DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

IMPROVED COMPOSITIONS OF DIMETHYL FUMARATE

BACKGROUND
The present invention relates to pharmaceutical compositions containing fumaric acid derivative(s) and processes of preparation thereof. Fumaric acid derivatives were first approved in Germany for the treatment of psoriasis in 1994 under the brand name of Fumaderm®, which contains dimethyl fumarate (DMF) and other fumarate ester salts. Recently, a drug product containing DMF as sole active agent (Tecfidera®) has been approved in the United States for the treatment of relapsing forms of multiple sclerosis. As there are limited choices of drugs for treatment of this disease condition, DMF holds the potential to be the first line treatment in multiple sclerosis because of its oral administration, better efficacy and less adverse events.
Formulating DMF or other fumaric acid derivatives is known to have difficulties. The sublimation property of DMF is well known in the art; sublimation may result in loss of active agent during manufacturing and storage. Also, since DMF comes as highly crystalline material, compression process becomes difficult because of combined effect of abrasion and sublimation. Nevertheless, many pharmaceutical compositions comprising dialkyl fumarates and/or alkyl hydrogen fumarates are known in the art. For instance, European Patent No. 188 749 discloses compositions comprising fumaric acid derivatives for the treatment of psoriasis. U.S. Patent No. 4,959,389 discloses compositions comprising salts of monoalkyl fumarates alone or in combination with dialkyl fumarates. U.S. Patent No’s 6,277,882 and 6,355,676 disclose microtablets containing alkyl hydrogen fumarates. U.S. Patent No. 6,509,376 discloses pharmaceutical preparations comprising one or more dialkyl fumarates in the form of enteric-coated micro-tablets and micro-pellets (filled into hard gelatin capsules). DE 38 34 794 discloses pharmaceutical preparations comprising one or more fumaric acid derivatives in the form of e.g. hard gelatine capsules filled with granulate of said derivatives which are made by a conventional granulation process.
Since DMF is a high dose active agent, the dosage form tends to be larger, which may interfere with patient compliance. In this regard, U.S. Patent Application Publication No. US 20130/216615 discloses a microtablet composition containing up to 95% of DMF filled into a capsule dosage form. The manufacturing process involves compression of a mixture of DMF and excipients into microtablets. However, microtablets prepared by such a process involving large amount of DMF are not likely to produce pharmaceutically acceptable compositions, e.g., the tensile strength of microtablets containing more than 95% of DMF was shown to be unacceptable. There are other concerns as well which make such microtablets difficult to manufacture such as low binding, more friability and weight variation.
One more disadvantage associated with compositions of fumaric acid derivatives is their adverse effects because of their high dose requirement, e.g. Fumaderm®, which is available as enteric coated tablets causes irritation of the gastrointestinal tract that may result in nausea, vomiting, and diarrhea.
While the pharmaceutical compositions of the prior art may, to certain extent, overcome the above discussed disadvantages of fumaric acid derivatives, an improvement is still required.
Thus, it is desirable to develop an easy to manufacture pharmaceutical composition containing a fumaric acid derivative, which reduces gastrointestinal related side effects and at the same time may accommodate larger active agent quantity.

SUMMARY OF THE INVENTION
In an embodiment, the present invention relates to pharmaceutical composition comprising discrete particles of fumaric acid derivative and pharmaceutically acceptable excipient.
In an embodiment, the pharmaceutical composition of the present invention may be a capsule.
In an embodiment, the capsule may be coated with at least one layer of coating.
In an embodiment, the capsule may be coated with at least one layer of enteric coating.
In an embodiment, the discrete particles may be selected from granules and pellets.
In an embodiment, the discrete particles may be coated with at least one layer of coating.
In an embodiment, the discrete particles may be coated with at least one layer of entering coating.
In an embodiment, the discrete particles coated with at least one layer of entering coating may be pellets.
In an embodiment, the fumaric acid derivative may be DMF.

DETAILED DESCRIPTION
In general, compositions of high dose active agents containing higher amount of excipients result in bigger size dosage forms, which are difficult to be administered and are less appealing to patients. It is ideal to have a composition that contains only active agent and no excipients. However, it is rare or impractical to have such a composition in pharmaceutical practice because most active agents have some property or the other, which makes addition of excipients in the composition imperative. Also, excipients are required for various reasons like modulating the active agent release, targeting its absorption, to stabilize the otherwise unstable active agent, to make the active agent processable during composition manufacturing etc.
The prior art compositions of fumaric acid derivatives contain low amount of active agent(s), which may necessitate a large dosage form. Some prior arts do disclose compositions containing high active agent content but they have other disadvantages, e.g., compositions described in U.S. Patent Application Publication No. US 20130/216615 require compression into mini-tablets. Also, such a composition by design is prone to certain defects e.g. low binding, more friability and weight variation.
The present invention provides an easy to manufacture pharmaceutical composition comprising fumaric acid derivative, free from prior art disadvantages. The composition of the present invention may contain a high amount of active agent(s) and may be prepared by conventional processes with no special requirements.
In an embodiment, the present invention relates to pharmaceutical composition comprising discrete particles of fumaric acid derivative and pharmaceutically acceptable excipient.
In an embodiment, the present invention relates to pharmaceutical composition comprising discrete particles of fumaric acid derivative and pharmaceutically acceptable excipient, wherein the discrete particles may be selected from granules and pellets.
Discrete particles and method of preparation - In an embodiment, the discrete particles may be selected from granules and pellets.
In an embodiment, the discrete particles may be granules.
Pharmaceutically acceptable granules containing fumaric acid derivative may be prepared by utilizing common manufacturing processes. The manufacturing processes may involve processes like dry granulation, wet granulation & extrusion.
Dry granulation – This process is widely used in pharmaceutical practice and is very well known to a person skilled in the art. In dry granulation, a powder blend is compacted by applying force onto the powder, which in general causes a considerable size enlargement. Typically there are two methods to obtain the compacts using dry granulation: slugging and roller compaction.
Wet granulation – This process is one of the oldest processes used and one of the most common processes known to a person skilled in the art. It is a process of size enlargement whereby small particles are gathered into larger aggregates (granules) in which the original particles can still be identified. In wet granulation, granules are formed by addition of a granulation liquid onto a powder bed which is under the influence of an agitating means. The granulating liquid may be selected from aqueous based or non-aqueous based liquids. The term granulation usually refers to processes whereby aggregates with sizes ranging from about 0.1 to about 2.0 mm are produced by agitation of moistened powders. The present invention may be carried out using conventional granulation methods such as rapid mixing granulation, fluidized bed granulation etc.
Extrusion - Extrusion is the process of pumping raw materials through a die of the desired cross-section. Extrusion process may be carried out at room temperature or near room temperature (cold extrusion) or at elevated temperature (e.g. Hot Melt Extrusion - HME). HME is an extrusion process carried out at elevated controlled temperature and pressure through a heated barrel into a product of uniform shape and density. HME involves compaction and conversion of blends from a powder or a granular mix into a product of uniform shape. The theoretical approach to understand the melt extrusion process may be summarized by classifying the whole procedure of HME into the following, (1) feeding of the extruder through a hopper, (2) mixing, grinding, reducing the particle size, venting, and kneading, (3) flow through the die, and (4) extrusion from the die and further downstream processing. The process is normally practiced by one or two rotating screws (either corotating or counter rotating) inside a stationary cylindrical barrel. A detailed review of the manufacturing process of HME is provided in literature e.g. “A review of Hot-Melt Extrusion: Process technology to Pharmaceutical Products”, Mohammad Maniruzzaman et al, ISRN Pharmaceutics, Volume 2012, Article ID 436763.
The extrusion process used to prepare the present invention may involve a solvent. The solvent may be a single solvent or a mixture of two or more solvents. The solvent(s) may be selected from aqueous based or non-aqueous solvents. Non-aqueous solvents are preferred as fumarates are prone to hydrolysis; however, aqueous based solvents may still be used. The non-aqueous solvent may be selected from any of the solvents generally known in the art e.g. isopropyl alcohol, methanol, ethanol, methylene chloride. Preferably, the solvent is isopropyl alcohol. If a solvent is used, it is preferred to add the solvent after initial mixing of DMF and excipient has taken place, i.e. in one of the zones (sections) after the feeding zone.
Granules obtained from such processes may be mixed with one or more excipients. Granules may also be subjected to particle size reduction as desired to get granules of acceptable size range. Typically, granules may have a particle size of less than 1000 microns. Preferably, the particle size ranges from 100-800 microns. Granules may be coated with at least one layer of coating; the coating may be enteric coating. Alternatively, uncoated granules may be filled into a capsule, which may be coated with at least one layer of coating; the coating may be enteric coating. The description of coating is provided in the relevant sections of this description.
Granules as described herein exhibit pharmaceutically acceptable flow and compaction. The flow of a powder may be examined by any of the methods known in the art, e.g, The United States Pharmacopeia (USP 29) recommends four methods for testing powder flow, 1) angle of repose, 2) compressibility index or Hausner ratio, 3) flow rate through an orifice, and 4) shear cell. In pharmaceutical practice, compressibility index or Hausner ratio is commonly used as a tool to assess the flowability of a powder blend. The Hausner ratio is calculated by the formula,
Hausner Ratio = Tapped Density / Bulk Density
A Hausner ratio greater than 1.25 is considered to be an indication of poor flowability. The final blend may have a Hausner ratio of less than 1.25. Preferably, the ratio is less than 1. More preferably, the ratio is less than 0.9.
Similar to Hausner ratio, compressibility index may be deduced from tapped and bulk density of powder blend and is calculated by the formula
Compressibility index = 100 x [1 – bulk density / tapped density]
A compressibility index greater than 25 is considered to be an indication of poor flowability, and below 15, of good flowability. The final blend may have a compressibility index of less than 25. Preferably, the compressibility index is less than 20. More preferably, compressibility index is less than 15.
In an embodiment, the discrete particles may be pellets.
Pellets as described herein may be prepared by conventional manufacturing processes such extrusion, which has been described earlier. During such extrusion process, mixture of a fumaric acid derivative and a pharmaceutically acceptable excipient is processed into active agent containing pellets of desired size. Alternatively, granules containing DMF and a pharmaceutically acceptable excipient may be processed into active agent containing pellets. The granules may be prepared by using earlier described processes e.g. dry granulation, wet granulation, extrusion. When granules are used to prepare pellets by extrusion, wet granules are preferred. The active agent containing pellets of the present invention may be subjected to spheronization to have spherical or nearly spherical shape. If pellets are to be coated with one or more layers of coating (e.g. enteric coating), spherical or nearly spherical pellets are desirable.
Pellets may also be obtained by coating of a fumaric acid derivative onto inert spherical substrates such as sugar sphere (also called as neutral pellets, nonpareil seeds, microgranules or sugar beads) or microcrystalline cellulose sphere (also called as microcrystalline cellulose bead). For the purpose of this invention, active agent coated inert substrates are also considered as pellets, which may be further coated with one or more layers of coating e.g. enteric coating.
In an embodiment, the pharmaceutical composition of the present invention may accommodate varying amount of active agent(s).
The total amount of fumaric acid derivative(s) in the composition may range from about 10% to about 95% w/w, about 20% to about 90% w/w, about 30% to about 80% w/w, about 40% to about 70% w/w, about 50% to about 70% w/w, about 50% to about 60% w/w and about 60% to about 70% w/w.
In an embodiment, the present invention relates to a pharmaceutical composition comprising discrete particles of a fumaric acid derivative and a pharmaceutically acceptable excipient, wherein the total amount of fumaric acid derivative(s) may range from about 40% to about 70% w/w.
In an embodiment, the present invention relates to a pharmaceutical composition comprising discrete particles of a fumaric acid derivative and a pharmaceutically acceptable excipient, wherein the total amount of fumaric acid derivative(s) may range from about 50% to about 70% w/w.
In an embodiment, the present invention relates to a pharmaceutical composition comprising discrete particles of a fumaric acid derivative and a pharmaceutically acceptable excipient, wherein the total amount of fumaric acid derivative(s) may range from about 50% to about 60% w/w.
In an embodiment, the present invention relates to a pharmaceutical composition comprising discrete particles of a fumaric acid derivative and a pharmaceutically acceptable excipient, wherein the total amount of fumaric acid derivative(s) may range from about 60% to about 70% w/w.
In an embodiment, the discrete particles of the present invention are further processed into a pharmaceutical composition. The composition may be selected from any pharmaceutical dosage form such as a tablet, a capsule etc. Alternatively, the discrete particles are filled into a sachet.
The excipients that may be used in preparation of pharmaceutical compositions of the present invention are generally known in the art.
Pharmaceutically acceptable excipients - Excipients to be used in preparing pharmaceutical compositions of the present invention (e.g. pellets, granules) include, for example, any one or more of diluents, binders, disintegrants, stabilizers, lubricants and glidants that are useful in preparation of pharmaceutical formulations.
Various useful diluents (fillers) include, but are not limited to, sugars such as lactose monohydrate, lactose anhydrous, mannitol; starches such as maize starch, corn starch; pregelatinized starches such as PCS PC10 from Signet Chemical Corporation and starch 1500; and cellulose derivatives such as crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include but are not limited to microcrystalline cellulose, Ceolus™ KG801, Avicel™ PH101, PH102, PH301, PH302 and PH-F20, PH-112, microcrystalline cellulose 114, and microcrystalline cellulose 112.
Other useful diluents include, but are not limited to, sorbitol, xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.
Various useful binders include, but are not limited to, hydroxypropylcellulose, also called HPC (e.g., Klucel™ LF and Klucel™ EXF), various grades of hydroxypropyl methylcellulose, also called hypromellose or HPMC (e.g., Methocel™ products), various grades, polyvinylpyrrolidone (PVP) or povidone (such as grades K25, K29, K30, and K90), copovidone (e.g., Plasdone™ S 630), various grades of polyethylene oxide (e.g. PEO WSR 303), Polyethylene glycols (e.g. PEG 6000, PEG 4000), powdered acacia, gelatin, guar gum, carbomers (e.g., Carbopol® products), methylcellulose, polymethacrylates, and starches.
Examples of disintegrants can include, for example, sodium starch glycolate, croscarmellose sodium, crospovidone and low substituted hydroxypropyl cellulose.
Useful stabilizers include, for example antioxidant, alkanizing agent and chelating agent.
Examples of suitable antioxidants include, but are not limited to, butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulfite, propyl gallate, tocopherol, citric acid, malic acid, and ascorbic acid.
The alkanizing agents include, but are not limited to alkali metal salt additive or alkaline earth metal salt additive. Alkali metal salt additives can be, for example, sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate and other suitable alkali metal salts.
Examples of chelating agents include, but are not limited to disodium EDTA, edetic acid, citric acid, and combinations thereof.
Useful lubricants include magnesium stearate, glyceryl monostearate, palmitic acid, talc, carnauba wax, calcium stearate, sodium stearate, sodium lauryl sulfate, magnesium lauryl sulfate, zinc stearate, polyoxyethylene monostearate, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and mixtures thereof.
One or more glidant materials, which improve the flow of powder blends, granules, pellets, and minimize dosage form weight variations, may be used. Useful glidants include, but are not limited to silicon dioxide, talc, and mixtures thereof.
Pellet coating with active agent – Pellet coating according to the present invention refers to the coating of an inert substrate with one or more components. The coating may contain one or more active agents and one or more excipients. The coating solution/dispersion may be aqueous or non-aqueous based. The process may be carried out by using conventional pellet coating apparatuses such as Wurster coating. Pellets so formed may then be coated with one or more layers of coating (e.g. enteric coating).
Coating of discrete particles/capsules - In an embodiment, the discrete particles may be coated with at least one layer of coating.
The coating may be non-functional coating such as film coating (e.g., to improve aesthetic appeal) or functional coating (e.g., protective coating, sustained release coating, enteric coating). The coating may be pH dependent coating or pH independent coating.
In an embodiment, the discrete particles may be coated with at least one layer of entering coating.
In an embodiment, the discrete particles of the present invention are filled into a capsule.
In an embodiment, the capsule may be coated with at least one layer of coating.
In an embodiment, the capsule may be coated with at least one layer of enteric coating.
Enteric coating - In an embodiment, the compositions of the present invention may be coated or partially coated with enteric coatings. The coating(s) may be, for example, enteric coating(s), seal coating(s), or combinations of enteric coating(s) and seal coating(s).
In embodiments, the compositions of the present invention are enteric-coated. The coating of the particles may be composed of different layers. The first coating or the seal coating as it is called in general isolates a particle from further coating layers. The seal coating may or may not contain an enteric coating polymer.
The seal coating may contain, for example, one or more plasticizers, one or more copolymers, one or more polymers, or combinations thereof.
The plasticizer may be, for example, 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 an lanolin alcohols, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, and triethyl citrate.
The copolymer may be, for example, a methacrylic acid-methacrylate copolymer or a methacrylic acid-ethylacrylate copolymer.
Additionally, the seal coating may contain one or more polymers, for example, cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl and methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, ethyl cellulose, and ethyl cellulose aqueous dispersions (AQUACOAT®, SURELEASE®), EUDRAGIT® RL 30 D, OPADRY®, EUDRAGIT® S and EUDRAGIT® L.
If present in the seal coating, the total amount of one or more copolymer(s) and/or one or more polymer(s) may range, for example, from a positive amount greater than 0% w/w to about 100% w/w, based on the weight of the seal coating. The amount of one or more copolymer(s) and/or one or more polymer(s) in the seal coating may range, for example, from about 10% w/w to about 100% w/w, from about 20% w/w to about 100% w/w, from about 30% w/w to about 100% w/w, from about 40% w/w to about 100% w/w, from about 50% w/w to about 100% w/w, from about 60% w/w to about 100% w/w, from about 70% w/w to about 100% w/w, from about 80% w/w to about 100% w/w, or from about 90% w/w to about 100% w/w, based on the weight of the seal coating.
The amount of one or more copolymer(s) and/or one or more polymer(s) in the seal coating may be, for example, about 10% w/w, about 20% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w, about 80% w/w, about 85% w/w, about 90% w/w, or about 95% w/w, based on the weight of the seal coating.
If present in the seal coating, the mean amount of plasticizer in the seal coating may range, for example, from a positive amount greater than 0% w/w to about 70% w/w, based on the weight of the seal coating.
The enteric coating may contain, for example, one or more plasticizers, one or more diluents, one or more lubricants, one or more copolymers, one or more polymers, and any combinations thereof.
The plasticizer(s) in the enteric coat may be the same or different than any plasticizer(s) in a seal coat, if present, and may be one of more of the plasticizers listed earlier.
The diluent(s) in the enteric coat may be the same or different than any diluent(s) in the composition. Additionally, the diluent(s) in the enteric coat may be the same or different than any diluent(s) in a seal coat, if present. The diluents are described under the relevant section of “pharmaceutically acceptable excipients” section of this description.
The lubricant(s) in the enteric coat may be the same or different than any lubricant(s) in the composition. Additionally, the lubricant(s) in the enteric coat may be the same or different than the copolymer(s) in a seal coat, if present. The lubricants are described under the relevant section of “pharmaceutically acceptable excipients” section of this description. In one embodiment, the lubricant is talcum (talc) that is optionally micronized.
The copolymer(s) in the enteric coat may be the same or different than the copolymer(s) in a seal coat, if present, and may be one or more of the copolymer(s) listed above. In one embodiment, the enteric coat contains one or more of a methyl acrylate-methyl methacrylate-methacrylic acid copolymer, a methacrylic acid-methyl methacrylate copolymer, a methacrylic acid-ethyl acetate copolymer and methacrylic Acid - ethyl Acrylate copolymer.
The enteric polymers used in this invention may be modified by mixing or layering with other known coating products that are not pH sensitive. Examples of such coating products include ethyl cellulose, hydroxylpropyl cellulose, neutral methacrylic acid esters with a small portion of trimethylammonioethyl methacrylate chloride, sold currently under the trade names EUDRAGIT® RS and EUDRAGIT® RL; a neutral ester dispersion without any functional groups, sold under the trade names EUDRAGIT® NE 30 D; and other pH independent coating products.
The total amount of the copolymer(s) and/or polymer(s) in the enteric coating may range, for example, from about 25% w/w to about 100% w/w, based on the weight of the enteric coating.
If present in an enteric coating, the total amount of lubricant(s) in the enteric coating may range, for example, from a positive amount greater than 0% w/w to about 50% w/w, based on the weight of the enteric coating.
If present in an enteric coating, the total amount of diluent(s) in the enteric coating may range, for example, from a positive amount greater than 0% w/w to about 50% w/w, based on the weight of the enteric coating.
If present in an enteric coating, the total amount of plasticizer(s) in the enteric coating may range, for example, from a positive amount greater than 0% w/w to about 30% w/w, based on the weight of the enteric coating.
Solvents for applying the coating materials may be, but are not limited to, water, acetone, hexane, ethanol, methanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol, dichlormethane, trichloromethane and chloroform.
Coatings may be applied by any known means, including spraying. In some embodiments, the compositions are coated or partially coated with one or more seal coatings, for example one, two, three or more seal coatings. In some embodiments, the compositions are coated or partially coated with one or more enteric coatings, for example one, two, three or more enteric coatings. In some embodiments, the compositions are coated with one or more seal coatings and one or more enteric coatings. In some embodiments, the compositions are coated with one seal coating and one enteric coating.
The thickness (relative amount) of the polymer coating layer may affect the overall release rate. For practical purposes, the amount of polymer coating is from 10 to 200 wt , preferably from 20 to 100 wt , more preferably from 30 to 60 wt relative to the weight of the composition. In other words, from 10 to 200% etc. weight gain. As is well-known to the person skilled in the art, the smaller the particle size, the more polymer material is needed to provide a coating layer with enteric protection.
In an embodiment, the present invention relates to a pharmaceutical composition comprising discrete particles of a fumaric acid derivative.
The term fumaric acid derivative in the context of present invention denotes one or more fumaric acid derivatives. E.g., compositions of the present invention may contain one or more of fumaric acid derivatives. In an embodiment, a fumaric acid derivative may be selected from a mono alkyl fumarate or dialkyl fumarate, their pharmaceutically acceptable salt or combinations thereof.
In an embodiment, a fumaric acid derivative may be selected from monomethyl fumarate (MMF), monoethyl fumarate (MEF), dimethyl fumarate (DMF), their pharmaceutically acceptable salt or combinations thereof.
In an embodiment, a fumaric acid derivative may be selected from dimethyl fumarate (DMF), its pharmaceutically acceptable salt or combinations thereof.
In an embodiment, a fumaric acid derivative is dimethyl fumarate (DMF).
In some embodiments, a pharmaceutical composition of the present invention may contain a total amount of about 60 mg to about 1000 mg of dimethyl fumarate. The composition may, for example, contain a total amount of DMF effective for treatment, prophylaxis, or amelioration of multiple sclerosis. The effective amount may range, but is not limited to, a total amount of about 60 mg to about 800 mg DMF, about 60 mg to about 720 mg DMF, 60 mg to about 500 mg DMF, about 60 mg to about 480 mg DMF, about 60 mg to about 420 mg DMF, about 60 mg to about 360 mg DMF, about 60 mg to about 240 mg DMF, about 60 mg to about 220 mg DMF, about 60 mg to about 200 mg DMF, about 60 mg to about 180 mg DMF, about 60 mg to about 160 mg DMF, about 60 mg to about 140 mg DMF, about 60 mg to about 120 mg DMF, about 60 mg to about 100 mg DMF, about 60 mg to about 80 mg DMF, about 80 mg to about 480 mg DMF.
The composition may contain, but is not limited to, a total amount of DMF of about 60 mg DMF, about 80 mg DMF, about 100 mg DMF, about 120 mg DMF, about 140 mg DMF, about 160 mg DMF, about 180 mg DMF, about 200 mg DMF, about 220 mg DMF, about 240 mg DMF, about 260 mg DMF, about 280 mg DMF, about 300 mg DMF, about 320 mg DMF, about 340 mg DMF, about 360 mg DMF, about 380 mg DMF, about 400 mg DMF, about 420 mg DMF, about 450 mg DMF, about 480 mg DMF, or about 500 mg DMF.
In some embodiments, DMF is the only active agent in the composition. DMF may have average particle size of less than 1000 microns. Preferably, the average particle size is less than 500 microns. More preferably, the average particle size is less than 250 microns.
The compositions of the present invention are to be used in medicine, typically for the prevention and/or treatment of any of the diseases treatable by dialkyl fumarates, e.g. for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, Crohn disease, multiple sclerosis, etc. They may also be used in combination with one or more active agents in a combination therapy, wherein the other active agensts may be administered in parallel in a separate dosage form or, together compositions of this invention, in a single combination dosage form.
Based on the final composition, the final dosage form comprising dimethyl fumarate may be administered once a day or several times per day, typically two or three times per day.
In certain specific aspects, the present invention is provided using illustrative examples which should not be construed as limiting the scope of the disclosure.

EXAMPLES
Example 1 – Pellets prepared by coating on inert substrates
Ingredients Function 120mg 240mg %w/w
mg/cap mg/cap
Seal coating (10%)
Sugar spheres (#40/50) Inert core 41.00 82.00 16.2
HPMC 5cps Binder 3.73 7.45 1.5
Triethyl citrate Plasticizer 0.37 0.745 0.1
Water Solvent Q.s. Q.s. --
Total -- 45.10 90.20 --
Active agent loading
Seal coated pellets Inert core 45.00 90.00 --
Dimethyl fumarate API 120.00 240.00 47.3
HPMC 5cps Binder 7.50 15.00 3.0
Methanol Solvent Q.s. Q.s. --
Total -- 172.50 345.00 --
Enteric Coating-1 (5%)
Active agent loaded Pellets Active agent loaded Pellets 172.50 345.00 --
Eudragit L 100 Enteric Polymer 7.19 14.38 2.8
Triethyl citrate Plasticizer 0.72 1.44 0.3
Talc Anti-tacking agent 0.72 1.44 0.3
IPA Solvent Q.s. Q.s. --
Water Solvent Q.s Q.s --
Total -- 181.13 362.26 --
Enteric Coating-2 (40%)
Enteric Coating-1 Pellets Enteric Coated pellets 181.13 362.26 --
Eudragit L30D-55 Enteric Polymer 59.88 119.76 23.6
Triethyl Citrate Plasticizer 6.00 12.00 2.4
Talc Anti-tacking agent 6.00 12.00 2.4
Simethicone Anti-Foaming agent 0.60 1.20 0.2
Water Solvent Q.s. Q.s. --
Total -- 253.61 507.22 100

Manufacturing Procedure
1) Sift sugar spheres and collect sieve fraction of #40/#50 mesh
2) Spray the seal coating solution on #40#50 mesh fraction of sugar spheres using Wurster fluid-bed process.
3) Spray the active agent solution on seal coated pellets using Wurster fluid-bed process.
4) Dry the active agent loaded pellets and screen to collect desired size fraction
5) Spray the enteric coating -I (Eudragit L100) solution on active agent loaded pellets using wurster fluid-bed process.
6) Dry the enteric coated pellets and screen to collect desired size fraction
7) Spray the enteric coating -II (Eudragit L30D-55) solution on pellets obtained from Step 6 using fluid-bed processor.
8) Fill the required quantity of pellets in capsules.

Example 2 – Pellets prepared by extrusion
Ingredients Function 120mg 240mg %w/w
mg/cap mg/cap
Composition for extrusion
Dimethyl fumarate API 120.00 240.00 62.0
Polyvinylpyrrolidone (PVP) Binder 5.00 10.00 2.6
IPA Solvent Q.s Q.s --
Total 125.00 250.00 --
Enteric Coating-1 (10%)
Eudragit L 100 Enteric Polymer 10.41 20.83 5.4
Triethyl citrate Plasticizer 1.04 2.83 0.7
Talc Anti-tacking agent 1.04 2.83 0.7
IPA Solvent q.s Q.s --
Water Solvent q.s Q.s --
Total 138.25 276.50 --
Enteric Coating-2 (40%)
Eudragit L30D-55 Enteric Polymer 45.70 91.40 23.6
Triethyl Citrate Plasticizer 4.57 9.14 2.4
Talc Anti-tacking agent 4.57 9.14 2.4
Simethicone Anti-foaming agent 0.46 0.91 0.2
Water Solvent q.s Q.s --
Total 193.55 387.10 100

Manufacturing Procedure
1) Sift dimethyl fumarate and a part of binder through appropriate sieve.
2) Add dimethyl fumarate to extruder through feeder-I.
3) Add binder solution (part of binder + IPA) to extruder through feeder-II.
4) Evaporate the solvent during process to get dry extrudate.
5) Mill dry extrudates of step 4 to get spherical particles.
6) Spray the enteric coating -I (Eudragit L100) solution on spherical particles obtained using fluid-bed processor.
7) Spray the enteric coating -II (Eudragit L30D-55) solution on enteric coating–I particles using fluid-bed processor.
8) Fill the required quantity of pellets in capsules.

Example 3 - Pellets prepared by extrusion
Ingredients Function 120mg 240mg %w/w
mg/cap mg/cap
Composition for extrusion
Dimethyl Fumarate API 120.00 240.00 56.0
Microcrystalline cellulose Diluent 25.00 50.00 11.7
Polyethylene glycol Binder 15.00 30.00 7.0
Croscarmellose sodium Disintegrate 10.00 20.00 4.7
Purified water Solvent q.s. q.s. --
Total 170.00 340.00 --

Enteric Coating-1 (5%)
Eudragit L100 Enteric Polymer 7.13 14.25 3.3
Triethyl citrate Plasticizer 0.71 1.42 0.3
Talc Anti-tacking agent 0.71 1.42 0.3
Isopropyl Alcohol Solvent q.s. q.s. --
Total 178.55 357.09 --
Enteric Coating-2 (20%)
Eudragit L30D-55 Enteric polymer 98.34 196.69 13.8
Triethyl citrate Plasticizer 2.95 5.90 1.4
Talc Anti-tacking agent 2.95 5.90 1.4
Simethicone Anti-foaming agent 0.30 0.59 0.1
Water Solvent q.s. q.s. --
Total 214.25 428.50 100.0

Manufacturing procedure
1) Sift Dimethyl fumarate, Microcrystalline cellulose, Polyethylene glycol and croscarmellose sodium.
2) Granulate the dry mix with purified water.
3) Extrude the wet mass.
4) Spheronize the extrudates.
5) Dry the pellets in fluid bed processor.
6) Spray the enteric coating -1(Eudragit L 100) solution on spherical particles using Fluid bed processor.
7) Spray the enteric coating-2(Eudragit L 30D-55) solution on enteric coated particles.
8) Fill the required quantity of pellets in suitable size of HG capsules

Example 4 - Pellets prepared by extrusion
Ingredients Function 120mg 240mg %w/w
mg/cap mg/cap
Composition for extrusion
Dimethyl Fumarate API 120.00 240.00 59.51
Lactose monohydrate Diluent 7.50 15.00 3.72
Microcrystalline cellulose Diluent 15.00 30.00 7.44
L-HPC Disintegrant 15.00 30.00 7.44
Povidone Binder 2.50 5.00 1.24
Purified water Solvent q.s. q.s. --
Total 160.00 320.00 --
Enteric Coating-1 (5%)
Eudragit L100 Enteric Polymer 6.71 13.41 3.33
Triethyl citrate Plasticizer 0.67 1.34 0.33
Talc Anti-tacking agent 0.67 1.34 0.33
Isopropyl Alcohol Solvent q.s. q.s. --
Total 178.55 336.09 --
Enteric Coating-2 (20%)
Eudragit L30D-55 Enteric polymer 92.55 185.10 13.77
Triethyl citrate Plasticizer 2.78 5.55 1.37
Talc Anti-tacking agent 2.78 5.55 1.37
Simethicone Anti-foaming agent 0.28 0.55 0.14
Water Solvent q.s. q.s.
Total 201.64 403.27 100.00

Manufacturing procedure
1) Sift Dimethyl fumarate, Microcrystalline cellulose, Lactose monohydrate, L-HPC & povidone through specified sieve and load into a granulator.
2) Granulate the dry mix with purified water.
3) Extrude the wet mass.
4) Spheronize the extrudates.
5) Dry the pellets in fluid bed processor.
6) Spray the enteric coating -1 (Eudragit L 100) solution on spherical particles using Fluid bed processor.
7) Spray the enteric coating-2 (Eudragit L 30D-55) solution on enteric coated particles.
8) Fill the required quantity of pellets in suitable size of HG capsules.

Example 5 - Pellets prepared by extrusion
Ingredients Function 120mg 240mg %w/w
mg/cap
Composition for extrusion
Dimethyl fumarate API 120.00 240.00 55.45
Microcrystalline cellulose
Diluent 37.50 75.00 17.33
Mannitol Diluent 5.00 10.00 2.31
Sodium lauryl sulphate Solubilizer 1.75 3.50 0.81
Povidone K30 Binder 3.50 7.00 1.62
Croscarmellose sodium Disintegrant 5.00 10.00 2.31
Purified water Granulation solvent q.s. q.s. --
Isopropyl Alcohol Solvent q.s. q.s. --
Total 172.75 345.5 --
Enteric coating
Eudragit L30D-55 Enteric Polymer 36.00 72.00 16.64
Triethyl Citrate Plasticizer 3.60 7.20 1.66
Talc Anti-tacking agent 3.60 7.20 1.66
Purified Water Solvent q.s. q.s. --
Total 215.95 431.90 --
Talc Glidant 0.43 0.86 0.20
Total weight of enteric coated pellets 216.38 432.76 100.00

Manufacturing Procedure:

1) Sift dimethyl fumarate, microcrystalline cellulose, mannitol and croscarmellose through appropriate sieve, and mix them in a rapid mixer granulator (RMG) for appropriate time.
2) Dissolve sodium lauryl sulphate and povidone in water.
3) Granulate the step-1 mixture with step-2 granulating liquid
4) Extrudate the wet mass of step-3 through appropriate screen.
5) Spheronize the extrudates of step-4 to get desired pellets.
6) Dry the wet pellets of step-5 for required time.
7) Spray the enteric coating (Eudragit L30D-55) solution on dried spherical particles of step-6.
8) Blend the enteric coated pellets of step-7 with talc in a blender.
9) Fill the required quantity of pellets of step-8 in suitable size of HG capsules

Example 6 – Enteric coating of capsule
Ingredients Function 120mg 240mg %w/w
mg/cap mg/cap
Blend composition
Dimethyl fumarate API 120.00 240.00 62.0
Colloidal silicone dioxide Glidant 3.15 7.00 1.8
Magnesium Stearate Lubricant 1.50 3.00 0.7
Total 125.00 250.00 --
Enteric Coating-1 (10%)
Eudragit L 100 Enteric Polymer 10.41 20.83 5.4
Triethyl citrate Plasticizer 1.04 2.83 0.5
Talc Anti-tacking agent 1.04 2.83 0.5
IPA Solvent q.s q.s --
Water Solvent q.s q.s --
Total 138.25 276.50 --
Enteric Coating-2 (40%)
Eudragit L30D-55 Enteric Polymer 45.70 91.40 23.6
Triethyl Citrate Plasticizer 4.57 9.14 2.4
Talc Anti-tacking agent 4.57 9.14 2.4
Simethicone Anti-Foaming agent 0.46 0.91 0.2
Water Solvent q.s q.s --
Total 193.55 387.10 100

Manufacturing Procedure
1) Sift dimethyl fumarate, colloidal silicone dioxide and magnesium stearate through an appropriate sieve.
2) Blend dimethyl fumarate with colloidal silicone dioxide in a blender.
3) Lubricate blend from Step 2 with magnesium stearate in a blender.
4) Fill the blend obtained from Step 3 in to capsules.
5) Spray the enteric coating-I (Eudragit L100) solution on capsules using pan coating machine.
6) Spray the enteric coating-II (Eudragit L30D-55) solution on enteric coated-I capsules using pan coating machine.
7) Dry the enteric coated capsules of step 6.
,CLAIMS:1. A pharmaceutical composition comprising discrete particles of a fumaric acid derivative and a pharmaceutically acceptable excipient.
2. A pharmaceutical composition as per claim 1, wherein the discrete particles are granules.
3. A pharmaceutical composition as per claim 1, wherein the discrete particles are pellets.
4. A pharmaceutical composition as per claim 1, wherein the discrete particles are coated with at least one layer of coating.
5. A pharmaceutical composition as per claim 1, wherein the discrete particles are coated with at least one layer of enteric coating.
6. A pharmaceutical composition as per claim 1, wherein the composition is a capsule.
7. A pharmaceutical composition as per claim 6, wherein the composition is a capsule coated with at least one layer of coating.
8. A pharmaceutical composition as per claim 7, wherein the capsule is coated with at least one layer of enteric coating.
9. A pharmaceutical composition as per claim 1, wherein the fumaric acid derivative is dimethyl fumarate