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

HIGH DOSE STABLE FORMULATIONS OF DIMETHYL FUMARATE

BACKGROUND

The present invention relates to a pharmaceutical composition containing compound(s) that metabolize to monomethyl fumarate (MMF) and methods for treating, prophylaxis, or amelioration of neurodegenerative diseases including multiple sclerosis using such compositions in a subject. In embodiments, the compound that metabolizes to MMF is dimethyl fumarate (DMF).
Fumaric acid derivatives were first approved in Germany for the treatment of psoriasis in 1994 under the brand name of Fumaderm®, which contains 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 potential to be 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 ingredient during manufacturing and storage. Also, since DMF comes as highly crystalline material, compression process becomes difficult because of combined effect of abrasion and sublimation. Various compositions comprising dialkyl fumarates and/or alkyl hydrogen fumarates are known in the art. For instance, European Patent No. 188 749 discloses fumaric acid derivatives and compositions comprising the same 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 gelatine capsules), made by a conventional wet-granulation process, for use in transplantation medicine or for therapy of autoimmune diseases. 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 a granulate of said derivatives which are made by a conventional granulation way.
Since DMF is a high dose drug, 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 dry mixing of DMF and excipients that is then compressed into microtablets. However, microtablets prepared by such a process involving large amount of DMF are not likely to produce a pharmaceutically acceptable formulations, 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 makes such microtablets impractical such as low binding, more friability and weight variation.
One more issue associated with compositions of fumarates 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, satisfy above criteria, an improvement in the matter is still required.
Thus, it is desirable to develop a stable dosage form containing one or more compounds that metabolize to MMF, which also reduces the gastrointestinal related side effects as well as are easy to manufacture and can accommodate larger drug quantity per unit dosage without the problems associated with the prior art formulations.

SUMMARY OF THE INVENTION
In embodiments, the present invention relates to a pharmaceutical composition comprising one or more compounds that metabolize to MMF and one or more pharmaceutically acceptable excipients, wherein the total amount of one or more compounds that metabolize to MMF is more than 95% w/w of the composition.
In embodiments, the present invention relates to a granule composition comprising one or more compounds that metabolize to MMF and one or more pharmaceutically acceptable excipients, wherein the total amount of one or more compounds that metabolize to MMF is more than 95% w/w of the granule composition.
In embodiments, the present invention relates to a final blend composition comprising one or more compounds that metabolize to MMF and one or more pharmaceutically acceptable excipients, wherein the total amount of one or more compounds that metabolize to MMF is more than 95% w/w of the final blend composition.
In embodiments, the present invention relates to a mini-tablet composition comprising one or more compounds that metabolize to MMF and one or more pharmaceutically acceptable excipients, wherein the total amount of one or more compounds that metabolize to MMF is more than 95% w/w of the mini-tablet composition.
In embodiments, the present invention relates to a composition comprising one or more compounds that metabolize to MMF in its core and one or more pharmaceutically acceptable excipients, wherein the total amount of one or more compounds that metabolize to MMF is more than 95% w/w of the core.
In embodiments, the compositions of the present invention are coated with at least one layer of coating.
In embodiments, the compositions of the present invention are enteric coated.
In embodiments, the compositions of the present invention are further processed into dosage forms.
In embodiments, the compositions of the present invention are filled into capsules.
In embodiments, the compound that metabolizes to MMF is DMF.

DETAILED DESCRIPTION

Definitions
The term “core” means a part of formulation, which is devoid of any coating.
The term “mini-tablet” means a compact in the form of a small tablet less than about 3 mm in diameter (excluding any coating) that comprises one or more compounds that metabolize to MMF and one or more excipients.
The term ‘final blend’ refers to a blend of ingredients that provides the formulations of the present invention after a single processing step.
The term ‘stable’ for the purpose of this invention refers to chemical as well as physical stability. Examples of physical stability are integrity & tensile strength of the composition.
In general, compositions of high dose drugs containing higher amount of excipients normally result in bigger size formulations, which are difficult to be administered and are less appealing to the patients. It is ideal to have a formulation that contains only drug substance and no excipients. However, it is rare or impractical to have such a dosage form in pharmaceutical practice because most drug substances have some property or the other, which makes addition of excipients in the formulations imperative. Also, excipients are required for various reasons like modulating the drug release, targeting the drug absorption, to stabilize the otherwise unstable drug, to make the drug substance processable during formulation manufacturing etc.
In solid dosage form sphere, for high dose drugs like fumarates, it is desirable to have a dosage form with minimum amount of excipients. However, the solid oral dosage form may lose its physical stability due to decrease in the amount of excipient(s). The excipients impart various properties to the formulation, which make the dosage form stable e.g. binders hold all the components of the formulation together.
The present invention provides a stable pharmaceutical composition comprising one or more compounds that metabolize to MMF, with minimum amount of excipients. The formulation can be prepared by conventional formulation processes with no special requirements.
A compound that metabolizes to MMF may be present in the form of any of its pharmaceutically acceptable salts, solvates, esters and derivatives thereof. The doses of said compound may include from about 20 mg to about 1500 mg.
In embodiments, the present invention relates to a pharmaceutical composition comprising one or more compounds that metabolize to MMF and one or more pharmaceutically acceptable excipients, wherein the total amount of one or more compounds that metabolize to MMF is more than 95% w/w of the composition.
The pharmaceutical compositions of the present invention can be selected from powder, granules, core, mini-tablets and tablets. The pharmaceutical compositions of the present invention can also be processed further to prepare a dosage form, e.g. powder or granules or blend can be filled into a sachet, filled into a capsule or compressed into a tablet. Also, if mini-tablets are prepared, they can be filled into a capsule. Alternatively, the pharmaceutical compositions of the present invention can be administered to patients without further processing.
In embodiments, the present invention relates to a granule composition comprising one or more compounds that metabolize to MMF and one or more pharmaceutically acceptable excipients, wherein the total amount of one or more compounds that metabolize to MMF is more than 95% w/w of the granule composition.
In embodiments, the present invention relates to a final blend composition comprising one or more compounds that metabolize to MMF and one or more pharmaceutically acceptable excipients, wherein the total amount of one or more compounds that metabolize to MMF is more than 95% w/w of the final blend composition.

A pharmaceutically acceptable granule composition or final blend composition containing exceedingly high amount of one or more compounds that metabolize to MMF may be prepared by utilizing common manufacturing processes, which are not expected to produce a stable dosage form containing very high amount of active ingredient. The manufacturing processes may involve processes like dry granulation, granulation & hot melt extrusion. The granules obtained from such processes can be mixed with one or more excipients to form a final blend. Alternatively, the granules obtained can itself be used as the final blend. The granules obtained can be subjected to particle size reduction as desired to get granules of acceptable size range. The granules and the blend of the invention can have a particle size of less than 1000 microns. Preferably, the particle size ranges from 100-800 microns. The granules or final blend composition of the present invention may be coated with at least one layer of coating; the coating may be enteric coating.

Dry granulation – This process is widely used in the pharmaceutical practice and is very well known to a person skilled in the art. In dry granulation, the powder blend is compacted by applying a force onto the powder, which in general causes a considerable size enlargement. Principally there are two methods to obtain the compacts when using dry granulation: slugging and roller compaction.
Granulation – This process is one of the oldest processes used and is 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, permanent aggregates in which the original particles can still be identified. The term granulation usually refers to processes whereby aggregates with sizes ranging from ab. 0.1 to ab. 2.0 mm are produced by agitation of moistened powders. The present invention can be carried out using conventional granulation methods such as rapid mixing granulation, fluidized bed granulation etc.
Hot melt extrusion (HME) - Extrusion is the process of pumping raw materials at elevated controlled temperature and pressure through a heated barrel into a product of uniform shape and density. HME involves the compaction and conversion of blends from a powder or a granular mix into a product of uniform shape. The theoretical approach to understanding the melt extrusion process can be summarized by classifying the whole procedure of HME compaction 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.
The HME process used to prepare present invention can involve a solvent. The solvent can be a single solvent or a mixture of two or more solvents. The solvent(s) can 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 can 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.
Properties of granules/final blend – In embodiments, the present invention relates to a final blend composition comprising one or more compounds that metabolize to MMF and one or more pharmaceutically acceptable excipients, wherein the total amount of one or more compounds that metabolize to MMF is more than 95% w/w of the final blend composition, and wherein the blend exhibits pharmaceutically acceptable flow and compaction.
The final blend of the present invention, which can be granules itself without mixing with other excipients, may have excellent flow properties. The flow of a powder can 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 today’s pharmaceutical practice, compressibility index or Hausner ratio is commonly used as a tool to access 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 of the present invention 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 can 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 of the present invention 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.

The granules or final blend of the present invention can also be processed further to prepare a dosage form, e.g it can be filled into a sachet, filled into a capsule or compressed into a tablet or a mini-tablet. Also, if mini-tablets are prepared, they can be filled into a capsule. Preferably, the dosage form is a mini-tablet. More preferably, one or more mini-tablets are filled into a capsule.
In embodiments, the present invention relates to a mini-tablet composition comprising one or more compounds that metabolize to MMF and one or more pharmaceutically acceptable excipients, wherein the total amount of one or more compounds that metabolize to MMF is more than 95% w/w of the mini-tablet composition.
In embodiments, a mini-tablet is further coated with at least one layer of coating.
In embodiments, a mini-tablet is enteric coated.
In embodiments, the coated cores are filled into capsules.
Features of a mini-tablet - A mini-tablet of the present invention can have a mean diameter (excluding any coatings), for example, less than 3mm. The diameter may range from about 1 mm to about 3 mm. For example, the mini-tablets can have a mean diameter ranging from about 1 mm to about 2.5 mm. The mini-tablets can have a mean diameter of about 1.0 mm, about 2.0 mm, or about 3.0 mm.
As described earlier, increasing the quantity of active ingredient in a mini-tablet while keeping the table weight constant calls for decrease in excipient quantities. Such a mini-tablet would lose its stability because it would not have sufficient tensile strength. The mini-tablets of the present invention containing exceedingly high amount of active ingredient may have exceptional tensile strength, which is not expected otherwise. For example, the disclosure in the United States Patent Application Publication No US 2013/0216615 discloses that micro-tablets containing more than 95% w/w of DMF exhibited very poor tensile strength.
An embodiment of the present invention is a mini-tablet comprising one or more compounds that metabolize to MMF and one or more pharmaceutically acceptable excipients, wherein the total amount of one or more compounds that metabolize to MMF is more than 95% w/w of the mini-tablet and the mini-tablet has a tensile strength ranging from about 0.5 MPa to about 5 MPa at an applied pressure ranging from about 25 MPa to about 200 MPa.
Compact tensile strength can be determined by any means known in the art. For example, the following protocol could be employed. First, compact(s) are compressed to about 360 mg weight using an instrumented rotary tablet press equipped to measure compression force with round flat tooling of approximately 10 mm diameter. Next, measure the diametrial crushing strength using a suitable tablet hardness tester and then calculate tensile strength by the procedure reported by Newton (Newton, J. M., Journal of Pharmacy and Pharmacology, 26: 215-216 (1974)). See also Pandeya and Puri, KONA Powder and Particle Journal, 30: 211-220 (2013), Jarosz and Parrott, J. Pharm. Sci. 72(5):530-535 (1983), and Podczeck, Intl. J. Pharm. 436:214-232 (2012).
The composition, in the form of a compact, can have a tensile strength equal to or greater than 1.5 MPa at an applied or compaction pressure of about 100 MPa. For example, the tensile strength can range from about 2.0 to about 5.0 MPa (e.g., from about 2.5 to about 4.5 MPa, from about 3.0 to about 4.5 MPa or from about 3.5 to about 4.5 MPa) at an applied or compaction pressure of about 100 MPa. For example, the tensile strength can be about 4.0 MPa at an applied or compaction pressure of about 100 MPa.
In embodiments, the present invention relates to a composition comprising one or more compounds that metabolize to MMF in its core and one or more pharmaceutically acceptable excipients, wherein the total amount of one or more compounds that metabolize to MMF is more than 95% w/w of the core.
In embodiments, the core is selected from a pellet and a granule. Alternatively, the core may also be a powder particle.
In embodiments, a core is further coated with at least one layer of coating.
In embodiments, a core is enteric coated.
In embodiments, the coated cores are filled into capsules.
The core compositions of the present invention may be prepared by conventional manufacturing technologies such as hot melt extrusion (HME), granulation & dry granulation etc. HME & granulation processes have been described earlier and can be used to prepare core compositions of the present invention as well. The core compositions of the present invention can also be obtained from coating of one or more compounds that metabolize to MMF onto inert substrates like pellets. For the purpose of this invention, the drug coated pellets are considered as core compositions, which can be further coated with one or more layers of coating e.g. enteric coating.
Pellet coating with drug – Pellet coating according to the present invention refers to the coating of inert pellets such as sugar sphere or microcrystalline cellulose sphere with one or more components. The coating may contain drug substance and one or more excipients. The coating solution/dispersion may be aqueous or non-aqueous based. The process can be carried out by using conventional pellet coating apparatuses such as Wurster coating. The core composition containing drug so formed can then be coated with one or more layers of coating e.g. enteric coating. The description of coating is provided in the in relevant sections of this description.

Pharmaceutically acceptable excipients - Excipients to be used in preparing pharmaceutical compositions of the present invention include, for example, any one or more of diluents, binders, stabilizers, lubricants and glidants that are useful in preparation of pharmaceutical formulations.
Various useful fillers or diluents 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 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, etoprolol, 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 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.
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, or mini-tablets, and minimize dosage form weight variations, can be used. Useful glidants include, but are not limited to silicon dioxide, talc, and mixtures thereof.

Enteric coating - In an embodiment, compositions of the present invention are coated or partially coated with 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.
In an embodiment, is compositions of the present invention are enteric-coated. The coating of the composition may be composed of different layers. The first coating or the seal coating as it is called in general isolates the tablet cores from further coating layers. The seal coating may or may not contain an enteric coating polymer.
In an embodiment, the compositions of the present invention are filled into a capsule.
The seal coating can contain, for example, one or more plasticizers, one or more copolymers, one or more polymers, or combinations thereof.
The plasticizer can 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 can be, for example, a methacrylic acid-methacrylate copolymer or a methacrylic acid-ethylacrylate copolymer.
Additionally, the seal coating can contain one or more polymers, for example, cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl and methylcellulose, polyvinylpyrrolidone, a polyvinylpyrrolidone/vinyl acetate copolymer, ethyl cellulose, and ethyl cellulose aqueous dispersions (AQUACOAT®, SURELEASE®), EUDRAGIT® RL 30 D, OPADRY®, EUDRAGIT® S, EUDRAGIT® L, and the like.
If present in the seal coating, the total amount of one or more copolymer(s) and/or one or more polymer(s) in the seal coating can 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 can 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 can 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 can 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 can contain, for example, one or more plasticizers, one or more fillers, one or more lubricants, one or more copolymers, one or more polymers, and any combinations thereof.
The plasticizer(s) in the enteric coat can be the same or different than any plasticizer(s) in a seal coat, if present, and can be one of more of the plasticizers listed above.
The filler(s) in the enteric coat can be the same or different than any filler(s) in the composition. Additionally, the filler(s) in the enteric coat can be the same or different than any filler(s) in a seal coat, if present, and can be one or more of the fillers listed above.
The lubricant(s) in the enteric coat can be the same or different than any lubricant(s) in the composition. Additionally, the lubricant(s) in the enteric coat can be the same or different than the copolymer(s) in a seal coat, if present, and can be one or more of the lubricants listed above. In one embodiment, the lubricant is talculm (talc) that is optionally micronized.
The copolymer(s) in the enteric coat can be the same or different than the copolymer(s) in a seal coat, if present, and can 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 (EUDRAGIT® FS 30 D), a methacrylic acid-methyl methacrylate copolymer and a methacrylic acid-ethyl acetate copolymer.
The enteric polymers used in this invention can 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 can 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 can range, for example, from a positive amount greater than 0% w/w to about 58% w/w, based on the weight of the enteric coating.
If present in an enteric coating, the total amount of filler(s) in the enteric coating can range, for example, from a positive amount greater than 0% w/w to about 5.0% w/w, based on the weight of the enteric coating.
Solvents for applying the coating materials, can be, but are not limited to, water, acetone, hexane, ethanol, methanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol, dichlormethane, trichloromethane, chloroform, and the like.
Coatings can 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 embodiments, the present invention relates to a pharmaceutically acceptable composition comprising compounds or pharmaceutically acceptable salt thereof, that metabolizes to monomethyl fumarate (MMF).
In embodiments, the compound that metabolizes to MMF is DMF.
In some embodiments, a method according to the invention comprises orally administering a dosage form that provides a total amount of about 60 mg to about 1000 mg of dimethyl fumarate. The dosage form can, for example, contain a total amount of DMF effective for treatment, prophylaxis, or amelioration of multiple sclerosis. The effective amount can 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 dosage form can 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 ingredient in the composition. DMF can have particle size of less than 1000 microns. Preferably, the particle size is less than 500 microns. More preferably, the 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 substances in a combination therapy, wherein the other active substance 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 construes as limiting the scope of the disclosure.

EXAMPLES

Example 1 – Mini-tablets prepared by HME granulation
Ingredients 1A 1B 1C 1D 1E
%w/w
Granulation
Dimethyl Fumarate 96.02 96.02 96.02 96.02 96.02
PVP K-90 1.98 - - - -
HPMC 15 cps - 1.98 - - -
HPC - - 1.98 - -
PEO WSR 303 - - - 1.98 -
PEG-6000 - - - - 1.98
Isopropyl alcohol (IPA) q.s. q.s q.s q.s q.s
Extra-granular
Aerosil 1 1 1 1 1
Magnesium Stearate 1 1 1 1 1
Mini-Tablets 100 100 100 100 100
HME parameters
Screw Type Twin Screw
Zone temperature 25°C - Zone 1 to 4
35°C – Zone 5 to 7

Manufacturing process
(1) Intra-granular materials i.e. DMF and a binder (of each example separately) were fed to feeder zone of Hot-Melt Extruder separately. The apparatus has total of seven zones.
(2) IPA was added at the rate of 0.7ml/min in the next zone and the material was allowed to mix in zone 3.
(3) The mixture was allowed to be conveyed to zone 5 through zone 4, where it was mixed at 35°C.
(4) The granules formed were collected after the mixture was passed through zone 6 & 7.
(5) The resultant granules were mixed with extra-granular excipients to get the final blend.
(6) One portion of the final blend of step 5 was compressed into mini-tablets of 2mm in size and 10mg each in weight.
(7) Other portion of the final blend of step 5 was compressed into mini-tablets of 1.5mm in size and 6.25mg in weight.
(8) The resultant mini-tablets of step 6 and 7 were coated with 2.5% w/w of a layer containing Eudragit L100 & Triethyl citrate (TEC) using IPA as solvent (Delayed release coat I).
(9) The coated mini-tablets of step 8 were further coated with 52% w/w of a layer containing Eudragit L30D55, simethicone, Talc & TEC (Delayed release coat II).
(10) The coated mini-tablets of step 9 were filled into capsules.

Example 2 – Mini-tablets prepared by dry granulation
Ingredients % w/w
Dimethyl Fumarate 97
Aerosil 2
Magnesium Stearate 1
Mini-Tablet 100

Manufacturing process
(1) DMF, Aerosil and magnesium stearate was mixed and fed to a roller compacter.
(2) The flakes obtained from roller compaction were milled to get the granules.
(3) The granules of step 2 were mixed to get the final blend.
(4) The compression of final blend into mini-tablets and coating was carried out as described in example 1.

Example 3 – Pellets prepared by Wurster process
Ingredients 3A 3B
% w/w
Base pellet (Sugar sphere or MCC pellet) 2 2
HPMC (K4M/K15M/K100M) 2 -
PVP K 90 - 2
Dimethyl Fumarate 96 96
Methanol q.s. q.s.
Methylene chloride q.s. q.s.
Core 100 100

Manufacturing process
(1) Binder solution preparation – Binder polymer (HPMC in example 3A and PVP in example 3B) was dissolved in a solution of methanol and methylene chloride. DMF was then added and dissolved (in case of HPMC as binder, the solution was prepared with different viscosity grades separately).
(2) Base pellets (either sugar spheres or MCC pellets) were warmed in a Wurster processor.
(3) The binder solution containing DMF was then sprayed onto the warmed base pellets till the required weight gain is achieved.
(4) The drug layered pellets were dried before collecting.
(5) The resultant dried drug coated pellets were coated in the same way as mini-tablets as described in example 1.

Example 4 – Pellets prepared by Centrifual coater
The quantitatively identical compositions of example 3 were prepared using centrifugal coater in place of Wurster coater.
,CLAIMS:WE CLAIM
1. A pharmaceutical composition comprising one or more compounds that metabolize to monomethyl fumarate and one or more pharmaceutically acceptable excipients, wherein the total amount of one or more compounds that metabolize to monomethyl fumarate is more than 95% w/w of the composition.
2. A pharmaceutical composition as per claim 1, wherein a compound that metabolize to monomethyl fumarate is dimethyl fumarate.
3. A pharmaceutical composition as per claim 1, wherein the composition is mini-tablet.
4. A pharmaceutical composition as per claim 1, wherein the composition is granule composition.
5. A pharmaceutical composition as per claim 1, wherein the composition is final blend composition.
6. A pharmaceutical composition as per claim 1, wherein the composition is coated with at least one layer of coating.
7. A pharmaceutical composition as per claim 6, wherein at least one layer of coating is enteric coating.
8. A pharmaceutical composition as per claim 1, wherein the composition is further processed into a dosage from.
9. A pharmaceutical composition as per claim 1, wherein the composition is filled into a capsule.