Pharmaceutical Compositions Comprising Dimethyl Fumarate

Abstract

Pharmaceutical compositions are described comprising (a) dimethyl fumarate, (b) a diluent selected from monosaccharides, disaccharides, starch and starch derivatives, calcium and magnesium inorganic salts, sugar alcohols, and mixtures thereof, (c) microcrystalline cellulose and (d) croscarmellose sodium, wherein the dimethyl fumarate is not covered with a gastro-resistant coating. These compositions are intended for the treatment of some inflammatory autoimmune diseases or disorders.

Claims

1. A pharmaceutical composition in the form of a gastro-resistant tablet, which pharmaceutical composition is enteric-coated and comprises, based on the total weight of the tablet previous to coating: (a) 20-30 wt. % of dimethyl fumarate; (b) 25-35 wt. % of a diluent selected from lactose, D-glucose (dextrose), sucrose, fructose, galactose, calcium carbonate, dibasic calcium phosphate, calcium sulphate, magnesium carbonate, isomalt, mannitol, maltitol, sorbitol, xylitol, and mixtures thereof; (c) 35-45 wt. % of microcrystalline cellulose; (d) 1-10 wt. % of croscarmellose sodium; and wherein the dimethyl fumarate is not covered with a gastro-resistant coating.

2-4. (canceled)

5. A pharmaceutical composition according to claim 1, further comprising (e) at least one glidant.

6. A pharmaceutical composition according to claim 5, wherein the glidant (e) is selected from calcium phosphate, calcium silicate, powdered cellulose, magnesium silicate, magnesium trisilicate, silicon dioxide, talc, colloidal silica, colloidal anhydrous silica and mixtures thereof.

7. A pharmaceutical composition according to claim 1, further comprising (f) at least one lubricant.

8. A pharmaceutical composition according to claim 7, wherein the lubricant (f) is selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, potassium benzoate, light mineral oil, hydrogenated vegetable oils, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, stearic acid, zinc stearate, and mixtures thereof.

9-14. (canceled)

15. A pharmaceutical composition according to claim 1 comprising, based on the total weight the tablet previous to coating: (a) 25 wt. % of dimethyl fumarate; (b) 30 wt. % of lactose; (c) 40 wt. % of microcrystalline cellulose; (d) 4 wt. % of croscarmellose sodium; (e) 0.5 wt. % of at least one glidant; (f) 0.5 wt. % at least one lubricant.

16-18. (canceled)

19. A pharmaceutical composition according to claim 5, further comprising (f) at least one lubricant.

20. A pharmaceutical composition according to claim 6, further comprising (f) at least one lubricant.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0033] The term “treatment” as used herein refers to the treatment of a disease or medical condition in a human patient which includes:

(a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient;
(b) ameliorating the disease or medical condition, i.e., causing regression of the disease or medical condition in a patient;
(c) suppressing the disease or medical condition, i.e., slowing the development of the disease or medical condition in a patient; or
(d) alleviating the symptoms of the disease or medical condition in a patient.

[0034] The term “therapeutically effective amount” of a compound as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as “therapeutically effective amount”. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.

[0035] The term “not covered with a gastro-resistant coating” as used herein means that dimethyl fumarate particles are not previously coated with pharmaceutical acceptable polymers such as ethylcellulose, methacrylic/acrylic acid copolymers or ammonio methacrylate copolymers (such as ammonio methacrylate copolymer type A or B, or methacrylic acid copolymer A or B), polyvinyl acetate polymer, methacryl-ethylacetate polymer; or hydrophilic excipients such as polyethylene glycol (PEG), povidone, hydroxyl propyl cellulose (HPC), hydroxyethyl starch (HES) or hydroxypropyl methyl cellulose (HPMC).

(a) Dimethyl Fumarate

[0036] Dimethyl fumarate (Dimethyl (E)-butenedioate; CAS RN 624-49-7) is the methyl ester of fumaric acid, which presents the molecular formula C.sub.6H.sub.8O.sub.4 and the molecular mass 144.13 g/mol and the following chemical formula

##STR00001##

[0037] According to the German Medicines Codex 2004 (DAC 2004) it is a white crystalline powder having a melting point in the range from 102-105° C.

[0038] The crystallographic properties of dimethyl fumarate are described Kooijman H et al, Acta Cryst. (2004), E60, 917-0918.

[0039] Dimethyl fumarate can be obtained by reacting fumaric acid and methanol under the presence of concentrated sulphuric acid as catalyst (Ma Hongfei, Chemical industry Times, 2005, Vol. 19, No. 4, 18-19)

[0040] Typically, the dimethyl fumarate is sieved and/or milled to control its particle size. In a preferred embodiment the dimethyl fumarate has a particle size distribution d(10) between 5-20 μm, a d(50) between 30-70 μm, and a d(90) between 80-150 μm, measured using the laser diffraction particle size analyzer Mastersizer 2000 (Malvern Instruments).

(b) The Diluent

[0041] Diluents are fillers designated to make up the required bulk of the dosage form, i.e. tablet, when the drug dosage itself is inadequately to produce this bulk (The Theory and Practice of Industrial Pharmacy, 3rd edition, 1986, ISBN 0-8121-0977-5).

[0042] Typically, the diluent is selected from monosaccharides, disaccharides, starch and starch derivatives, calcium and magnesium inorganic salts, sugar alcohols, and mixtures thereof.

[0043] Monosaccharides are colourless, crystalline solids that are freely soluble in water but insoluble in nonpolar solvents. The simplest monosaccharides are the two three-carbon trioses: glyceraldehyde, an aldotriose, and dihydroxyacetone, a ketotriose. Monosaccharides with four, five, six, and seven carbon atoms in their backbones are called, respectively, tetroses, pentoses, hexoses, and heptoses (Lehninger Principles of Biochemistry, 4th edition). Suitable monosaccharides according to the invention are D-ribose, D-arabinose, D-xylose, D-glucose (dextrose), D-mannose, D-galactose and D-fructose.

[0044] Disaccharides consist of two monosaccharides joined covalently by an O-glycosidic bond, which is formed when a hydroxyl group of one sugar reacts with the anomeric carbon of the other (Lehninger Principles of Biochemistry, 4th edition). Suitable disaccharides according to the invention are lactose, maltose (α-D-glucopyranosyl-(1-4)-D-glucopyranose), sucrose (α-D-glucopyranosyl β-D-fructofuranoside) and trehalose (α-D-glucopyranosyl α-D-glucopyranoside).

[0045] Starch (CAS RN 9005-25-8; molecular formula (C.sub.6H.sub.10O.sub.5).sub.n where n=300-1000) is a natural homopolysaccharide, which consists of linear amylose and branched amylopectin, two polysaccharides based on α-(D)-glucose. Both polymers are organized in a semicrystalline structure, and in the starch granule, amylopectin forms the crystalline portion. Starch occurs as an odourless and tasteless, fine, white to off-white powder. It consists of very small spherical or ovoid granules or grains whose size and shape are characteristic for each botanical variety (Handbook of Pharmaceutical Excipients, 6th edition, 2009; ISBN 9780853697923, UK).

[0046] Starch derivatives according to the invention refer to partially or fully pregelatinized starch (starch that has been chemically and/or mechanically processed to rupture all or part of the starch granules), hydrolized starch, dextrinized starch, alkaline-modified starch (with sodium hydroxide or potassium hydroxide), bleached starch (with hydrogen peroxide), enzyme-treated starch, monostarch phosphate, monostarch phosphate, hydroxypropylated starch, hydroxyethyl starch, octenyl succinic anhydride (OSA) starch, cationic starch (adding positive electrical charge to starch), carboxymethylated starch (with monochloroacetic acid adding negative charge), or mixtures thereof.

[0047] Calcium and magnesium inorganic salts according to the invention refer to calcium carbonate, dibasic calcium phosphate, calcium sulphate, magnesium carbonate, or mixtures thereof.

[0048] Sugar alcohols are polyalcohols resulting from the reduction of the carbonyl group in a monosaccharide to a hydroxyl group. They are white, water-soluble solids that occur naturally and are used widely in the food industry as thickeners and sweeteners. Suitable sugar alcohols according to the invention are erythritol, isomalt, lactitol, mannitol, maltitol, sorbitol and xylitol.

[0049] Preferably, the diluent (b) is selected from lactose, D-glucose (dextrose), sucrose (D-sucrose), fructose (D-fructose), galactose (D-galactose), starch, calcium carbonate, dibasic calcium phosphate, calcium sulphate, magnesium carbonate, isomalt, mannitol, maltitol, sorbitol, xylitol, and mixtures thereof.

[0050] In a preferred embodiment, the diluent (b) is selected from fructose, lactose, dibasic calcium phosphate, mannitol, and mixtures thereof. In a more preferred embodiment, the diluent (b) is lactose.

[0051] Fructose

[0052] Fructose (D-fructose) is a monosaccharide that occurs as odourless, colourless crystals or a white crystalline powder with a very sweet taste (CAS RN 57-48-7; molecular formula C.sub.6H.sub.12O.sub.6; molecular weight 180.16 g/m). Fructose occurs naturally in honey and a large number of fruits. It may be prepared from inulin, dextrose, or sucrose by a number of methods. Commercially, fructose is mainly manufactured by crystallization from high-fructose syrup derived from hydrolyzed and isomerized cereal starch or cane and beet sugar (Handbook of Pharmaceutical Excipients, 6th edition, 2009).

[0053] Lactose

[0054] Lactose is a natural monosaccharide, obtained from milk, which consist of one galactose and one glucose moiety. Lactose occurs as white to off-white crystalline particles or powder. It is odourless and slightly sweet-tasty. The Handbook of Pharmaceutical Excipients, 6th edition, 2009, describes different lactose types which are suitable according to the current invention: anhydrous lactose (CAS RN 63-42-3; molecular formula O.sub.12H.sub.22O.sub.11; molecular weight 342.30 g/m), inhalation lactose, lactose monohydrate (CAS RN 5989-81-1; molecular formula C.sub.12H.sub.22O.sub.11.H.sub.2O; molecular weight 360.31 g/m), and spray-dried lactose, which is a mixture of amorphous lactose (1:1 mixture of α-and-β-lactose) and lactose monohydrate.

[0055] In a preferred embodiment, the lactose is selected from lactose monohydrate or spray-dried lactose, preferably spray-dried lactose.

[0056] Typically, the spray-dried lactose has a bulk density between 0.55 and 0.68 g/cm.sup.3 and a tapped density between 0.65 and 0.75 g/cm.sup.3. In a preferred embodiment the spray-dried lactose has a particle size distribution (retained on air jet sieve, cumulative) 75 μm (US standard #200) 60-80%, 106 μm (US standard #140) 30-55% and 250 μm (US standard #60) 0.0-0.5%.

Dibasic Calcium Phosphate

[0057] Dibasic calcium phosphate according to the invention refers to anhydrous dibasic calcium phosphate and dibasic calcium phosphate hydrate.

[0058] Anhydrous dibasic calcium phosphate (calcium phosphate, dibasic anhydrous; CAS RN 7757-93-9; molecular formula CaHPO.sub.4; molecular weight 136.06 g/m) is a white, odourless, tasteless powder or crystalline solid, which occurs as triclinic crystals (Handbook of Pharmaceutical Excipients, 6th edition, 2009).

[0059] Dibasic calcium phosphate hydrate (calcium phosphate, dibasic dihydrate; CAS RN 7789-77-7; molecular formula CaHPO.sub.4.2H.sub.2O; molecular weight 172.09 g/m) is a white, odourless, tasteless powder or crystalline solid, which occurs as monoclinic crystals (Handbook of Pharmaceutical Excipients, 6th edition, 2009).

[0060] In a preferred embodiment, the dibasic calcium phosphate is anhydrous dibasic calcium phosphate.

Mannitol

[0061] Mannitol (D-mannitol; CAS RN 69-65-8; molecular formula C.sub.6H.sub.14O.sub.6; molecular weight 182.17 g/m) is a hexahydric alcohol related to mannose and is isomeric with sorbitol. Mannitol occurs as a white, odourless, crystalline powder, or free flowing granules. It has a sweet taste, approximately as sweet as glucose and half as sweet as sucrose, and imparts a cooling sensation in the mouth. The Handbook of Pharmaceutical Excipients, 6th edition, 2009, describes different commercially available grades of mannitol which are suitable according to the current invention such as Pearlitol 300 DC, Pearlitol 400 DC and Pearlitol 500 DC; all manufactured by Roquette Frères.

(c) Microcrystalline Cellulose

[0062] Microcrystalline cellulose (CAS RN 9004-34-6; molecular formula (C.sub.6H.sub.10O.sub.5).sub.n where n is approx. 220; molecular weight approx. 36000 g/m) is a purified, partially depolymerized cellulose that occurs as a white, odourless, tasteless, crystalline powder composed of porous particles (Handbook of Pharmaceutical Excipients, 6th edition, 2009).

[0063] Typically, the microcrystalline cellulose has a bulk density between 0.28 and 0.33 g/cm.sup.3. In a preferred embodiment the microcrystalline cellulose has a particle size distribution d(10) between 25-50 μm, a d(50) between 100-150 μm, and a d(90) between 195-280 μm, measured using a laser diffraction particle size analyzer Mastersizer (Malvern Instruments).

(d) Croscarmellose Sodium

[0064] Croscarmellose sodium (cellulose, carboxymethyl ether, sodium salt, crosslinked; CAS RN 74811-65-7) is a crosslinked polymer of carboxymethyl cellulose sodium. Croscarmellose sodium occurs as an odourless, white or grayish white powder (Handbook of Pharmaceutical Excipients, 6th edition, 2009).

[0065] Typically, the croscarmellose sodium has a bulk density around 0.529 g/cm.sup.3 and a tapped density between around 0.819 g/cm.sup.3. In a preferred embodiment the microcrystalline cellulose has a particle size distribution d(10) of not more than 25 μm, a d(50) between 25-55 μm, and a d(90) of not less than 60 μm, measured using a laser diffraction particle size analyzer Mastersizer (Malvern Instruments).

The Pharmaceutical Compositions

[0066] Typically, the present invention provides pharmaceutical compositions comprising (a) dimethyl fumarate, (b) a diluent selected from monosaccharides, disaccharides, starch and starch derivatives, calcium and magnesium inorganic salts, sugar alcohols, and mixtures thereof, (c) microcrystalline cellulose and (d) croscarmellose sodium, wherein the dimethyl fumarate is not covered with a gastro-resistant coating.

[0067] Preferably, the diluent (b) is selected from lactose, D-glucose (dextrose), sucrose, fructose, galactose, starch, calcium carbonate, dibasic calcium phosphate, calcium sulphate, magnesium carbonate, isomalt, mannitol, maltitol, sorbitol, xylitol, and mixtures thereof.

[0068] In a preferred embodiment, the diluent (b) is selected from lactose, dibasic calcium phosphate, isomalt, mannitol, and mixtures thereof. In a more preferred embodiment, the diluent (b) is lactose.

[0069] In a particular preferred embodiment, the present invention provides pharmaceutical compositions comprising (a) dimethyl fumarate, (b) lactose, (c) microcrystalline cellulose and (d) croscarmellose sodium.

[0070] In a preferred embodiment, the pharmaceutical composition as defined above further comprises (e) at least one glidant.

[0071] Typically, the glidant (e) is selected from calcium phosphate, calcium silicate, powdered cellulose, magnesium silicate, magnesium trisilicate, magnesium carbonate, magnesium oxide, magnesium lauryl sulphate, sodium lauryl sulphate starch, silicon dioxide, talc, colloidal silica, colloidal anhydrous silica (colloidal silicon dioxide or fumed silicon dioxide) and mixtures thereof.

[0072] Preferably, the glidant (e) is selected from colloidal silica anhydrous, talc, or a combination thereof, more preferably colloidal anhydrous silica.

[0073] In a preferred embodiment, the pharmaceutical composition as defined above further comprises (f) at least one lubricant.

[0074] Typically, the lubricant (f) is selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol (in particular polyethylene glycol 4000 and 6000), sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, potassium benzoate, light mineral oil, hydrogenated vegetable oils (in particular hydrogenated castor oil), glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, stearic acid, zinc stearate, and mixtures thereof.

[0075] Preferably, the lubricant (f) is magnesium stearate.

[0076] In a preferred embodiment, in the pharmaceutical composition as defined above the weight ratio (c) microcrystalline cellulose to (b) diluent is in the range from 2:5 to 5:2, preferably in the range from 2:1 to 1:2, more preferably 4:3.

[0077] In another preferred embodiment, in the pharmaceutical composition as defined above the weight ratio (c) microcrystalline cellulose to (c) dimethyl fumarate is in the range from 5:1 to 1:5, preferably in the range from 3:1 to 1:3, more preferably 8:5.

[0078] In another preferred embodiment, in the pharmaceutical composition as defined above the weight ratio (b) diluent to (c) dimethyl fumarate is in the range from 5:1 to 1:5, preferably in the range from 3:1 to 1:3, more preferably 6:5.

[0079] In another preferred embodiment, in the pharmaceutical composition as defined above the weight ratio (c) microcrystalline cellulose to (d) croscarmellose sodium is in the range from 30:1 to 1:5, preferably in the range from 20:1 to 1:2, more preferably 10:1.

[0080] In another preferred embodiment, in the pharmaceutical composition as defined above the weight ratio (b) diluent to (d) croscarmellose sodium is in the range from 20:1 to 1:5, preferably in the range from 10:1 to 1:3, more preferably 15:2.

[0081] The pharmaceutical composition of the invention may optionally contain other conventional ingredients such as anti-oxidants, colorants, flavouring agents, preservatives and taste-masking agents.

[0082] In a preferred embodiment, the pharmaceutical composition of the invention is administered orally (peroral administration; per os (latin)).

[0083] Typically, the pharmaceutical composition of the invention is a solid dosage form, i.e. immediate-release tablet, immediate-release capsule, delayed-release tablet, delayed-release capsule, sustained-release tablet, sustained-release capsule, soluble tablet, dispersible tablet, effervescent tablet, chewable tablet, chewable gum, buccal tablet, sublingual tablet, orally disintegrating tablet, lozenge, pastille, hard gelatin capsule or soft gelatin capsule.

[0084] Preferably, the pharmaceutical composition of the invention is in the form of a delayed-release tablets, more preferably a gastro-resistant (enteric coated) tablet. Gastro-resistant tablets are delayed-release tablets that are intended to resist the gastric fluid and to release their active substance(s) in the intestinal media. Usually they are prepared from granules or particles already covered with a gastro-resistant coating or in certain cases by covering tablet cores with a gastro-resistant coating (enteric coated tablets) (European Pharmacopoeia 6.0, 2007, ISBN 9789287160546). In a preferred embodiment, the pharmaceutical composition of the invention is in the form of a gastro-resistant (enteric coated) tablet prepared by covering tablet cores with a gastro-resistant coating.

[0085] As previously indicated, the dimethyl fumarate is not covered with a gastro-resistant coating, i.e. dimethyl fumarate particles are not previously coated with pharmaceutical acceptable polymers or hydrophilic excipients when the tablet core (tablet previous to coating) is prepared.

[0086] Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The formulation of tablets is discussed in detail in Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, ISBN 0781746736.

[0087] Coatings on tablet cores usually consist of a mixture of substances, for example, one or more plasticizers, one or core polymers, one or more copolymers, one or more glidants, one or more pigments, or mixtures thereof. Coating of tablet cores is discussed in detail in Pharmaceutical Manufacturing Handbook: Production and Processes, 2008, ISBN 9780470259580.

[0088] Examples of suitable plasticizers in the coating (compounds which reduce the minimum film-forming temperatures as well as the glass transition temperature) include one or more of acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, cellulose acetate phthalate, chlorbutanol, dextrin, dibutyl phthalate, dibutyl secacate, diethyl phthalate, dimethyl phthalate, glycerin, glycerin monostearate, hypromellose phthalate, mannitol, mineral oil, lanolin alcohol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, triethyl citrate, dibutyl sebacate, polyethylene glycol and propylene glycol.

[0089] Examples of suitable polymers in the coating include one or more of methacrylic acid polymers, acrylic polymers, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose acetate succinate (HPMCAS), ethylcellulose (EC), carboxymethyl ethylcellulose (CMEC), poly(vinyl alcohol) (PVA), and polyvinyl acetate phthalate (PVAP). These polymers are available as aqueous dispersions, powders or organic solutions (e.g. alcohols, acetone). An example of commercially available organic solution is a mixture of poly(vinyl alcohol), methacrylic acid copolymer-type C, polyethylene glycol, talc, a neutralizing agent and pigment; marketed under the trade name OPADRY 200 by Colorcon, Inc.

[0090] Examples of suitable copolymers in the coating include one or more of methacrylic acid-methyl methacrylate (50:50) copolymer, methacrylic acid-methyl methacrylate (30:70) copolymer, methacrylic acid-ethylacrylate (50:50) copolymer, or a methacrylic acid-methyl acrylate-methyl methacrylate copolymer. These copolymers are available as aqueous dispersions, powders or organic solutions (e.g. alcohols, acetone). Examples of commercially available copolymers include the methacrylic acid copolymers marketed under the trade name EUDRAGIT® by Evonik, which include EUDRAGIT® L 30 D-55 (methacrylic acid-ethyl acrylate copolymer (1:1), 30% aqueous dispersion), EUDRAGIT® L 100-55 (methacrylic acid-ethyl acrylate copolymer (1:1), powder form), EUDRAGIT® L 100 (methacrylic acid-methyl methacrylate copolymer (1:1), powder form), EUDRAGIT® L 12,5 (methacrylic acid-methyl methacrylate copolymer (1:1), 12.5% organic solution), EUDRAGIT® S 100 (methacrylic acid-methyl methacrylate copolymer (1:2), powder form), EUDRAGIT® S 12,5 (methacrylic acid-methyl methacrylate copolymer (1:1), 12.5% organic solution) and EUDRAGIT® FS 30 D (methacrylic acid-methyl acrylate-methyl methacrylate copolymer, 30% aqueous dispersion).

[0091] Examples of suitable glidants in the coating include talc or glycerol monostearate.

[0092] Examples of suitable pigments in the coating include titanium dioxide, aluminium lakes, indigo carmine lakes or iron oxide pigments.

[0093] In a particular embodiment, the coating is carried out by means of a coating formulation which comprises i) one or more polymers and/or copolymers, ii) one or more glidants, iii) one or more plasticizers, and iv) one or more pigments. Optionally, the coating formulation can comprise one or more antifoam agents.

[0094] In a particular embodiment, the pharmaceutical composition of the invention is in the form of a gastro-resistant (enteric coated) tablet and comprises, based on the total weight of the tablet previous to coating (tablet core):

(a) 20-30 wt. % of dimethyl fumarate (not previously covered with a gastro-resistant coating);
(b) 25-35 wt. % of a diluent selected from lactose, D-glucose (dextrose), sucrose, fructose, galactose, starch, calcium carbonate, dibasic calcium phosphate, calcium sulphate, magnesium carbonate, isomalt, mannitol, maltitol, sorbitol, xylitol, and mixtures thereof;
(c) 35-45 wt. % of microcrystalline cellulose;
(d) 1-10 wt. % of croscarmellose sodium.

[0095] In another particular embodiment, the pharmaceutical composition of the invention is in the form of a gastro-resistant (enteric coated) tablet and comprises, based on the total weight of the tablet previous to coating (tablet core):

(a) 20-30 wt. % of dimethyl fumarate (not previously covered with a gastro-resistant coating);
(b) 25-35 wt. % of a diluent selected from lactose, dibasic calcium phosphate, isomalt, mannitol, and mixtures thereof;
(c) 35-45 wt. % of microcrystalline cellulose;
(d) 1-10 wt. % of croscarmellose sodium.

[0096] In a particular preferred embodiment, the pharmaceutical composition of the invention is in the form of a gastro-resistant (enteric coated) tablet and comprises, based on the total weight of the tablet previous to coating (tablet core):

(a) 20-30 wt. % of dimethyl fumarate (not previously covered with a gastro-resistant coating);
(b) 25-35 wt. % of lactose;
(c) 35-45 wt. % of microcrystalline cellulose;
(d) 1-10 wt. % of croscarmellose sodium.

[0097] In a preferred embodiment, the pharmaceutical compositions in the form of a gastro-resistant (enteric coated) tablet as defined above further comprises (e) at least one glidant.

[0098] Preferably, the glidant (e) is selected from colloidal silica anhydrous, talc, or a combination thereof, more preferably colloidal anhydrous silica.

[0099] When the gastro-resistant (enteric coated) tablet as defined above comprises (e) at least one glidant, the glidant (or combination of glidants) is present in an amount ranging from 0.1 to 5 wt. %, preferably from 0.2 to 3 wt. %, more preferably from 0.1 to 1 wt. %, based on the total weight of the tablet previous to coating (tablet core).

[0100] In another preferred embodiment, the pharmaceutical composition in the form of a gastro-resistant (enteric coated) tablet as defined above further comprises (f) at least one lubricant.

[0101] Preferably, the lubricant (f) is magnesium stearate.

[0102] When the gastro-resistant (enteric coated) tablet as defined above comprises (f) at least one lubricant, the lubricant (or combination of lubricants) is present in an amount ranging from 0.1 to 10 wt. %, preferably from 0.2 to 5 wt. %, more preferably from 0.1 to 2 wt. %, based on the total weight of the tablet previous to coating (tablet core).

[0103] In a particular embodiment, the pharmaceutical composition of the invention is in the form of a gastro-resistant (enteric coated) tablet and comprises, based on the total weight of the tablet previous to coating (tablet core):

(a) 20-30 wt. % of dimethyl fumarate (not previously covered with a gastro-resistant coating);
(b) 25-35 wt. % of lactose;
(c) 35-45 wt. % of microcrystalline cellulose;
(d) 1-10 wt. % of croscarmellose sodium;
(e) 0.1-5 wt. % of at least one glidant; preferably selected from colloidal anhydrous silica, talc, or a combination thereof; more preferably colloidal silica anhydrous;
(f) 0.1-10 wt. % of at least one lubricant, preferably magnesium stearate.

[0104] In a preferred embodiment, the pharmaceutical composition of the invention is in the form of a gastro-resistant (enteric coated) tablet and comprises, based on the total weight of the tablet previous to coating (tablet core):

(a) 25 wt. % of dimethyl fumarate (not previously covered with a gastro-resistant coating);
(b) 30 wt. % of lactose;
(c) 40 wt. % of microcrystalline cellulose;
(d) 4 wt. % of croscarmellose sodium;
(e) 0.5 wt. % of at least one glidant; preferably selected from colloidal anhydrous silica, talc, or a combination thereof; more preferably colloidal silica anhydrous;
(f) 0.5 wt. % of at least one lubricant, preferably magnesium stearate.

[0105] In a particular preferred embodiment, the pharmaceutical composition of the invention is in the form of a gastro-resistant (enteric coated) tablet and comprises, based on the total weight of the tablet previous to coating (tablet core):

(a) 30 mg of dimethyl fumarate (not previously covered with a gastro-resistant coating);
(b) 36 mg of lactose;
(c) 48 mg of microcrystalline cellulose;
(d) 4.8 mg of croscarmellose sodium;
(e) 0.6 mg of colloidal anhydrous silica;
(f) 0.6 mg of magnesium stearate.

[0106] In another particular preferred embodiment, the pharmaceutical composition of the invention is in the form of a gastro-resistant (enteric coated) tablet and comprises, based on the total weight of the tablet previous to coating (tablet core):

(a) 120 mg of dimethyl fumarate (not previously covered with a gastro-resistant coating);
(b) 144 mg of lactose;
(c) 192 mg of microcrystalline cellulose;
(d) 19.2 mg of croscarmellose sodium;
(e) 2.4 mg of colloidal anhydrous silica;
(f) 2.4 mg of magnesium stearate.

[0107] In a preferred embodiment, when the pharmaceutical composition of the invention is in the form of a gastro-resistant (enteric coated) tablet, the tablet core does not contain further excipients than the described above, i.e. (b) diluent, (c) microcrystalline cellulose, (d) croscarmellose sodium and optionally (e) colloidal anhydrous silica; and (f) magnesium stearate.

[0108] The invention also relates to a pharmaceutical composition as defined above for use in the treatment or prevention of inflammatory or autoimmune diseases or disorders, in particular inflammatory or autoimmune diseases or disorders selected from rheumatoid arthritis, multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus (SLE), myastenia gravis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, Sjoegren's syndrome, autoimmune hemolytic anemia (AIHA), type I diabetes or psoriasis; in particular for use in the treatment or prevention of multiple sclerosis or psoriasis.

[0109] The invention also provides the use of a pharmaceutical composition as defined above for the manufacture of a medicament for the treatment or prevention of inflammatory or autoimmune diseases or disorders, in particular inflammatory or autoimmune diseases or disorders selected from rheumatoid arthritis, multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus (SLE), myastenia gravis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, Sjoegren's syndrome, autoimmune hemolytic anemia (AIHA), type I diabetes or psoriasis; in particular for the treatment or prevention of multiple sclerosis or psoriasis.

[0110] The invention further relates to a method for treating a subject afflicted with inflammatory or autoimmune diseases or disorders, in particular inflammatory or autoimmune diseases or disorders selected from rheumatoid arthritis, multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus (SLE), myastenia gravis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, Sjoegren's syndrome, autoimmune hemolytic anemia (AIHA), type I diabetes or psoriasis; in particular for treating a subject afflicted with multiple sclerosis or psoriasis; which comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition as defined in above.

[0111] The invention also relates to a process for manufacturing a pharmaceutical composition as described above, the process comprising the steps of:

i) mixing (a) dimethyl fumarate, wherein the dimethyl fumarate is not previously covered with a gastro-resistant coating, (b) a diluent selected from monosaccharides, disaccharides, starch and starch derivatives, calcium and magnesium inorganic salts, sugar alcohols, and mixtures thereof, (c) microcrystalline cellulose, (d) croscarmellose sodium, and optionally other pharmaceutical excipients, to form a homogenous blend; and
ii) optionally sieving the blend.

[0112] The invention also provides pharmaceutical compositions obtainable by this process.

[0113] In a preferred embodiment, the process for manufacturing a pharmaceutical composition as described above comprising the steps of:

i) mixing (a) dimethyl fumarate, wherein the dimethyl fumarate is not previously covered with a gastro-resistant coating, (b) a diluent selected from monosaccharides, disaccharides, starch and starch derivatives, calcium and magnesium inorganic salts, sugar alcohols, and mixtures thereof, (c) microcrystalline cellulose, (d) croscarmellose sodium, and (e) at least one glidant to form a homogenous blend;
ii) optionally sieving the blend;
iii) adding (e) at least one glidant to the previous blend and mixing the resulting blend; and
iv) optionally sieving the final blend.

[0114] The invention also relates to pharmaceutical compositions obtainable by this process.

[0115] The invention also relates to a process for manufacturing gastro-resistant (enteric-coated) tablets as described above, the process comprising the steps of:

i) tableting the blend described above to obtain tablet cores; and
ii) coating the tablet cores.

[0116] The invention also provides gastro-resistant (enteric-coated) tablets obtainable by this process. The invention also provides a combination which comprises (1) a pharmaceutical composition as defined above and (2) a therapeutically effective amount of a compound that reduces or eliminates flushing.

[0117] Flushing is known as a side effect of fumaric acid esters since early clinical studies and has led to the discontinuation of treatment in some patients (Nieboer C et al., Journal of the American Academy of Dermatology, 1989, 20:4, 601-608); Nieboer C et al., Dermatologica, 1990, 181:33-37). Thus, “a compound that reduces or eliminates flushing” refers to the ability of a compound to reduce the severity of flushing when it occurs, or result in fewer flushing events than would otherwise occur. As used herein the term “therapeutically effective amount” means an amount sufficient to reduce the severity of flushing when it occurs, or result in fewer flushing events than would otherwise occur. An amount adequate to accomplish this is defined as a “therapeutically effective amount”.

[0118] The active compounds in the combination may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.

[0119] Also provided is a product comprising (1) a pharmaceutical composition as defined above and (2) a therapeutically effective amount of a compound that reduces or eliminates flushing, as a combined preparation for simultaneous, separate or sequential use in the treatment of a human or animal patient suffering from or susceptible to a pathological condition or disease as defined above.

[0120] Also provided is a kit of parts comprising (1) a pharmaceutical composition as defined above, together with instructions for simultaneous, separate or sequential use in combination with (2) a therapeutically effective amount of a compound that reduces or eliminates flushing, for the treatment of a human or animal patient suffering from or susceptible to a pathological condition or disease as defined above.

[0121] Also provided is a package comprising (1) a pharmaceutical composition as defined above and (2) a therapeutically effective amount of a compound that reduces or eliminates flushing, for simultaneous, separate or sequential use in the treatment of a pathological condition or disease as defined above.

[0122] Typically, the compound that reduces or eliminates flushing (2) is selected from acetylsalicylic acid, laropripant ((−)-[(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetic acid), COX inhibitors, or a combination thereof.

[0123] As used herein, the term COX inhibitor refers to a compound that inhibits both the cyclooxygenase-1 enzyme and the cyclooxygenase-2 enzyme. In one embodiment, the compound has a cyclooxygenase-1 IC.sub.50 value of less than about 200 μM, preferably of less than about 100 μM, more preferably of less than about 50 μM, even more preferably of less than about 20 μM, and a cyclooxygenase-2 IC.sub.50 value of less than about 50 μM, preferably of less than 25 μM, more preferably of less than about 15 μM, even more preferably of less than about 2 μM, in the human whole blood assay (as described in Brideau et al., Inflamm Res., 45: 68-74 (1996)) and also has a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition (determined as the ratio IC.sub.50 COX-1/IC.sub.50 COX-2) of at least 0.1, preferably of at least 0.5, more preferably of at least 1, even more preferably of at least 2, and most preferably of at least 10.

[0124] In an embodiment, the COX inhibitor is selected from the group consisting of oxicams, piroxicam, meloxicam, isoxicam, tenoxicam, sudoxicam, CP-14,304, salicylates, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, fendosal, acetic acid derivatives, aceclofenac, diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, etodolac, ketorolac, fenamates, mefenamic, meclofenamic, flufenamic, niflumic, tolfenamic acids, propionic acid derivatives, acetaminophen (paracetamol), ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, piketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofen, pyrazoles, phenylbutazone, oxyphenbutazone, feprazone, azapropazone, trimethazone, apricoxib, celecoxib, cimicoxib, deracoxib, etoricoxib, lumiracoxib, parecoxib sodium, rofecoxib, selenocoxib-1, valdecoxib, 2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one (ABT-963), 4-(4-Cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide (JTE-522), N-[2-Cyclohexyloxy-4-nitrophenyl]methanesulfonamide (NS 398), (E)-(5)-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474), 5(R)-thiosulfonamide-3(2H)-benzofuranone (SVT-2016), N-[7-[(methanesulfonyl)amino]-4-oxo-6-phenoxy-4H-1-benzopyran-3-yl] formamide (T-614), BMS-347070 (Bristol Myers Squibb), GSK-644784 (GlaxoSmithKline), RS 57067 (Roche Bioscience), SC-75416 (Pfizer), SC-58125 (Pfizer), SD-8381, 4-Methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1H-pyrrole, 2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole, 3-(2,4-difluorophenoxy)-6-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyran-4-one, 3-(4-chlorophenoxy)-6-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyran-4-one, 3-(4-bromo-2-fluorophenoxy)-6-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyran-4-one, 3-(4-chloro-2-fluorophenoxy)-6-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyran-4-one, 3-(2,4-difluorophenoxy)-6-methyl-2-(4-(methylsulfinyl)phenyl)-4H-pyran-4-one, 3-(4-chloro-2-fluorophenoxy)-6-methyl-2-(4-(methylsulfinyl)phenyl)-4H-pyran-4-one, (S)-3-(2,4-difluorophenoxy)-6-methyl-2-(4-(methylsulfinyl)phenyl)-4H-pyran-4-one, (S)-3-(4-bromo-2-fluorophenoxy)-6-methyl-2-(4-(methylsulfinyl)phenyl)-4H-pyran-4-one, (S)-3-(4-chloro-2-fluorophenoxy)-6-methyl-2-(4-(methylsulfinyl)phenyl)-4H-pyran-4-one, (R)-3-(2,4-difluorophenoxy)-6-methyl-2-(4-(methylsulfinyl)phenyl)-4H-pyran-4-one, (R)-3-(4-bromo-2-fluorophenoxy)-6-methyl-2-(4-(methylsulfinyl)phenyl)-4H-pyran-4-one, (R)-3-(4-chloro-2-fluorophenoxy)-6-methyl-2-(4-(methylsulfinyl)phenyl)-4H-pyran-4-one, 4-(3-(2-fluorophenyl)-2-oxo-2,3-dihydrooxazol-4-yl)benzenesulfonamide, 4-(2-oxo-3-m-tolyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide, 4-(2-oxo-3-p-tolyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide, (R)-4-(4-(methylsulfinyl)phenyl)-3-phenylfuran-2(5H)-one, (S)-4-(4-(methylsulfinyl)phenyl)-3-phenylfuran-2(5H)-one, 4-(4-(methylsulfinyl)phenyl)-3-phenylfuran-2(5H)-one, 5-chloro-6′-methyl-3-(4-(methylsulfinyl)phenyl)-2,3′-bipyridine, (S)-5-chloro-6′-methyl-3-(4-(methylsulfinyl)phenyl)-2,3′-bipyridine, (R)-5-chloro-6′-methyl-3-(4-(methylsulfinyl)phenyl)-2,3′-bipyridine, and their pharmaceutically acceptable salts, their solvates, their N-oxides, their stereoisomers or their deuterated derivates thereof.

[0125] In a preferred embodiment, the COX inhibitor is selected from the group consisting of aceclofenac, diclofenac, acetaminophen (paracetamol), ibuprofen, naproxen, apricoxib, celecoxib, cimicoxib, deracoxib, etoricoxib, lumiracoxib, parecoxib sodium, rofecoxib, selenocoxib-1, valdecoxib, 2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one (ABT-963), 4-(4-Cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide (JTE-522), N-[2-Cyclohexyloxy-4-nitrophenyl]methanesulfonamide (NS 398), (E)-(5)-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474), 5(R)-thiosulfonamide-3(2H)-benzofuranone (SVT-2016), N-[7-[(methanesulfonyl)amino]-4-oxo-6-phenoxy-4H-1-benzopyran-3-yl] formamide (T-614), 3-(2,4-difluorophenoxy)-6-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyran-4-one, 4-(3-(2-fluorophenyl)-2-oxo-2,3-dihydrooxazol-4-yl)benzenesulfonamide, 4-(2-oxo-3-m-tolyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide, 4-(2-oxo-3-p-tolyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide, and their pharmaceutically acceptable salts, their solvates, their N-oxides, their stereoisomers or their deuterated derivates thereof.

[0126] In a further preferred embodiment, the COX inhibitor is selected from the group consisting of aceclofenac, diclofenac, acetaminophen (paracetamol), ibuprofen, naproxen, apricoxib, celecoxib, cimicoxib, deracoxib, etoricoxib, lumiracoxib, parecoxib sodium, rofecoxib, selenocoxib-1, valdecoxib, 3-(2,4-difluorophenoxy)-6-methyl-2-(4-(methylsulfonyl)phenyl)-4H-pyran-4-one, 4-(3-(2-fluorophenyl)-2-oxo-2,3-dihydrooxazol-4-yl)benzenesulfonamide, 4-(2-oxo-3-m-tolyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide, 4-(2-oxo-3-p-tolyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide, and their pharmaceutically acceptable salts, their solvates, their N-oxides, their stereoisomers or their deuterated derivates thereof.

[0127] The invention also provides a combination which comprises (1) a pharmaceutical composition as defined above and (3) a therapeutically effective amount of a proton pump inhibitor (PPI). Proton pump inhibitors are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production and, therefore, reduce the gastrointestinal distress.

[0128] Typically, the proton pump inhibitor (PPI) is selected from dexlansoprazole, esomeprazole, ilaprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole or mixtures thereof.

[0129] In a preferred embodiment, the proton pump inhibitor (PPI) is selected from lansoprazole, omeprazole, pantoprazole or mixtures thereof.

[0130] The active compounds in the combination may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.

[0131] Also provided is a product comprising (1) a pharmaceutical composition as defined above and (3) a therapeutically effective amount of a proton pump inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of a human or animal patient suffering from or susceptible to a pathological condition or disease as defined above.

[0132] Also provided is a kit of parts comprising (1) a pharmaceutical composition as defined above, together with instructions for simultaneous, separate or sequential use in combination with (3) a therapeutically effective amount of a proton pump inhibitor, for the treatment of a human or animal patient suffering from or susceptible to a pathological condition or disease as defined above.

[0133] Also provided is a package comprising (1) a pharmaceutical composition as defined above and (3) a therapeutically effective amount of a proton pump inhibitor, for simultaneous, separate or sequential use in the treatment of a pathological condition or disease as defined above.

[0134] The invention also provides a triple combination which comprises (1) a pharmaceutical composition as defined above, (2) a therapeutically effective amount of a compound that reduces or eliminates flushing as defined above and (3) a therapeutically effective amount of a proton pump inhibitor (PPI) as defined above.

[0135] The following examples are given in order to provide a person skilled in the art with a sufficiently clear and complete explanation of the present invention, but should not be considered as limiting of the essential aspects of its subject, as set out in the preceding portions of this description.

EXAMPLES

Example 1—Bulk Composition

[0136] A 60 kg bulk composition was prepared by mixing the amounts of the ingredients detailed in Table 1.

TABLE-US-00001 TABLE 1 Bulk composition Ingredient Weight (Kg) % Dimethyl fumarate 15 25 Lactose 18 30 Microcrystalline cellulose 24 40 Croscarmellose sodium 2.4 4 Silica colloidal anhydrous 0.3 0.5 Magnesium Stearate 0.3 0.5 Total 60 100

[0137] Dimethyl fumarate, lactose, microcrystalline cellulose, croscarmellose sodium and silica colloidal anhydrous were mixed together to form a blend. The blend was then passed through a 0.8 mm sieve. The sieved blend was mixed again. The resulting was then again passed through a 0.8 mm sieve and finally mixed again.

[0138] Magnesium stearate was passed through a 0.5 mm sieve and added to the previous blend, which was mixed to obtain the final blend.

Example 2—Tablets

2.1. Tablets of the Invention

[0139] The final blend of Example 1 was divided in two homothetic parts to obtain tablets with different strengths (30 and 120 mg of dimethyl fumarate). 12 Kg of bulk composition were tableted by direct compression with a rotary tableting machine to obtain 100,000 tablet cores with a final weight of 120 mg (30 mg of dimethyl fumarate) and 6.5 mm of diameter.

[0140] 48 Kg of bulk composition were tableted by direct compression with a rotary tableting machine to obtain 100,000 tablet cores with a final weight of 480 mg (120 mg of dimethyl fumarate) and 11 mm of diameter.

[0141] The tablet cores were then coated with an aqueous film coating suspension comprising triethyl citrate, simethicone, talc and titanium dioxide suspended in water and methacrylic acid-ethyl acrylate copolymer (1:1) 30% aqueous dispersion (see amounts in Table 2). In the case of the 120 mg of dimethyl fumarate tablet cores, the coating suspension also contained indigo carmine lake and sodium hydroxide.

TABLE-US-00002 TABLE 2 Tablets with lactose 30 mg tablet 120 mg tablet Ingredient weight (mg) weight (mg) Core Dimethyl fumarate 30 120 Lactose 36 144 Microcrystalline cellulose 48 192 Croscarmellose sodium 4.8 19.2 Silica colloidal anhydrous 0.6 2.4 Magnesium Stearate 0.6 2.4 Coating Methacrylic acid - ethyl acrylate 11.56 45.98 copolymer (1:1) 30% aqueous dispersion Talc 5.78 22.94 Triethyl citrate 1.16 4.61 Simethicone 0.06 0.24 Titanium dioxide 0.29 4.61 Indigo carmine Lake 1.77 1N Sodium hydroxide solution 5.29

[0142] The enteric-coated tablets described above can be distinguished not only by the colour but also by the size (lower dose—smaller diameter; higher dose—higher diameter), which is beneficial for visually impaired people.

[0143] In addition, stability studies were conducted with the enteric-coated tablets described above following stability guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Tablets were stored in a climatic chamber at 40° C./75% Relative Humidity for 6 months, 30° C./65% Relative Humidity for 12 months and at 25° C./60% Relative Humidity for 24 months. The appearance, water content, hardness, dissolution and related substances was tested at regular intervals. The results concluded that the tablets were stable. Therefore, no limitation for the storage conditions is needed.

2.2. Additional Tablets of the Invention

[0144] In a same manner as described above, 30 and 120 mg dimethyl fumarate enteric-coated tablets were prepared but replacing lactose by fructose, mannitol and dibasic calcium phosphate (CaHPO.sub.4 2H.sub.2O) as indicated in Tables 3, 4 and 5. Stability studies were conducted with this tablets at 40° C./75% Relative Humidity for 6 months in a climatic chamber. The results concluded that the tablets were stable.

TABLE-US-00003 TABLE 3 Tablets with fructose 30 mg tablet 120 mg tablet Ingredient weight (mg) weight (mg) Core Dimethyl fumarate 30 120 Fructose 36 144 Microcrystalline cellulose 48 192 Croscarmellose sodium 4.8 19.2 Silica colloidal anhydrous 0.6 2.4 Magnesium Stearate 0.6 2.4 Coating Methacrylic acid - ethyl acrylate 11.56 45.98 copolymer (1:1) 30% aqueous dispersion Talc 5.78 22.94 Triethyl citrate 1.16 4.61 Simethicone 0.06 0.24 Titanium dioxide 0.29 4.61 Indigo carmine Lake 1.77 1N Sodium hydroxide solution 5.29 (4.54% aqueous dispersion)

TABLE-US-00004 TABLE 4 Tablets with mannitol 30 mg tablet 120 mg tablet Ingredient weight (mg) weight (mg) Core Dimethyl fumarate 30 120 Mannitol 36 144 Microcrystalline cellulose 48 192 Croscarmellose sodium 4.8 19.2 Silica colloidal anhydrous 0.6 2.4 Magnesium Stearate 0.6 2.4 Coating Methacrylic acid - ethyl acrylate 11.56 45.98 copolymer (1:1) 30% aqueous dispersion Talc 5.78 22.94 Triethyl citrate 1.16 4.61 Simethicone 0.06 0.24 Titanium dioxide 0.29 4.61 Indigo carmine Lake 1.77 1N Sodium hydroxide solution 5.29

TABLE-US-00005 TABLE 5 Tablets with dibasic calcium phosphate 30 mg tablet 120 mg tablet Ingredient weight (mg) weight (mg) Core Dimethyl fumarate 30 120 Dibasic calcium phosphate 36 144 Microcrystalline cellulose 48 192 Croscarmellose sodium 4.8 19.2 Silica colloidal anhydrous 0.6 2.4 Magnesium Stearate 0.6 2.4 Coating Methacrylic acid - ethyl acrylate 11.56 45.98 copolymer (1:1) 30% aqueous dispersion Talc 5.78 22.94 Triethyl citrate 1.16 4.61 Simethicone 0.06 0.24 Titanium dioxide 0.29 4.61 Indigo carmine Lake 1.77 1N Sodium hydroxide solution 5.29

2.3. Comparative Experiments

[0145] In a same manner as described above, 120 mg dimethyl fumarate enteric-coated tablets were prepared but replacing lactose by microcrystalline cellulose. Stability studies were conducted with this tablets at 40° C./75% Relative Humidity for 6 months in a climatic chamber. The results concluded that the tablets were not stable.

Example 3—Dissolution Test

[0146] The dissolution rate of dimethyl fumarate in the enteric-coated tablets of the invention described above was determined following a standard dissolution test for solid dosage forms. These dissolution tests are described in the European Pharmacopoeia 6.0, Chapter 2.9.3 and in the US Pharmacopoiea USP36-N F31, Chapter 711.

[0147] The dissolution testing was carried out as follows: A USP apparatus II (paddles) with 1 L vessels was used. Bath temperature was set to 37° C.±0.5° C. and paddle speed to 75 rpm. One tablet is placed in one vessel containing 750 mL 0.1N HCl (pH 1.2) over 2 h. After that the pH is changed to 6.2 by adding 220 mL 0.2 M sodium phosphate buffer (0.05 M phosphate buffer). The tablet is maintained under the buffered pH over 2 h. After that, samples are taken at each sampling time point (every 10 or 20 min). Dimethyl fumarate is detected by UV; cell volume 0.1 cm.sup.3, detector wavelength 220 nm, reference wavelength 400-500 nm.

[0148] The pharmaceutical compositions of the invention present a dissolution profile similar to Fumaderm®, despite having reduced the number of active ingredients and having different excipients. Additionally, no relevant differences were observed among the different dissolution profiles of the pharmaceutical compositions of the invention obtained using lactose, fructose, mannitol or dibasic calcium phosphate in the tablet core.

[0149] Modifications, which do not affect, alter, change or modify the essential aspects of the pharmaceutical compositions described, are included within the scope of the present invention