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WO2020112060A1 - Composition comprenant du fumarate de diméthyle - Google Patents

Composition comprenant du fumarate de diméthyle 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
Authority
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
English (en)
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
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 AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of WO2020112060A1 publication Critical patent/WO2020112060A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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:

Landscapes

  • 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

La présente invention concerne une composition pharmaceutique comprenant du fumarate de diméthyle, au moins un excipient pharmaceutiquement acceptable et des granulés enrobés comportant au moins deux couches de revêtement.
PCT/TR2019/050965 2018-11-30 2019-11-18 Composition comprenant du fumarate de diméthyle Ceased WO2020112060A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2018/18307 2018-11-30
TR2018/18307A TR201818307A2 (tr) 2018-11-30 2018-11-30 Di̇meti̇l fumarat i̇çeren bi̇r kompozi̇syon

Publications (1)

Publication Number Publication Date
WO2020112060A1 true WO2020112060A1 (fr) 2020-06-04

Family

ID=70854331

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2019/050965 Ceased WO2020112060A1 (fr) 2018-11-30 2019-11-18 Composition comprenant du fumarate de diméthyle

Country Status (2)

Country Link
TR (1) TR201818307A2 (fr)
WO (1) WO2020112060A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116251074A (zh) * 2023-04-19 2023-06-13 成都百裕制药股份有限公司 一种富马酸二甲酯肠溶片以及肠溶胶囊
EP4346796A1 (fr) 2021-06-04 2024-04-10 Zim Laboratories Limited Compositions à libération retardée de fumarate de diméthyle

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016081676A1 (fr) * 2014-11-19 2016-05-26 Biogen Ma Inc. Formulation de bille pharmaceutique comprenant du fumarate de diméthyle
US20160228388A1 (en) * 2014-11-04 2016-08-11 Adamas Pharmaceuticals, Inc. Methods of administering amantadine compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160228388A1 (en) * 2014-11-04 2016-08-11 Adamas Pharmaceuticals, Inc. Methods of administering amantadine compositions
WO2016081676A1 (fr) * 2014-11-19 2016-05-26 Biogen Ma Inc. Formulation de bille pharmaceutique comprenant du fumarate de diméthyle

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Pharmaceutical dosage forms-tablets", TABLETTING OF MULTIPARTICULATE MODIFIED RELEASE SYSTEMS, 2016, pages 511 *
GAUR, PRAVEEN KUMAR ET AL.: "Film coating technology: past, present and future", JOURNAL OF PHARMACEUTICAL SCIENCES AND PHARMACOLOGY, vol. 1.1, 2014, pages 57 - 67 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4346796A1 (fr) 2021-06-04 2024-04-10 Zim Laboratories Limited Compositions à libération retardée de fumarate de diméthyle
EP4346796A4 (fr) * 2021-06-04 2025-04-30 Zim Laboratories Limited Compositions à libération retardée de fumarate de diméthyle
CN116251074A (zh) * 2023-04-19 2023-06-13 成都百裕制药股份有限公司 一种富马酸二甲酯肠溶片以及肠溶胶囊

Also Published As

Publication number Publication date
TR201818307A2 (tr) 2020-06-22

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