WO2019132838A1 - Compositions pharmaceutiques de dabigatran - Google Patents

Compositions pharmaceutiques de dabigatran Download PDF

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Publication number
WO2019132838A1
WO2019132838A1 PCT/TR2018/050900 TR2018050900W WO2019132838A1 WO 2019132838 A1 WO2019132838 A1 WO 2019132838A1 TR 2018050900 W TR2018050900 W TR 2018050900W WO 2019132838 A1 WO2019132838 A1 WO 2019132838A1
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WO
WIPO (PCT)
Prior art keywords
poly
acid
pharmaceutical composition
composition according
water
Prior art date
Application number
PCT/TR2018/050900
Other languages
English (en)
Inventor
Ali TÜRKYILMAZ
Arzu Palantöken
Yildiz GÜLKOK
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 EP18847286.4A priority Critical patent/EP3731830A1/fr
Publication of WO2019132838A1 publication Critical patent/WO2019132838A1/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
    • A61K9/50—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars

Definitions

  • the present invention relates to pharmaceutical compositions for oral administration comprising a core comprising dabigatran etexilate free base or a pharmaceutically acceptable salt of dabigatran etexilate and a separating layer and an acid layer.
  • Dabigatran etexilate (Formula 1 ), which is already known from WO 98/37075, is a direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrilation.
  • Thrombin is a multifunctional enzyme which converts fibrinogen to fibrin, cross-linking fibrin monomers via activation of factor XIII and augmenting further thrombin production via the activation of factors V and VIII. It also activates platelets, generates anticoagulant activity via activation of protein C and initiates numerous cellular processes.
  • the methane sulphonic acid addition salt of dabigatran etexilate which is commercially available under the trade name PRADAXA® immediate release capsule (in the strength of 75, 1 10, 150 mg), is disclosed in EP1870100, wherein also disclosed, pellet formulation of dabigatran etexilate methanesulphonate.
  • This composition is formulated with a core material consisting of organic acid and an active layer which encloses the core.
  • Each PRADAXA® capsule contains the following inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropylcellulose, tartaric acid, carrageenan, potassium chloride, talc, titanium dioxide, and gelatin.
  • WO2012/077136 is directed to the oxalate salt of dabigatran etexilate and besides, its hydrochloride salt is identified in EP1877395.
  • weakly basic drugs such as dabigatran and dabigatran etexilate
  • weakly basic drugs are formulated with an acidic excipient.
  • Patent application EP1658056 discloses a conventional tablet formulation comprising dabigatran etexilate, organic acid with a solubility in water of > 1 g / 250 ml at 20°C together with conventional excipients and fillers. But in the patent application EP1658056, there is no insulating layer between the active agent and the organic acid.
  • W003/074056 discloses a composition contains the following components: a core material comprising an organic acid, an insulating layer which separates the acid core from the layer containing the active substance and an active agent layer.
  • Patent application WO2012001 156 relates to a process for the preparation of a solid oral dosage form comprising dabigatran etexilate.
  • the pellets comprise a neutral core comprised of sucrose, microcrystalline cellulose or starch, or a commercially available tartaric acid pellet; the tartaric acid layer, the isolating layer, the active pharmaceutical ingredient layer and, optionally, an overcoat.
  • Dabigatran etexilate is also less stable in acidic environment. To avoid this stability problem, many solutions were offered in the prior art. Separating layer between the acidic core and the active substance layer is the most preferred way. In this invention, the separating layer is used and in comparison to prior art, the composition of this invention is more stable since the active agent is not in the outer layer of the composition.
  • the main object of the present invention is to provide pH-independent pharmaceutical compositions for oral administration comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient.
  • a further object of the present invention is to provide stable pharmaceutical compositions which are not prone to phase transformation and degradation.
  • the pharmaceutical composition for oral administration comprises:
  • a core comprising dabigatran etexilate free base or a pharmaceutically acceptable salt of dabigatran etexilate and at least one pharmaceutically acceptable excipient
  • a separating layer comprising at least one pharmaceutically acceptable excipient
  • the separating layer is between the core and the acid layer.
  • dabigatran etexilate free base refers to dabigatran etexilate which is free from other forms of the active moiety, especially acid addition salts.
  • dabigatran etexilate free base or a pharmaceutically acceptable salt of dabigatran etexilate is present in an amount of between 30.00% and 80.00%, preferably between 40.00% and 60.00% and more preferably it is 45.00% to 60.00% by weight of the total formulation.
  • dabigatran etexilate free base or a pharmaceutically acceptable salt of dabigatran etexilate is present in an amount of between 30 to 350 mg, preferably 50 to 300 mg and more preferably it is 50 to 250 mg.
  • said at least one pharmaceutically acceptable excipient in the core is filler or binder.
  • suitable fillers are selected from a group comprising microcrystalline cellulose, lactose, mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate, polyols, dextrose, maltitol or mixtures thereof.
  • the filler is microcrystalline cellulose.
  • the filler is present in an amount of between 5.0% and 50.0% by weight of the total formulation.
  • Suitable binders are selected from a group comprising polyvinylpyrrolidone, carnauba wax, pullulan, glyceryl behenate, polycarbophil, polyvinyl acetate, cellulose acetate phthalate, hydroxypropyl starch, sugars, tragacanth gum, cetostearyl alcohol, acacia mucilage, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, cellulose derivatives such as hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, ethyl cellulose, microcrystalline cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, carrageenan, guar gum, polymethacrylates, methacrylate polymers, collagens, gelatin, agar, alginate, xanthan gum, hy
  • the core further comprises one or more pharmaceutically acceptable excipient which is selected from a group comprising anticaking agents, water-soluble polymers or mixtures thereof.
  • Suitable water-soluble polymer is selected from the group comprising hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose and derivatives, ethylcellulose and ethyl hydroxyethylcellulose, carboxymethylcellulose (CMC), methyl cellulose (MC), polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyethylene oxide (PEO), polyethylene oxide-b-propylene oxide), polyoxyethylene (POE), poly vinyl pyrrolidone (PVP), polyethylenimine (PEI), poly(N-vinylpyrrolidone/vinyl acetate), polyvinylpyrollidone PVP K-90, polyacrylic acid and copolymers, poly(vinylamine) hydrochloride, poly(acrylic acid sodium salt), poly(methacrylic acid), poly(methylacrylic acid sodium salt), poly(ethylene/acrylic acid), poly(2-hydroxyethyl methacrylate/methacrylic acid
  • the water-soluble polymer in the core is hydroxypropyl cellulose (HPC).
  • Suitable anticaking agents are selected from a group comprising talc, magnesium silicate, magnesium trisilicate, magnesium oxide, hydroxypropyl cellulose, hydroxyethyl cellulose, hydrophobic colloidal silica, guar gum, colloidal silicon dioxide, calcium silicate, calcium phosphate or mixtures thereof.
  • the anticaking agent in the core is talc.
  • said at least one pharmaceutically acceptable excipient in the separating layer is selected from water-soluble excipients, water-insoluble excipients or mixtures thereof.
  • Suitable water-soluble excipients are selected from the group comprising hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose and derivatives, ethylcellulose and ethyl hydroxyethylcellulose, carboxymethylcellulose (CMC), methyl cellulose (MC), polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyethylene oxide (PEO), polyethylene oxide-b-propylene oxide), polyoxyethylene (POE), poly vinyl pyrrolidone (PVP), polyethylenimine (PEI), poly(N-vinylpyrrolidone/vinyl acetate), polyvinylpyrollidone PVP K-90, polyacrylic acid and copolymers, poly(vinylamine) hydrochloride, poly(acrylic acid sodium salt), poly(methacrylic acid), poly(methylacrylic acid sodium salt), poly(ethylene/acrylic acid), poly(2-hydroxyethyl methacrylate/methacryl
  • the water-soluble excipients are hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG) in the separating layer.
  • HPMC hydroxypropyl methylcellulose
  • PEG polyethylene glycol
  • Suitable water-insoluble excipients are selected from a group comprising talc, magnesium silicate, magnesium trisilicate, magnesium oxide, colloidal silicon dioxide, calcium silicate, calcium phosphate or mixtures thereof.
  • the water-insoluble excipient in the seprating layer is talc.
  • the weight ratio of water-insoluble excipients to water-soluble excipients in the separating layer is between 0.01 and 0.5, the stability of the composition is ensured.
  • this ratio is between 0.01 and 0.2. More preferably this ratio is between 0.5 and 0.1 .
  • Choices of the excipients in the separating layer is important for the stability of the composition since dabigatran etexilate is not stable in the acid environment.
  • the water-soluble excipient is polyethylene glycol.
  • polyethylene glycol is present in an amount of between 0.10% and 10.00% by weight of the total formulation, preferably between 0.10% and 5.00%.
  • the water-soluble excipient is hydroxypropyl methylcellulose.
  • hydroxypropyl methylcellulose is present in an amount of between 5.00% and 20.00% by weight of the total formulation.
  • polyethylene glycol and hydroxypropyl methylcellulose are used together in the separating layer as water-soluble excipients.
  • the weight ratio of polyethylene glycol to hydroxypropyl methycellulose is between 0.005 and 2.00. This preferred selection of range assures the enhanced stability during the shelf-life.
  • the organic acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid or aspartic acid or hydrates or salts thereof.
  • the organic acid is present in an amount of between 5.00% and 30.00% by weight of the total formulation.
  • the acid layer further comprises at least one pharmaceutically acceptable excipient which is selected from water-soluble polymers, anticaking agent or mixtures thereof.
  • Suitable water-soluble polymers are selected from the group comprising hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose and derivatives, ethylcellulose and ethyl hydroxyethylcellulose, carboxymethylcellulose (CMC), methyl cellulose (MC), polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyethylene oxide (PEO), polyethylene oxide-b-propylene oxide), polyoxyethylene (POE), poly vinyl pyrrolidone (PVP), polyethylenimine (PEI), poly(N-vinylpyrrolidone/vinyl acetate), polyvinylpyrollidone PVP K-90, polyacrylic acid and copolymers, poly(vinylamine) hydrochloride, poly(acrylic acid sodium salt), poly(methacrylic acid), poly(methylacrylic acid sodium salt), poly(ethylene/acrylic acid), poly(2-hydroxyethyl methacrylate/methacrylic acid
  • the water-soluble polymer in the acid layer is hydroxpropyl cellulose.
  • Suitable anticaking agents in the acid layer are selected from a group comprising talc, magnesium silicate, magnesium trisilicate, magnesium oxide, hydroxypropyl cellulose, hydroxyethyl cellulose, hydrophobic colloidal silica, guar gum, colloidal silicon dioxide, calcium silicate, calcium phosphate or mixtures thereof.
  • the weight ratio of dabigatran etexilate free base or a pharmaceutically acceptable salt of dabigatran etexilate to organic acid is between 0.1 and 10. Preferably this ratio is between 0.5 and 2.0.
  • Suitable salts of dabigatran etexilate are selected from a group comprising mesylate, maleate, malonate, citrate, tosylate, esylate, tartrate, oxalate or camphor sulfonate.
  • suitable salts of dabigatran etexilate are selected from maleate, malonate, citrate, tosylate, esylate, tartrate, oxalate or camphor sulfonate.
  • the active agent is in the form of free base.
  • the composition comprises; a. 5.00% to 50.00% dabigatran etexilate free base or a pharmaceutically acceptable salt of dabigatran etexilate
  • the core comprising dabigatran etexilate or a pharmaceutically acceptable salt of dabigatran etexilate is obtained by spheronization method.
  • pelletization and granulation techniques available to prepare drug loaded spherical particles or granules.
  • Spheronization is one of them and utilized in formulation of beads and pellets. Limitations related to bioavailability and site specific drug delivery can be overcome by this technique.
  • compositions mentioned above are prepared by following these steps:
  • dabigatran suspension • Adding dabigatran etexilate free base or a pharmaceutically acceptable salt of dabigatran etexilate and talc to the mixture to form dabigatran suspension

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques destinées à être administrées par voie orale comprenant un noyau comprenant une base libre d'étéxilate de dabigatran ou un sel pharmaceutiquement acceptable d'étéxilate de dabigatran et une couche de séparation et une couche acide.
PCT/TR2018/050900 2017-12-27 2018-12-26 Compositions pharmaceutiques de dabigatran WO2019132838A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP18847286.4A EP3731830A1 (fr) 2017-12-27 2018-12-26 Compositions pharmaceutiques de dabigatran

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2017/22186 2017-12-27
TR2017/22186A TR201722186A2 (tr) 2017-12-27 2017-12-27 Dabi̇gatranin farmasöti̇k kompozi̇syonlari

Publications (1)

Publication Number Publication Date
WO2019132838A1 true WO2019132838A1 (fr) 2019-07-04

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Application Number Title Priority Date Filing Date
PCT/TR2018/050900 WO2019132838A1 (fr) 2017-12-27 2018-12-26 Compositions pharmaceutiques de dabigatran

Country Status (3)

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EP (1) EP3731830A1 (fr)
TR (1) TR201722186A2 (fr)
WO (1) WO2019132838A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111921003A (zh) * 2020-09-04 2020-11-13 东南大学 一种磁响应热疗可控降解栓塞微球及其制备方法与应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998037075A1 (fr) 1997-02-18 1998-08-27 Boehringer Ingelheim Pharma Kg Heterocycles bicycliques disubstitues, production et utilisation comme medicaments
WO2003074056A1 (fr) 2002-03-07 2003-09-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Forme de presentation a administrer par voie orale pour l'ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionique et ses sels
EP1658056A1 (fr) 2003-08-16 2006-05-24 Boehringer Ingelheim International Gmbh Comprime contenant l'ethylester de l'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionique ou ses sels
EP1877395A2 (fr) 2005-04-27 2008-01-16 Boehringer Ingelheim International GmbH Sels de l'ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionique physiologiquement compatibles
WO2012001156A2 (fr) 2010-07-01 2012-01-05 Krka, Tovarna Zdravil, D.D., Novo Mesto Formes pharmaceutiques posologiques orales comprenant de l'étéxilate de dabigatran et ses sels pharmaceutiquement acceptables
WO2012077136A2 (fr) 2010-12-06 2012-06-14 Msn Laboratories Limited Procédé de préparation de dérivés de benzimidazole et de leurs sels
CN103127109B (zh) * 2013-02-05 2014-08-13 南京华威医药科技开发有限公司 含达比加群酯或其盐和水合物的药用组合
US20170049764A1 (en) * 2014-11-03 2017-02-23 Solipharma Llc Dosing Preparation of Dabigatran Etexilate or a Salt Thereof and a Preparation Method Thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998037075A1 (fr) 1997-02-18 1998-08-27 Boehringer Ingelheim Pharma Kg Heterocycles bicycliques disubstitues, production et utilisation comme medicaments
WO2003074056A1 (fr) 2002-03-07 2003-09-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Forme de presentation a administrer par voie orale pour l'ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionique et ses sels
EP1870100A1 (fr) 2002-03-07 2007-12-26 Boehringer Ingelheim Pharma GmbH & Co. KG Composition pharmaceutique pour application orale à base de mésylate d'éthyl-(2-(4-(hexyloxycarbonylamidino)phenylaminomethyl)-1-methyl-1H-benzimidazole-5-carbonyl)-2-pyridylamino)propionate
EP1658056A1 (fr) 2003-08-16 2006-05-24 Boehringer Ingelheim International Gmbh Comprime contenant l'ethylester de l'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionique ou ses sels
EP1877395A2 (fr) 2005-04-27 2008-01-16 Boehringer Ingelheim International GmbH Sels de l'ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionique physiologiquement compatibles
WO2012001156A2 (fr) 2010-07-01 2012-01-05 Krka, Tovarna Zdravil, D.D., Novo Mesto Formes pharmaceutiques posologiques orales comprenant de l'étéxilate de dabigatran et ses sels pharmaceutiquement acceptables
WO2012077136A2 (fr) 2010-12-06 2012-06-14 Msn Laboratories Limited Procédé de préparation de dérivés de benzimidazole et de leurs sels
CN103127109B (zh) * 2013-02-05 2014-08-13 南京华威医药科技开发有限公司 含达比加群酯或其盐和水合物的药用组合
US20170049764A1 (en) * 2014-11-03 2017-02-23 Solipharma Llc Dosing Preparation of Dabigatran Etexilate or a Salt Thereof and a Preparation Method Thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111921003A (zh) * 2020-09-04 2020-11-13 东南大学 一种磁响应热疗可控降解栓塞微球及其制备方法与应用

Also Published As

Publication number Publication date
TR201722186A2 (tr) 2019-07-22
EP3731830A1 (fr) 2020-11-04

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