FIELD OF THE INVENTION
The present invention relates to pharmaceutical composition comprising dimethyl fumarate and process of preparation thereof.
The present invention also relates to capsule comprising multiple enteric-coated dimethyl fumarate tablets and process of preparation thereof.
_ Thepresent invention also relates tomethod of using-the pharmaceutical composition- ~ comprising dimethyl fumarate which comprises administration of the composition to a subject in need thereof.
i
The present invention also relates to compositions comprising dimethyl fumarate for use in the treatment or prevention of inflammatory or autoimmune diseases or disorders.
BACKGROUND OF THE INVENTION
Inflammatory or autoimmune diseases or disorders such as rheumatoid arthritis, multiple sclerosis (MS), amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus (SLE), myasthenia gravis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, Sjoegren's syndrome, autoimmune hemolytic anemia (AIHA), type I diabetes or psoriasis, are a major health burden especially in industrialized countries. These disorders in general cannot be cured, but the condition can be controlled or reduced in many cases.
Fumaric acid esters (FAE) are chemical compounds derived from unsaturated dicarboxylic fumaric acid and have been used in the treatment of psoriasis for years, originally proposed by the German chemist Walter Schweckendiek.
In 1994, Fumaderm® (Fumapharm AG), a mixture of dimethyl fumarate (DMF) and calcium, magnesium and zinc salts of monoethyl fumarate (MEF), was approved for the treatment of psoriasis in Germany. Fumaderm is available in two different dosage strengths: low strength tablets (Fumaderm® initial) containing 30 mg dimethylfumarate, 67 mg ' Ca-ethylhydrogenfumarat, 5 mg Mg-ethylhydrogenfumarate and 3 mg . Zn-ethylhydrogenfumarate; and high strength tablets (Fumaderm®) containing 120 mg dimethylfumarate, 87 mg Ca-ethylhydrogenfumarate, 5 mg Mg-ethylhydrogenfumarate and 3 mg_Zn-ethylhydrog_enfumarate.
Both Fumaderm initial and Fumaderm is enteric-coated tablet containing the following excipients: croscarmellose sodium, talc, magnesium stearate, coloring agent E!71 and E132 (only in Fumadenrr), methacrylic acid-methylmethacrylate-copolymer (1:1), methacrylic acid-ethylacrylate- copolymer (1:1), Macrogot 6000, simethicone, povidone, triethyl citrate, microcrystalline cellulose, and highly disperse silicon dioxide.
In addition, the tablets-should be stored-not above 25°C. (Fumaderm® initial-/ Fumaderm®; ~ Summary of Product Characteristics, version February 2009). FAE therapy is associated with adverse events such as gastrointestinal complaints, flushing or decreasing in lymphocyte. counts. In order to improve safety and efficacy of Fumaderm , guidelines for the treatment of severe psoriasis with FAE were established in 1999 (Mrowietz U. et al, British Journal of Dermatology 1999, 141 , 424-429). The two dosage strengths of Fumaderm® are intended to be applied in an individually base dosage regime starting with Fumaderm® initial in an escalating dose, and after some weeks of treatment, e.g. three weeks, switching to Fumaderm .
In March 2013, Tecfidera (Biogen), dimethyl fumarate delayed-release capsules for oral use, was approved by the US FDA for the treatment of patients with relapsing forms of multiple sclerosis.
Tecfidera is provided as hard gelatin delayed-release capsules for oral administration, . containing 120 mg or 240 mg of dimethyl fumarate and containing the following excipients: microcrystalline cellulose, silicified microcrystalline cellulose, croscarmellose sodium, talc, silica colloidal silicon dioxide, magnesium stearate, triethyl citrate, methacrylic acid copolymer - Type A, methacrylic acid copolymer dispersion, simethicone (30% emulsion), sodium lauryl sulphate, and polysorbate 80. In addition, the capsules should be stored at 15 to 25°C (Tecfidera® approved labelling text dated March 27, 2013). Tecfidera® has to be administered in an escalating dose, 120 mg for the 7 first days twice daily and, after that, the 240 mg dose twice daily.
WO2006/037342, WO2007/042034, WO2010/079221 and WO2010/079222 describe controlled release pharmaceutical compositions comprising as an active substance one or more fumaric acid esters selected from di-(CrCs) alkylesters of fumaric acid, i.e. dimethyl fumarate, and mono-(Ci-Cs) alkylesters „of fyrnaric, acid. An-, particular,^these documents

describe that the fumaric acid esters, particularly dimethyl fumarate, are in the form of granules, particles or (micro-)crystals which are covered with a gastro-resistant coating previous to be manufactured to tablets or capsules, which are latter on enteric coated. This coating of the dimethyl fumarate granules, particles or (micro-) crystals allows that the active ingredient be delivered in a manner that is prolonged, slow and/or delayed compared to Fumaderm .
US 6,355,676 and I IS 6,509,376 describe pharmaceutical compositions in the Turin of enteric-coated micro-tablets or micro-pellets comprising dimethyl fumarate, where the size or the mean diameter, respectively, of the pellets or micro-tablets is in the range from 300 to 2,000 um, especially in the range of 500 or 1,000 urn. US 6,355,676 and US 6,509,376 describe pharmaceutical compositions comprising dimethyl fumarate in the form of capsules containing enteric-coated micro-tablets. According to US 6,355,676 and US 6,509,376 the micro-tablets may present an improved tolerance in the gastrointestinal tract versus conventional tablets.
WO2013/119677 describes pharmaceutical compositions comprising dimethyl fumarate wherein the total amount of dimethyl fumarate in the composition ranges from 43 to 95 wt%.
WO20.13/076216 describes particles of dimethyl fumarate having a particle size distribution D50 of between 50 and 1000 um coated by at least one layer comprising a pharmaceutically acceptable pH-dependent enteric-resistant polymer.
WO2015/086467 describes a pharmaceutical composition comprising (a) dimethyl fumarate, (b) a diluent selected from monosaccharides,, disaccharides, starch and starch derivatives, calcium and magnesium inorganic salts, sugar alcohols, or mixture thereof, (c) microcrystalline cellulose and (d) croscarmellose sodium, wherein the dimethyl fumarate is not covered with a gastro-resistant coating.
WO2016/081671 describes a pharmaceutical composition in the form of a tablet comprising: (i) dimethyl fumarate as an active substance, wherein the active substance is present in the amount of 30- 90% by weight of the tablet, and (ii) one or more extended release polymer matrix present in the amount of 1-70% by weight of the tablet, wherein the active substance is distributed throughout the matrix.

WO2016/08I676 describes a pharmaceutical composition in the form of a bead comprising: an inert core; a first layer surrounding the inert core, wherein the first layer comprises dimethyl fumarate; and an enteric coating surrounding the first layer. Wherein the inert core comprises one or more inert substance selected from the group consisting of starch, dextrose, sucrose, lactose, maltose, and microcrystalline cellulose.
WO2016/113754 describes a pharmaceutical composition in the form of granules comprising: (i) Dimethyl fumarate (ii) Enteric polymers, and optionally (iii) One or more excipients. WO '754 also describes a pharmaceutical composition in the form of granules comprising: (i) Dimethyl fumarate (ii) One or more enteric polymers selected from the group consisting of ■ methacrylate copolymers, hypromellose phthalate, cellulose acetate phthalate, hypromellose acetate succinate; (iii) Fillers selected from microcrystalline cellulose, silicified microcrystalline cellulose, sugars, polysaccharides or mixture thereof; (iv) Disintegrants selected from crospovidone, sodium starch glycolate, croscarmellose sodium, microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch; (v) Lubricants and glidants selected from colloidal silicon dioxide, maize starch, talc, magnesium stearate, calcium stearate, sodium stearyl fumarate.
WO2016/147108 describes a delayed release capsule dosage form comprising plurality of tablets comprising dimethyl fumarate and one or more pharmaceutically acceptable excipients wherein, the mean diameter of tablet is more than about 5 mm.
WO2016/194004 describes an oral pharmaceutical composition comprising; dimethyl fumarate and a pharmaceutically acceptable agent that inhibits the enzyme catalyzed degradation of dimethyl fumarate, said composition when compared to a composition devoid of the agent provides an increased bioavailability in humans such that the dose of dimethyl . fumarate is reduced by at least about 10%.
WO2016/205270 describes Dimethyl fumarate (DMF) particles having a volume median diameter (D50) between 50 um and 100 um.
However, none of the aforementioned prior art documents describe low drug load enteric-coated dimethyl fumarate tablets of different strengths, i.e. dose-proportionate tablets, having the same qualitative composition ancLmaintajnine the same ,wt% of all the-components, only

varying the tablet mass and wherein the composition is free ,of monosaccharides, disaccharides, starch and starch derivatives, calcium and magnesium inorganic salts, sugar alcohols, or mixture thereof.
Thus there has been a long felt need for low drug load enteric-coated dimethyl fumarate tablets of different strengths, i.e. dose-proportionate tablets, having low tablet mass and wherein the composition is free of monosaccharides, disaccharides, starch and starch derivatives; calcium and magnesiurnlhorganic~sairs, sugar alcohols, or mixture thereof. The present invention relates to low drug load enteric-coated dimethyl fumarate tablets of different strengths having acceptable/equivalent tolerance in the gastrointestinal tract as that of micro-tablets.
SUMMARY OF THE INVENTION
Aspect of the present invention relates to pharmaceutical compositions comprising dimethyl fumarate and one or more pharmaceutically acceptable excipients.
Aspect of the present invention relates to delayed release compositions comprising dimethyl fumarate and one or more pharmaceutically acceptable excipients.
Aspect of the present invention relates to a delayed release capsule comprising dimethyl fumarate and one or more pharmaceutically acceptable excipients.
Aspect of the present invention relates to a delayed release composition comprising multiple enteric coated tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutically acceptable excipients, wherein the tablet diameter is from about 5 mm to about 7 mm.
Aspect of the present invention relates to a delayed release capsule dosage form comprising multiple enteric coated tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutically acceptable excipients, wherein the tablet diameter is from about 5 mm to about 7 mm.

■ Aspect of the present invention relates to a delayed release capsule dosage form comprising multiple enteric coated tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutically acceptable excipients, wherein the tablet diameter is about 6 mm.
Aspect of the present invention relates to a delayed release capsule dosage form comprising multiple tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutical^ acceptable excipients~selected from diluent, disintegrant, glidant, lubricant and combinations thereof, wherein the tablet diameter is from about 5 mm to about 7 mm.
Aspect of the present invention relates to a delayed release capsule dosage form comprising multiple enteric coated tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, glidant, lubricant and combinations thereof, wherein the tablet diameter is about 6 mm.
Aspect of the present invention relates to a delayed release capsule dosage form comprising multiple enteric coated tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutically acceptable excipients selected from Microcrystalline cellulose, Silicified microcrystalline cellulose, Croscarmellose sodium, colloidal silicon dioxide, talc, Magnesium stearate and combinations thereof, wherein the tablet diameter is about 6 mm.
Aspect of the present invention relates to" a delayed release capsule prepared by the process comprising steps of:
i) blending dimethyl fumarate, one or more pharmaceutically acceptable excipients,
ii) compressing the blend of step (i) in to tablets,
iii) coating the tablets of step (ii) using enteric coating polymers,
iv) Filling the multiple tablets of step (iii) into capsules.
Aspect of the present invention relates to a delayed release capsule comprising multiple enteric coated tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutically acceptable excipients, wherein the diameter of tablet is from about 5 mm to about 7 mm and the capsule is an enteric coated capsule.

Aspect of the present invention relates to a delayed release capsule comprising of multiple tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutically acceptable excipients, wherein the diameter of tablet is about 6 mm and the capsule is an enteric coated capsule.
Aspect of the present invention relates to a delayed release capsule prepared by the process comprising steps of:
i) blending dimethyl fumarate, one or more pharmaceutically acceptable excipients,
ii) compressing the blend of step (i) in to tablets,
iii) Filling the multiple tablets of step (ii) into capsules,
iv) coating the capsules of step (iii) using enteric coating polymers.
Aspect of the present invention relates to a method of treating patients with relapsing forms of multiple sclerosis in a patient in need thereof, comprising administering to the patient the delayed release composition comprising dimethyl fumarate and one or more pharmaceutically acceptable excipients.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, "a" or "an" means one or more unless otherwise specified.
Open terms such as ."include," "including," "contain," "containing" and the like mean "comprising"
The term "about" used herein means a deviation within 10% of actual value.
The term "treating" refers to administering a therapy in an amount, manner, or mode effective to improve a condition, symptom, or parameter associated with a disorder.
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.
The term "prophylaxis" or the term "ameliorating" refers to preventing a disorder or preventing progression of a disorder, to either a statistically significant degree or to a degree detectable to one skilled in the art.
The term "or" can be conjunctive or disjunctive.
The term "compact" means a compressed composition comprising DMF and one or more excipients. The DMF and excipients can be homogeneously or heterogeneously mixed in the compact. The term "microtablet" means a compact in the form of a small (micro) tablet of about 1 mm to about 3 mm in diameter (excluding any coating) that comprises DMF and one or more excipients. The DMF and excipients can be homogeneously or heterogeneously mixed in the microtablet. The term "tablet" means a compact in the form of a small (micro) tablet of about 6 mm to.about 9 mm in diameter (excluding any coating) that comprises DMF and one or more excipients. The DMF and excipients can be homogeneously or heterogeneously mixed in the microtablet.
The term "coated microtablet" means a microtablet that is fully or partially coated by one or more coatings. The term "coated tablet" means a core tablet that is fully or partially coated by one or more coatings.
The term "Multiple tablet(s)" means more than one compressed tablet having > about 5 mm diameter and less than about 7 mm. Usually "Multiple tablet(s)" means around 2-10 tablets are filled into capsule. Preferably 3 Enteric coated / uncoated tablets filled into a capsule dosage form comprising 120mg of Dimethyl fumarate & 6 enteric coated / uncoated tablets filled into a capsule dosage form comprising 240mg of Dimethyl fumarate.
The term "low drug loaded" means a composition/dosage unit containing less than about 50% of active agent/drug or less than about 45% of active agent/drug in core tablet and/or coated tablet (Enteric coated or Seal coated).

Unless otherwise specified, the term "% vv/w" is the percent of an ingredient in a composition (e.g., a microtablet or tablet) excluding the weight of any coating component(s) (e.g., copolymer(s) forming an enteric coating) fully or partially coating the microtablet or tablet.
The term "DMF:! or "Dimethyl fumarate1' (Dimethyl (E)-butenedioate; CAS RN 624-49-7) is the methyl ester of fumaric acid, which presents the molecular formula CeHgt^ and the molecular mass 144.13 g/mol and the following chemical formula
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.
The crystallographic properties of dimethyl fumarate are described Kooijman H et al, Acta Cryst. (2004), E60, 0917-0918.
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).
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 of d (10) NMT 20 urn, d (50) NMT 75 urn, d (90) NMT 200 urn, measured using the laser diffraction particle size analyzer Mastersizer 2000 (Malvern Instruments).
The term "Microcrystalline cellulose" (CAS RN 9004-34-6; molecular formula (c«Hi«°5)" 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).
The term "Silicified microcrystalline cellulose" is a synergistic, intimate physical mixture of two components: microcrystalline cellulose and colloidal silicon dioxide. Silicified microcrystalline cellulose contains 2% w/w colloidal silicon dioxide (Handbook of

The term "Croscannellose sodium" (cellulose, carboxymethyl ether, sodium salt, crosslinked; CAS RN 7481 1 -65-7) is a crosslinked polymer of carboxymethyl cellulose sodium. Croscannellose sodium occurs as an odourless, white or grayish white powder (Handbook of Pharmaceutical Excipients, 6th edition, 2009).
The term "glidant" 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) or mixture thereof. Preferably, the glidant (s) is selected from colloidal silica anhydrous, talc, or a combination thereof, more preferably colloidal anhydrous silica.
The term "lubricant" 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 palmitbstearate, stearic acid, zinc stearate,. or mixture thereof. Preferably, the lubricant is magnesium stearate.
The term "sugar alcohols" refers to erythritol, isomalt, lactitol, mannitol, maltitol, sorbitol and xylitol.
The term "calcium and magnesium inorganic salts" refer to calcium carbonate, dibasic calcium phosphate, calcium sulphate, magnesium carbonate, or mixture thereof.
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
E^&let$(Jfe§\$itfi£gas^
The term "enteric-coated or "enteric coated" or "enteric coating" as used herein means that dimethyl fumarate microtablet or more tablet coated with pharmaceutical acceptable polymers. 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 mixture thereof. Coating of tablet cores is discussed in detail in Pharmaceutical Manufacturing Handbook: Production and Processes, 2008, ISBN 9780470259580.
Examples of suitable copolymers for enteric 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 Evo.nik, 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 - methyi 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). Preferred enteric copolymers include Methacrylic acid-methyl acrylate copolymer, Methacrylic acid-ethyl acrylate copolymer, phthalates, succinates, sodium alginate, Hydroxypropyl methylcellulose acetate succinate.
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 sebacate, diethyl. phthalate, dimethyl phthalate, glycerin, glycerin monostearate, hypromellose phthalate, mannitol, mineral oil, £ f|a^olin)a-Icphpl^palmitic^agidytgc^yjthyljeng glycol,,-1 p§i$y|n$ acetate: pfitfialate, propylene

glycol, 2-pyrrolidone, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, triethyl citrate, dibutyl sebacate, polyethylene glycol and propylene glycol.
Examples of suitable antitacking agent in the coating include talc or glycerol monostearate.
Examples of suitable pigments in the coating include titanium dioxide, aluminium lakes, indigo carmine lakes or iron oxide pigments.
In embodiments, the present invention provides delayed release compositions comprising dimethyl fumarate and one or more pharmaceutically acceptable excipients.
In embodiments, the present invention provides a delayed release capsule comprising dimethyl fumarate and one or more pharmaceutically acceptable excipients.
r
In embodiments, the present invention provides a capsule dosage form comprising enteric-coated dimethyl fumarate tablets and process of preparation thereof.
In embodiments, the present invention provides low drug loaded enteric-coated dimethyl fumarate tablets.
In embodiments, the present invention provides a capsule comprising enteric-coated dimethyl fumarate tablets.
In embodiments, the present invention provides a capsule dosage form comprising low drug loaded enteric-coated dimethyl fumarate tablets.
In embodiments, the present invention provides a low drug loaded enteric-coated dimethyl fumarate tablets comprising (a) dimethyl fumarate, (b) microcrystalline cellulose and/or silicified microcrystalline cellulose and (c) croscarmellose sodium.
In embodiments, the present invention provides a low drug loaded enteric-coated dimethyl fumarate tablets comprising (a) dimethyl fumarate, (b) microcrystalline cellulose and/or silicified microcrystalline cellulose and (c) croscarmellose sodium, wherein the tablet is free

of monosaccharides, disaccharides, starch and starch derivatives, calcium and magnesium inorganic salts, sugar alcohols, or mixture thereof.
In embodiments, the present invention provides a capsule dosage form comprising enteric-coated dimethyl fumarate tablets, wherein the said active agent dimethyl fumarate is present in an amorphous form or crystalline form or a mixture of amorphous form and crystalline form.
In embodiments, the present invention provides a delayed release composition comprising multiple enteric coated tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutically acceptable excipients, wherein the tablet diameter is from about 5 mm to about 7 mm.
In embodiments, the present invention provides a delayed release capsule dosage form comprising multiple enteric coated tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutically acceptable excipients, wherein the tablet diameter is from about 5 mm to about 7 mm.
■i In embodiments, the present invention provides a delayed release capsule dosage form comprising multiple enteric coated tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutically acceptable excipients, wherein the tablet diameter is about 6 mm.
In embodiments, the present invention provides a delayed release capsule dosage form comprising multiple enteric coated tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, glidant, lubricant and combinations thereof, wherein the tablet diameter is from about 5 mm to about 7 mm.
In embodiments, the present invention provides a delayed release capsule dosage form comprising multiple enteric coated tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, glidant, lubricant and combinations thereof, wherein the tablet diameter is about 6 mm.

In embodiments, the present invention provides a delayed release capsule dosage form comprising multiple enteric coated tablets comprising less than about .43% w/vvof dimethyl fumarate and one or more pharmaceutically acceptable excipients selected from Microcrystalline cellulose, Silicified microcrystalline cellulose, Croscarmellose sodium, colloidal silicon dioxide, talc, Magnesium stearate and combinations thereof, wherein the tablet diameter is about 6 mm.
In embodiments, the present invention provides a delayed release capsule prepared by the process comprising steps of:
i) blending dimethyl fumarate, one or more pharmaceutically acceptable excipients,
ii) compressing the blend of step (i) in to tablets,
iii) coating the tablets of step (ii) using enteric coating polymers,
iv) Filling the multiple tablets of step (iii) into capsules.
In embodiments, the present invention provides a delayed release capsule comprising of multiple tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutically acceptable excipients, wherein the diameter of tablet is from about 5 mm to about 7 mm and the capsule is an enteric coated capsule.
In embodiments, the present invention provides a delayed release capsule comprising multiple tablets comprising less than about 43% w/w of dimethyl fumarate and one or more pharmaceutically acceptable excipients, wherein the diameter of tablet is about 6 mm and the capsule is an enteric coated capsule.
In embodiments,, the present invention provides a process of preparing capsule dosage form comprising low drug loaded enteric-coated dimethyl fumarate tablets.
In embodiments, the present invention provides a delayed release capsule prepared by the process comprising steps of:
i) blending dimethyl fumarate, one or more pharmaceutically acceptable excipients,
ii) compressing the blend of step (i) in to tablets,
iii) filling the multiple tablets of step (ii) into capsules c M T iv^rcoatmg^the capsulesjof^step^iii).using enteric Goating4)olymers. r- t~.

Jn embodiments, the present invention provides a hard gelatin capsule filled with dimethyl fumarate enteric coated tablets comprising (a) dimethyl fumarate, (b) microcrystalline cellulose and/or silicified microcrystalline cellulose and (c) croscarmellose sodium, wherein the tablet is free of monosaccharides, disaccharides, starch and starch derivatives,.calcium ' and magnesium inorganic salts, sugar alcohols, or mixture thereof.
In embodiments,-the -present invention provides a method of-using-the--pharmaceutical composition comprising dimethyl fumarate which comprises administration of the composition to a subject in need thereof.
In embodiments, the present invention provides a method of treating patients with relapsing forms of multiple sclerosis in a patient in need thereof, comprising administering to the patient the delayed release composition comprising dimethyl fumarate and one or more pharmaceutically acceptable excipients.
In embodiments, the present invention provides a composition comprising dimethyl fumarate ■ for use in the treatment or prevention of inflammatory or autoimmune diseases or disorders.
In embodiments, the present invention provides low drug loaded enteric-coated dimethyl fumarate tablets comprising (a) dimethyl fumarate, (b) microcrystalline cellulose and/or silicified microcrystalline cellulose and (c) croscarmellose sodium.
In embodiments, the present invention provides low drug loaded enteric-coated dimethyl fumarate tablets comprising (a) less than about 43% w/w of dimethyl fumarate, (b) microcrystalline cellulose and/or silicified microcrystalline cellulose and (c) croscarmellose sodium.
'In embodiments, the present invention provides low drug loaded enteric-coated dimethyl fumarate tablets comprising (a) less than about 43% w/w of dimethyl fumarate, (b) microcrystalline cellulose and/or silicified microcrystalline cellulose, (c) croscarmellose sodium and (d) lubricant and/or glidant.

In certain embodiments, the present invention provides low drug loaded enteric-coated dimethyl fumarate tablets comprising (a) less than about 43% w/w of dimethyl fumarate, (b) microcrystalline cellulose and/or silicified microcrystalline cellulose, (c) croscarinellose sodium and (d) lubricant and (e) glidant.
In certain embodiments, the present invention provides low drug loaded enteric-coated dimethyl fumarate tablets comprising less than about 43% w/w of dimethyl fumarate, microcrystalline cellulose and/or silicified microcrystalline cellulose, magnesium stearate and colloidal silicon dioxide.
In certain embodiments, the present invention provides low t drug loaded enteric-coated dimethyl fumarate tablets comprising less than about 43% w/w of dimethyl fumarate, microcrystalline cellulose and/or silicified microcrystalline cellulose, croscarmellose sodium, lubricant and glidant, wherein the tablet is free of monosaccharides, disaccharides, starch and starch derivatives, calcium and magnesium inorganic salts, sugar alcohols, or mixture thereof.
In certain embodiments, the present invention provides low drug loaded enteric-coated dimethyl fumarate tablets comprising less'than about 43% w/w of dimethyl fumarate, along with microcrystalline cellulose and/or silicified microcrystalline cellulose, croscarmellose sodium, magnesium stearate and colloidal silicon dioxide, wherein the tablet is free of monosaccharides, disaccharides, starch and starch derivatives, calcium and magnesium. inorganic salts, sugar alcohols, or mixture thereof.
In certain embodiments, the present invention provides low drug loaded enteric-coated dimethyl fumarate tablets comprising less than about 43% w/w of dimethyl fumarate, along with microcrystalline cellulose and/or silicified microcrystalline cellulose, croscarmellose sodium, magnesium stearate and colloidal silicon dioxide.
In certain embodiments, a process is provided for making a capsule containing low drug loaded enteric-coated dimethyl fumarate tablets which comprises the following steps: Step-(a): Sifting
Step^(b): Blending & Lubrication E fSfep-(6)FG5rmpfeslionCH Ett'U AT. 2 2 f G 2 >' 2 G % 7 ' t 4 •• S S.

Step-(d): Optional seal coating Step-(e): Enteric coating Step-(f): Capsule filling
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, (n) one or more glidants, (iii) one or more plasticizers, and (iv) one or more pigments. Optionally, the coating formulation can comprise one or more antifbam agents.
In embodiments, the present invention provides a process of making a capsule comprising low drug loaded enteric-coated dimethyl fumarate tablets.
In embodiments, the composition of the present invention is packed into a suitable container such as a blister or a bottle. The pack optionally may contain an antioxidant and/or oxygen absorbent.
In embodiments, the present invention provides 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), myasthenia 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.
In embodiments, the present invention provides 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), myasthenia 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

The following examples are intended to serve as illustrations of the present invention only
and do not restrict the scope of the invention in any manner whatsoever.
Example 1: Capsules containing low drug loaded enteric-coated dimethyl fumarate tablets
S. Qty per unit (mg)
Ingredients
No 120mg ]~ 240 mg
Core Tablet
1 I Dimethyl Fumarate I 120.00 1 240.00
2 Silicified Microcrystalline Cellulose 145.00 290.00
3 Croscaimellose sodium 20.00 : 40.00
4 Colloidal Silicon dioxide 2^50 : 5^00 ~
5 Magnesium Stearate 2.50 5.00
Weight of core tablet (mg) 290.00 580.00
Seal Coat
6 I EudragitLlOO I 6XK) I 12.00
7 Triethyl Citrate L00 Z00
8 Talc L00 lOO
9 Purified Water Q^S QlJ
~~10 Isopropyl Alcohol USP Q!S Q^S
Weight of Seal coated tablet (mg) 298.00 596.00
Enteric Coat
I Eudragit L 30D I 20.00 I 40.00
"aTl Eudragit L100-55 20.00 40.00
11
b. Polysorbate 80 0.46 0.92
c. Sodium Lauryl Sulfate (XL4 ■ " 0.28
12 Triethyl Citrate 3~00 6\00 ~
___ _____ IO.OO 20.00
14 Purified Water
Weight of enteric coated tablet (mg) 351.60 703.20
15 Hard gelatin capsule shells (Green/Green, Size '0') - 1 No
16 Hard gelatin capsule shells IH (Green/White, Size '0') 1 No
ATF fkOiS -fluarititv sufficient u P &t w & T

J. Manufacturing process of core tablet:
1.1 Dimethyl fumarate, Silicified microcrystalline cellulose, croscarmellose sodium and
colloidal silicon dioxide were sifted through suitable mesh.
1.2 Magnesium stearate was sifted through suitable mesh.
1.3 Step 1.1 material was blended for 10 minutes and lubricated for 5 minutes with sifted magnesium stearate,
1.4 Step 1.3 material was compressed into tablets using 6.4 mm round shaped tablet tooling.
2. Manufacturing process of Seal Coated tablet:
1.5 Purified water was taken into suitable container and mixed with 1PA. The solvent mixture was divided into two parts, Part I and Part II.
1.6 Eudragit LI00-55 was added to Part 1 solvent mixture and stirred continuously for clear solution. Triethyl citrate was added to the solution under continuous stirring.
1.7 Talc was added to Part II solvent mixture and homogenized and then added to Step 1.6 material and homogenized dispersion was mixed for about 10 minutes.
1.8 Core tablets of step ! .4 were loaded into perforated coating pan coating machine and were subjected to pre-warm conditions for certain time period at 25 ±5°C.
1.9 The coating dispersion of Step 1.7 was sprayed onto the core tablets of Step' 1.8 at inlet temperature of 35 ± 10°C and bed temperature of 25±5°C till the target weight build up achieved.
2.0 The coated tablets were dried in perforated pan coater.
3. Manufacturing process of Enteric Coated tablet:
2.1 Purified water was taken into suitable container and mixed with IP A. The solvent mixture was divided into two parts, Part I and Part II.
2.2 Eudragit L30D was added to Part I solvent mixture and stirred continuously for clear solution. Triethyl citrate was added to the solution under continuous stirring.
2.3 Talc was added to Part II solvent mixture and homogenized for about 30 min to 45 min and then added to Step 2.1 material and homogenized dispersion was mixed for about 10 minutes.
2.4 Seal coated tablets of step 2.0 were loaded into perforated coating pan coating machine and were subjected to pre-warm conditions for certain time period at 25 ±5°C.

2.5 The coating dispersion of Step 2.3 was sprayed onto the core tablets of step 2.4 at inl< temperature of 35 ± 10°C and bed temperature of 25±5°C til! the target weight build u achieved.
2.6 The coated tablets were dried in perforated pan coater for 30.-45 min.
4. Capsule Filling:
Enteric coated tablets were filled into a Size '0' capsule shell.

1. Manufacturing process of core tablet:
1.1 Dimethyl fumarate, microcrystalline cellulose, croscarmellose sodium and colloidal
silicon dioxide were sifted through suitable mesh.
1.2 Magnesium stearate was sifted through suitable mesh.
1.3 Step \A materia! was blended for 10 minutes and lubricated for 5 minutes with sifted magnesium stearate.
1.4 Step 1.3 material was compressed into tablets using 6.4 mm round shaped tablet tooling.
2. Capsule Filling:
1.5 Compressed tablets were filled into a Size '0' capsule shell.
3. Manufacturing process of Enteric Coated capsule:
1.6 Purified water was taken into suitable container and mixed with 1PA. The solvent mixture was divided into two parts, Part I and Part II.
1.7 Eudragit L30D was added to Part I solvent mixture and stirred continuously for clear solution. Triethyl citrate was added to the solution under continuous stirring.
1.8 Talc was added to Part II solvent mixture and homogenized for about 30 min to 45 min and then added'to Step 1.6 material and homogenized dispersion was mixed for about 10 minutes.
1.9 Capsules filled with tablets of step 1.5 were loaded into perforated coating pan coating machine and were subjected to pre-warm conditions for certain time period at 25 ±5°C.

2.0 The coating dispersion of Step 1.8 was sprayed onto the core tablets of step 1.9 at inlet temperature of 35 ± 10°C and bed temperature of 25±5°C till the target weight build up achieved.
2.1 The coated capsules were dried in perforated pan coater for 30-45 min.