EP2908802A1 - Formulation pharmaceutique orale solide contenant du ticagrélor - Google Patents

Formulation pharmaceutique orale solide contenant du ticagrélor

Info

Publication number
EP2908802A1
EP2908802A1 EP13792574.9A EP13792574A EP2908802A1 EP 2908802 A1 EP2908802 A1 EP 2908802A1 EP 13792574 A EP13792574 A EP 13792574A EP 2908802 A1 EP2908802 A1 EP 2908802A1
Authority
EP
European Patent Office
Prior art keywords
cellulose
formulation according
hygroscopic
formulation
binder
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Withdrawn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
EP13792574.9A
Other languages
German (de)
English (en)
Inventor
Gregor Sedmak
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.)
Zentiva KS
Original Assignee
Zentiva KS
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 Zentiva KS filed Critical Zentiva KS
Publication of EP2908802A1 publication Critical patent/EP2908802A1/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Withdrawn legal-status Critical Current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
    • A61K9/20—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
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a solid oral pharmaceutical formulation containing ticagrelor as the active pharmaceutical constituent and a preparation method of this formulation.
  • WO 1999/005143 was generically described in WO 1999/005143 and specifically mentioned in EP 1 135 391. This document also describes a method of its preparation, as well as the use of ticagrelor in treatment or prevention of myocardial infarction, stroke, diseases of peripheral vessels, etc.
  • WO 2001/092262 describes 4 polymorphous and an amorphous form of ticagrelor.
  • WO 2011/067571 describes cocrystals with various coformers such as glycolic, salicylic, succinic, malonic and 4-hydroxy-3-methoxybenzenecarboxylic acids.
  • WO 2008/024044 describes a solid formulation that comprises one or more fillers, one or more binders, preferably one or more disintegrants and preferably one or more lubricants.
  • the sodium salt of carboxymethylstarch was used as a disintegrant in the amount of 3 % by weight.
  • WO2008/024045 describes a very similar solid formulation that comprises one or more fillers, one or more binders, preferably one or more disintegrants and preferably one or more lubricants. This document indicates that the use of disintegrants is necessary. Particular examples mentioned in the document contain 2-6 % by weight of a disintegrant, which is the sodium salt of carboxymethylstarch.
  • WO 2011/076749 deals with the particle size of ticagrelor which was used in the formulation as ticagrelor is well-known as a poorly soluble compound.
  • disintegrants were used in amounts in the range of 4-6% by weight.
  • Ticagrelor is sold under the trade name Brilique for prevention of arteriothrombotic events in the form of coated tablets.
  • the marketed formulation also contains the sodium salt of carboxymethylstarch as the disintegrant. Disclosure of Invention
  • This invention relates to a solid oral pharmaceutical formulation containing ticagrelor with the chemical name (lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5- (propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-l,2- cyclopentanediol, which further contains at least one non-hygroscopic filler and/or at least one non-hygroscopic binder that do not have a disintegrating effect.
  • the non-hygroscopic filler means a water-soluble filler, sugar alcohols being generally preferred, such as glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, compressible sugars. Hydroxypropyl cellulose or maltose, for example, can be used as the non-hygroscopic binder.
  • the composition in accordance with this invention preferably contains 0.5- 30% by weight of the binder, preferably 1-7% by weight of the binder and most preferably 2-4% by weight of the binder.
  • non-hygroscopic refers to a material that has a low capability of receiving and holding water. Or, put it in a better way, the term non-hygroscopic refers to a material that has an equilibrium moisture content lower than 6% by weight. This value is determined by Dynamic Vapour Sorption (DVS) at the relative humidity of 60% and temperature of 25 °C. The equilibrium moisture content is determined based on the sorption isothermal curve measured using the DVS method at the relative humidity of 60% and temperature of 25 °C.
  • DVS Dynamic Vapour Sorption
  • disintegrants in a formulation does not need to have an impact on increasing the biological availability of the active substance. This property is more influenced by sufficient humidification of the active substance present in the formulation. If such a composition can be prepared that will dissolve sufficiently quickly without the use of disintegrants, disintegrants only become a superfluous constituent that does not have any real effect.
  • Disintegrants represent a class of excipients that are generally considered as special excipients.
  • the price of special excipients i.e. disintegrants, is much higher than the price of commonly used excipients such as fillers.
  • the price of disintegrants such as the sodium salt of carboxymethylstarch or the sodium salt of croscarmellose may normally be several times higher than the price of general fillers as mannitol or calcium hydrogen phosphate.
  • disintegrants act is not clear so far. Mechanisms assumed in the past include, e.g., soaking with water, swelling, shape memory, repellency to the other constituents, heating during humidification.
  • the ability of disintegrants to bring water to the porous network of the tablet is essential for efficient disintegration. This explanation was provided by the Encyclopaedia of Pharmaceutical Technology, 3 rd issue, Informa Healthcare USA, Inc., 2007.
  • disintegrants are generally hygroscopic or very hygroscopic materials. According to the Handbook of Pharmaceutical Excipients, 6 th issue, Pharmaceutical Press, 2009 the sodium salt of croscarmellose and sodium salt of carboxymethylstarch exhibit the same characteristics.
  • WO2008/024045 describes that the use of a composition that contains one or more fillers, one or more binders, preferably one or more disintegrants and preferably one or more lubricants is suitable for efficient releasing of at least 90% of ticagrelor. Contrary to the findings of the prior art we have found out that a ticagrelor composition with any known form of ticagrelor (crystalline, amorphous or in a cocrystal form) that contains at least one non-hygroscopic filler and/or at least one non-hygroscopic binder that do not feature the disintegration effect will achieve efficient release of at least 90% of ticagrelor.
  • disintegrant refers to any material that swells or soaks in contact with water.
  • the term disintegrant comprises, e.g., the group of compounds such as: povidone, crospovidone, starch, pregelatinized starch, sodium salt of carboxymethyl cellulose, hydroxypropyl starch, microcrystalline cellulose, calcium salt of carboxymethylcellulose, sodium salt of crosslinked carboxymethylcellulose, potassium salt of polacrilin, low- substituted hydroxypropyl cellulose, sodium or calcium alginate, sodium docusate, methyl cellulose, agar, guar gum, chitosan and alginic acid.
  • the composition of ticagrelor conveniently contains no or less than 2% of a disintegrant.
  • the pharmaceutical composition of ticagrelor contains substantially no disintegrant.
  • the composition of ticagrelor contains a non-hygroscopic filler.
  • a water-soluble filler is preferred.
  • Suitable fillers are, e.g., monosaccharides, oligosaccharides and sugar alcohols such as glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol and lactitol, compressible sugars, calcium hydrogen phosphate dihydrate and their mixtures. Lactose, mannitol and xylitol are preferred.
  • the composition of ticagrelor contains a non-hygroscopic binder.
  • Suitable binders are, e.g., povidone, copovidone, powdered, crystalline or microcrystalline cellulose, siliconized microcrystalline cellulose, cellulose derivatives such as hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose, starch, pregelatinized starch, polymethacrylates and their mixtures.
  • the formulation of ticagrelor contains 0.5 to 30% by weight of the binder, preferably from 1 to 7%, and most conveniently from 2 to 4% by weight of the binder.
  • the composition of ticagrelor typically contains at least 1 surfactant.
  • Suitable surfactants are, e.g., anionic, cationic, ampholytic and/or non-ionic surfactants such as the sodium salt of lauryl sulphate, cetrimide, N-dodecyl-N,N-dimethyl betaine, polysorbates (e.g. T weens ® ), poloxamers and their mixtures.
  • the sodium salt of lauryl sulphate is the preferred compound.
  • the surfactant is used, in the formulation of ticagrelor, in an amount of from 0.1 to 4.0% by weight, most preferably in the range of from 0.5 to 2.0%.
  • composition of ticagrelor typically contains at least 1 lubricant and/or anti-adhesive compound selected, e.g., among magnesium stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, colloidal silicon dioxide, magnesium trisilicate and their mixtures.
  • lubricant and/or anti-adhesive compound selected, e.g., among magnesium stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, colloidal silicon dioxide, magnesium trisilicate and their mixtures.
  • Stearic acid, magnesium stearate, sodium stearyl fumarate and colloidal silicon dioxide are especially preferred.
  • the tablet of ticagrelor can be conveniently coated with any suitable coating.
  • a suitable coating agent for ticagrelor tablets is selected, e.g., from methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polymers of acrylic acid, ethyl cellulose, cellulose acetate phtalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol, sodium salt of carboxymethyl cellulose, cellulose acetate, gelatine, copolymers of methacrylic acid, polyethylene glycol, shellac, sucrose, titanium dioxide and camauba wax. Polyethylene glycol, hydroxypropylmethyl cellulose and polyvinyl alcohol are preferred. Examples
  • Ticagrelor is granulated in wet conditions together with either lactose monohydrate or xylitol or mannitol or maltitol (either using granulation by kneading or with the use of a common granulator with a fluidized bed) with an aqueous solution of either hydroxypropyl cellulose or maltose.
  • Sodium lauryl sulphate is preferably added to the granulation solution.
  • the obtained granulate is dried and screened through a 1mm sieve.
  • the sieved granulate is then mixed with either lactose monohydrate or xylitol or mannitol or isomaltose or maltose in a suitable mixing device for 20 minutes. After this pre-mixing magnesium stearate is added to the mixture and the mixture is stirred for another 3 minutes so that a suitable tabletting mixture can be obtained. This mixture is then compressed into tablets in a rotary tabletting device.
  • Ticagrelor was granulated in dry conditions together with mannitol or lactose monohydrate or xylitol and preferably with sodium lauryl sulphate in a rotary compactor with a variable gap size.
  • the obtained granulate was screened through a 1mm sieve.
  • the sieved granulate is mixed with either lactose monohydrate or xylitol or mannitol or isomaltose or maltose or lactitol in a suitable mixing device for 20 minutes. After pre-mixing magnesium stearate is added to the mixture and the mixture is stirred for another 3 minutes so that a mixture ready for tabletting can be obtained. This mixture is then compressed into tablets in a rotary tabletting device.
  • Ticagrelor is mixed with lactose monohydrate or xylitol or mannitol or isomaltose or maltose or lactitol in a suitable mixing device for 20 minutes. After pre-mixing magnesium stearate is added to the mixture and the mixture is stirred for another 3 minutes so that a mixture ready for tabletting in a rotary tabletting device can be obtained.
  • Tablets obtained in accordance with Examples 1 to 3 are conveniently coated with a common coating material
  • Constituents of the coating mixture are dissolved or suspended in a sufficient quantity of water to provide the coating solution. Then, tablets are coated with this solution in a suitable device and finally they are dried.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Inorganic Chemistry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)

Abstract

L'invention concerne une formulation pharmaceutique orale solide contenant du ticagrélor, sous le nom chimique de (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophényl)cyclopropyl]amino]- 5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyéthoxy)-1,2- cyclopentanediol, comprenant au moins un diluant non hygroscopique et/ou au moins un liant non hygroscopique, ni le diluant ni le liant ne présentant un effet de désintégration quelconque. La préparation de la formulation est possible par granulation humide, granulation sèche ou compression directe.
EP13792574.9A 2012-10-16 2013-10-15 Formulation pharmaceutique orale solide contenant du ticagrélor Withdrawn EP2908802A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2012-705A CZ2012705A3 (cs) 2012-10-16 2012-10-16 Pevná orální farmaceutická formulace obsahující ticagrelor
PCT/CZ2013/000130 WO2014059955A1 (fr) 2012-10-16 2013-10-15 Formulation pharmaceutique orale solide contenant du ticagrélor

Publications (1)

Publication Number Publication Date
EP2908802A1 true EP2908802A1 (fr) 2015-08-26

Family

ID=49619770

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13792574.9A Withdrawn EP2908802A1 (fr) 2012-10-16 2013-10-15 Formulation pharmaceutique orale solide contenant du ticagrélor

Country Status (13)

Country Link
EP (1) EP2908802A1 (fr)
JP (1) JP6301934B2 (fr)
KR (1) KR20150067153A (fr)
CN (1) CN104661649A (fr)
BR (1) BR112015008076A2 (fr)
CZ (1) CZ2012705A3 (fr)
EA (1) EA201590745A1 (fr)
HK (1) HK1205456A1 (fr)
IL (1) IL238036B (fr)
MX (1) MX2015003866A (fr)
UA (1) UA116784C2 (fr)
WO (1) WO2014059955A1 (fr)
ZA (1) ZA201501954B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020021110A1 (fr) 2018-07-27 2020-01-30 Krka, D.D., Novo Mesto Composition pharmaceutique de ticagrélor

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KR20160012706A (ko) * 2014-07-25 2016-02-03 동아에스티 주식회사 서방성 제제
CN111544407A (zh) * 2015-04-29 2020-08-18 江苏恒瑞医药股份有限公司 一种替格瑞洛或其可药用盐的制剂
CN105193759B (zh) * 2015-09-18 2018-07-03 乐普药业股份有限公司 一种替格瑞洛片及其制备方法
CN106667926B (zh) * 2015-11-09 2020-01-17 石药集团中奇制药技术（石家庄）有限公司 一种法匹拉韦片剂及其制备方法
TR201601835A2 (tr) * 2016-02-12 2017-08-21 Ali Raif Ilac Sanayi Ve Ticaret Anonim Sirketi Ti̇kagrelor i̇çeren formülasyonlar i̇çi̇n üreti̇m yöntemi̇
CN107530288B (zh) * 2016-04-21 2022-01-25 阿斯利康(瑞典)有限公司 口腔崩解片
TR201617983A2 (tr) * 2016-12-07 2018-06-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Ti̇cagrelorun kati oral farmasöti̇k bi̇leşi̇mleri̇
KR102610876B1 (ko) * 2018-03-05 2023-12-06 주식회사 파마코스텍 티카그렐러 푸마르산 i형 결정 및 그 제조방법
WO2019170244A1 (fr) 2018-03-08 2019-09-12 Pharmaceutical Oriented Services Ltd. Formulation de comprimé contenant du ticagrelor
CN111450067A (zh) * 2019-01-18 2020-07-28 北京万全德众医药生物技术有限公司 一种替格瑞洛分散片及其制备方法
CN116370423A (zh) * 2023-02-28 2023-07-04 天津力生制药股份有限公司 一种替格瑞洛口腔崩解片及其制备方法

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AR017014A1 (es) 1997-07-22 2001-08-22 Astrazeneca Ab Compuestos de triazolo [4,5-d]pirimidina, composiciones farmaceuticas, uso de los mismos para preparar medicamentos y procesos para la preparacionde dichos compuestos
JPH11199517A (ja) * 1997-10-31 1999-07-27 Meiji Seika Kaisha Ltd 口腔内速崩壊性錠剤
TWI229674B (en) 1998-12-04 2005-03-21 Astra Pharma Prod Novel triazolo[4,5-d]pyrimidine compounds, pharmaceutical composition containing the same, their process for preparation and uses
GB0013407D0 (en) 2000-06-02 2000-07-26 Astrazeneca Ab Forms of a chemical compound
WO2007018057A1 (fr) * 2005-08-05 2007-02-15 Freund Corporation Comprime se desintegrant rapidement dans la cavite buccale et son procede de fabrication
TWI482772B (zh) 2006-08-21 2015-05-01 Astrazeneca Ab 適合口服且包含三唑并[4,5-d]嘧啶衍生物之組合物
WO2008024044A1 (fr) * 2006-08-21 2008-02-28 Astrazeneca Ab Compositions pour administration orale comprenant un dérivé de triazolo [4, 5] pyrimidine
US8883802B2 (en) 2009-12-03 2014-11-11 Astrazeneca Ab Co-crystals of a triazolo [4,5-D] pyrimide platelet aggregation inhibitor
ES2548845T3 (es) 2009-12-23 2015-10-21 Ratiopharm Gmbh Forma de dosificación farmacéutica sólida de ticagrelor y ácido acetilsalicílico

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020021110A1 (fr) 2018-07-27 2020-01-30 Krka, D.D., Novo Mesto Composition pharmaceutique de ticagrélor

Also Published As

Publication number Publication date
IL238036A0 (en) 2015-05-31
JP2015533129A (ja) 2015-11-19
KR20150067153A (ko) 2015-06-17
JP6301934B2 (ja) 2018-03-28
BR112015008076A2 (pt) 2017-07-04
MX2015003866A (es) 2015-07-17
IL238036B (en) 2019-05-30
CZ2012705A3 (cs) 2014-04-23
HK1205456A1 (en) 2015-12-18
ZA201501954B (en) 2017-04-26
CN104661649A (zh) 2015-05-27
WO2014059955A1 (fr) 2014-04-24
EA201590745A1 (ru) 2015-08-31
UA116784C2 (uk) 2018-05-10

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