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WO2020112060A1 - A composition comprising dimethyl fumarate - Google Patents

A composition comprising dimethyl fumarate Download PDF

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Publication number
WO2020112060A1
WO2020112060A1 PCT/TR2019/050965 TR2019050965W WO2020112060A1 WO 2020112060 A1 WO2020112060 A1 WO 2020112060A1 TR 2019050965 W TR2019050965 W TR 2019050965W WO 2020112060 A1 WO2020112060 A1 WO 2020112060A1
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WO
WIPO (PCT)
Prior art keywords
coating
coated pellets
phthalate
pellets according
cellulose
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/TR2019/050965
Other languages
French (fr)
Inventor
Ali Turkyilmaz
Arzu PALANTOKEN
Fatih MOLLAOGLU
Dicle GUNER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret AS
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Filing date
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Publication of WO2020112060A1 publication Critical patent/WO2020112060A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising dimethyl fumarate, at least one pharmaceutically acceptable excipient and coated pellets which have at least two coating layers.
  • 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
  • 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 enteric coated minitablets.
  • TECFIDERA ® is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of granulated dimethyl fumarate enteric coated minitablets.
  • the patent application WO2015130998 A1 discloses a formulation, comprising fumarate ester as an active agent, lactic acid, polyoxyl 40 hydrogenated castor oil, polyvinylpyrrolidone, the mixture of mono and diglycerides.
  • oral pharmaceutically compositions comprise controlled release enteric soft capsules.
  • Enteric coat comprises, gelatin, glycerol, methylacrylic acid copolymer, triethyl citrate, ammonia, water and titanium dioxide.
  • EP2811994 A4 discloses comprising dimethyl fumarate and the pharmaceutically acceptable salt thereof that metabolize to monomethyl fumarate with certain pharmacokinetic parameters and methods for treating, prophylaxis, or amelioration of neurodegenerative diseases including multiple sclerosis using such compositions in a subject.
  • the patent application WO 2017114594 A1 discloses a pharmaceutical composition in the form of a granulate, a pellet or a mini-tablet comprising inner enteric coating layer. Also, the composition comprises a disintegrant is present in the amount of between 4.0% and 12.0%.
  • the pharmaceutical composition comprises coated pellets.
  • Coated pellets have at least two coating layers, one of them is inner coating layer which is film coating. It provides to prevent sublimation of dimethyl fumarate. Also, it provides surprising effects without side-effect.
  • dimethyl fumarate dissolves in suspension to form a coating solution. Then, the coating solution comprising dimethyl fumarate coat the pellets. This helps to prevent sublimation of dimethyl fumarate. Therefore, the pharmaceutical composition is obtained having excellent content uniformity.
  • the improved pharmaceutical composition of dimethyl fumarate has excellent pharmacotechnical properties (flowability and homogeneity, good content uniformity) and desired dissolution profile, a high solubility and a long-term stability.
  • the main object of the present invention is to provide the pharmaceutical composition having a desired dissolution profile, desired bioavailability and a long shelf life stability by the help of at least two coating layers.
  • a further object of the present invention is to provide a simple, cost-efficient, and time-saving process for the preparing the pharmaceutical composition comprising dimethyl fumarate.
  • neutral pellet refers drug-free cores which can be coated by a solution or suspension of API.
  • coated pellet refers a neutral pellet comprising an active ingredient and having at least two coating but, one of the coatings is enteric coating.
  • a coated pellet comprises a neutral pellet and dimethyl fumarate wherein the neutral pellet is coated with dimethyl fumarate to form coated pellets.
  • Suitable neutral pellets are selected from the group comprising sugars, non-pareils pellets, calcium carbonate, lactose, mannitol, tartaric acid, starch, citric acid, sucrose-maize starch, microcrystalline cellulose, polyols, carnauba wax, silica, lactose-starch, lactose-cellulose or mixtures thereof.
  • the neutral pellets are preferably present in the amount of between 10.0% and 40%, preferably between 15.0% and 35.0% by weight of a composition.
  • the coated pellets comprise dimethyl fumarate and at least one pharmaceutically acceptable excipient wherein the pellets having at least two coating layers.
  • Said at least two coating layers are an inner coating layer and an outer coating layer.
  • the inner coating layer is a film coating and the outer coating layer is an enteric coating.
  • the weight ratio of the enteric coating to the film coating is 0.6-30.0, preferably the ratio is 1.0-20.0, preferably the ratio is 1.5-15.0.
  • the amount of dimethyl fumarate is preferably present in the amount of between 30.0% and 45.0%, preferably between 35.0% and 42.0% by weight of a pharmaceutical composition.
  • the film-coating helps to provide the desired dissolution profile by preventing sublimation of dimethyl fumarate.
  • the enteric coating provides resistance to acidity of pellets until the capsule reaches the small intestine. With the help of the enteric coating, the pellets are dissolved in intestine not in the stomach.
  • Coating agents may be interacted with active agents or excipients. However, in this invention selected coating agents are not chemically interacted with the formulation. They also provide chemical stability for the formulation.
  • the enteric coating comprises at least one enteric coating agent.
  • Suitable enteric coating agents are selected from the group comprising hydroxypropylmethyl cellulose phthalate, poly(methacrylic acid, methyl methacrylate) 1 :1 and/or poly(methacrylic acid, ethyl acrylate), cellulose acetate phthalate, cellulose acetate succinate, hydroxpropyl cellulose, hydroxpropyl ethylcellulose, hydroxpropyl ethylcellulose phthalate, hydroxyl propyl methyl cellulose, hydroxyethyl cellulose phthalate, methylcellulose phthalate, polyvinyl acetate, polyvinyl acetate phthalate, polyvinylacetate hydrogen phthalate, cellulose ester phthalates, cellulose ether phthalates, sodium cellulose acetate phthalate, starch, starch acid phthalate, cellulose acetate butyrate, cellulose acetate maleate, cellulose acetate
  • the film coating comprising at least one film coating agent.
  • suitable film-coating agents are selected from the group comprising hydroxypropyl methylcellulose, triacetin/glycerol triacetin, talc, polymethacrylates, , lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), lecithin, polyethylene glycol (PEG), macrogol-PEG, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, macrogol, coloring agent or mixtures thereof.
  • the inner coating provides high chemical and mechanical stability.
  • This coating also provides the enteric coating to enhance the adhesion to the pellets.
  • the coated pellets further comprise a coating solution comprising dimethyl fumarate. Coating the pellets with coating solution comprising dimethyl fumarate is called loading of the active substance.
  • the coated pellets comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising binders, plasticizers, adsorbent or mixtures thereof.
  • Suitable binders are selected from the group comprising polyvinylpyrrolidone, carbomers, carboxymethylcellulose sodium, calcium carbonate, calcium phosphate, calcium sulfate, cellulose, dextrin, shellac, zein, gelatin, polymethacrylates, pregelatinized starch, sodium alginate, gums, synthetic resins, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, collagens, agar, alginate, alginic acid, hyaluronic acid, pectin, polysaccharides, poloxamer, polyacrylamide, aluminium hydroxide, laponit, bentonit, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
  • plasticizers make a composition to achieve improved compound processing characteristics, compatibility, processibility, permanence and other performance properties while also providing flexibility in the end-use product.
  • Suitable plasticizers are selected from the group comprising triethyl citrate, diethyl phthalate, cetyl alcohol, propylene glycol, acetyl triethyl citrate, diacetylated monoglyceride, dibutyl phthalate, dibutyl sebacate, polyethylene glycols of different molecular weights, triacetin, tributyl citrate, dimethyl phthalate, glycerin, mannitol, petrolatum and lanolin alcohols, propylene glycol or mixtures thereof.
  • the plasticizers are preferably present in the amount of between 1.0% and 25%, preferably between 1.0% and 15.0% by weight of a pharmaceutical composition.
  • the preferred plasticizer is triethyl citrate, diethyl phthalate, cetyl alcohol or mixtures thereof.
  • This selected plasticizer and the amount of the plasticizer provides making pellet formation easy and effective. So, it provides desired dissolution profile of active agent.
  • Suitable adsorbent is selected from silicon dioxide, aluminum magnesium silicate or mixtures thereof.
  • the adsorbent is preferably present in the amount of between 0.1 and 5.0% by weight to the total weight of a pharmaceutical composition.
  • the preferred adsorbent is silicon dioxide.
  • At least one pharmaceutically acceptable excipient is selected from the group comprising polyvinylpyrrolidone, triethyl citrate, diethyl phthalate or cetyl alcohol, silicon dioxide or mixtures thereof.
  • the pharmaceutically acceptable excipients which are plasticizers, binders, adsorbents are mixed with pure water to prepare a suspension. After, dimethyl fumarate dissolves in the suspension and obtained the coating solution. Therefore, the pharmaceutical composition is obtained having excellent content uniformity.
  • the suspension is formed with water and so, dimethyl fumarate can be solved easily.
  • the pellets are free of disintegrant.
  • said disintegrant is croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, sodium alginate.
  • the final dosage form of the present invention is in the form of capsules or sachets.
  • the coated pellets are filled into said capsules or sachets.
  • the pharmaceutical composition can be prepared by pellet coating techniques.
  • Example 1 Enteric coated pellets
  • Example 3 Capsule comprising enteric coated pellets
  • Example 4 Capsule comprising enteric coated pellets
  • the process for the preparation of the composition comprises the following steps:
  • the process for the preparation of the composition comprises the following steps:

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to a pharmaceutical composition comprising dimethyl fumarate, at least one pharmaceutically acceptable excipient and coated pellets which have at least two coating layers.

Description

A COMPOSITION COMPRISING DIMETHYL FUMARATE
Field of the invention
The present invention relates to a pharmaceutical composition comprising dimethyl fumarate, at least one pharmaceutically acceptable excipient and coated pellets which have at least two coating layers.
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 (CeHsCU) 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 enteric 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 WO2015130998 A1 discloses a formulation, comprising fumarate ester as an active agent, lactic acid, polyoxyl 40 hydrogenated castor oil, polyvinylpyrrolidone, the mixture of mono and diglycerides. In particular, oral pharmaceutically compositions comprise controlled release enteric soft capsules. Enteric coat comprises, gelatin, glycerol, methylacrylic acid copolymer, triethyl citrate, ammonia, water and titanium dioxide.
The patent application EP2811994 A4 discloses comprising dimethyl fumarate and the pharmaceutically acceptable salt thereof that metabolize to monomethyl fumarate with certain pharmacokinetic parameters and methods for treating, prophylaxis, or amelioration of neurodegenerative diseases including multiple sclerosis using such compositions in a subject.
The patent application WO 2017114594 A1 discloses a pharmaceutical composition in the form of a granulate, a pellet or a mini-tablet comprising inner enteric coating layer. Also, the composition comprises a disintegrant is present in the amount of between 4.0% and 12.0%.
In comparison to prior art, in the present invention, the pharmaceutical composition comprises coated pellets. Coated pellets have at least two coating layers, one of them is inner coating layer which is film coating. It provides to prevent sublimation of dimethyl fumarate. Also, it provides surprising effects without side-effect.
Furthermore, in comparison to prior art, in the present invention, dimethyl fumarate dissolves in suspension to form a coating solution. Then, the coating solution comprising dimethyl fumarate coat the pellets. This helps to prevent sublimation of dimethyl fumarate. Therefore, the pharmaceutical composition is obtained having excellent content uniformity.
In the present invention, the improved pharmaceutical composition of dimethyl fumarate has excellent pharmacotechnical properties (flowability and homogeneity, good content uniformity) and desired dissolution profile, a high solubility and a long-term stability. Detailed description of the Invention
The main object of the present invention is to provide the pharmaceutical composition having a desired dissolution profile, desired bioavailability and a long shelf life stability by the help of at least two coating layers.
A further object of the present invention is to provide a simple, cost-efficient, and time-saving process for the preparing the pharmaceutical composition comprising dimethyl fumarate.
The term "neutral pellet” refers drug-free cores which can be coated by a solution or suspension of API.
The term "coated pellet” refers a neutral pellet comprising an active ingredient and having at least two coating but, one of the coatings is enteric coating.
According to one embodiment of the present invention, a coated pellet comprises a neutral pellet and dimethyl fumarate wherein the neutral pellet is coated with dimethyl fumarate to form coated pellets.
Suitable neutral pellets are selected from the group comprising sugars, non-pareils pellets, calcium carbonate, lactose, mannitol, tartaric acid, starch, citric acid, sucrose-maize starch, microcrystalline cellulose, polyols, carnauba wax, silica, lactose-starch, lactose-cellulose or mixtures thereof. The neutral pellets are preferably present in the amount of between 10.0% and 40%, preferably between 15.0% and 35.0% by weight of a composition.
According to one embodiment of the present invention, the coated pellets comprise dimethyl fumarate and at least one pharmaceutically acceptable excipient wherein the pellets having at least two coating layers. Said at least two coating layers are an inner coating layer and an outer coating layer. The inner coating layer is a film coating and the outer coating layer is an enteric coating. Surprisingly, it has been found that using film coating as inner coating and enteric coating as outer coating provides improved stability and better dissolution profile to the composition.
According to one embodiment of the present invention, the weight ratio of the enteric coating to the film coating is 0.6-30.0, preferably the ratio is 1.0-20.0, preferably the ratio is 1.5-15.0. According to one embodiment of the present invention, the amount of dimethyl fumarate is preferably present in the amount of between 30.0% and 45.0%, preferably between 35.0% and 42.0% by weight of a pharmaceutical composition.
According to one embodiment of the present invention, the film-coating helps to provide the desired dissolution profile by preventing sublimation of dimethyl fumarate. The enteric coating provides resistance to acidity of pellets until the capsule reaches the small intestine. With the help of the enteric coating, the pellets are dissolved in intestine not in the stomach.
Therefore, the desired dissolution can be achieved. Furthermore, it is very important to choose the coating agents. Coating agents may be interacted with active agents or excipients. However, in this invention selected coating agents are not chemically interacted with the formulation. They also provide chemical stability for the formulation.
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 hydroxypropylmethyl cellulose phthalate, poly(methacrylic acid, methyl methacrylate) 1 :1 and/or poly(methacrylic acid, ethyl acrylate), cellulose acetate phthalate, cellulose acetate succinate, hydroxpropyl cellulose, hydroxpropyl ethylcellulose, hydroxpropyl ethylcellulose phthalate, hydroxyl propyl methyl cellulose, hydroxyethyl cellulose phthalate, methylcellulose phthalate, polyvinyl acetate, polyvinyl acetate phthalate, polyvinylacetate hydrogen phthalate, cellulose ester phthalates, cellulose ether phthalates, sodium cellulose acetate phthalate, starch, starch acid phthalate, cellulose acetate butyrate, cellulose acetate maleate, cellulose acetate trimellitate, cellulose acetate propionate, cellulose acetate phthalate, ammonium methacrylate copolymers, hydrogels, hydroxypropylmethyl cellulose acetate succinate polymers, polyvinyl acetate phthalate polymers or mixtures thereof. The enteric coating agents are preferably present in the amount of between 3.0% and 15.0%, preferably between 4.0% and 13.0%, preferably between 5.0% and 10.0% by weight of a pharmaceutical composition.
According to one embodiment of the present invention, the film coating comprising at least one film coating agent. Suitable film-coating agents are selected from the group comprising hydroxypropyl methylcellulose, triacetin/glycerol triacetin, talc, polymethacrylates, , lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), lecithin, polyethylene glycol (PEG), macrogol-PEG, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, macrogol, coloring agent or mixtures thereof.
According to one embodiment of the present invention, the inner coating, film coating, provides high chemical and mechanical stability. This coating also provides the enteric coating to enhance the adhesion to the pellets.
According to one embodiment of the present invention, the coated pellets further comprise a coating solution comprising dimethyl fumarate. Coating the pellets with coating solution comprising dimethyl fumarate is called loading of the active substance.
According to one embodiment of the present invention, the coated pellets comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising binders, plasticizers, adsorbent or mixtures thereof.
Suitable binders are selected from the group comprising polyvinylpyrrolidone, carbomers, carboxymethylcellulose sodium, calcium carbonate, calcium phosphate, calcium sulfate, cellulose, dextrin, shellac, zein, gelatin, polymethacrylates, pregelatinized starch, sodium alginate, gums, synthetic resins, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, collagens, agar, alginate, alginic acid, hyaluronic acid, pectin, polysaccharides, poloxamer, polyacrylamide, aluminium hydroxide, laponit, bentonit, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof. The binders are preferably present in the amount of between 0.1% and 5.0%, preferably between 0.5% and 4.0% by weight of a pharmaceutical composition. The preferred binder is polyvinylpyrrolidone.
Typically, plasticizers make a composition to achieve improved compound processing characteristics, compatibility, processibility, permanence and other performance properties while also providing flexibility in the end-use product.
Suitable plasticizers are selected from the group comprising triethyl citrate, diethyl phthalate, cetyl alcohol, propylene glycol, acetyl triethyl citrate, diacetylated monoglyceride, dibutyl phthalate, dibutyl sebacate, polyethylene glycols of different molecular weights, triacetin, tributyl citrate, dimethyl phthalate, glycerin, mannitol, petrolatum and lanolin alcohols, propylene glycol or mixtures thereof. The plasticizers are preferably present in the amount of between 1.0% and 25%, preferably between 1.0% and 15.0% by weight of a pharmaceutical composition. The preferred plasticizer is triethyl citrate, diethyl phthalate, cetyl alcohol or mixtures thereof.
This selected plasticizer and the amount of the plasticizer provides making pellet formation easy and effective. So, it provides desired dissolution profile of active agent.
Suitable adsorbent is selected from silicon dioxide, aluminum magnesium silicate or mixtures thereof. The adsorbent is preferably present in the amount of between 0.1 and 5.0% by weight to the total weight of a pharmaceutical composition. The preferred adsorbent is silicon dioxide.
According to one embodiment of the present invention, at least one pharmaceutically acceptable excipient is selected from the group comprising polyvinylpyrrolidone, triethyl citrate, diethyl phthalate or cetyl alcohol, silicon dioxide or mixtures thereof.
According to one embodiment of the present invention, the pharmaceutically acceptable excipients which are plasticizers, binders, adsorbents are mixed with pure water to prepare a suspension. After, dimethyl fumarate dissolves in the suspension and obtained the coating solution. Therefore, the pharmaceutical composition is obtained having excellent content uniformity.
According to one embodiment of the present invention, it is not necessary to use a disintegrant in the pharmaceutical composition because the suspension is formed with water and so, dimethyl fumarate can be solved easily.
According to one embodiment of the present invention, the pellets are free of disintegrant.
According to one embodiment of the present invention, said disintegrant is croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, sodium alginate.
According to one embodiment of the present invention, the final dosage form of the present invention, the pharmaceutical composition, is in the form of capsules or sachets. The coated pellets are filled into said capsules or sachets. According to one embodiment of the present invention, the pharmaceutical composition can be prepared by pellet coating techniques.
Example 1 : Enteric coated pellets
Figure imgf000008_0001
Example 2: Enteric coated pellets
Figure imgf000008_0002
Example 3: Capsule comprising enteric coated pellets
Figure imgf000008_0003
Example 4: Capsule comprising enteric coated pellets
Figure imgf000009_0001
*Film coating
Figure imgf000009_0002
**Enteric coating
Figure imgf000009_0003
Process for example 1 or 2;
The process for the preparation of the composition comprises the following steps:
Loading of the active substance
a) blending plasticizers with binders and adsorbent,
b) mixing with pure water to prepare suspension,
c) adding dimethyl fumarate and mixing to obtain the coating solution
d) adding neutral pellets to the fluid bed dryer,
e) then, coating neutral pellets with the coating solution comprising dimethyl fumarate,
Film coating layer
f) mixing hydroxy propyl methyl cellulose, triacetin/glycerol triacetin, talc as film coating agents to obtain the film coating g) then, coating the coated pellets comprising active agent with the film coating to obtain a film coating,
Enteric coating laver
h) mixing enteric coating agents to obtain the enteric coating
i) then, coating the film-coated pellets comprising active agent with the enteric coating to obtain the enteric coating,
j) then, filling the enteric coated pellets into capsules.
Process for example 3 or 4:
The process for the preparation of the composition comprises the following steps:
Loading of the active substance
a) blending triethyl citrate, diethyl phthalate or cetyl alcohol with polyvinylpyrrolidone and silicon dioxide,
b) mixing with pure water to prepare suspension,
c) adding dimethyl fumarate and mixing to obtain the coating solution
d) adding neutral pellets to the fluid bed dryer,
e) then, coating neutral pellets with the coating solution comprising dimethyl fumarate
Film coating laver
f) mixing hydroxy propyl methyl cellulose, triacetin/glycerol triacetin, talc as film coating agents to obtain the film coating
g) then, coating the coated pellets comprising active agent with the film coating to obtain the film coating,
Enteric coating laver
h) mixing enteric coating agents to obtain the enteric coating
i) then, coating the film-coated pellets comprising the active agent with the enteric coating to obtain the enteric coating,
j) Then, filling the enteric coated pellets into capsules.

Claims

1. A coated pellet comprising a neutral pellet and dimethyl fumarate wherein the neutral pellet is coated with dimethyl fumarate to form coated pellets.
2. The coated pellets according to claim 1 , wherein the neutral pellets are selected from the group comprising sugars, non-pareils pellets, calcium carbonate, lactose, mannitol, tartaric acid, starch, citric acid, sucrose-maize starch, microcrystalline cellulose, polyols, carnauba wax, silica, lactose-starch, lactose-cellulose or mixtures thereof.
3. The coated pellets according to claim 1 , wherein said at least two coating layers are an inner coating layer and an outer coating layer.
4. The coated pellets according to claim 3, wherein the inner coating layer is a film coating and the outer coating layer is an enteric coating.
5. The coated pellets according to claim 4, wherein the weight ratio of the enteric coating to the film coating is 0.6-30.0.
6. The coated pellets according to claim 1 , wherein the amount of dimethyl fumarate is present between 30.0% and 45.0% by weight of a pharmaceutical composition.
7. The coated pellets according to claim 4, wherein the enteric coating comprising at least one enteric coating agent.
8. The coated pellets according to claim 7, wherein the enteric coating agents are selected from the group comprising hydroxypropyl methyl cellulose phthalate, poly(methacrylic acid, methyl methacrylate) 1 :1 and/or poly(methacrylic acid, ethyl acrylate), cellulose acetate phthalate, cellulose acetate succinate, hydroxpropyl cellulose, hydroxpropyl ethylcellulose, hydroxpropyl ethylcellulose phthalate, hydroxyl propyl methyl cellulose, hydroxyethyl cellulose phthalate, methylcellulose phthalate, polyvinyl acetate, polyvinyl acetate phthalate, polyvinylacetate hydrogen phthalate, cellulose ester phthalates, cellulose ether phthalates, sodium cellulose acetate phthalate, starch, starch acid phthalate, cellulose acetate butyrate, cellulose acetate maleate, cellulose acetate trimellitate, cellulose acetate propionate, cellulose acetate phthalate, ammonium methacrylate copolymers, hydrogels, hydroxypropylmethyl cellulose acetate succinate polymers, polyvinyl acetate phthalate polymers or mixtures thereof.
9. The coated pellets according to claim 3, wherein the film coating comprising at least one film coating agent.
10. The coated pellets according to claim 1 , further comprising at least one pharmaceutically acceptable excipient which is selected from the group comprising binders, plasticizers, adsorbent or mixtures thereof.
11. The coated pellets according to claim 10, wherein the plasticizers are selected from the group comprising triethyl citrate, diethyl phthalate, cetyl alcohol, propylene glycol, acetyl triethyl citrate, diacetylated monoglyceride, dibutyl phthalate, dibutyl sebacate, polyethylene glycols of different molecular weights, triacetin, tributyl citrate, dimethyl phthalate, glycerin, mannitol, petrolatum and lanolin alcohols, propylene glycol or mixtures thereof.
12. The coated pellets according to claim 11 , wherein the plasticizers are triethyl citrate, diethyl phthalate, cetyl alcohol or mixtures thereof.
13. The coated pellets according to claim 12, wherein the plasticizers are present in the amount of between 1.0% and 25% by weight of a pharmaceutical composition.
14. The coated pellets according to claim 1 , wherein at least one pharmaceutically acceptable excipient is selected from the group comprising polyvinylpyrrolidone, triethyl citrate, diethyl phthalate or cetyl alcohol, silicon dioxide or mixtures thereof.
15. The coated pellets according to claim 14, wherein a pharmaceutical composition is free of disintegrant.
16. The coated pellets according to any preceding claim, wherein a pharmaceutical composition is capsules or sachets and the coated pellets are filled into capsules or sachets.
17. The coated pellets according to claim 16, wherein the pharmaceutical composition is prepared by pellet coating techniques.
18. The coated pellets according to any preceding claim, comprising;
a. 30.0% to 45.0% by weight of dimethyl fumarate,
b. 10% to 40% by weight of neutral pellet,
c. 0.1 % to 5.0% by weight of triethyl citrate,
d.1.0% to 20.0% by weight of diethyl phthalate or cetyl alcohol,
e. 0.1 % to 5.0% by weight of polyvinylpyrrolidone, f. 0.1% to 5.0% by weight of silicon dioxide of the pharmaceutical composition and g. film coating agents
h. enteric coating agents
19. Process for preparing the coated pellets according to claim 18, comprising the following steps;
Loading of the active substance
a) blending triethyl citrate, diethyl phthalate or cetyl alcohol with polyvinylpyrrolidone and silicon dioxide,
b) mixing with pure water to prepare suspension,
c) adding dimethyl fumarate and mixing to obtain the coating solution
d) adding neutral pellets to the fluid bed dryer,
e) then, coating neutral pellets with the coating solution comprising dimethyl fumarate
Film coating laver
f) mixing hydroxy propyl methyl cellulose, triacetin/glycerol triacetin, talc as film coating agents to obtain the film coating
g) then, coating the coated pellets comprising active agent with the film coating to obtain the film coating,
Enteric coating laver
h) mixing enteric coating agents to obtain the enteric coating
i) then, coating the film-coated pellets comprising the active agent with the enteric coating to obtain the enteric coating,
j) Then, filling the enteric coated pellets into capsules.
PCT/TR2019/050965 2018-11-30 2019-11-18 A composition comprising dimethyl fumarate Ceased WO2020112060A1 (en)

Applications Claiming Priority (2)

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TR2018/18307 2018-11-30
TR2018/18307A TR201818307A2 (en) 2018-11-30 2018-11-30 A COMPOSITION CONTAINING DIMETHYL FUMARATE

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Cited By (2)

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EP4346796A1 (en) 2021-06-04 2024-04-10 Zim Laboratories Limited Delayed release compositions of dimethyl fumarate

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Publication number Priority date Publication date Assignee Title
EP4346796A1 (en) 2021-06-04 2024-04-10 Zim Laboratories Limited Delayed release compositions of dimethyl fumarate
EP4346796A4 (en) * 2021-06-04 2025-04-30 Zim Laboratories Limited DELAYED-RELEASE COMPOSITIONS OF DIMETHYL FUMARATE
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