren hergestellt.According to a particularly preferred embodiment, the pharmaceutical preparation is in the form of microtablets or micropellets. These preferably have a size or an average diameter of <5000 micrometers, preferably 300 to 2500 micrometers, in particular 300 to 1000 micrometers for pellets and 1000 to 2500 micrometers for micro-tablets. By administering the fumaric acid derivatives in the form of microtablets, which is preferred according to the invention, the gastrointestinal irritations or side effects that cannot be excluded when administering conventional single-unit dose tablets can be further reduced. This is presumably due to the fact that the microtablets, preferably enteric-coated microtablets, are already distributed in the stomach and thus enter the intestine in portions, where the active ingredients are released in locally smaller doses at the same total dose. This in turn prevents local irritation of the intestinal epithelial cells, which results in the better gastrointestinal tolerance of the microtablets compared to conventional tablets. The fumaric acid derivatives contained in the preparations according to the invention are produced, for example, in accordance with the process described in EP 0 312 679.
HerstellungsbeispielePreparation Examples
Grundsätzlich können die erfindungsgemäßen oralen Zubereitungen in Form von Tabletten oder Mikrotabletten nach klassischen Tablettierverfahren hergestellt werden. Anstelle dieser klassischen Tablettiermethoden können auch andere Methoden zur Herstellung von Tabletten angewandt werden, wie die Direkttablettierung, sowie Verfahren zur Herstellung fester Dispersionen nach der Schmelzmethode und der Sprühtrocknungsmethode.In principle, the oral preparations according to the invention can be produced in the form of tablets or microtablets using conventional tableting methods. Instead of these classic tableting methods, other methods for producing tablets can also be used, such as direct tableting, and processes for producing solid dispersions using the melting method and the spray drying method.
Die Tabletten können mit magensaftresistenten Überzügen versehen sein. Der magensaftre- sistente Überzug kann in einem klassischen Dragierkessel aufgeleert oder aufgesprüht werden. Die Beschichtung kann aber auch in einer Bögelschichtapparatur erfolgen. Weiterhin kann die Tablette mit einem Filmcoat versehen werden.The tablets can be provided with enteric coatings. The enteric coating can be poured on or sprayed on in a classic coating pan. However, the coating can also be carried out in a layered layer apparatus. The tablet can also be provided with a film coat.
Im Folgenden werden zur Erläuterung der erfmdungsgemäßen Verwendung verschiedene Beispiele für die Herstellung bevorzugter Arzneimittel gegeben. Die Beispiele sollen die vorliegende Erfindung lediglich veranschaulichen, diese jedoch nicht einschränken.Various examples of the production of preferred medicaments are given below to explain the use according to the invention. The examples are only intended to illustrate the present invention, but not to limit it.
Beispiel 1example 1
Herstellung von Filmtabletten mit magensaftresistentem Überzug enthaltend 100,0 mg Mo- nomethylfumarat-Ca-Salz, entsprechend 78 mg Fumarsäure.Production of film-coated tablets with an enteric coating containing 100.0 mg of monomethyl fumarate Ca salt, corresponding to 78 mg of fumaric acid.
10 kg Monomethylfumarat-Ca-Salz werden zerkleinert, intensiv gemischt und unter entsprechenden Vorsichtsmaßnahmen (Atemmaske, Handschuhe, Schutzanzug etc.) mittels eines Siebes 800 homogenisiert. Anschließend wird ein Hilfsstoffgemisch folgender Zusammensetzung hergestellt: 21 kg Stärkederivat (STA-RX 1500®), 2 kg mikrokristalline Cellulose (Avicel PH 101®), 0,6 kg Polyvinylpyrrolidon (PVP, Kollidon®25), 4 kg Pri ogel®, 0,3 kg kollodiale Kieselsäure (Aerosil®).10 kg of monomethyl fumarate Ca salt are crushed, mixed intensively and homogenized by means of a sieve 800 under appropriate precautionary measures (breathing mask, gloves, protective suit, etc.). An auxiliary mixture of the following composition is then produced: 21 kg of starch derivative (STA-RX 1500 ® ), 2 kg of microcrystalline cellulose (Avicel PH 101 ® ), 0.6 kg polyvinylpyrrolidone (PVP, Kollidon ® 25), 4 kg Pri ogel ® , 0.3 kg colloidal silica (Aerosil ® ).
Das gesamte Pulvergemisch wird mit dem Wirkstoff versetzt, gemischt, mittels eines Siebes 200 homogenisiert und mit einer 2 %-igen wäßrigen Lösung von Polyvinylpyrrolidon (PVP, Kollidon®25) auf übliche Weise zu einem Bindemittelgranulat verarbeitet und in trockenem Zustand mit der äußeren Phase gemischt. Diese besteht aus 2 kg eines sogenannten FST- Komplexes, enthaltend 80 % Talk, 10 % Kieselsäure und 10 % Magnesiumstearat.The entire powder mixture is mixed with the active ingredient, mixed, homogenised by means of a sieve 200 and processed with a 2% aqueous solution of polyvinyl pyrrolidone (PVP, Kollidon ® 25) in the usual manner into a binder granulate and mixed in a dry state with the outer phase , This consists of 2 kg of a so-called FST complex, containing 80% talc, 10% silica and 10% magnesium stearate.
Es wird anschließend auf übliche Weise zu gewölbten Tabletten von 400 mg Gewicht und 10,0 mm Durchmesser gepreßt. Anstelle dieser klassischen Tablettiermethoden können auch andere Methoden zur Herstellung von Tabletten angewendet werden, wie Direkttablettierung sowie feste Dispersionen nach der Schmelzmethode und der Sprühtrocknungsmethode.It is then pressed in the usual way into curved tablets of 400 mg in weight and 10.0 mm in diameter. Instead of these classic tableting methods, other methods for producing tablets can also be used, such as direct tableting and solid dispersions using the melting method and the spray drying method.
MagensaftresistenzEnteric Coating
Es wird eine Lösung von 2,250 kg Hydroxypropylmethylcellulosephthalat (HPMCP, Phar- macoat HP®50) in einem Lösungsmittelgemisch von 2,50 1 demineralisiertem Wasser, 13 1 Aceton Ph.Helv. VII und 13 1 Ethanol (94 Gewichtsprozent) gelöst und die Lösung mit 0,240 kg Rizinusöl (Ph.Eur. II) versetzt. Die Lösung wird im Dragierkessel auf traditionelle Weise in Portionen auf die Tablettenkerne auf geleert oder aufgesprüht bzw. in einem Wirbelschichtapparat entsprechender Konstruktion aufgetragen.A solution of 2.250 kg hydroxypropylmethyl cellulose phthalate (HPMCP, Pharmacoat HP ® 50) in a solvent mixture of 2.50 1 demineralized water, 13 1 acetone Ph.Helv. VII and 13 1 ethanol (94 percent by weight) dissolved and 0.240 kg castor oil (Ph.Eur. II) was added to the solution. The solution is poured or sprayed onto the tablet cores in portions in the coating pan in a traditional manner or applied in a fluidized bed apparatus of the appropriate construction.
Nach entsprechender Trocknung wird anschließend der Filmüberzug angebracht. Dieser setzt sich zusammen aus einer Lösung von Eudragit E® 12,5 % 4,8 kg, Talcum Ph. Eur. II 0,34 kg, Titan (VΙ)-oxid Cronus RN 56® 0,52 kg, Farblack ZLT-2 blau (Siegle) 0,21 kg und Polyethylenglycol 6000 Ph.Helv. VII 0,12 kg in einem Lösungsmittelgemisch von 8,2 kg 2-Propanol Ph.Helv. VII, 0,06 kg Glycerintriacetat (Triacetin®) und 0,2 kg Aqua demi- neralisata. Nach homogener Verteilung im Dragier kessel oder Wirbelschichtbett wird getrocknet und auf übliche Weise poliert. Beispiel 2After appropriate drying, the film coating is then applied. This consists of a solution of Eudragit E ® 12.5% 4.8 kg, Talcum Ph.Eur.II 0.34 kg, titanium (VΙ) oxide Cronus RN 56 ® 0.52 kg, color varnish ZLT-2 blue (Siegle) 0.21 kg and polyethylene glycol 6000 Ph. Helv. VII 0.12 kg in a solvent mixture of 8.2 kg 2-propanol Ph.Helv. VII, 0.06 kg glycerol triacetate (Triacetin ® ) and 0.2 kg Aqua demineralisata. After homogeneous distribution in the coating pan or fluidized bed, the mixture is dried and polished in the customary manner. Example 2
Herstellung von magensaftresistenten Kapseln, enthaltend 86,5 mg Monoethylfumarat-Ca-Preparation of enteric-coated capsules containing 86.5 mg of monoethyl fumarate-Ca
Salz und 110,0 mg Dimethylfumarat, entsprechend insgesamt 150 mg Fumarsäure.Salt and 110.0 mg dimethyl fumarate, corresponding to a total of 150 mg fumaric acid.
8,65 kg Monoethylfumarat-Ca-Salz und 11 kg Dimethylfumarat werden mit einem Gemisch bestehend aus 15 kg Stärke, 6 kg Lactose Ph. Helv. VII, 2 kg mikrokristalliner Cellulose (Avicel®), 1 kg Polyvinylpyrrolidon (Kollidon®25) und 4 kg Primogel® intensiv gemischt und unter entsprechenden Vorsichtsmaßnahmen (Atemmaske, Handschuhe, Schutzanzug etc.) mittels eines Siebes 800 homogenisiert.8.65 kg of monoethyl fumarate calcium salt and 11 kg of dimethyl fumarate are mixed with a mixture consisting of 15 kg of starch, 6 kg of lactose Ph. Helv. VII, 2 kg of microcrystalline cellulose (Avicel ® ), 1 kg of polyvinylpyrrolidone (Kollidon ® 25) and 4 kg Primogel ® mixed intensively and homogenized with appropriate precautions (breathing mask, gloves, protective suit etc.) using a sieve 800.
Das gesamte Pulvergemisch wird mit einer 2 %-igen wäßrigen Lösung von Polyvinylpyrrolidon (Kollidon®25) auf übliche Weise zu einem Bindemittelgranulat verarbeitet und in getrocknetem Zustand mit der äußeren Phase gemischt. Diese besteht aus 0,35 kg kolloidaler Kieselsäure (Aerosil®), 0,5 kg Magnesiumstearat und 1,5 kg Talkum Ph. Helv. VII. Das homogene Gemisch wird anschließend in entsprechende Kapseln in Portionen von 500,0 mg abgefüllt, welche abschließend auf übliche Weise mit einem magensaftresistenten Überzug, bestehend aus Hydroxypropylethylcellulosephatalat und Rizinusöl als Weichmacher, versehen werden. Die Abfüllung kann ebenfalls anstelle von Hartgelatinekapseln in entsprechende magensaftresistente Kapseln, bestehend aus einem Gemisch von CelluUoseacetatphthalat (CAP) und Hydroxypropylethylcellulosephthalat (HPMCP), erfolgen.The entire powder mixture is processed with a 2% aqueous solution of polyvinylpyrrolidone (Kollidon ® 25) in the usual manner into a binder granulate and mixed in the dry state with the outer phase. This consists of 0.35 kg of colloidal silica (Aerosil ® ), 0.5 kg of magnesium stearate and 1.5 kg of talc Ph. Helv. VII. The homogeneous mixture is then filled into appropriate capsules in 500.0 mg portions, which finally in the usual way with an enteric coating consisting of hydroxypropylethyl cellulose phatalate and castor oil as a plasticizer. Instead of hard gelatin capsules, the filling can also take place in corresponding gastro-resistant capsules, consisting of a mixture of cellulose acetate phthalate (CAP) and hydroxypropylethyl cellulose phthalate (HPMCP).
Beispiel 3Example 3
Herstellung von magensaftresistenten Mikrotabletten in Kapseln, enthaltend 87,0 Monoethylfumarat Ca-Salz, 120 mg Dimethylfumarat, 5,0 mg Monoethylfumarat Mg-Salz und 3,0 mg Monoethylfumarat Zn-Salz, entsprechend insgesamt 164 mg Fumarsäure ("Forte"- Tabletten).Production of enteric-coated micro-tablets in capsules containing 87.0 monoethyl fumarate Ca salt, 120 mg dimethyl fumarate, 5.0 mg monoethyl fumarate Mg salt and 3.0 mg monoethyl fumarate Zn salt, corresponding to a total of 164 mg fumaric acid ("Forte" tablets) ,
8,7 kg Monoethylfumarat Ca-Salz, 12 kg Dimethylfumarat, 0,5 kg Monoethylfumarat Mg- Salz, 0,3 kg Monoethylfumarat Zn-Salz werden zerkleinert, intensiv gemischt und mittels eines Siebs 800 unter entsprechenden Vorsichtsichtsmaßnahmen (Atemmaske, Handschuhe, Schutzanzug, etc.) homogenisiert. Es wird ein Hilfsstoffgemisch folgender Zusammensetzung hergestellt: 18 kg Stärkederivat (STA-RX 1500), 0,3 kg Cellulose mikrokristallin (A- civel PH 101), 0,75 kg PVP (Kollidon 120), 4 kg Primogel, 0,25 kg Kieselsäure kolloidal (Aerosil) . Das gesamte Pulvergemisch wird mit dem Wirkstoffgemisch versetzt und mittels eines Siebes 200 homogenisiert und mit einer 2% -igen wäßrigen Lösung von Polyvinylpyrrolidon (Kollidon K25) auf übliche Weise zu einem Bindemittelgranulat verarbeitet und in trockenem Zustand mit der äußeren Phase gemischt. Diese besteht aus 0,5 kg Magnesi- umstearat und 1,5 kg Talkum. Das Pulvergemisch wird anschließend auf übliche Weise zu gewölbten Mikrotabletten von 10,0 mg Bruttomasse und 2,0 mm Durchmesser gepreßt. Anstelle dieser klassischen Tablettiermethode können auch andere Methoden zur Herstellung von Tabletten verwendet werden, wie Direkttablettierung sowie feste Dispersionen nach der Schmelzmethode und die Sprühtrocknungsmethode.8.7 kg of monoethyl fumarate Ca salt, 12 kg of dimethyl fumarate, 0.5 kg of monoethyl fumarate, Mg salt, 0.3 kg of monoethyl fumarate, Zn salt are crushed, mixed intensively and using a sieve 800 with appropriate precautionary measures (respiratory mask, gloves, Protective suit, etc.) homogenized. An excipient mixture of the following composition is produced: 18 kg starch derivative (STA-RX 1500), 0.3 kg cellulose microcrystalline (Acivel PH 101), 0.75 kg PVP (Kollidon 120), 4 kg Primogel, 0.25 kg Colloidal silica (Aerosil). The entire powder mixture is mixed with the active ingredient mixture and homogenized by means of a sieve 200 and processed with a 2% aqueous solution of polyvinylpyrrolidone (Kollidon K25) in the usual way to a binder granulate and mixed in a dry state with the outer phase. This consists of 0.5 kg magnesium stearate and 1.5 kg talc. The powder mixture is then pressed in the usual way to curved micro-tablets of 10.0 mg gross mass and 2.0 mm in diameter. Instead of this classic tabletting method, other methods for producing tablets can also be used, such as direct tableting and solid dispersions using the melting method and the spray drying method.
Der magensaftresistente Überzug kann in einem klassischen Dragierkessel aufgeleert oder aufgesprüht sowie in einer Wirbelschichtapparatur aufgebracht werden. Zum Erreichen der Magensaftresistenz wird portionsweise eine Lösung von 2,250 kg Hydroxypropylmethyl- cellulosephfhalat (HPMCP, Pharmacoat HP 50), in einem Gemisch folgender Lösungsmittel aufgelöst: Aceton 13 1, Ethanol 94 Gewichtsprozent denaturiert mit 2 % Keton 13,5 1 und Aqua demineralisata 2,5 1. Zu der fertigen Lösung wird als Weichmacher Rizinusöl 0,240 kg zugegeben und auf übliche Weise in Portionen auf die Tablettenkerne aufgetragen.The enteric coating can be poured on or sprayed on in a classic coating pan and applied in a fluidized bed apparatus. To achieve gastric juice resistance, a solution of 2.250 kg of hydroxypropylmethyl cellulose phthalate (HPMCP, Pharmacoat HP 50) is dissolved in portions in a mixture of the following solvents: acetone 13 1, ethanol 94% by weight denatured with 2% ketone 13.5 1 and aqua demineralisata 2, 5 1. 0.240 kg of castor oil is added to the finished solution as a plasticizer and applied in portions to the tablet cores in the usual way.
Filmcoat: Nach beendeter Trocknung wird anschließend in der gleichen Apparatur eine Suspension folgender Zusammensetzung als Filmcoat aufgetragen: Talk 0,340 kg, Titan (VI)- oxid Cronus RN 56 0,4 kg, Farblack L-Rotlack 86837 0,324 kg, Eudragit E 12,5 % 4,8 kg und Polyethlenglycol 6000 pH 11 XI 0,12 kg in einem Lösungsmittelgemisch folgender Zusammensetzung: 2-Propanol 8,17 kg, Aqua demineralisata 0,2 kg und Glycerintracetat (Tri- acetin) 0,6 kg.Film coat: After drying is complete, a suspension of the following composition is then applied as a film coat in the same apparatus: talc 0.340 kg, titanium (VI) oxide Cronus RN 56 0.4 kg, color varnish L-red varnish 86837 0.324 kg, Eudragit E 12.5 % 4.8 kg and polyethylene glycol 6000 pH 11 XI 0.12 kg in a solvent mixture of the following composition: 2-propanol 8.17 kg, aqua demineralisata 0.2 kg and glycerol tracetate (triacetine) 0.6 kg.
Die magensaftresistenten Mikrotabletten werden anschließend in Hartgelantine-Steckkapseln zu 500,0 mg netto Gewicht eingefüllt und verschlossen. Beispiel 4The enteric-coated micro-tablets are then filled into hard gelatin capsules of 500.0 mg net weight and sealed. Example 4
Herstellung von magensaftresistenten Mikrotabletten in Kapseln, enthaltend 120,0 mg Dimethylfumarat, entsprechend 96 mg FumarsäureProduction of enteric-coated micro-tablets in capsules containing 120.0 mg of dimethyl fumarate, corresponding to 96 mg of fumaric acid
12 kg Dimethylfumarat werden zerkleinert, und mittels eines Siebes 800 unter entsprechenden Vorsichtsmaßnahmen (Atemmaske, Handschuhe, Schutzanzug etc.) homogenisiert. Es wird ein Hilfsstoffgemisch folgender Zusammensetzung hergestellt: 17,5 kg Stärkederivat (STA- RX® 1500), 0,30 kg Cellulose mikrokristallin (Avicel® PH 101), 0,75 kg PVP (Kollidon® 120), 4 kg Primogel®, 0,25 kg Kieselsäure kollodial (Aerosil®). Das gesamte Pulvergemisch wird mit dem Wirkstoff versetzt, gemischt, mittels eines Siebes 200 homogenisiert und mit einer 2 %-igen wäßrigen Lösung von Polyvinylpyrrolidon (Kollidon® K25) auf übliche Weise zu einem Bindemittelgranulat verarbeitet und in trockenem Zustand mit der äußeren Phase gemischt. Diese besteht aus 0,5 kg Mg-Stearat und 1,5 kg Talkum.12 kg of dimethyl fumarate are crushed and homogenized using a sieve 800 with appropriate precautions (breathing mask, gloves, protective suit, etc.). An excipient mixture of the following composition is produced: 17.5 kg starch derivative (STARX® 1500), 0.30 kg cellulose microcrystalline (Avicel® PH 101), 0.75 kg PVP (Kollidon® 120), 4 kg Primogel®, 0.25 kg colloidal silica (Aerosil®). The entire powder mixture is mixed with the active ingredient, mixed, homogenized using a sieve 200 and processed with a 2% aqueous solution of polyvinylpyrrolidone (Kollidon® K25) in the usual way to form a binder granulate and mixed in a dry state with the outer phase. This consists of 0.5 kg Mg stearate and 1.5 kg talc.
Das Pulvergemisch wird anschließend auf übliche Weise zu gewölbten Tabletten von 10,0 mg Bruttomasse und 2,0 mm Durchmesser gepresst.The powder mixture is then pressed in the usual way into curved tablets of 10.0 mg gross mass and 2.0 mm in diameter.
Zum Erreichen der Magensaftresistenz wird hier bspw. portionenweise eine Lösung von 2,25 kg Hydroxypropylmethylcellulosephfhalat (HPMCP, Pharmacoat® HP 50) in einem Gemisch folgender Lösungsmittel aufgelöst: Aceton 13 1, Ethanol (94 Gew.-% denaturiert mit 2 % Keton) 13,5 1 und Aqua demineralisata 1,5 1. Zu der fertigen Lösung wird als Weichmacher Rizinusöl (0,24 kg) zugegeben und auf übliche Weise in Portionen auf die Tablettenkerne aufgetragen.To achieve gastric juice resistance, a solution of 2.25 kg of hydroxypropylmethylcellulose phthalate (HPMCP, Pharmacoat® HP 50) is dissolved in portions in a mixture of the following solvents: acetone 13 1, ethanol (94% by weight denatured with 2% ketone) 13 , 5 1 and Aqua demineralisata 1.5 1. Castor oil (0.24 kg) is added to the finished solution as a plasticizer and applied in portions to the tablet cores in the usual way.
Nach beendeter Trocknung wird anschließend in der gleichen Apparatur eine Suspension folgender Zusammensetzung als Filmcoat aufgetragen: Talk 0,34 kg, Titan-(VI)-oxid Cronus RN 56 0,4 kg, Farblack L-Rotlack 86837 0,324 kg, Eudragit E 12,5 % 4,8 kg und Polyethylenglycol 6000 pH 11 XI 0,12 kg in einem Lösungsmittelgemisch folgender Zusammensetzung: 2- Propanol 8,17 kg, Aqua demineralisata 0,2 kg und Glycerintriacetat (Triacetin) 0,6 kg. Die magensaftresistenten Mikrotabletten werden anschließend in Hartgelatine-Steckkapseln zu 400 mg Nettogewicht eingefüllt und verschlossen.After drying is complete, a suspension of the following composition is then applied as a film coat in the same apparatus: talc 0.34 kg, titanium (VI) oxide Cronus RN 56 0.4 kg, color varnish L-red varnish 86837 0.324 kg, Eudragit E 12, 5% 4.8 kg and polyethylene glycol 6000 pH 11 XI 0.12 kg in a solvent mixture of the following composition: 2-propanol 8.17 kg, aqua demineralisata 0.2 kg and glycerol triacetate (triacetin) 0.6 kg. The enteric-coated micro-tablets are then filled into hard gelatin capsules with a net weight of 400 mg and sealed.
Beispiel 5Example 5
Herstellung von magensaf resistenten Mikrotabletten in Kapseln, enthaltend 120,0 mg Dimethylfumarat, entsprechend 96 mg FumarsäureProduction of gastro-resistant micro-tablets in capsules containing 120.0 mg dimethyl fumarate, corresponding to 96 mg fumaric acid
12 kg Dimethylfumarat werden zerkleinert und wie oben homogenisiert. Es wird ein Hilfs- stoffgemisch folgender Zusammensetzung hergestellt: 23,2 kg mikrokristalline Cellulose (A- vicel® PH 200), 3 kg Croscarmelose Natrium (AC-Di-SOL-SD-711), 2,5 kg Talkum, 0,1 kg Siliciumdioxid wasserfrei (Aerosil® 200) und 1 kg Mg-Stearat. Das gesamte Pulvergemisch wird mit dem Wirkstoff versetzt und homogen gemischt. Das Pulvergemisch wird anschließend mittels Direkttablettierung zu gewölbten Tabletten von 10,0 mg Bruttomasse und 2,0 mm Durchmesser gepreßt.12 kg of dimethyl fumarate are crushed and homogenized as above. An excipient mixture of the following composition is produced: 23.2 kg of microcrystalline cellulose (Vicel® PH 200), 3 kg of croscarmelose sodium (AC-Di-SOL-SD-711), 2.5 kg of talc, 0.1 kg of anhydrous silicon dioxide (Aerosil® 200) and 1 kg of magnesium stearate. The entire powder mixture is mixed with the active ingredient and mixed homogeneously. The powder mixture is then pressed by means of direct tableting to give curved tablets of 10.0 mg gross mass and 2.0 mm in diameter.
Anschließend wird eine Lösung von 0,94 Eudragit® L in Isopropanol hergestellt, die zusätzlich 0,07 kg Dibutylphthalat enthält. Diese Lösung wird auf die Tablettenkerne aufgesprüht. Danach wird eine Dispersion von 17,32 kg Eudragit® L D-55 und einer Mischung aus 2,8 kg Mikrotalkum, 2 kg Macrogol 6000 und 0,07 kg Dimeticon in Wasser hergestellt und auf die Kerne aufgesprüht.A solution of 0.94 Eudragit® L in isopropanol is then prepared, which also contains 0.07 kg of dibutyl phthalate. This solution is sprayed onto the tablet cores. A dispersion of 17.32 kg of Eudragit® L D-55 and a mixture of 2.8 kg of microtalkum, 2 kg of Macrogol 6000 and 0.07 kg of Dimeticon is then prepared in water and sprayed onto the cores.
Die magensaftresistenten Mikrotabletten werden anschließend in Hartgelatine-Steckkapseln zu 650 mg Nettogewicht eingefüllt und verschlossen.The enteric-coated micro-tablets are then filled into hard gelatin capsules with a net weight of 650 mg and sealed.
Beispiel 6Example 6
NF-kappaB Translokation in den ZellkernNF-kappaB translocation into the cell nucleus
NF-kappa-B (p65) wurde in den Vektor pEGFP-Cl eingefügt, der EGFP (green fluorescent Protein), verknüpft mit einem Zytomegalovirus-Promoter (Clontech), enthielt. Dies führt zur Expression eines fluoreszierenden NF-kappaB. HUNEC -Zellen wurden zwischen der dritten und fünften Passage in mit Gelatine beschichteten Kulturplatten mit zwölf Vertiefungen (Costar) ausgesät und auf 80 bzw. 90 % Konfluenz wachsen gelassen. Die Zellen wurden an- schließend unter Anwendung des Kalziumphosphat-Präzipitationsverfahrens transfiziert. Genauer wurden die Zellen hierzu mit Dulbecco's modified Eagles medium (DMEM) konditio- niert, das 1 μg DNS pro Vertiefung enthaltende Präzipitat nach 2 Stunden zugesetzt und die Zellen für weitere 4 Stunden inkubiert. Nach dem Waschen mit HBSS (Hanks balanced salt solution) wurde Kulturmedium zugesetzt und die Zellen für weitere 18 Stunden wachsen gelassen, bevor sie stimuliert wurden.NF-kappa-B (p65) was inserted into the vector pEGFP-Cl, which contained EGFP (green fluorescent protein) linked to a cytomegalovirus promoter (Clontech). This leads to the expression of a fluorescent NF-kappaB. HUNEC cells were seeded between the third and fifth passages in 12-well gelatin-coated culture plates (Costar) and grown to 80 and 90% confluency, respectively. The cells were finally transfected using the calcium phosphate precipitation method. More specifically, the cells were conditioned with Dulbecco's modified Eagles medium (DMEM), the precipitate containing 1 μg DNA per well was added after 2 hours and the cells were incubated for a further 4 hours. After washing with HBSS (Hanks balanced salt solution), culture medium was added and the cells were allowed to grow for a further 18 hours before being stimulated.
Für die Versuche wurden die Zellen mit 40 μM/1 Dimethylfumarat konditioniert, wobei Parallelansätze ohne DNS als Kontrolle dienten. 2 Stunden nach Konditionierungsbeginn wurden die Zellen mit 10 ng/ml TNF-alpha für die in Tabelle 1 angegebenen Zeiten stimuliert.For the experiments, the cells were conditioned with 40 μM / 1 dimethyl fumarate, whereby parallel batches without DNA served as a control. 2 hours after the start of conditioning, the cells were stimulated with 10 ng / ml TNF-alpha for the times given in Table 1.
Die Zellen wurden anschließend lysiert, der Überstand verworfen und die Zellkerne in Doun- ce-Puffer mit Protease-Inhibitoren gesammelt (lOmM Tris-HCL pH 7,6, 0,5 mM MgCl, 10 μg/ml Leupeptin, 10 μg/ml Aprotinin, 1 mM Phenylmethylsulfonylfluorid, 1.8 mg/ml Joda- cetamid). Nach Zentrifugation für 10 min. bei 1200 g, 4°C, wurden die Zellkerne auf einem FACscanflow Cytometer (Becton Dickinson) analysiert.The cells were then lysed, the supernatant discarded and the cell nuclei were collected in donut buffer with protease inhibitors (10 mM Tris-HCl pH 7.6, 0.5 mM MgCl, 10 μg / ml leupeptin, 10 μg / ml aprotinin , 1 mM phenylmethylsulfonyl fluoride, 1.8 mg / ml iodoacetamide). After centrifugation for 10 min. at 1200 g, 4 ° C, the cell nuclei were analyzed on a FACscanflow cytometer (Becton Dickinson).
Tabelle 1 : Anzahl der NF-kappaB(p65) positiven KerneTable 1: Number of NF-kappaB (p65) positive nuclei
(Prozentangaben bezogen auf alle NF-kappaB-transfizierten Zellen)(Percentages based on all NF-kappaB-transfected cells)
Aus der Tabelle ist ersichtlich, dass Dimethylfumarat in einer Konzentration von 40 μM/1 die TNF-induzierte Translokation von NF-kappaB in den Zellkern inhibierte. Beispiel 7From the table it can be seen that dimethyl fumarate in a concentration of 40 μM / 1 inhibited the TNF-induced translocation of NF-kappaB into the cell nucleus. Example 7
Inhibition der NF-kappaB stimulierten TranskriptionInhibition of NF-kappaB-stimulated transcription
Ein dreifacher Repeat der AP- 1 -Konsensus-Site (Bindungsstelle) (48bp, 3 x TGTGATGACTCAGGTT) und ein dreifach Repeat der NF-kappa_B Konsensus-Site (60bp, 3 x AATCGTGGAATTTCCTCTGA), flankiert von Spel-Bindungsstellen (nicht gezeigt), wurden in die Spel-Stelle des pTK-UBT-luc Vektors (de Martin, Gene 124, 137-38, 1993) insertiert. Ein 1,3 kb Konstrukt des E-Selektin Promotors, der sich von bp - 1285 bis bp +482 erstreckte, wurde in die Ndel-Stelle des pMAM Neo-luc- Vektors (Clontech) insertiert.A triple repeat of the AP-1 consensus site (binding site) (48 bp, 3 x TGTGATGACTCAGGTT) and a triple repeat of the NF-kappa_B consensus site (60 bp, 3 x AATCGTGGAATTTCCTCTGA), flanked by Spel binding sites (not shown), were inserted into the Spel site of the pTK-UBT-luc vector (de Martin, Gene 124, 137-38, 1993). A 1.3 kb construct of the E-selectin promoter, ranging from bp - 1285 to bp +482, was inserted into the Ndel site of the pMAM Neo-luc vector (Clontech).
HUVEC-Zellen wurden wie in Beispiel 6 beschrieben mit den so erhaltenen Konstrukten transfiziert. Für die Transfektion wurden 2,5 μg des jeweiligen Promoterkonstrukts pro Vertiefung zugesetzt. Um die Transfektioneffizienz zu überprüfen wurden als Kontrolle Cotrans- fektionen mit 500 ng eines pSV-beta Galactosidase-Kontrollvektors (Promega Corp., Madi- son, WI, USA) in jedem Experiment durchgeführt. 2 Tage nach Transfektion wurden die Zellen für 2 Stunden mit 10 ng/ml TNF-alpha mit und ohne Zusatz von 6 μg/ml Dimethylfumarat (DMF) stimuliert. Die Zellen wurden anschließend durch Trypsinierung geerntet, pel- letisiert, gewaschen und in 200 μl "reporter lysis puffer" (Promega) für 15 min. gemäß den Herstellerangaben resuspendiert.HUVEC cells were transfected with the constructs thus obtained as described in Example 6. For the transfection, 2.5 μg of the respective promoter construct were added per well. In order to check the transfection efficiency, cotransfections with 500 ng of a pSV-beta galactosidase control vector (Promega Corp., Madison, WI, USA) were carried out in each experiment as a control. 2 days after transfection, the cells were stimulated for 2 hours with 10 ng / ml TNF-alpha with and without the addition of 6 μg / ml dimethyl fumarate (DMF). The cells were then harvested by trypsinization, pelletized, washed and in 200 μl "reporter lysis buffer" (Promega) for 15 min. resuspended according to the manufacturer's instructions.
Die Luciferase-Aktivität wurde mit einem Berthold AutoLumat LB9507 Luminometer unter Verwendung des Luciferase-Testsystems (Promega) gemessen. Die Beta-Galactosidase- Aktivität wurde unter Verwendung des Beta-Galactosidase-Enzymtestsystems von Promega ermittelt. Die mit den jeweiligen Promoterkonstrukten erhaltenen Luciferase-Aktivitäten wurden auf die Beta-Galactosidase-Aktivität normalisiert. Die Schwankungebreite der Beta- Galactosidase- Aktivität innerhalb der einzelnen Experimente lag unterhalb von 10 %. In Tabelle 2 sind die jeweiligen Ergebnisse als x-faches gegenüber der Basislinie angegeben. Tabelle 2: Anstieg der TranskriptionLuciferase activity was measured on a Berthold AutoLumat LB9507 luminometer using the Luciferase test system (Promega). Beta-galactosidase activity was determined using the Promega beta-galactosidase enzyme assay system. The luciferase activities obtained with the respective promoter constructs were normalized to the beta-galactosidase activity. The range of variation in beta-galactosidase activity within the individual experiments was below 10%. Table 2 shows the respective results as x times compared to the baseline. Table 2: Increase in transcription
Relativer Anstieg der Luciferase-Aktivität (gemessen als x-facher Anstieg gegenüber der Basislinie) nach TNF-Stimulation (10 ng/ml) mit oder ohne 40 μM 1 Dimethylfumarat (DMF), n = 6Relative increase in luciferase activity (measured as an x-fold increase compared to the baseline) after TNF stimulation (10 ng / ml) with or without 40 μM 1 dimethyl fumarate (DMF), n = 6
Aus der Tabelle 2 ist ersichtlich, dass Dimethylfumarat die TNF-induzierte Transkription eines NF-kappaB-abhängigen Gens inhibierte, jedoch nicht die Transkription eines AP-1- abhängigen Gens. Die Dimethylfumarathemmung ist daher NF-kappaB-spezifisch. From Table 2 it can be seen that dimethyl fumarate inhibited the TNF-induced transcription of an NF-kappaB-dependent gene, but not the transcription of an AP-1-dependent gene. Dimethyl fumarate inhibition is therefore NF-kappaB-specific.

Claims

Anwaltsakte: 53 637 VPatentansprüche Attorney's file: 53 637 V patent claims
1. Verwendung eines oder mehrerer Fumarsaurederivate zur Herstellung einer pharmazeutischen Zubereitung zur Behandlung von NF-kappaB beeinflussbaren Erkrankungen.1. Use of one or more fumaric acid derivatives for the production of a pharmaceutical preparation for the treatment of NF-kappaB influenceable diseases.
2. Verwendung nach Anspruch 1, dadurch gekennzeichnet, dass das Fumarsäurederivat ausgewählt ist aus der Gruppe, bestehend aus ggf. substituierten Fumarsäu- redialkylestern und Fumarsäuremonoalkylestern in Form der freien Säure oder ihrer Salze und Mischungen derselben.2. Use according to claim 1, characterized in that the fumaric acid derivative is selected from the group consisting of optionally substituted fumaric acid dialkyl esters and fumaric acid monoalkyl esters in the form of the free acid or its salts and mixtures thereof.
3. Verwendung gemäß Anspruch 2, bei der der Fumarsäuredialkylester der Formel3. Use according to claim 2, in which the fumaric acid dialkyl ester of the formula
entspricht, worin Ri und R2, die jeweils gleich oder verschieden sein können, unabhängig voneinander einen linearen, verzweigten, cyclischen, gesättigten oder ungesättigten Cι-24-Alkylrest oder einen C5-20 Arylrest bedeuten und diese Reste gegebenenfalls mit Halogen (F, Cl, Br, I), Hydroxy, Cι-4-Alkoxy, Nitro oder Cyano substituiert sind.in which R 1 and R 2, which can each be the same or different, independently of one another denote a linear, branched, cyclic, saturated or unsaturated C 24 alkyl radical or a C 5-20 aryl radical and these radicals optionally with halogen (F, Cl, Br, I), hydroxy, C 4 alkoxy, nitro or cyano are substituted.
4. Verwendung gemäß einem der Ansprüche 2 und 3, dadurch gekennzeichnet, dass es sich bei den Resten Ri und R2 um Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, sec- Butyl, t-Butyl, Pentyl, Cyclopentyl, 2-Ethylhexyl, Hexyl, Cyclohexyl, Heptyl, Cyc- loheptyl, Octyl, Vinyl, Allyl, 2-Hydroxy ethyl, 2- oder 3-Hydroxypropyl, 2,3- Dihydroxypropyl, 2-Methoxy ethyl, Methoxymethyl oder 2- oder 3-Mefhoxypropyl handelt.4. Use according to one of claims 2 and 3, characterized in that the radicals R 1 and R 2 are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2- or 3-hydroxypropyl, 2,3- Dihydroxypropyl, 2-methoxy ethyl, methoxymethyl or 2- or 3-mefhoxypropyl.
5. Verwendung gemäß Anspruch 2, bei der der Fumarsäuremonoalkylester der Formel5. Use according to claim 2, in which the fumaric acid monoalkyl ester of the formula
entspricht, worincorresponds to what
- Ri die in den Ansprüchen 3 oder 4 gegebene Bedeutung hat,Ri has the meaning given in claims 3 or 4,
- A Wasserstoff, ein Alkali- oder Erdalkalimetallkation oder ein physiologisch verträgliches Übergangsmetallkation, vorzugsweise ausgewählt unter Li+, Na+, K+, Mg2+, Ca2+, Zn2+, Fe2+ und Mn2+, ist undA is hydrogen, an alkali or alkaline earth metal cation or a physiologically compatible transition metal cation, preferably selected from Li + , Na + , K + , Mg 2+ , Ca 2+ , Zn 2+ , Fe 2+ and Mn 2+ , and
- n gleich 1 oder 2 ist und der Valenz von A entspricht.- n is 1 or 2 and corresponds to the valence of A.
6. Verwendung gemäß einem der vorstehenden Ansprüche, dadurch gekennzeichnet, dass es sich bei dem Fumarsäurederivat um eines oder mehrere, ausgewählt aus der Gruppe, umfassend Fumarsäuredimethylester, Fumarsäurediefhylester, Fumarsäuremefhy- lefhylester, Methylhydrogenfumarat, Ethylhydrogen umarat, Calciummefhylfumarat, Calciumethylfumarat, Magnesiummethylfumarat, Magnesiumethylmmarat, Zink- methylfumarat, Zinkemylfumarat, Eisenmethylfumarat und Eisenethylfumarat, und Mischungen derselben handelt.6. Use according to any one of the preceding claims, characterized in that the fumaric acid derivative is one or more selected from the group comprising dimethyl fumarate, diethyl fumarate, methyl fumarate, methyl fumarate, ethyl hydrogen fumarate, calcium methyl fumarate, calcium ethyl fumarate, calcium ethyl fumarate, calcium ethyl fumarate, Zinc methyl fumarate, zinc methyl fumarate, iron methyl fumarate and iron ethyl fumarate, and mixtures thereof.
7. Verwendung gemäß Anspruch 6, dadurch gekennzeichnet, dass es sich bei dem Fumarsäurederivat um den Fumarsäuredimethylester (Dimethylfumarat) handelt.7. Use according to claim 6, characterized in that the fumaric acid derivative is the fumaric acid dimethyl ester (dimethyl fumarate).
8. Verwendung eines oder mehrerer Fumarsaurederivate zur Herstellung einer pharmazeutischen Zubereitung zur Therapie von NF-kappaB beeinflussbaren Erkrankungen ausgewählt aus der Gruppe, die umfasst: die progressive systemische Sklerodermie, die Osteochondritis syphüitica (Wegener's Disease), die Cutis marmorata, (Livedo Reticularis), die Behcet-Disease, die Panarte- ritis, die Colitis ulcerosa, die Vasculitis, die Osteoarthritis, die Gicht, die Aterioskle- rosis, die Reiter's Erkrankung, die bronchozentische Granulomatose, Encephalitis- Typen, den Endotoxin-Schock (septisch-toxischer Schock), die Sepsis, die Pneumo- nie, die Encephalomyelitis, die Anorexia nervosa, die Hepatitis (die akute Hepatitis, die chronische Hepatitis, die toxische Hepatitis, die Alkoholhepatitis, die virale Hepatitis, die Gelbsucht, die Leberinsuffizienz und die cytomegalovirale Hepatitis), die Rennert T Lymphomatosis, die mesangiale Nephritis, die Postangioplastie-Restenose, das Reperfusionssyndrom, die cytomegalovirale Retinopathie, Adenovirale Erkrankungen wie adenovirale Erkältungserkrankungen, adenovirales Pharyngoconjunctival- fieber, und adenovirale Ophthalmie, AIDS, das Guillain-Barre-Syndrom, die posther- petische oder postzoster Neuralgie, die inflammatorische demyelinisierende Polyneu- ropathie, die Mononeuropafhia multiplex, die Mukoviszidose, Morbus Bechterew, Barett-Ösophagus, EBV-(Epstein-Barr-Virus)-Infektion, das kardiale Remodeling, interstitielle Zystitis, Diabetes mellitus Typ II, die Strahlensensibilisierung maligner Tumore, die Mehrfachresistenz maligner Zellen auf Chemotherapeutika, Granuloma annulare und Krebserkrankungen wie Mamma Karzinom, Kolonkarzinom, Melanom, primäres Leberzellkarzinom, Adenokarzinom, Kaposi Sarkom, Prostatakarzinom, Leukämie wie die akute myeloische Leukämie, das multiple Myelom (Plasmozytom), Burkitt-Lymphom, und den Castleman-Tumor.8. Use of one or more fumaric acid derivatives for the production of a pharmaceutical preparation for the therapy of NF-kappaB-controllable diseases selected from the group comprising: progressive systemic scleroderma, osteochondritis syphüitica (Wegener's Disease), cutis marmorata, (Livedo Reticularis), Behcet disease, panartitis, ulcerative colitis, vasculitis, osteoarthritis, gout, atherosclerosis, Reiter's disease, bronchocentic granulomatosis, types of encephalitis, endotoxin shock (septic-toxic shock), sepsis, pneumonia, encephalomyelitis, anorexia nervosa, hepatitis (acute hepatitis, chronic hepatitis, the toxic hepatitis, alcohol hepatitis, viral hepatitis, jaundice, hepatic insufficiency and cytomegaloviral hepatitis), Rennert T lymphomatosis, mesangial nephritis, postangioplasty restenosis, reperfusion syndrome, cytomegaloviral retinopathy, adenoviral diseases such as adenoviral disease - fever, and adenoviral ophthalmia, AIDS, Guillain-Barre syndrome, di e postherpetic or postzosteric neuralgia, inflammatory demyelinating polyneuropathy, mononeuropafhia multiplex, cystic fibrosis, ankylosing spondylitis, beret esophagus, EBV (Epstein-Barr virus) infection, cardiac remodeling, interstitial cystitis, diabetes Type II, radiation sensitization of malignant tumors, multiple resistance of malignant cells to chemotherapeutic agents, granuloma annular and cancer diseases such as breast cancer, colon cancer, melanoma, primary liver cell carcinoma, adenocarcinoma, Kaposi sarcoma, prostate cancer, leukemia leukemia such as acute myomaoma, multiple cell cancer , Burkitt's lymphoma, and the Castleman tumor.
9. Verwendung gemäß Anspruch 8, dadurch gekennzeichnet, dass das Fumarsäurederivat ausgewählt ist aus der Gruppe, bestehend aus Fumarsäuredialkylestern und Fu- marsäuremonoaikylestern in Form der freien Säure oder eines Salzes und Mischungen davon.9. Use according to claim 8, characterized in that the fumaric acid derivative is selected from the group consisting of fumaric acid dialkyl esters and fumaric acid monoaikylesters in the form of the free acid or a salt and mixtures thereof.
10. Verwendung gemäß Anspruch 9, bei der der Fumarsäuredialkylester der Formel10. Use according to claim 9, in which the fumaric acid dialkyl ester of the formula
entspricht, worin Ri und R2, die jeweils gleich oder verschieden sein können, unabhängig voneinander einen linearen, verzweigten, cyclischen, gesättigten oder ungesättigten Cι-24-Alkylrest oder einen C5-20 Arylrest bedeuten und diese Reste gegebe- ' nenfalls mit Halogen (F, Cl, Br, I), Hydroxy, Cι-4-Alkoxy, Nitro oder Cyano substituiert sind. corresponds, wherein Ri and which may be the same or different, each R2 is independently a linear, branched, cyclic, saturated or unsaturated Cι-24 alkyl group or a C5-20 aryl radical and these radicals gegebe- 'appropriate, with halogen (F , Cl, Br, I), hydroxy, -CC 4 alkoxy, nitro or cyano are substituted.
11. Verwendung gemäß einem der Ansprüche 9 und 10, dadurch gekennzeichnet, dass es sich bei den Resten Ri und R2 um Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, sec- Butyl, t-Butyl, Pentyl, Cyclopentyl, 2-Ethylhexyl, Hexyl, Cyclohexyl, Heptyl, Cyc- loheptyl, Octyl, Vinyl, Allyl, 2-Hydroxy ethyl, 2- oder 3-Hydroxypropyl, 2,3- Dihydroxypropyl, 2-Methoxy ethyl, Methoxymethyl oder 2- oder 3-Methoxypropyl handelt.11. Use according to one of claims 9 and 10, characterized in that the radicals R 1 and R 2 are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2- or 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-methoxy ethyl, methoxymethyl or 2- or 3- Is methoxypropyl.
12. Verwendung gemäß Anspruch 9, bei der der Fumarsäuremonoalkylester der Formel12. Use according to claim 9, in which the fumaric acid monoalkyl ester of the formula
entspricht, worincorresponds to what
- Ri die in den Ansprüchen 3 oder 4 gegebene Bedeutung hat,Ri has the meaning given in claims 3 or 4,
- A Wasserstoff, ein Alkali- oder Erdalkalimetallkation oder ein physiologisch verträgliches Übergangsmetallkation, vorzugsweise ausgewählt unter Li+, Na+, K+, Mg2+, Ca2+, Zn2+, Fe2+ und Mn2+, ist undA is hydrogen, an alkali or alkaline earth metal cation or a physiologically compatible transition metal cation, preferably selected from Li + , Na + , K + , Mg 2+ , Ca 2+ , Zn 2+ , Fe 2+ and Mn 2+ , and
- n gleich 1 oder 2 ist und der Valenz von A entspricht.- n is 1 or 2 and corresponds to the valence of A.
13. Verwendung gemäß einem der Ansprüche 8 bis 12, dadurch gekennzeichnet, dass eine Dosiseinheit der pharmazeutischen Zubereitung eine 1-500 mg, vorzugsweise 10-300 mg und am meisten bevorzugt 10-200 mg Fumarsäure entsprechende Menge an Fumarsäurederivat(en) enthält.13. Use according to one of claims 8 to 12, characterized in that a unit dose of the pharmaceutical preparation is a 1-500 mg, preferably Contains 10-300 mg and most preferably 10-200 mg of fumaric acid corresponding amount of fumaric acid derivative (s).
14. Verwendung gemäß einem der vorstehenden Ansprüche 8 bis 13 zur Herstellung einer pharmazeutischen Zubereitung zur oralen, parenteralen, rektalen, transdermalen, dermalen, nasalen, pulmonalen (Inhalation) oder ophfhalen Verabreichung, vorzugsweise zur oralen Verabreichung.14. Use according to one of the preceding claims 8 to 13 for the production of a pharmaceutical preparation for oral, parenteral, rectal, transdermal, dermal, nasal, pulmonary (inhalation) or ophthalmic administration, preferably for oral administration.
15. Verwendung gemäß Anspruch 14, bei der die pharmazeutische Zubereitung zur oralen Verabreichung in Form von Unit-Dose-Tabletten, Mikrotabletten, Mikropellets bzw. Granulat, wobei die Mikrotabletten, Mikropellets oder das Granulat gegebenenfalls verkapselt oder in Sachets abgefüllt sind, Kapseln oder Trinklösungen vorliegt.15. Use according to claim 14, in which the pharmaceutical preparation for oral administration in the form of unit-dose tablets, microtablets, micropellets or granules, the microtablets, micropellets or the granules optionally being encapsulated or filled into sachets, capsules or drinking solutions is present.
16. Verwendung gemäß Anspruch 15, dadurch gekennzeichnet, dass die festen Dosisformen mit einem magensaftresistenten Überzug versehen sind.16. Use according to claim 15, characterized in that the solid dosage forms are provided with an enteric coating.
17. Verwendung gemäß Anspruch 8, dadurch gekennzeichnet, dass die erhaltenen Dosiseinheiten der pharmazeutischen Zubereitung einzeln oder im Gemisch bevorzugt enthalten:17. Use according to claim 8, characterized in that the dose units of the pharmaceutical preparation obtained, individually or in a mixture, preferably contain:
10-500 mg Dialkylfumarat, insbesondere Dimethylfumarat und/oder Diethylmmarat, 10-500 mg Calciumalkylfumarat, insbesondere Calciummethylfumarat und/oder Cal- ciumethylfumarat, 0-250 mg Zinkalkylmmarat, insbesondere Zinkmethylfumarat und/oder Zinkethyl- fumarat, 0-250 mg Alkylhydrogenfumarat, insbesondere Methylhydrogenfumarat und/oder10-500 mg of dialkyl fumarate, in particular dimethyl fumarate and / or diethyl mmate, 10-500 mg of calcium alkyl fumarate, in particular calcium methyl fumarate and / or calcium ethyl fumarate, 0-250 mg of zinc alkyl fumarate, in particular zinc methyl fumarate and / or zinc ethyl fumarate, 0-250 mg of alkyl hydrogen fumarate, in particular Methyl hydrogen fumarate and / or
Ethylhydrogenfumarat und 0-250 mg Magnesiumalkylmmarat, insbesondere Magnesiummethylfumarat und/oder Magnesiumethylfumarat wobei die Summe der genannten Mengen einem Äquivalent von 10-500 mg, vorzugsweise 10-300 mg und am meisten bevorzugt 100 mg Fumarsäure entspricht. Ethyl hydrogen fumarate and 0-250 mg magnesium alkyl fumarate, in particular magnesium methyl fumarate and / or magnesium ethyl fumarate, the sum of the stated amounts corresponding to an equivalent of 10-500 mg, preferably 10-300 mg and most preferably 100 mg fumaric acid.
8. Verwendung nach einem der Ansprüche 15 oder 16, dadurch gekennzeichnet, dass die Zubereitung in Form von Mikrotabletten oder Mikropellets mit einer Größe von < 5000 μm und bevorzugt einer Größe von 300-1000 μ für die Pellets und 1000- 2500um für die Mikrotabletten vorliegt. 8. Use according to one of claims 15 or 16, characterized in that the preparation is in the form of microtablets or micropellets with a size of <5000 microns and preferably a size of 300-1000 microns for the pellets and 1000-2500 microns for the microtablets ,
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