EP3551172A1 - Compositions pharmaceutiques de dabigatran - Google Patents

Compositions pharmaceutiques de dabigatran

Info

Publication number
EP3551172A1
EP3551172A1 EP17821820.2A EP17821820A EP3551172A1 EP 3551172 A1 EP3551172 A1 EP 3551172A1 EP 17821820 A EP17821820 A EP 17821820A EP 3551172 A1 EP3551172 A1 EP 3551172A1
Authority
EP
European Patent Office
Prior art keywords
sodium
dabigatran etexilate
pharmaceutical composition
composition according
free base
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.)
Withdrawn
Application number
EP17821820.2A
Other languages
German (de)
English (en)
Inventor
Ali TÜRKYILMAZ
Arzu Palantöken
Yildiz GÜLKOK
Gökce SÖZER BÜRKÜT
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 EP3551172A1 publication Critical patent/EP3551172A1/fr
Withdrawn legal-status Critical Current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
    • A61K9/48—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
    • A61K31/33—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a pharmaceutical composition in the form of encapsulated mini tablets comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient.
  • 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-valcular 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, 150mg), 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, carragenan, 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. Also, it is known in the prior art that dabigatran etexilate is a weakly basic compound and therefore it has high solubility in acidic media.
  • Dabigatran etexilate have been associated with gastrointestinal disorders such as ulcers and gastrointestinal bleeding.
  • the administration of dabigatran etexilate may make some patients more susceptible to the ulcerogenic effects of ulcerogenic stimuli. It appears that a major factor contributing to the development of these gastrointestinal disorders is the presence of acid in the stomach and upper small intestine.
  • the main object of the present invention is to provide a pharmaceutical composition in the form of encapsulated mini tablets comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient with safe and effective dissolution profile, an easy process and reduced adverse effects.
  • mini tablet refers to small tablets with a diameter equal to or less than 4 mm that are typically filled into a capsule or further compressed into larger tablets. Thickness of this mini tablets equal to or less than 3 mm.
  • the mini tablets have round shape and smooth surface to ease coating process.
  • Mini tablets have many advantages. Due to increased surface in relation to volume, the drug can be released more efficiently incase of mini-tablets. Some benefits of mini- tablets include excellent size uniformity, regular shape and a smooth surface. In mini tablets, smooth surface offers an excellent substrate for coating with polymeric systems. It can be concluded that pharmaceutical mini-tablets offer several advantages when compared to single unit dosage forms and are also good substitutes for granules and pellets. They have well defined size, shape, surface, low degree of porosity and high mechanical strength. Due to significant smaller dimensions of the mini tablets, when compared to normal tablets, they pass through the stomach at a more even rate. As a result, the concentration of the drug in the blood can be easily reproduced. It has been found that, dissolution and stability problems are overcome by using mini tablet form.
  • 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 pharmaceutically acceptable salts of dabigatran etexilate is present in an amount of between 10.00 and 60.00 %, preferably between 20.00 and 50.00 % and more preferably it is 30.00 to 40.00 % by weight of total formulation.
  • dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran 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.
  • at least one pharmaceutically acceptable excipient is disintegrant.
  • the pharmaceutical composition comprises preferably at least two different disintegrants.
  • the amount of total disintegrants is at least 40% by weight of total formulation.
  • the amount of total disintegrants is between 40% and 60% by weight of total formulation. More preferably the amount of total disintegrants is between 40% and 50% by weight of total formulation.
  • Suitable disintegants are selected from a group comprising starch, sodium starch glycolate, microcrystalline cellulose, crospovidone (cross-linked polyvinil pyrrolidone), povidone, poloxomer, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
  • the disintegrants are selected from a group comprising microcrystalline cellulose, pregelatinized starch and sodium starch glycolate.
  • microcrystalline cellulose is present in an amount of between 10.00% and 60.00%, preferably between 15.00% and 50.00%, more preferably between 25.00% and 40.00 by weight of total formulation
  • pregelatinized starch is present in an amount of between 1 .00% and 30.00%, preferably between 5.00% and 20.00%, more preferably between 10.00% and 15.00% by weight of total formulation
  • sodium starch glycolate is present in an amount of between 0.1 % and 8.00%, preferably between 0.25% and 4.00%, more preferably between 0.5% and 2.00% by weight of total formulation.
  • the pharmaceutical composition further comprises lubricants, glidants, fillers or mixtures thereof.
  • Suitable lubricants are selected from a group comprising sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyseryl palmito sulphate, sodium lauryl sulphate or mixtures thereof.
  • the lubricant is selected from a group comprising magnesium stearate and sodium stearyl fumarate. According to this embodiment, the lubricant is present an amount of between 0.1 % and 10.00%, preferably 0.1 % and 5.00% and more preferably 0.1 % and 3.00% by weight of total formulation.
  • Suitable glidants are selected from a group comprising colloidal silicon dioxide, talc, aluminium silicate or mixtures thereof.
  • the glidant is colloidal silicon dioxide.
  • the glidant is present an amount of between 0.1 % and 10.00%, 0.5% and 5.00% and more preferably 0.9% and 3.00% by weight of total formulation.
  • Suitable fillers are selected from a group comprising mannitol, spray-dried mannitol, lactose, lactose monohydrate, 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 lactose.
  • the filler is present an amount of between 5.00% and 50.00%, 10.00% and 40.00% and more preferably 15.00% and 30.00% by weight of total formulation.
  • Suitable salts of dabigatran etexilate are selected from a group comprising mesylate, maleate, malonate, citrate, tosylate, esylate, tartrate, oxalate, camphor sulfonate.
  • suitable salts of dabigatran etexilate are selected from maleate, malonate, citrate, tosylate, esylate, tartrate, oxalate, camphor sulfonate.
  • the pharmaceutical composition in the form encapsulated mini tablets comprises:
  • magnesium stearate 0.1 to 10.00 % magnesium stearate
  • the pharmaceutical composition in the form encapsulated mini tablets comprises:
  • Example 1 Capsule containing mini tablets
  • Example 2 Capsule containing mini tablets
  • compositions mentioned above are prepared by following these steps:
  • Example 3 Capsule containing mini tablets
  • compositions mentioned above are prepared by following these steps:

Landscapes

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

Abstract

La présente invention concerne une composition pharmaceutique sous la forme de mini-comprimés encapsulés comprenant une base libre de dabigatran étexilate ou des sels pharmaceutiquement acceptables de dabigatran étexilate et au moins un excipient pharmaceutiquement acceptable.
EP17821820.2A 2016-12-07 2017-12-06 Compositions pharmaceutiques de dabigatran Withdrawn EP3551172A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2016/17984A TR201617984A2 (tr) 2016-12-07 2016-12-07 Dabi̇gatranin farmasöti̇k kompozi̇syonlari
PCT/EP2017/081639 WO2018104370A1 (fr) 2016-12-07 2017-12-06 Compositions pharmaceutiques de dabigatran

Publications (1)

Publication Number Publication Date
EP3551172A1 true EP3551172A1 (fr) 2019-10-16

Family

ID=60582497

Family Applications (2)

Application Number Title Priority Date Filing Date
EP17205599.8A Withdrawn EP3332770A1 (fr) 2016-12-07 2017-12-06 Compositions pharmaceutiques de dabigatran
EP17821820.2A Withdrawn EP3551172A1 (fr) 2016-12-07 2017-12-06 Compositions pharmaceutiques de dabigatran

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP17205599.8A Withdrawn EP3332770A1 (fr) 2016-12-07 2017-12-06 Compositions pharmaceutiques de dabigatran

Country Status (4)

Country Link
EP (2) EP3332770A1 (fr)
EA (1) EA201991288A1 (fr)
TR (2) TR201617984A2 (fr)
WO (1) WO2018104370A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113933400B (zh) * 2020-06-29 2024-01-12 石药集团恩必普药业有限公司 一种达比加群酯原料药或制剂中基因毒性杂质的检测方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE121699A1 (es) 1997-02-18 1999-12-08 Boehringer Ingelheim Pharma Heterociclos biciclicos disustituidos como inhibidores de la trombina
SI1870100T1 (sl) 2002-03-07 2012-05-31 Boehringer Ingelheim Int Metansulfonat etil estra heksiloksikarbonilamino imino metil fenilamino metil metil H benzimidazol karbonil piridin il amino propionske kisline
DE102005020002A1 (de) 2005-04-27 2006-11-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg Physiologisch verträgliche Salze von 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester
WO2012077136A2 (fr) 2010-12-06 2012-06-14 Msn Laboratories Limited Procédé de préparation de dérivés de benzimidazole et de leurs sels
IN2013CH05441A (fr) * 2013-11-26 2015-05-29 Aurobindo Pharma Ltd
IN2014MU01042A (fr) * 2014-03-26 2015-10-02 Cadila Healthcare Ltd

Also Published As

Publication number Publication date
TR201617984A2 (tr) 2018-06-21
WO2018104370A1 (fr) 2018-06-14
EP3332770A1 (fr) 2018-06-13
EA201991288A1 (ru) 2019-10-31
TR201619828A2 (en) 2018-06-21

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