WO2020112059A2 - The delayed release capsule comprising dimethyl fumarate - Google Patents

The delayed release capsule comprising dimethyl fumarate Download PDF

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Publication number
WO2020112059A2
WO2020112059A2 PCT/TR2019/050964 TR2019050964W WO2020112059A2 WO 2020112059 A2 WO2020112059 A2 WO 2020112059A2 TR 2019050964 W TR2019050964 W TR 2019050964W WO 2020112059 A2 WO2020112059 A2 WO 2020112059A2
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WO
WIPO (PCT)
Prior art keywords
delayed release
dimethyl fumarate
capsule
release capsule
capsule according
Prior art date
Application number
PCT/TR2019/050964
Other languages
French (fr)
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WO2020112059A3 (en
Inventor
Ali Turkyilmaz
Arzu PALANTOKEN
Fatih MOLLAOGLU
Dicle GUNER
Original Assignee
Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi filed Critical Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority to EP19888384.5A priority Critical patent/EP3886835A4/en
Publication of WO2020112059A2 publication Critical patent/WO2020112059A2/en
Publication of WO2020112059A3 publication Critical patent/WO2020112059A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release

Definitions

  • the present invention relates to a delayed release capsule comprising dimethyl fumarate and at least one pharmaceutically acceptable excipient wherein the particle size d (0.8) of dimethyl fumarate is less than 250 pm.
  • MS Multiple sclerosis
  • MS is the most common autoimmune disorder affecting the central nervous system.
  • Multiple sclerosis also known as disseminated sclerosis or encephalomyelitis disseminata
  • MS is a demyelinating disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to communicate, resulting in a wide range of signs and symptoms, including physical, mental and sometimes psychiatric problems.
  • MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). Between attacks, symptoms may disappear completely; however, permanent neurological problems often occur, especially as the disease advances.
  • DMF Dimethyl fumarate
  • E dimethyl (E)- butenedioate (0 6 H 8 0 4 )
  • MS multiple sclerosis
  • Dimethyl Fumarate is marketed by BIOGEN under the trademark TECFIDERA ® .
  • This formulation, TECFIDERA ® is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of granulated dimethyl fumarate enterically coated minitablets.
  • TECFIDERA ® is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of granulated dimethyl fumarate enterically coated minitablets.
  • the patent application WO2013076216 (A1 ) discloses a formulation, comprising particles of dimethyl fumarate coated by at least one layer of a pH-dependent entero-resistant polymer. The particles are formulated into a pharmaceutical preparation or dosage form for oral administration of dimethyl fumarate.
  • the patent application CN104523602 (A) discloses a formulation, comprising enteric-coated pellet of dimethyl fumarate.
  • the dimethyl fumarate enteric-coated pellet comprises a core, an intermediate coating layer and an enteric layer. But, the application does not provide a simple and low-cost production method.
  • the improved a delayed release capsule of dimethyl fumarate has desired dissolution profile, a desired disintegration profile and a long-term stability.
  • the main object of the present invention is to provide a delayed release capsule with desired content uniformity which overcomes the above described problems in the prior art and has additive advantages over them.
  • the other object of the present invention is to provide a delayed release capsule comprising dimethyl fumarate to provide high stability and desired dissolution profile.
  • particle size distribution means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (i.e. Malvern analysis).
  • d(0.1 ) means, the size at which 10% by volume of the particles are finer and d(0.5) means the size at which 50% by volume of the particles are finer and d (0.9) means the size at which %90 by volume of the particles are finer.
  • the advantages of the present invention are even more significant, as the problem of homogeneity is even more likely to occur when active substance and some excipients are incorporated in one final dosage form, especially when these are very different regarding the dose and particle size. Improved content uniformity efficiently contributes to a marked increase in bioavailability.
  • a delayed release capsule comprises dimethyl fumarate and at least one pharmaceutically acceptable excipient wherein the particle size d (0.8) of dimethyl fumarate is less than 250 pm.
  • the particle size of dimethyl fumarate provides surprisingly improved content uniformity and desired dissolution profile.
  • dimethyl fumarate has a particle size d (0.8) less than 250 pm, preferably a particle size d (0.8) 249 pm to 180 pm, preferably a particle size d (0.8) 180 pm to 100 pm, preferably a particle size d (0.8) 100 pm to 25 pm.
  • dimethyl fumarate has a particle size d (0.1) less than 250 pm, preferably a particle size d (0.1 ) 200 pm to 1 pm, preferably a particle size d (0.1 ) 150 pm to 1 pm, preferably a particle size d (0.1 ) 100 pm to 1 pm, preferably a particle size d (0.1 ) 80 pm to 1 pm, preferably it has a particle size d (0.1 ) 30 pm to 1 pm.
  • dimethyl fumarate has a particle size d (0.5) less than 300 pm, preferably a particle size d (0.5) 300 pm to 200 pm, preferably a particle size d (0.5) 200 pm to 120 pm, preferably a particle size d (0.5) 120 pm to 90 pm, preferably it has a particle size d (0.5) 90 pm to 10 pm.
  • dimethyl fumarate has a particle size d (0.9) less than 400 pm, preferably a particle size d (0.9) 400 pm to 300 pm, preferably a particle size d (0.9) 300 pm to 200 pm and preferably a particle size d (0.9) 200 pm to 100 pm and preferably a particle size d (0.9) 100 pm to 30 pm.
  • dimethyl fumarate has a particle size d (0.1) 30 pm to 1 pm, a particle size d (0.5) 90 pm to 10 pm, a particle size d (0.8) 100 pm to 25 pm, a particle size d (0.9) 100 pm to 30 pm.
  • the amount of dimethyl fumarate in the capsule is between 18.0% to 70.0% by weight, between 25.0% to 50.0% by weight. According to one embodiment of the present invention, the amount of dimethyl fumarate in the capsule is between 30% to 46%, more preferably between 35% to 43% by weight.
  • the dosage form of dimethyl fumarate is a capsule filled with mini-tablets or granules.
  • mini-tablets is filled into the capsule wherein mini-tablets have at least one coating.
  • the coating is film-coating and or enteric coating.
  • mini tablets are coated with at least one film- coating and an enteric coating.
  • the film-coating is applied at two steps.
  • the first step of film coating is called pre-coating
  • the second step of film-coating is applied after enteric coating.
  • first film coating (pre-coating) is applied
  • the second enteric coating is applied and last second film coating is applied.
  • the film-coating comprises film coating agents which are selected from the group comprising hydroxypropylmethyl cellulose, triacetin/glycerol triacetate, talc or mixtures thereof.
  • the enteric coating comprises at least one enteric coating agent.
  • Suitable enteric coating agents are selected from the group comprising poly (vinyl acetate phthalate), cellulose acetate trimellitate, dibutyl phthalate, polyethylene glycol, talc, gelatin, glycerol, methacrylic acid/ethylacrylate 1 :1 co polymer, titanium dioxide, triethyl citrate or mixtures thereof.
  • the selected enteric coating agent is methacrylic acid/ethylacrylate 1 :1 co polymer, talc, titanium dioxide, triethyl citrate in the capsule filled with mini-tablets.
  • film-coatings and enteric coating provide high chemical and mechanical stability. Also, coatings especially enteric coating prevent damage to the stomach of the dimethyl fumarate.
  • granules are filled into the capsule wherein the capsule is enteric capsule.
  • Granules are obtained with dry granulation. Used granules provide higher flowability and help better filling of capsule, therefore a simple and low-cost production method is employed. As a result of dry granulation of dimethyl fumarate with fillers, binders, and glidants, the final granules are obtained. And the final granules are filled into the enteric capsules.
  • the enteric capsule shell it is very important to choose ingredients of the enteric capsule shell. It may be interacted with active agents or excipients.
  • cellulosic enteric derivatives are not chemically interact with the formulation. So, contrary to prior art, capsule shell comprises cellulosic enteric derivatives, especially HPMC. It provides chemical stability for the formulation.
  • Suitable enteric capsule shell agents are selected from the group comprising hypromellose (HPMC), hypromellose acetate succinate (HPMC-AS), titanium dioxide, hypromellose phthalate (HPMCP), glutaric anhydride, gellan gum, pullulan, hydroxypropyl starch, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, polyoxyethylene, polyoxypropylene, succinic anhydrate, sorbitol, palmitoyl chloride or mixtures thereof.
  • HPMC hypromellose
  • HPMC-AS hypromellose acetate succinate
  • HPMCP hypromellose phthalate
  • glutaric anhydride glutaric anhydride
  • gellan gum pullulan
  • pullulan hydroxypropyl starch
  • hydroxypropyl cellulose hydroxypropyl cellulose
  • ethyl cellulose methyl cellulose
  • succinic anhydrate sorbitol, palmitoyl chloride
  • these enteric capsules may further comprise enteric coated using any of the known enteric coating agents.
  • enteric-coating helps to provide the desired dissolution profile.
  • the amount of the enteric coating agents in the capsule filled with granules are between 1.0% to 8.0% by, preferably between 2.0% to 6.0% by weight.
  • the capsule comprises and at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, binders, disintegrants, lubricants, glidants or mixtures thereof.
  • suitable fillers are selected from the group comprising microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, glyceryl palmitostearate, hydrogenated vegetable oil type I, isomalt, kaolin, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, polyvinylpyrrolidone, simethicone, sodium alginate, sodium chloride, sorbitol
  • the amount of the filler in the capsule is between 20.0% to 50.0%, preferably between 25.0% to 45.0%, more preferably between 30.0% to 40.0% by weight.
  • Suitable binders are selected from the group comprising polyvinylpyrrolidone, gelatin, sugars, glucose, natural gums, synthetic celluloses, polymethacrylate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose or mixtures thereof; preferably the binder is polyvinylpyrrolidone.
  • the amount of the binder in the capsule is between 1.0% to 10.0%, preferably between 2.0% to 5.0% by weight.
  • polyvinylpyrrolidone is used as binder because compatible with most organic and inorganic pharmaceutical ingredients and it is appropriate for using delayed release.
  • polyvinylpyrrolidone is used for easy availability and low cost.
  • the weight ratio of polyvinylpyrrolidone to the weight of dimethyl fumarate in the capsule is between 0.01 -10.0, preferably the ratio is 0.05-5.0, more preferably the ratio is 0.05-1 .0.
  • Suitable disintegrants are selected from the group comprising hydroxypropyl starch, alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, powdered cellulose, chitosan, colloidal silicon dioxide, croscarmellose sodium, crospovidone, docusate sodium, guar gum, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, povidone, sodium alginate, sodium starch glycolate, starch, and pregelatinized starch or mixtures thereof, preferably the disintegrant is crospovidone.
  • the amount of the disintegrant in the capsule is between 1.0% to 12.0%, preferably between 3.0% to 10.0% by weight.
  • Suitable glidants are selected from the group comprising colloidal silicon dioxide, calcium phosphate, calcium silicate, powdered cellulose, magnesium stearate, magnesium silicate, magnesium trisilicate, silicon dioxide or mixtures thereof, preferably the glidant is colloidal silicon dioxide.
  • the amount of the glidant in the capsule is between 0.1% to 3.0% by weight.
  • the capsule of the present invention is free of talc except for coatings and capsule shell.
  • Suitable lubricants are selected from the group comprising canola oil, hydroxyethyl cellulose, lauric acid, leucine, mineral oil, poloxamers, polyvinyl alcohol, oxtyldodecanol, sodium hyaluronate, sterilizable maize starch, triethanolamine, calcium stearate, magnesium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type I, light mineral oil, magnesium lauryl sulfate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium chloride, sodium lauryl sulfate, stearic acid, and zinc stearate or mixtures thereof, preferably the lubricant is magnesium stearate.
  • the amount of the lubricant in the capsule is between 0.1% to 3.0% by weight.
  • a delayed release capsule comprising between 25.0% to 50.0% by weight of dimethyl fumarate, between 20.0% to 50.0% by weight of at least one filler, between 1.0% to 10.0% by weight of at least one binder, between 1.0% to 12.0% by weight of at least one disintegrant, between 0.1% to 3.0% by weight of at least one lubricant and between 0.1 % to 3.0% by weight of at least one glidant.
  • This example describes the delayed release capsule comprising dimethyl fumarate.
  • the active ingredient and excipients are given below:
  • Example 1 Granules in enteric capsule of dimethyl fumarate
  • Example 2 Granules in enteric capsule of dimethyl fumarate
  • Process for preparing the enteric capsule comprising the following steps; a) mixing dimethyl fumarate, half of microcrystalline cellulose, polyvinylpyrrolidone and half of colloidal silicon dioxide
  • Example 3 Mini-tablet in the capsule of dimethyl fumarate
  • Process for preparing the capsule comprising the following steps; a) mixing dimethyl fumarate, half of microcrystalline cellulose, polyvinylpyrrolidone, colloidal silicon dioxide for 10 minutes;
  • step (b) sieving half of magnesium stearate and adding the powder mixture of step (a) then mixing for 3 minutes; c) dry granulation of the mixed components;
  • step (d) adding this mixture step (d) in step (c) mixture then mixing for 5 minutes;
  • step (e) sieving the remaining part of magnesium stearate and adding it to step (e) mixture then mixing for 3 minutes
  • h) coating with the mini tablet pre-coating 30%-35% of all coating is pre-coating which comprises hydroxypropyl methyl cellulose, triacetin/glycerol triacetate, talc.
  • enteric coating which comprises methacrylic acid/ethylacrylate 1 :1 co-polymer, talc, titanium dioxide, triethyl citrate.
  • film-coating which comprises hydroxypropylmethyl cellulose, triacetin/glycerol triacetate, talc, k) filling the mini tablets into capsules.

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Abstract

The present invention relates to a delayed release capsule comprising dimethyl fumarate and at least one pharmaceutically acceptable excipient wherein the particle size d (0.8) of dimethyl fumarate is less than 250 µm.

Description

THE DELAYED RELEASE CAPSULE COMPRISING DIMETHYL FUMARATE
Technical Aspect
The present invention relates to a delayed release capsule comprising dimethyl fumarate and at least one pharmaceutically acceptable excipient wherein the particle size d (0.8) of dimethyl fumarate is less than 250 pm.
Background of the Invention
Multiple sclerosis (MS) is the most common autoimmune disorder affecting the central nervous system. Multiple sclerosis, also known as disseminated sclerosis or encephalomyelitis disseminata, is a demyelinating disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to communicate, resulting in a wide range of signs and symptoms, including physical, mental and sometimes psychiatric problems. MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). Between attacks, symptoms may disappear completely; however, permanent neurological problems often occur, especially as the disease advances.
Dimethyl fumarate (DMF) corresponding to the compound dimethyl (E)- butenedioate (06H804) is an anti-inflammatory mostly used for treating multiple sclerosis (MS). Its chemical structure is shown in the Formula I.
Figure imgf000002_0001
Formula 1
Dimethyl Fumarate is marketed by BIOGEN under the trademark TECFIDERA®. This formulation, TECFIDERA®, is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of granulated dimethyl fumarate enterically coated minitablets. There are various patents in the state of the art in relation to dimethyl fumarate which is first described in US6509376 B1 and also discloses its indication.
The patent application WO2013076216 (A1 ) discloses a formulation, comprising particles of dimethyl fumarate coated by at least one layer of a pH-dependent entero-resistant polymer. The particles are formulated into a pharmaceutical preparation or dosage form for oral administration of dimethyl fumarate.
The patent application CN104523602 (A) discloses a formulation, comprising enteric-coated pellet of dimethyl fumarate. The dimethyl fumarate enteric-coated pellet comprises a core, an intermediate coating layer and an enteric layer. But, the application does not provide a simple and low-cost production method.
In the prior art, there are many pharmaceutical compositions comprising dimethyl fumarate, but it is needed to develop a formulation which has a desired disintegration profile and long term stability for use and desired content uniformity.
In the present invention, the improved a delayed release capsule of dimethyl fumarate has desired dissolution profile, a desired disintegration profile and a long-term stability.
Description of the Invention
The main object of the present invention is to provide a delayed release capsule with desired content uniformity which overcomes the above described problems in the prior art and has additive advantages over them.
The other object of the present invention is to provide a delayed release capsule comprising dimethyl fumarate to provide high stability and desired dissolution profile.
As used herein,‘particle size distribution’ means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (i.e. Malvern analysis). The term d(0.1 ) means, the size at which 10% by volume of the particles are finer and d(0.5) means the size at which 50% by volume of the particles are finer and d (0.9) means the size at which %90 by volume of the particles are finer.
The advantages of the present invention are even more significant, as the problem of homogeneity is even more likely to occur when active substance and some excipients are incorporated in one final dosage form, especially when these are very different regarding the dose and particle size. Improved content uniformity efficiently contributes to a marked increase in bioavailability.
According to one embodiment of the present invention, a delayed release capsule comprises dimethyl fumarate and at least one pharmaceutically acceptable excipient wherein the particle size d (0.8) of dimethyl fumarate is less than 250 pm. The particle size of dimethyl fumarate provides surprisingly improved content uniformity and desired dissolution profile.
According to one embodiment of the present invention, dimethyl fumarate has a particle size d (0.8) less than 250 pm, preferably a particle size d (0.8) 249 pm to 180 pm, preferably a particle size d (0.8) 180 pm to 100 pm, preferably a particle size d (0.8) 100 pm to 25 pm.
According to one embodiment of the present invention, dimethyl fumarate has a particle size d (0.1) less than 250 pm, preferably a particle size d (0.1 ) 200 pm to 1 pm, preferably a particle size d (0.1 ) 150 pm to 1 pm, preferably a particle size d (0.1 ) 100 pm to 1 pm, preferably a particle size d (0.1 ) 80 pm to 1 pm, preferably it has a particle size d (0.1 ) 30 pm to 1 pm.
According to one embodiment of the present invention, dimethyl fumarate has a particle size d (0.5) less than 300 pm, preferably a particle size d (0.5) 300 pm to 200 pm, preferably a particle size d (0.5) 200 pm to 120 pm, preferably a particle size d (0.5) 120 pm to 90 pm, preferably it has a particle size d (0.5) 90 pm to 10 pm.
According to one embodiment of the present invention, dimethyl fumarate has a particle size d (0.9) less than 400 pm, preferably a particle size d (0.9) 400 pm to 300 pm, preferably a particle size d (0.9) 300 pm to 200 pm and preferably a particle size d (0.9) 200 pm to 100 pm and preferably a particle size d (0.9) 100 pm to 30 pm.
According to one embodiment of the present invention, dimethyl fumarate has a particle size d (0.1) 30 pm to 1 pm, a particle size d (0.5) 90 pm to 10 pm, a particle size d (0.8) 100 pm to 25 pm, a particle size d (0.9) 100 pm to 30 pm.
According to one embodiment of the present invention, the amount of dimethyl fumarate in the capsule is between 18.0% to 70.0% by weight, between 25.0% to 50.0% by weight. According to one embodiment of the present invention, the amount of dimethyl fumarate in the capsule is between 30% to 46%, more preferably between 35% to 43% by weight.
According to one embodiment of the present invention, the dosage form of dimethyl fumarate is a capsule filled with mini-tablets or granules.
According to one embodiment of the present invention, mini-tablets is filled into the capsule wherein mini-tablets have at least one coating.
According to one embodiment of the present invention, the coating is film-coating and or enteric coating.
According to one embodiment of the present invention, mini tablets are coated with at least one film- coating and an enteric coating. The film-coating is applied at two steps. The first step of film coating is called pre-coating, the second step of film-coating is applied after enteric coating. In other words, first film coating (pre-coating) is applied, the second enteric coating is applied and last second film coating is applied.
In mini tablets, high solubility for dimethyl fumarate is essential in order to achieve desired content uniformity. Pre-coating increases the solubility of dimethyl fumarate. This helps to achieve desired dissolution profile and bioavailability.
According to one embodiment of the present invention, the film-coating comprises film coating agents which are selected from the group comprising hydroxypropylmethyl cellulose, triacetin/glycerol triacetate, talc or mixtures thereof.
According to one embodiment of the present invention, the enteric coating comprises at least one enteric coating agent. Suitable enteric coating agents are selected from the group comprising poly (vinyl acetate phthalate), cellulose acetate trimellitate, dibutyl phthalate, polyethylene glycol, talc, gelatin, glycerol, methacrylic acid/ethylacrylate 1 :1 co polymer, titanium dioxide, triethyl citrate or mixtures thereof.
According to one embodiment of the present invention, the selected enteric coating agent is methacrylic acid/ethylacrylate 1 :1 co polymer, talc, titanium dioxide, triethyl citrate in the capsule filled with mini-tablets. In further, film-coatings and enteric coating provide high chemical and mechanical stability. Also, coatings especially enteric coating prevent damage to the stomach of the dimethyl fumarate.
According to one embodiment of the present invention, granules are filled into the capsule wherein the capsule is enteric capsule.
Granules are obtained with dry granulation. Used granules provide higher flowability and help better filling of capsule, therefore a simple and low-cost production method is employed. As a result of dry granulation of dimethyl fumarate with fillers, binders, and glidants, the final granules are obtained. And the final granules are filled into the enteric capsules.
According to one embodiment of the present invention, it is very important to choose ingredients of the enteric capsule shell. It may be interacted with active agents or excipients. In this invention, it has been found that cellulosic enteric derivatives are not chemically interact with the formulation. So, contrary to prior art, capsule shell comprises cellulosic enteric derivatives, especially HPMC. It provides chemical stability for the formulation.
Suitable enteric capsule shell agents are selected from the group comprising hypromellose (HPMC), hypromellose acetate succinate (HPMC-AS), titanium dioxide, hypromellose phthalate (HPMCP), glutaric anhydride, gellan gum, pullulan, hydroxypropyl starch, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, polyoxyethylene, polyoxypropylene, succinic anhydrate, sorbitol, palmitoyl chloride or mixtures thereof.
Alternately, these enteric capsules may further comprise enteric coated using any of the known enteric coating agents. The enteric-coating helps to provide the desired dissolution profile.
According to one embodiment of the present invention, the amount of the enteric coating agents in the capsule filled with granules are between 1.0% to 8.0% by, preferably between 2.0% to 6.0% by weight.
According to one embodiment of the present invention, the capsule comprises and at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, binders, disintegrants, lubricants, glidants or mixtures thereof. Suitable fillers are selected from the group comprising microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, glyceryl palmitostearate, hydrogenated vegetable oil type I, isomalt, kaolin, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, polyvinylpyrrolidone, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar spheres, sulfobutylether beta-cyclodextrin, tragacanth, trehalose, polysorbate 80, xylitol or mixtures thereof. Preferably the filler is microcrystalline cellulose.
According to one embodiment of the present invention, the amount of the filler in the capsule is between 20.0% to 50.0%, preferably between 25.0% to 45.0%, more preferably between 30.0% to 40.0% by weight.
Suitable binders are selected from the group comprising polyvinylpyrrolidone, gelatin, sugars, glucose, natural gums, synthetic celluloses, polymethacrylate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose or mixtures thereof; preferably the binder is polyvinylpyrrolidone.
According to one embodiment of the present invention, the amount of the binder in the capsule is between 1.0% to 10.0%, preferably between 2.0% to 5.0% by weight.
In the present invention, polyvinylpyrrolidone is used as binder because compatible with most organic and inorganic pharmaceutical ingredients and it is appropriate for using delayed release. In addition to these, polyvinylpyrrolidone is used for easy availability and low cost.
In one embodiment of the invention, the weight ratio of polyvinylpyrrolidone to the weight of dimethyl fumarate in the capsule is between 0.01 -10.0, preferably the ratio is 0.05-5.0, more preferably the ratio is 0.05-1 .0.
Suitable disintegrants are selected from the group comprising hydroxypropyl starch, alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, powdered cellulose, chitosan, colloidal silicon dioxide, croscarmellose sodium, crospovidone, docusate sodium, guar gum, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, povidone, sodium alginate, sodium starch glycolate, starch, and pregelatinized starch or mixtures thereof, preferably the disintegrant is crospovidone. According to one embodiment of the present invention, the amount of the disintegrant in the capsule is between 1.0% to 12.0%, preferably between 3.0% to 10.0% by weight.
Suitable glidants are selected from the group comprising colloidal silicon dioxide, calcium phosphate, calcium silicate, powdered cellulose, magnesium stearate, magnesium silicate, magnesium trisilicate, silicon dioxide or mixtures thereof, preferably the glidant is colloidal silicon dioxide.
According to one embodiment of the present invention, the amount of the glidant in the capsule is between 0.1% to 3.0% by weight.
It has been found that colloidal silicon dioxide is more effective in terms of fluidity and homogeneity compared to talc. Thus, the capsule of the present invention is free of talc except for coatings and capsule shell.
Suitable lubricants are selected from the group comprising canola oil, hydroxyethyl cellulose, lauric acid, leucine, mineral oil, poloxamers, polyvinyl alcohol, oxtyldodecanol, sodium hyaluronate, sterilizable maize starch, triethanolamine, calcium stearate, magnesium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type I, light mineral oil, magnesium lauryl sulfate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium chloride, sodium lauryl sulfate, stearic acid, and zinc stearate or mixtures thereof, preferably the lubricant is magnesium stearate.
According to one embodiment of the present invention, the amount of the lubricant in the capsule is between 0.1% to 3.0% by weight.
According to one embodiment of the invention is to obtain a delayed release capsule comprising between 25.0% to 50.0% by weight of dimethyl fumarate, between 20.0% to 50.0% by weight of at least one filler, between 1.0% to 10.0% by weight of at least one binder, between 1.0% to 12.0% by weight of at least one disintegrant, between 0.1% to 3.0% by weight of at least one lubricant and between 0.1 % to 3.0% by weight of at least one glidant. Examples
This example describes the delayed release capsule comprising dimethyl fumarate. The active ingredient and excipients are given below:
Example 1 : Granules in enteric capsule of dimethyl fumarate
Figure imgf000009_0001
Example 2: Granules in enteric capsule of dimethyl fumarate
Figure imgf000009_0002
Process for example 1 and example 2
Process for preparing the enteric capsule comprising the following steps; a) mixing dimethyl fumarate, half of microcrystalline cellulose, polyvinylpyrrolidone and half of colloidal silicon dioxide
b) adding magnesium stearate and mixing
c) preparing dry granulation of the mixed components and sieving
d) obtaining the first part of the granule e) then, adding crospovidone, the remaining part of microcrystalline cellulose and the remaining part of colloidal silicon dioxide and mixing to obtain the granules (final granule)
f) filling the granules into enteric capsules
g) optionally, coating capsules with a coating comprising an enteric coating agent.
Ingredients of the enteric capsule shell
Figure imgf000010_0002
Example 3: Mini-tablet in the capsule of dimethyl fumarate
Figure imgf000010_0001
Process for example 3
Process for preparing the capsule comprising the following steps; a) mixing dimethyl fumarate, half of microcrystalline cellulose, polyvinylpyrrolidone, colloidal silicon dioxide for 10 minutes;
b) sieving half of magnesium stearate and adding the powder mixture of step (a) then mixing for 3 minutes; c) dry granulation of the mixed components;
d) mixing crospovidone and the remaining part of microcrystalline cellulose;
e) adding this mixture step (d) in step (c) mixture then mixing for 5 minutes;
f) sieving the remaining part of magnesium stearate and adding it to step (e) mixture then mixing for 3 minutes
g) compressing the blended mixture to form minitablet
h) coating with the mini tablet pre-coating, 30%-35% of all coating is pre-coating which comprises hydroxypropyl methyl cellulose, triacetin/glycerol triacetate, talc.
i) then coating the mini tablet with enteric coating, 45%-55% of all coating is enteric coating which comprises methacrylic acid/ethylacrylate 1 :1 co-polymer, talc, titanium dioxide, triethyl citrate.
j) finally, coating the mini tablets with film coating, 14%- 18% of all coating is film-coating which comprises hydroxypropylmethyl cellulose, triacetin/glycerol triacetate, talc, k) filling the mini tablets into capsules.

Claims

1 . A delayed release capsule comprising dimethyl fumarate and at least one pharmaceutically acceptable excipient wherein the particle size d (0.8) of dimethyl fumarate is less than 250 pm.
2. The delayed release capsule according to claim 1 , wherein the particle size d (0.8) of dimethyl fumarate is 249 pm to 180 pm.
3. The delayed release capsule according to claim 2, wherein the particle size d (0.8) of dimethyl fumarate is 180 pm to 100 pm.
4. The delayed release capsule according to claim 1 , wherein the amount of dimethyl fumarate in the capsule is between 18.0% to 70.0% by weight, preferably between 25 to 50.
5. The delayed release capsule according to claim 4, wherein the amount of dimethyl fumarate in the capsule is between 35.0% to 43.0% by weight.
6. The delayed release capsule according to any preceding claims, wherein the dosage form of dimethyl fumarate is a capsule filled with mini-tablets or granules.
7. The delayed release capsule according to claim 6, wherein mini-tablets in the capsule have at least one coating.
8. The delayed release capsule according to claim 7, wherein the coating is film coating or enteric coating.
9. The delayed release capsule according to claim 6, wherein granules are filled into an enteric capsule.
10. The delayed release capsule according to any preceding claims, wherein the capsule comprising at least one pharmaceutically acceptable excipient is selected from the group comprising disintegrants, fillers, binders, glidants, lubricants or mixtures thereof.
1 1. The delayed release capsule according to claim 10, wherein the binders are selected from the group comprising polyvinylpyrrolidone, gelatin, sugars, glucose, natural gums, synthetic celluloses, polymethacrylate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose or mixtures thereof; preferably the binder is polyvinylpyrrolidone.
12. The delayed release capsule according to claim 1 1 , wherein the weight ratio of polyvinylpyrrolidone to dimethyl fumarate in the capsule is 0.01 -10.0, preferably the ratio is 0.05-5.0, more preferably the ratio is 0.05-1 .0.
13. The delayed release capsule according to claim 10, wherein the glidants are selected from the group comprising colloidal silicon dioxide, calcium phosphate, calcium silicate, powdered cellulose, magnesium stearate, magnesium silicate, magnesium trisilicate, silicon dioxide or mixtures thereof.
14. The delayed release capsule according to claim 3, wherein the glidant is colloidal silicon dioxide and the amount of the glidant in the capsule is between 0.1% to 3.0% by weight.
15. The delayed release capsule according to any preceding claims, wherein the capsule is free of talc except for coatings and capsule shell.
16. The delayed release capsule according to any preceding claims, wherein the capsule comprising;
a. 25.0% w/w and 50.0% w/w of dimethyl fumarate
b. 30.0% w/w and 45.0% w/w of microcrystalline cellulose
c. 3.0% w/w and 10.0% w/w of crospovidone
d. 0.3% w/w and 3.0% w/w of colloidal silicon dioxide
e. 0.1% w/w and 2.0% w/w of magnesium stearate
f. 1.0% w/w and 10.0% w/w of polyvinylpyrrolidone by weight of the total composition.
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WO2016113754A2 (en) * 2015-01-14 2016-07-21 Leiutis Pharmaceuticals Pvt, Ltd. Novel oral dosage forms of dimethyl fumarate
AU2016279997B2 (en) * 2015-06-17 2021-10-21 Biogen Ma Inc. Dimethyl fumarate particles and pharmaceutical compositions thereof
WO2017145036A1 (en) * 2016-02-25 2017-08-31 Aurobindo Pharma Ltd Pharmaceutical compositions comprising dimethyl fumarate
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