DESC:PHARMACEUTICAL COMPOSITIONS OF DIMETHYL FUMARATE

FIELD OF THE INVENTION
The invention relates to oral pharmaceutical compositions of dimethyl fumarate and process for the preparation of such compositions.

BACKGROUND OF THE INVENTION
Dimethyl fumarate is the methyl ester of fumaric acid and is chemically known as dimethyl (E) butenedioate with molecular formula C6H8O4 and following structural formula:

Dimethylfumarate is commercially available as hard gelatin delayed-release capsules for oral administration under the trade name TECFIDERA®. TECFIDERA capsules contain 120 mg or 240 mg of dimethyl fumarate as active ingredient and 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. The capsule shell, printed with black ink, contains the following inactive ingredients: gelatin, titanium dioxide, FD&C blue 1; brilliant blue FCF, yellow iron oxide and black iron oxide. TECFIDERA® is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

US Patent No. 6,509,376 and US Patent No. 8,759,393 disclose capsule formulations containing microtablets or micropellets of alkyl fumarates like dimethyl fumarate.
US Patent Publications Nos. 20130216615 and 20150209318 disclose capsules composition comprising enteric coated microtablets and the uncoated microtablets comprises from about 43% w/w to about 95% w/w of dimethyl fumarate.

SUMMARY OF THE INVENTION
In one general aspect there is provided a pharmaceutical composition comprising: i) mini tablets comprising dimethyl fumarate and atleast one pharmaceutically acceptable excipient,
ii) Optional seal coating
iii) Enteric coating layer comprising atleast one enteric coating polymer
iv) filling the enteric coated mini tablets into capsules,
wherein the total amount of dimethyl fumarate in the uncoated tablets is more than 95%.
In another general aspect there is provided process for the preparation of oral solid pharmaceutical compositions comprising dimethyl fumarate, where in the total amount of dimethyl fumarate in the uncoated tablets is more than 95%.
Embodiments of the present invention may include one or more of the following features for example the pharmaceutical composition may further include one or more pharmaceutical acceptable excipients. The pharmaceutical acceptable excipients may include diluent, disintegrant, surfactant, binder, lubricant, glidant, plasticizer, anti-foaming agents, anti-tacking agent, opacifying agent, and the like.
The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION
The inventors of the present invention have developed a pharmaceutical composition comprising: i) mini tablets comprising dimethyl fumarate and atleast one pharmaceutically acceptable excipient,
ii) Optional seal coating
iii) Enteric coating layer comprising atleast one enteric coating polymer
iv) Filling the enteric coated mini tablets into capsules,
wherein the total amount of dimethyl fumarate in the uncoated tablets is more than 95%.
As used herein, the term ' dimethyl fumarate ' is used in broad sense to include not only the dimethyl fumarate per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, - pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.
The term "mini tablet" means a a small tablet of about 1 mm to about 3 mm in diameter (excluding any coating) that comprises dimethyl fumarate and one or more excipients.
Preferably, the total amount of dimethyl fumarate in the uncoated tablets is from about 95.5% to about 99.5%, more preferably from about 96% to about 99%.
The composition can comprise a total amount of pharmaceutically acceptable excipient(s), in an amount of about 0.5% to about 5.0% w/w, based on the total weight of the composition, excluding the weight of any coating.
Diluent includes, but are not limited to, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, sugars such as sucrose; sugar alcohols such as mannitol, sorbitol, erythritol; and mixtures thereof. Diluent may generally be added to increase the bulk volume of the powder to facilitate granulation or compression. The diluent may be present in an amount ranging from 0.1% to 5% by weight of the composition.
Disintegrant includes, but are not limited to, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate and mixtures thereof. The disintegrant may be present in an amount ranging from 0.1% to 5% by weight of the composition.
Binder includes, but are not limited to, carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins and the like. Binder may be used as a component of the coat to ensure proper adhesion of the subsequent coats. The binder may be present in an amount ranging from 0% to 4% by weight of the composition.
Lubricant includes, but are not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and mixtures thereof. Glidant includes talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate; and mixtures thereof. The lubricant and/or glidant may be present in an amount ranging from 0% to 4% by weight of the composition.
In some embodiments, the composition can be optionally coated or partially coated by one or more coatings. The coating(s) can be pH independent or pH dependent. The coating(s) can be, for example, enteric coatings, seal coatings, or combinations of enteric coatings and seal coatings.
The seal coating can contain plasticizers, copolymers, polymers, surfactants or combinations thereof.
The enteric coating can contain, plasticizers, anti-foaming agents, anti-tacking agents, polymers, copolymers, surfactants or combinations thereof.
Plasticizer may be used in a coat to increase the flexibility and strength of the layer and includes, but are not limited to, propylene glycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, diacetylated monoglyceride, dibutyl phthalate, dibutyl sebacate; or mixtures thereof. The plasticizer may be present in an amount ranging from 0.1% to 20% by weight of the composition.
Antifoaming agent includes, but are not limited to, dimethicone, simethicone, and mixtures thereof.
Anti-tacking agent includes, but are not limited to, talc, kaolin, finely divided silicon dioxide, glyceryl monostearate, and the like.
The copolymer includes, but are not limited to, methacrylic acid-methacrylate copolymer, methacrylic acid-ethylacrylate copolymer, polyvinylpyrrolidone/vinyl acetate copolymer and the like.
Polymers includes, but are not limited to, cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl and methylcellulose, polyvinylpyrrolidone, ethyl cellulose, and ethyl cellulose aqueous dispersions (AQUACOAT®, SURELEASE®), EUDRAGIT® RL 30 D, OPADRY®, EUDRAGIT® S, EUDRAGIT® L, and the like.
Surfactants includes, but are not limited to, nonionic or ionic surfactants, where nonionic surfactants includes, but are not limited to, polyoxyethylated glycol monoethers, cetomacrogol, sorbitan esters (Spans) and polysorbates (Tweens), polyoxyethylene-polyoxypropylene copolymers such as poloxameres, sugar esters with fatty acids with 10 to 22 C atoms. Ionic surfactants selected from anionic surfactants such as organic sulphonates, sulphates e.g. sodium lauryl sulphate, potassium laurate or cationic surfactants selected from the group consisting of organic quaternary ammonium halides, cetrimide, a mixture consisting of tetradecyl (about 68%), dodecyl (about 22%), hexadecyltrimethylammonium bromides (about 7%) and benzalkonium chloride.
Opacifying agent may be used in a coat to prevent photo-degradation and includes, but are not limited to, titanium dioxide, iron oxides, and the like.
Solvents for applying the coating materials includes, but are not limited to, water, acetone, hexane, ethanol, methanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol, dichlormethane, trichloromethane, chloroform, and the like.
In some embodiments, the coated mini tablets are placed in a capsule. The capsule can contain, from about 10 to about 40 mini tablets.
Capsules considered are soft gelatin, hard gelatin, HPMC, polysaccharide or starch capsules as plugged, welded or glued capsules, of different size, colour, and water content. Preferably, hard gelatin capsules.
In one embodiment, patients with multiple sclerosis are administered a capsule containing 240 mg DMF, twice daily for a total daily dose of 480 mg, wherein the capsule contains multiple mini tablets comprising more than 95% w/w dimethyl fumarate, by weight of the mini tablets without any coatings. In one embodiment, the mini tablets are first coated with a seal coat and then coated with an enteric coat.
The pharmaceutical compositions as described herein may be prepared by admixing dimethyl fumarate and atleast one pharmaceutically acceptable excipient followed by granulating and/or compressing into mini tablets. Optional seal coating of the mini tablets followed by enteric coating or directly enteric coating.
In one embodiment, stable pharmaceutical composition of dimethyl fumarate may be prepared by
a) mixing dimethyl fumarate and at least one pharmaceutically acceptable excipient selected from the group consisting of diluent, disintegrant, glidant/lubricant and binder;
b) granulating with a solvent or a binder solution,
c) drying the granules;
d) mixing the granules with at least one pharmaceutically acceptable excipient; and compressing into mini tablets.
e) optionally coating the mini tablets with a seal coat;
f) coating the product obtained above with an enteric coat;
g) filling the enteric-coated mini tablets into capsules.
In another embodiment, stable pharmaceutical composition of dimethyl fumarate may be prepared by
a) mixing dimethyl fumarate and at least one pharmaceutically acceptable excipient selected from the group consisting of diluent, disintegrant, glidant/lubricant and binder;
b) dry granulating the above mixture,
c) mixing the granules with at least one pharmaceutically acceptable excipient; and compressing into mini tablets.
d) optionally coating the mini tablets with a seal coat;
e) coating the product obtained above with an enteric coat;
f) filling the enteric-coated mini tablets into capsules.
In another embodiment, stable pharmaceutical composition of dimethyl fumarate may be prepared by
a) mixing dimethyl fumarate and at least one pharmaceutically acceptable excipient selected from the group consisting of diluent, disintegrant, glidant/lubricant and binder;
b) compressing the mixture into mini tablets.
d) optionally coating the mini tablets with a seal coat;
e) coating the product obtained above with an enteric coat;
f) filling the enteric-coated mini tablets into capsules.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1-
Table 1
S.No Ingredients mg/Capsule
120 mg 240 mg
Stage 1: Core tablets
1 Dimethyl fumarate IH 120 240
2 Microcrystalline cellulose
USP-NF 1 2
3 Croscarmellose sodium USP-NF 2 4
4 Colloidal silicon dioxide USP-NF 1.5 3
5 Magnesium stearate
USP-NF 0.5 1
Core tablets weight 125 250
Stage 2: Barrier/Seal coating
6 Opadry enteric coating system 940580021 white, IH 7.125 14.25
7 Polysorabate 80 USP-NF 0.072 0.144
8 Isopropyl alcohol qs qs
9 Purified water qs qs
Stage 3: Enteric coating
10 Acryl EZE II Optimized aqueous acrylic enteric system 493Z180022 white, IH 9.3 18.6
11 Polysorabate 80 USP-NF 0.124 0.248
12 Sodium lauryl sulfate, USP 0.093 0.186
13 Simethicone, USP 0.038 0.076
14 Purified water qs qs
15 Talc 0.75 1.5
Total net fill weight 142.5 285.0
Stage 4: Capsulation
HG capsules size, IH Size “0” Size “0”
Number of Mini tablets /capsule 16 32
Note: Opadry enteric coating system 940580021 white contains Methacrylic acid Methyl Acrylate copolymer (1:1) , Triethyl citrate, Titanium dioxide and Talc.
Acryl EZE II Optimized aqueous acrylic enteric system 493Z180022 white contains Methacrylic acid ethyl acrylate copolymer (1:1), Talc, Titanium dioxide, Poloxamer 407, calcium silicate, sodium bicarbonate and sodium lauryl sulfate.

Manufacturing Process:
1. Dimethyl fumarate, microcrystalline cellulose and Croscarmellose sodium were sifted through 30# mesh by using vibratory sifter.
2. Sifted materials was transferred into contabin blender and then blended for 10 minutes.
3. Colloidal silicon dioxide and Magnesium stearate were sifted through 30# mesh.
4. Sifted materials was transferred into contabin blender and then blended for 3 minutes.
5. Blended material was compressed into mini tablets with a tablet weight of 7 to 10 mg by using 2 mm punches.
6. Step 5 mini tablets were seal coated with coating suspension containing Opadry enteric coating system 940580021 white and Polysorbate 80 in a mixture of Isopropyl alcohol and water.
7. Above seal coated tablets were coated with coating suspension containing Acryl EZE II Optimized aqueous acrylic enteric system 493Z180022 white, Sodum lauryl sulfate , Polysorbate 80 and simethicone emulsion in purified water (88:12).
8. Step -7 enteric coated tablets were lubricated with talc.
9. Step -8 coated tablets were filled into Size “0” HG capsule. (30-34 mini tablets for 240 mg strength & 15-17 mini tablets for 120 mg strength).
,CLAIMS:We Claim:
1. A pharmaceutical composition comprising:
i) mini tablets comprising dimethyl fumarate and atleast one pharmaceutically acceptable excipient,
ii) Optional seal coating
iii) Enteric coating layer comprising atleast one enteric coating polymer
iv) filling the enteric coated mini tablets into capsules,
wherein the total amount of dimethyl fumarate in the uncoated tablets is more than 95%.
2. The pharmaceutical composition according to claim 1, wherein the total amount of dimethyl fumarate in the uncoated tablets is from about 95.5% to about 99.5%
3. The pharmaceutical composition according to claim 2, wherein the total amount of dimethyl fumarate in the uncoated tablets is from about 96% to about 99%
4. The pharmaceutical composition according to claim 1, wherein the uncoated tablets comprises 0.5% to about 5.0% w/w of pharmaceutically acceptable excipients.
5. The pharmaceutical composition according to claim 1, wherein the uncoated tablet is having diameter of about 1 mm to about 3 mm.
6. The pharmaceutical composition according to claim 1, wherein the capsule contains from about 10 to about 40 coated mini tablets.