WO2017056107A1 - Compositions pharmaceutiques de fumarate de diméthyle - Google Patents

Compositions pharmaceutiques de fumarate de diméthyle Download PDF

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Publication number
WO2017056107A1
WO2017056107A1 PCT/IN2016/050324 IN2016050324W WO2017056107A1 WO 2017056107 A1 WO2017056107 A1 WO 2017056107A1 IN 2016050324 W IN2016050324 W IN 2016050324W WO 2017056107 A1 WO2017056107 A1 WO 2017056107A1
Authority
WO
WIPO (PCT)
Prior art keywords
dimethyl fumarate
tablets
pharmaceutical composition
enteric
pharmaceutically acceptable
Prior art date
Application number
PCT/IN2016/050324
Other languages
English (en)
Inventor
Satyanarayana VATTIKUTI
Krishna Murthy Bhavanasi
Rami Reddy BHIMAVARAPU
Venkaiah Chowdary Nannapaneni
Original Assignee
Natco Pharma Ltd
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 Natco Pharma Ltd filed Critical Natco Pharma Ltd
Publication of WO2017056107A1 publication Critical patent/WO2017056107A1/fr

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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
    • A61K9/48—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
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates

Definitions

  • the invention relates to oral pharmaceutical compositions of dimethyl fumarate and process for the preparation of such compositions.
  • Dimethyl fumarate is the methyl ester of fumaric acid and is chemically known as dimethyl (E) butenedioate with molecular formula C H8O4 and following structural formula:
  • Dimethylfumarate is commercially available as hard gelatin delayed-release capsules for oral administration under the trade name TECFIDERA ® .
  • TECFIDERA capsules contain 120 mg or 240 mg of dimethyl fumarate as active ingredient and microcrystalline cellulose, silicified microcrystalline cellulose, croscarmellose sodium, talc, silica colloidal silicon dioxide, magnesium stearate, triethyl citrate, methacrylic acid copolymer - Type A, methacrylic acid copolymer dispersion, simethicone (30% emulsion), sodium lauryl sulphate, and polysorbate 80.
  • the capsule shell printed with black ink, contains the following inactive ingredients: gelatin, titanium dioxide, FD&C blue 1; brilliant blue FCF, yellow iron oxide and black iron oxide.
  • TECFIDERA ® is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
  • US Patent No. 6,509,376 and US Patent No. 8,759,393 disclose capsule formulations containing microtablets or micropellets of alkyl fumarates like dimethyl fumarate.
  • US Patent Publications Nos. 20130216615 and 20150209318 disclose capsules composition comprising enteric coated microtablets and the uncoated microtablets comprises from about 43% w/w to about 95% w/w of dimethyl fumarate.
  • a pharmaceutical composition comprising: i) mini tablets comprising dimethyl fumarate and atleast one pharmaceutically acceptable excipient,
  • Embodiments of the present invention may include one or more of the following features for example the pharmaceutical composition may further include one or more pharmaceutical acceptable excipients.
  • the pharmaceutical acceptable excipients may include diluent, disintegrant, surfactant, binder, lubricant, glidant, plasticizer, anti-foaming agents, anti-tacking agent, opacifying agent, and the like.
  • the inventors of the present invention have developed a pharmaceutical composition
  • a pharmaceutical composition comprising: i) mini tablets comprising dimethyl fumarate and atleast one pharmaceutically acceptable excipient,
  • dimethyl fumarate ' is used in broad sense to include not only the dimethyl fumarate per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, - pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.
  • mini tablet means a a small tablet of about 1 mm to about 3 mm in diameter (excluding any coating) that comprises dimethyl fumarate and one or more excipients.
  • the total amount of dimethyl fumarate in the uncoated tablets is from about 95.5% to about 99.5%, more preferably from about 96% to about 99%.
  • the composition can comprise a total amount of pharmaceutically acceptable excipient(s), in an amount of about 0.5% to about 5.0% w/w, based on the total weight of the composition, excluding the weight of any coating.
  • Diluent includes, but are not limited to, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, sugars such as sucrose; sugar alcohols such as mannitol, sorbitol, erythritol; and mixtures thereof. Diluent may generally be added to increase the bulk volume of the powder to facilitate granulation or compression. The diluent may be present in an amount ranging from 0.1% to 5% by weight of the composition.
  • Disintegrant includes, but are not limited to, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate and mixtures thereof.
  • the disintegrant may be present in an amount ranging from 0.1% to 5% by weight of the composition.
  • Binder includes, but are not limited to, carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins and the like. Binder may be used as a component of the coat to ensure proper adhesion of the subsequent coats. The binder may be present in an amount ranging from 0% to 4% by weight of the composition.
  • Lubricant includes, but are not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and mixtures thereof.
  • Glidant includes talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate; and mixtures thereof.
  • the lubricant and/or glidant may be present in an amount ranging from 0% to 4% by weight of the composition.
  • the composition can be optionally coated or partially coated by one or more coatings.
  • the coating(s) can be pH independent or pH dependent.
  • the coating(s) can be, for example, enteric coatings, seal coatings, or combinations of enteric coatings and seal coatings.
  • the seal coating can contain plasticizers, copolymers, polymers, surfactants or combinations thereof.
  • the enteric coating can contain, plasticizers, anti-foaming agents, anti-tacking agents, polymers, copolymers, surfactants or combinations thereof.
  • Plasticizer may be used in a coat to increase the flexibility and strength of the layer and includes, but are not limited to, propylene glycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, diacetylated monoglyceride, dibutyl phthalate, dibutyl sebacate; or mixtures thereof.
  • the plasticizer may be present in an amount ranging from 0.1% to 20% by weight of the composition.
  • Antifoaming agent includes, but are not limited to, dimethicone, simethicone, and mixtures thereof.
  • Anti-tacking agent includes, but are not limited to, talc, kaolin, finely divided silicon dioxide, glyceryl monostearate, and the like.
  • the copolymer includes, but are not limited to, methacrylic acid-methacrylate copolymer, methacrylic acid-ethylacrylate copolymer, polyvinylpyrrolidone/vinyl acetate copolymer and the like.
  • Polymers includes, but are not limited to, cellulose derivatives such as hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl and methylcellulose, polyvinylpyrrolidone, ethyl cellulose, and ethyl cellulose aqueous dispersions (AQUACOAT®, SURELEASE®), EUDRAGIT® RL 30 D, OPADRY®, EUDRAGIT® S, EUDRAGIT® L, and the like.
  • cellulose derivatives such as hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl and methylcellulose
  • polyvinylpyrrolidone ethyl cellulose
  • EUDRAGIT® RL 30 D OPADRY®
  • EUDRAGIT® S EUDRAGIT® L
  • Surfactants includes, but are not limited to, nonionic or ionic surfactants, where nonionic surfactants includes, but are not limited to, polyoxyethylated glycol monoethers, cetomacrogol, sorbitan esters (Spans) and polysorbates (Tweens), polyoxyethylene- polyoxypropylene copolymers such as poloxameres, sugar esters with fatty acids with 10 to 22 C atoms.
  • Ionic surfactants selected from anionic surfactants such as organic sulphonates, sulphates e.g.
  • sodium lauryl sulphate, potassium laurate or cationic surfactants selected from the group consisting of organic quaternary ammonium halides, cetrimide, a mixture consisting of tetradecyl (about 68%), dodecyl (about 22%), hexadecyltrimethylammonium bromides (about 7%) and benzalkonium chloride.
  • Opacifying agent may be used in a coat to prevent photo-degradation and includes, but are not limited to, titanium dioxide, iron oxides, and the like.
  • Solvents for applying the coating materials includes, but are not limited to, water, acetone, hexane, ethanol, methanol, propanol, isopropanol, butanol, isobutanol, sec- butanol, tert-butanol, dichlormethane, trichloromethane, chloroform, and the like.
  • the coated mini tablets are placed in a capsule.
  • the capsule can contain, from about 10 to about 40 mini tablets.
  • Capsules considered are soft gelatin, hard gelatin, HPMC, polysaccharide or starch capsules as plugged, welded or glued capsules, of different size, colour, and water content.
  • hard gelatin capsules Preferably, hard gelatin capsules.
  • patients with multiple sclerosis are administered a capsule containing 240 mg DMF, twice daily for a total daily dose of 480 mg, wherein the capsule contains multiple mini tablets comprising more than 95% w/w dimethyl fumarate, by weight of the mini tablets without any coatings.
  • the mini tablets are first coated with a seal coat and then coated with an enteric coat.
  • compositions as described herein may be prepared by admixing dimethyl fumarate and atleast one pharmaceutically acceptable excipient followed by granulating and/or compressing into mini tablets.
  • stable pharmaceutical composition of dimethyl fumarate may be prepared by
  • stable pharmaceutical composition of dimethyl fumarate may be prepared by
  • stable pharmaceutical composition of dimethyl fumarate may be prepared by
  • Blended material was compressed into mini tablets with a tablet weight of 7 to 10 mg by using 2 mm punches.
  • Step 5 mini tablets were seal coated with coating suspension containing Opadry enteric coating system 940580021 white and Polysorbate 80 in a mixture of Isopropyl alcohol and water.
  • Step -7 enteric coated tablets were lubricated with talc.
  • Step -8 coated tablets were filled into Size "0" HG capsule. (30-34 mini tablets for 240 mg strength & 15-17 mini tablets for 120 mg strength).

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

Compositions pharmaceutiques orales de fumarate de diméthyle et procédé pour la préparation de telles compositions.
PCT/IN2016/050324 2015-09-28 2016-09-27 Compositions pharmaceutiques de fumarate de diméthyle WO2017056107A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN5172CH2015 2015-09-28
IN5172/CHE/2015 2015-09-28

Publications (1)

Publication Number Publication Date
WO2017056107A1 true WO2017056107A1 (fr) 2017-04-06

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PCT/IN2016/050324 WO2017056107A1 (fr) 2015-09-28 2016-09-27 Compositions pharmaceutiques de fumarate de diméthyle

Country Status (1)

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WO (1) WO2017056107A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3977986A4 (fr) * 2019-05-31 2022-07-20 CURACLE Co., Ltd. Comprimé gastrorésistant contenant du fumarate de diméthyle

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6509376B1 (en) 1998-11-19 2003-01-21 Fumapharm Ag Utilization of dialkyfumarates
WO2010126605A1 (fr) * 2009-04-29 2010-11-04 Biogen Idec Ma Inc. Traitement de la neurodégénérescence et de la neuroinflammation
WO2013119677A1 (fr) * 2012-02-07 2013-08-15 Biogen Idec Ma Inc. Compositions pharmaceutiques contenant du fumarate de diméthyle

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6509376B1 (en) 1998-11-19 2003-01-21 Fumapharm Ag Utilization of dialkyfumarates
US20070248663A1 (en) * 1998-11-19 2007-10-25 Joshi Rejendra K Utilization of Dialkylfumerates
US8759393B2 (en) 1998-11-19 2014-06-24 Biogen Idec International Gmbh Utilization of dialkylfumarates
WO2010126605A1 (fr) * 2009-04-29 2010-11-04 Biogen Idec Ma Inc. Traitement de la neurodégénérescence et de la neuroinflammation
WO2013119677A1 (fr) * 2012-02-07 2013-08-15 Biogen Idec Ma Inc. Compositions pharmaceutiques contenant du fumarate de diméthyle
US20130216615A1 (en) 2012-02-07 2013-08-22 David Goldman Pharmaceutical Compositions Containing Dimethyl Fumarate
US20150209318A1 (en) 2012-02-07 2015-07-30 Biogen Ma Inc. Pharmaceutical compositions containing dimethyl fumarate

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3977986A4 (fr) * 2019-05-31 2022-07-20 CURACLE Co., Ltd. Comprimé gastrorésistant contenant du fumarate de diméthyle

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