WO2017182908A1 - Compositions pharmaceutiques d'apixaban - Google Patents

Compositions pharmaceutiques d'apixaban Download PDF

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Publication number
WO2017182908A1
WO2017182908A1 PCT/IB2017/052046 IB2017052046W WO2017182908A1 WO 2017182908 A1 WO2017182908 A1 WO 2017182908A1 IB 2017052046 W IB2017052046 W IB 2017052046W WO 2017182908 A1 WO2017182908 A1 WO 2017182908A1
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WO
WIPO (PCT)
Prior art keywords
apixaban
pharmaceutical composition
sodium
cellulose
solid pharmaceutical
Prior art date
Application number
PCT/IB2017/052046
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English (en)
Inventor
Deepak Pragjibhai GONDALIYA
Ketan Tulsidas SAVJANI
Bhavesh Vikrambhai BHAVSAR
Ronak Rajendrabhai PATEL
Mukund Keshav Gurjar
Original Assignee
Emcure Pharmaceuticals Limited
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Application filed by Emcure Pharmaceuticals Limited filed Critical Emcure Pharmaceuticals Limited
Publication of WO2017182908A1 publication Critical patent/WO2017182908A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients and process for preparation of such compositions.
  • the present invention also relates to the use of compositions comprising apixaban for treating or preventing the risk of thromboembolic disorders such as deep vein thrombosis, pulmonary embolism, non-valvular atrial fibrillation.
  • Apixaban which is chemically known as 4,5,6,7-tetrahydro-l-(4-methoxyphenyl)-7-oxo-6-[4- (2-oxo-l-piperidinyl)phenyl]-lH-pyrazolo[3,4-c]pyridine-3-carboxamide was first disclosed by Pinto et al in US 6,967,208. The document further discloses that the compounds of the invention may be administered in the form of a pharmaceutical composition together with a pharmaceutically acceptable vehicle, diluent, or carrier and use of same for the treatment or prevention of a thromboembolic disorders.
  • Jiacheng et al in WO 2003/049681A2 discloses process for the preparation of apixaban and other pyrazole -pyridine derivatives.
  • apixaban is a poorly soluble compound.
  • the poor solubility results in slow and incomplete drug release and poor bioavailability. Therefore, it discloses a composition comprising crystalline apixaban particles having a maximally limited mean particle size and a pharmaceutically acceptable diluent or carrier.
  • the disclosed compositions have the particle size d (0.9) less than 89 ⁇ of active ingredient to meet appropriate dissolution rate.
  • the document provides granulation process for making tablets, it emphasize that the dry granulation provides better dissolution profile when compared with a tablet made by wet granulation.
  • Richard in WO 2010/147978A1 discloses solubility-improved form of apixaban wherein the dosage form provides controlled release of apixaban.
  • the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
  • the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein Apixaban is in crystalline or amorphous form. If crystalline apixaban is used for making the pharmaceutical compositions, the according to present invention, it can be micronized or un-micronized form.
  • the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein Apixaban is in crystalline, preferably in N- 1 form.
  • the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein apixaban composition is prepared by judiciously selecting the excipients.
  • the various excipients used in the compositions are selected from the group comprising of binders, diluents, disintegrants, lubricants, wetting agents or surfactants.
  • the present invention relates to a process for preparation of pharmaceutical compositions comprising Apixaban or pharmaceutically acceptable salts thereof. Typically, the processes such as wet granulation, dry granulation, direct compression, solid dispersion or hydrophilization are used to manufacture the pharmaceutical compositions according to present invention.
  • the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein apixaban is in solid dispersion, optionally containing a polymer.
  • the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein apixaban is in hydrophilized form.
  • the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof and method of preparation of such compositions.
  • Apixaban means the chemical compound 1 -(4methoxyphenyl)-7-oxo- 6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4c]pyridine-3-carboxamide.
  • various salts, polymorphs, solvates, enantiomers, stereoisomers could also be used.
  • the compound could be used as amorphous, crystalline or mixtures thereof.
  • the active agent can be used in range of 0.5-20% w/w of the total composition.
  • the amount of active agent present in the composition according to present invention is in the range of 1% to 10 % w/w and more preferably from 2% to 5% w/w.
  • the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein Apixaban is used in micronized or un- micronized form.
  • micronized Apixaban means particles of Apixaban having d (0.9) equal to or less than about of 50 ⁇ , particularly between 1 ⁇ to 50 ⁇ , more particularly between 2 ⁇ to 20 ⁇ . It is observed that compositions prepared by using Apixaban of particles d (0.9) about 20 ⁇ exhibited required dissolution properties.
  • d(0.9) indicates that about 90% of particles measured have a size less than the defined d (0.9) value, and that about 10% of particles measured have a size greater than the defined d(0.9) value.
  • the particle size distribution of apixaban particles of the present invention may be determined using an optical microscopic method, sedimentation techniques, for example, pipette analysis using an Andreas sen pipette, sedimentation scales, photo sedimentometers or sedimentation in a centrifugal force field, pulse methods, for example, using a Coulter counter, or sorting by means of gravitational or centrifugal force, sieve analysis, laser diffraction or ultrasound attenuation spectroscopy.
  • the particle size distribution of apixaban particles of the present invention is particularly determined through laser diffraction using a Malvern® Mastersizer laser diffraction instrument.
  • particles refers to individual drug substance particles whether the particles exist singly or are agglomerated.
  • the pharmaceutical composition of the present invention may further comprise one or more pharmaceutically acceptable excipients judiciously selected from a group comprising diluents, binders, disintegrants, lubricants, wetting agents or surfactants, coloring agents, flavoring agents or any other excipients known in the art.
  • diluents include but are not limited to corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch, pregelatinized starch or mixtures thereof.
  • diluent is selected from dicalcium phosphate, microcrystalline cellulose, lactose, mannitol, starch. Diluents can be present alone or as mixture of more than one in the range up to 95% by weight of the composition.
  • binders include but are not limited to polyvinylpyrrolidone, starch mucilage, pregelatinized starch, sodium alginate, alginic acid, acacia mucilage, tragacanth, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, microcrystalline cellulose, ethyl cellulose, polyethylene glycol, hydroxyethyl cellulose, hydroxy propyl cellulose, methyl cellulose, polymethacrylates, carboxyvinyl polymers, carbopols, dextrin, gelatin, guar gum and combinations thereof.
  • binder is selected from starch, hydroxy propyl cellulose, hydroxypropylmethyl cellulose. Binders can be present alone or as mixture of more than one in the range up to 35% by weight of the composition.
  • disintegrants include but are not limited to cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose (crosscarmellose sodium), calcium carboxymethyl cellulose, microcrystalline cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose and combinations thereof.
  • disintegrant is selected from cross-linked polyvinylpyrrolidone, sodium starch glycolate, crosscarmellose sodium.
  • Disintegrants can be present alone or as mixture of more than one in the range up to 30% by weight of the composition.
  • Surfactants or wetting agents can be selected from hydrophilic surfactants or lipophilic surfactants or mixtures thereof.
  • the surfactants can be anionic, nonionic, cationic and zwittetionic surfactants.
  • Suitable examples of wetting agents or surfactants include but are not limited to sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate, sulphosuccinates such as sodium dioctyl sulphosuccinate, partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, partial fatty acid esters of sorbitan such as sorbitan monolaurate, partial fatty acid esters of polyhydroxyethylene sorbitan such as polyethylene glycol sorbitan monolaurate, monostearate or monooleate, polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acid esters, ethylene oxide -propylene oxide block copolymers (Pluronic®) or eth
  • Suitable examples of lubricants include but are not limited to calcium stearate, glyceryl palmitostearate, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and magnesium stearate or a mixture of one or more.
  • the lubricants can be used in the range of up to 3% by weight of the composition.
  • the pharmaceutical composition of Apixaban or pharmaceutically acceptable salts thereof according to present invention can be prepared by conventional processes such as dry granulation, wet granulation and direct compression.
  • the present inventors have found that the apixaban formulations having desired dissolution profile are preferably prepared by using direct compression process. The process involves co-sifting and mixing of apixaban and other excipients. The blend thus obtained is compressed to form tablets of desired size and hardness between 3-15kp. The tablets are further coated with functional or nonfunctional film coatings.
  • the film coating materials include cellulosic polymers such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose and the like, polyvinylpyrrolidone, natural gums etc.
  • the present invention provides pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof that are prepared by solid dispersion technique, utilizing conventional process for forming solid dispersions.
  • Such processes include mechanical, thermal and solvent processes.
  • Exemplary mechanical processes include milling and extrusion; thermal processes including high temperature fusion, solvent-modified fusion and melt-congeal processes; and solvent processes including non-solvent precipitation, spray-coating and spray-drying.
  • the solid dispersion of apixaban obtained according to present invention results in predominantly or at least a major portion (at least 70%) of apixaban being in the amorphous state.
  • the solid amorphous dispersions of apixaban is formed by "solvent processing,” which comprises the steps of dissolving apixaban and one or more polymers in a common solvent.
  • solvent which can be a mixture of compounds, will dissolve both apixaban and the polymer(s).
  • the solvent is rapidly removed by evaporation or by mixing with a non-solvent.
  • Exemplary processes to remove solvents are spray-drying, spray-coating (pan-coating, fluidized bed coating, etc.), and precipitation by rapid mixing of the polymer and apixaban solution with water, or some other non-solvent.
  • the polymers used for preparation of solid dispersion referred here are either cellulosic or non- cellulosic in nature.
  • Typical examples of few polymers are vinyl polymers and copolymers having substituents of hydroxyl, alkylacyloxy, or cyclicamido; polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinyl pyrrolidone; polyoxyethylene-polyoxypropylene copolymers, also known as poloxamers; and polyethylene polyvinyl alcohol copolymers, carboxylic acid-functionalized vinyl polymers, such as the carboxylic acid functionalized polymethacrylates and carboxylic acid functionalized polyacrylates such as the EUDRAGITS® manufactured by Rohm Tech Inc., of Maiden, Mass.; amine -functionalized polyacrylates and polymethacrylates; proteins; and carboxylic acid functional
  • Exemplary commercial grades of such copolymers include the EUDRAGITS, which are copolymers of methacrylates and acrylates, and the PLURONICS supplied by BASF, which are polyoxyethylene-polyoxypropylene copolymers, cellulosic polymers such as cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose and hydroxypropyl cellulose acetate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate,
  • polymer is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrolidone as sinle or as mixtures thereof.
  • the polymers employed are used in the range of about 0.5-50% by weight of the composition.
  • the solvents used for above processes include those that are acceptable for preparation of pharmaceutical compositions.
  • Typical examples are alcohols such as methanol, ethanol, n- propanol, iso-propanol, and butanol; ketones such as acetone, methyl ethyl ketone and methyl iso-butyl ketone; esters such as ethyl acetate and propylacetate; and various other solvents such as acetonitrile, methylene chloride, toluene, and 1,1, 1-trichloroethane. Lower volatility solvents such as dimethyl acetamide or dimethylsulfoxide can also be used. Mixtures of solvents, such as methanol and acetone, can also be used, as can mixtures with water, so long as the polymer and apixaban are sufficiently soluble.
  • alcohols such as methanol, ethanol, n- propanol, iso-propanol, and butanol
  • ketones such as acetone, methyl ethyl ketone and methyl iso-but
  • the solid dispersion preparation process involves:
  • the present invention provides pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein apixaban is present in hydrophilized form.
  • the hydrophilized form referred to in the present invention involves process in which: a. first granules comprising the apixaban, in hydrophilized form, are prepared by moist granulation; and
  • the granules are then converted into the pharmaceutical composition, if appropriate with addition of pharmaceutically suitable additives.
  • the moist granulation of process step (a) can be carried out in a mixer (mixer granulation) or in a fluidized bed (fluidized bed granulation) by introducing apixaban either to the pre-mixed bed of excipients as a solid or it is suspended in the granulating liquid.
  • apixaban suspended in the granulating liquid is introduced on to the pre-mixed bed of excipients.
  • the granulating liquid used according to the invention contains a solvent, optionally a hydrophilic binding agent and, if appropriate, a wetting agent.
  • the hydrophilic binding agent can be dispersed in the granulating liquid or preferably dissolved therein.
  • the solvents used for the granulating liquid can be organic solvents, such as, for example, ethanol, methylene chloride or acetone, or water or mixtures thereof.
  • hydrophilic binding agents employed for the granulating liquid are pharmaceutically suitable hydrophilic additives, preferably those which dissolve in the solvent of the granulating liquid.
  • hydrophilic polymers such as, for example, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low- substituted HPC), polyvinylpyrrolidone, polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon® VA64, BASF), gelatine, guar gum, partially hydrolysed starch, alginates or xanthan are employed.
  • HPMC is employed as a hydrophilic binding agent.
  • the hydrophilic binding agent can be present here in a concentration of 1 to 15% w/w
  • the present invention relates to pharmaceutical compositions of Apixaban or pharmaceutically acceptable salts thereof wherein apixaban is provided as immediate release dosage forms such as tablets, capsules, granules, multiparticulate systems or modified release dosage forms.
  • the modified release may be achieved by using methods known in the art, preferably by using functional coating.
  • the functional coating polymers include hydroxypropyl methyl cellulose, ethyl cellulose, cellulose actate phthalate, acrylate polymers available under brand name Eudragit L, Eudragit S, Kollicoat etc.
  • compositions of the present invention can be packed into suitable containers such as blisters, bottles or pouch. Further, the packages may optionally contain a desiccant or an antioxidant or oxygen absorbent or combinations thereof.
  • Example 1 The above test composition of Example 1 is prepared by following method:
  • Apixaban (micronized and/or unmicronized), Lactose, Microcrystalline Cellulose, Croscarmellose sodium, Sodium lauryl sulphate and Magnesium stearate were blended.
  • the blended raw materials were granulated using a dry granulation process. Then the dry granulated materials were blended with the extragranular materials.
  • the blended materials were compressed into tablets and film coated with a conventional coating dispersion.
  • Example 2 The above test composition of Example 2 is prepared by following method:
  • Apixaban (micronized and/or unmicronized), mannitol, pregelatinized starch, croscarmellose sodium, sodium lauryl sulphate and magnesium stearate were blended.
  • the blended raw materials were granulated using a dry granulation process. Then the dry granulated materials were blended with the extragranular materials.
  • the blended materials were compressed into tablets and film coated with a conventional coating dispersion.
  • Example 3 The above test composition of Example 3 is prepared by following method: Apixaban (micronized and/or unmicronized) and hydroxypropylmethylcellulose (optional) are dissolved in ethanol and methylene chloride. The solution thus prepared is sprayed onto the original mixture of microcrystalhne cellulose, lactose, sodium lauryl sulphate and croscarmellose as a granulating liquid in the course of a fluidized bed granulation or in rapid mixer granulator. After drying and sieving the resulting granules, magnesium stearate is added and mixed. The press-ready mixture thus obtained is compressed to give tablets of suitable size. The subsequent coating of the tablets is carried out using Opadry.
  • Example 4 The above test composition of Example 4 is prepared by following method:
  • Example 5 The above test composition of Example 5 is prepared by following method:
  • Example 6 The above test composition of Example 6 is prepared by following method:
  • Solution of apixaban (micronized and/or unmicronized), hydroxypropylmethylcellulose and sodium lauryl sulphate is prepared in solvent mixture of ethanol and methylene chloride.
  • the solution thus prepared is sprayed onto the physical mixture of microcrystalline cellulose, lactose and croscarmellose as a granulating liquid in the course of a fluidized bed granulation. After drying and sieving the resulting granules, lubricate with magnesium stearate.
  • the press-ready mixture thus obtained is compressed to give tablets having suitable size.
  • the subsequent coating of the tablets is carried out using Opadry dispersion.
  • Example 7 The above test composition of Example 7 is prepared by following method:
  • Hydroxypropylmethylcellulose and sodium lauryl sulphate are dissolved in water.
  • the micronized apixaban is suspended in this solution.
  • the suspension thus prepared is sprayed onto the physical mixture of microcrystalline cellulose, lactose and croscarmellose as a granulating liquid in the course of a fluidized bed granulation or in rapid mixer granulator. After drying and sieving the resulting granules, lubricate with magnesium stearate.
  • the press-ready mixture thus obtained is compressed to give tablets having suitable size.
  • the subsequent coating of the tablets is carried out using Opadry.

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Abstract

La présente invention concerne des compositions pharmaceutiques d'apixaban ou des sels pharmaceutiquement acceptables de celui-ci et d'excipients pharmaceutiquement acceptables et un procédé pour sa préparation. Les compositions ont été préparées par des procédés conventionnels en utilisant des excipients pharmaceutiquement acceptables. L'impact de la taille de particule sur les paramètres de dissolution de la formulation a également été étudié. Les compositions pharmaceutiques de la présente invention sont particulièrement utiles en tant que médicament, en particulier pour le traitement ou la prévention de troubles thromboemboliques tels que la thrombose veineuse profonde, l'embolie pulmonaire, la fibrillation auriculaire non valvulaire.
PCT/IB2017/052046 2016-04-18 2017-04-10 Compositions pharmaceutiques d'apixaban WO2017182908A1 (fr)

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IN201621013502 2016-04-18

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Cited By (12)

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Publication number Priority date Publication date Assignee Title
CN110123770A (zh) * 2019-06-20 2019-08-16 常州恒邦药业有限公司 一种阿哌沙班药物组合物及其制备方法
WO2019221488A1 (fr) * 2018-05-14 2019-11-21 Sinil Pharmaceutical Co., Ltd. Formulation pharmaceutique comprenant de l'apixaban et son procédé de préparation
EP3669866A1 (fr) 2018-12-19 2020-06-24 KRKA, d.d., Novo mesto Composition pharmaceutique comprenant de l'apixaban
CN113633616A (zh) * 2020-05-11 2021-11-12 鲁南制药集团股份有限公司 一种生物利用度高的固体制剂
CN113730369A (zh) * 2020-05-27 2021-12-03 石药集团欧意药业有限公司 一种阿哌沙班片剂组合物及其制备方法
WO2022115051A1 (fr) 2020-11-27 2022-06-02 Santa Farma Ilac Sanayii A.S. Procédé de compression directe pour formulations d'apixaban non micronisées
WO2022115052A1 (fr) 2020-11-27 2022-06-02 Santa Farma Ilac Sanayii A.S. Procédés améliorés de granulation par voie humide pour formulations comprenant de l'apixaban
EP4026541A1 (fr) 2021-01-08 2022-07-13 Sanovel Ilac Sanayi Ve Ticaret A.S. Comprimé revêtu d'un film d'apixaban
EP4026540A1 (fr) 2021-01-08 2022-07-13 Sanovel Ilac Sanayi Ve Ticaret A.S. Comprimé revêtu d'un film comprenant de l'apixaban
WO2023072967A1 (fr) 2021-10-27 2023-05-04 Pharma-Data S.A. Suspension d'apixaban et procédé de préparation
NL2029536B1 (en) * 2021-10-27 2023-05-26 Pharma Data S A Apixaban suspension and preparation method
WO2024144480A1 (fr) * 2022-12-29 2024-07-04 Pharmactive Ilac Sanayi Ve Ticaret A.S. Compositions pharmaceutiques comprenant de l'apixaban en tant que principe actif et d'autres excipients pertinents

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US20130045245A1 (en) * 2010-02-25 2013-02-21 Pfizer, Inc. Apixaban formulations
CN104644593A (zh) * 2013-11-23 2015-05-27 天津市汉康医药生物技术有限公司 阿哌沙班组合物及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130045245A1 (en) * 2010-02-25 2013-02-21 Pfizer, Inc. Apixaban formulations
CN104644593A (zh) * 2013-11-23 2015-05-27 天津市汉康医药生物技术有限公司 阿哌沙班组合物及其制备方法

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019221488A1 (fr) * 2018-05-14 2019-11-21 Sinil Pharmaceutical Co., Ltd. Formulation pharmaceutique comprenant de l'apixaban et son procédé de préparation
EP3669866A1 (fr) 2018-12-19 2020-06-24 KRKA, d.d., Novo mesto Composition pharmaceutique comprenant de l'apixaban
WO2020127819A2 (fr) 2018-12-19 2020-06-25 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant de l'apixaban
WO2020127819A3 (fr) * 2018-12-19 2020-07-30 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant de l'apixaban
CN110123770A (zh) * 2019-06-20 2019-08-16 常州恒邦药业有限公司 一种阿哌沙班药物组合物及其制备方法
CN113633616A (zh) * 2020-05-11 2021-11-12 鲁南制药集团股份有限公司 一种生物利用度高的固体制剂
CN113730369A (zh) * 2020-05-27 2021-12-03 石药集团欧意药业有限公司 一种阿哌沙班片剂组合物及其制备方法
CN113730369B (zh) * 2020-05-27 2023-07-14 石药集团欧意药业有限公司 一种阿哌沙班片剂组合物及其制备方法
WO2022115052A1 (fr) 2020-11-27 2022-06-02 Santa Farma Ilac Sanayii A.S. Procédés améliorés de granulation par voie humide pour formulations comprenant de l'apixaban
WO2022115051A1 (fr) 2020-11-27 2022-06-02 Santa Farma Ilac Sanayii A.S. Procédé de compression directe pour formulations d'apixaban non micronisées
EP4026541A1 (fr) 2021-01-08 2022-07-13 Sanovel Ilac Sanayi Ve Ticaret A.S. Comprimé revêtu d'un film d'apixaban
EP4026540A1 (fr) 2021-01-08 2022-07-13 Sanovel Ilac Sanayi Ve Ticaret A.S. Comprimé revêtu d'un film comprenant de l'apixaban
WO2022150029A1 (fr) * 2021-01-08 2022-07-14 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Comprimé pelliculé comprenant de l'apixaban
WO2022150030A3 (fr) * 2021-01-08 2022-08-25 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Comprimé pelliculé d'apixaban
WO2023072967A1 (fr) 2021-10-27 2023-05-04 Pharma-Data S.A. Suspension d'apixaban et procédé de préparation
NL2029536B1 (en) * 2021-10-27 2023-05-26 Pharma Data S A Apixaban suspension and preparation method
WO2024144480A1 (fr) * 2022-12-29 2024-07-04 Pharmactive Ilac Sanayi Ve Ticaret A.S. Compositions pharmaceutiques comprenant de l'apixaban en tant que principe actif et d'autres excipients pertinents

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