WO2017221209A1 - Formulations pharmaceutiques d'apixaban - Google Patents

Formulations pharmaceutiques d'apixaban Download PDF

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Publication number
WO2017221209A1
WO2017221209A1 PCT/IB2017/053761 IB2017053761W WO2017221209A1 WO 2017221209 A1 WO2017221209 A1 WO 2017221209A1 IB 2017053761 W IB2017053761 W IB 2017053761W WO 2017221209 A1 WO2017221209 A1 WO 2017221209A1
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Prior art keywords
pharmaceutical composition
apixaban
blend
composition
surfactant
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Ceased
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PCT/IB2017/053761
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English (en)
Inventor
Devidas Ashruba SANAP
Manish Hasmukhlal SHAH
Sanjay Chhagan Wagh
Makarand Krishnakumar Avachat
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Lupin Ltd
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Lupin Ltd
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    • 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
    • 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
    • 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 comprising Factor X a inhi bitors.
  • Present invention particularly relates to pharmaceutical composition comprising apixaban or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient
  • the present invention also relates to a process for the preparation of pharmaceutical composition comprising apixaban or a pharmaceutically acceptable salt thereof and the use of the pharmaceutical compositions for the treatment and/or prevention of thromboembolic disorders.
  • V KAs Vitamin K antagonists
  • U FH unfractionated heparin
  • L MWH low molecular weight heparin
  • Newer agents such as fondaparinux and enoxapari n sodi um have been developed as more effective anticoagulants and reported to have substantial ly low risk for heparin- i nduced thrombocytopenia compared with L MWH or U FH.
  • anticoagulants While anticoagulants are effective in treating and reducing the risk of thromboembolic conditions, they are associated with significant limitations that may lead to the risk for related, and potentially serious or fatal, bleeding events affecting their clinical use and acceptability.
  • These conventional anticoagulants like U FH, L MWH, and new agents like fondaparinux are administered parenterally, which is inconvenient and expensive with respect to the long-term use, and require a health care professional for its administration.
  • V itami n K antagonists are available for oral administration, they usually have a narrow therapeutic window and unpredictable therapeutic effect Many research studies are conducted to develop newer, more effective anticoagulants that can be administered oral ly.
  • Factor X a inhi bitors are found to be a class of compounds more efficacious for the treatment of thromboembolic disorders.
  • first agent developed was Rivaroxaban (X arelto ⁇ by j anssen Pharms) and approved by USFDA in 2011 for oral administration.
  • Apixaban is a selective direct inhibitor of factor X a that participates in the blood coagulation systenri without requiring antithrombin III - unlike other conventional agents. It is developed by Bristol Myers Squibb and approved by the U.S. FDA for reducing the risk of stroke and systemic embol ism in patients with nonvalvular atrial fibrillation, for the prophylaxis and treatment of deep vein thrombosis and pulmonary embolism in cases of hip or knee replacement
  • apixaban The synthesis of apixaban was first described in WO 2003/026652.
  • WO 2006/078331 rel ates to a process or apparatus for transform! ng a f i rst polymorph i nto a second polymorph of the same chemical material, and discloses the H2-2 form in a needle-shaped dehydrate.
  • US 2013/0045245 and US 2016/0243101 further disclose compositions comprising crystalline apixaban wherein the drug particles have a maximum size cutoff and a D90 of the active equal to or less than about 89 i m. According to the disclosure of the above appl ication, it was found that in a tablet composition, apixaban particles having a D 90 less than 89 i m lead to consistent in-vivo dissolution and consistent exposure of the active in humans.
  • the present invention provides pharmaceutical compositions for oral administration comprising a therapeutically effective amount of a selective factor X a inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • suitable techniques known in the prior art for particle size determination include, but are not limited to microscopy, sieving, sedimentation and/or laser light scattering methods.
  • Another aspect of the present invention provides a process for manufacturing a solid oral dosage form of a pharmaceutical composition
  • the pharmaceutical composition is prepared by a dry granulation process.
  • the pharmaceutical composition is prepared by wet granulation.
  • Another aspect of the present invention comprises the use of at least one surfactant as a pharmaceuti cal carri er i n an amount of from about 0.1 % to about 5% by weight
  • the present invention provides an immediate release pharmaceutical composition comprising Factor Xa inhibitors.
  • the present invention provides pharmaceutical composition(s) comprising apixaban having a larger particle size than disclosed in the prior art.
  • apixaban herein comprises various forms such as crystalline, amorphous, hydrates, anhydrates, solvates, pharmaceutical acceptable salts, enantiomers, polymorphs, esters, or derivatives thereof.
  • Apixaban may be obtained directly via the synthesis described in U.S. Pat. No. 6,967,208 and/or US 2006/0069258 (based on U.S. application Ser. No. 11/235,510 filed Sep. 26, 2005) or any other known process.
  • apixaban in crystalline form is used.
  • Various crystal line forms of apixaban known i n the prior art are within the scope of this invention, including but not limiting to, Form N-1, Form H2-2, Form M and others.
  • immediate release means that at least 70 wt % of a compound initially present in the dosage form is released within one hour or less following introduction to a use environment.
  • a " use environment can either mean various in- vivo fluids, such as the GI tract or the in- vitro environment of a test solution, such as phosphate buffered sal i ne.
  • the invention provides pharmaceutical compositions comprising apixaban particles having a D90 more than 89 i m and a pharmaceutically acceptable diluent or carrier.
  • T he ranges of particle size preferred for use in the present invention is D90 more than 89 i m, more preferably D 90 i s at I east about 100 1 m, even more preferably D 90 i s at I east about 110 1 m.
  • T he particle size distribution of apixaban particles as described in the specification is characterized by D90 values. "Dgo , is defined as 90% of the volume of particles havi ng a diameter less than a specified diameter.
  • apixaban particles having particle size distribution more than that disclosed in the prior arts, particularly D90 more than 89 i m is a typical feature of this invention.
  • patent application US 2013/0045245 is restricted to the use of smaller sized apixaban particles, specifically having D90 equal to or less than about 89 1 m i n order to achi eve consistent dissol uti on.
  • T he compositi ons of the present i nvention use apixaban particles havi ng the size higher than that disclosed in above application, but it still achieves consistent desired dissolution profile.
  • the particle size distribution stipulated herein refers to the particle sizes determined by using any known suitable techniques such as microscopy, sieving, sedimentation and/or laser light scattering techniques.
  • particles refers to individual drug substance particles. T he particles may exist as single particles or as agglomerations, however, if the size of the primary apixaban particles comprising the agglomerate are more than 89 ⁇ m individually, then the agglomerate itself is considered to meet the particle size requirements as described in this specification.
  • the present invention provides solid oral pharmaceutical compositions comprising apixaban with a D90 more than 89 1 m.
  • Solid oral pharmaceutical compositions of the present invention include, but are not limited to, tablets, pellets, granules, powders, capsules, microcapsules, microspheres, spheroids, pel lets filled in capsules, tablets in capsules, multilayer tablets, bi layer tablets, tri layer tablets, or premixed powders filled in capsul es.
  • the sol i d oral dosage form i s a tablet.
  • T his i nvention further provides a pharmaceutical composition comprisi ng the use of at least one surfactant or wetting agent
  • wetting agent_ or " surfactant , , as used herei n refers to a surface active agent or a mixture of agents that lower the interfacial tension between a solid & a liquid or two liquids.
  • surfactants aid in wetting of a hydrophobic drug i n a solid formulation to ensure efficient dissolution of the drug.
  • T he surfactant may be natural or synthetic in origin. Further, it may be non- ionic, anionic, cationic or amphoteric in nature.
  • surfactants that can be used in the present invention include, but are not l imited to, cremophors, polyethylene glycols, poloxamers, polysorbates, sodium lauryl sulphate, tragacanth, and/or mixtures thereof.
  • the surfactant used is sodium lauryl sulfate. In another embodiment of the present invention, the surfactant is a poloxamer. In yet another embodiment of the present invention, the surfactant is a mixture of sodi um lauryl sulfate and a poloxamer in an appropriate amount
  • the present invention comprises the use of one or more surfactants from about 0.1% to 5% by weight. In an embodiment of the present invention, surfactants used in the compositions range from about 2% to 4%. In an embodiment of the present invention, the formulations exhibit and in vitro dissolution profile such that the amount of the drug equivalent to 85 wt% dissolves within 30 minutes.
  • the suitable dissolution test is selected and it is carried out i n an aqueous media non-buffered or buffered to a pH range (1 to 7.6) found in the gastroi ntesti nal tract and control I ed at 37°C ( e 10°C ) .
  • V ari ous dosage forms such as tabl ets and capsules, can be studied for dissolution profile, in a standard prescribed manner.
  • the dosage form is a tablet typically paddles rotating at 50-75 rpm are used to test the dissolution rate of the tablets.
  • the amount of dissolved apixaban can be determined using suitable analytical techniques such as UV or H PLC.
  • the dissolution (in-vitro) test in addition to its application as a quality control technique, can more preferably be used to predict the biological (in-vivo) performance of the tablet
  • the dissolution test is performed in 900 mL of dissolution medium at 37° C, using USP Apparatus 2 (paddles) at a rotation speed of 75 rpm Samples are removed after 5, 10, 15, 20, 30, 45, and 60 minutes from test initiation and analyzed for apixaban.
  • 0.1 N HCI or 0.05 M sodium phosphate at a pH 6.8 containing 0.05% sodium lauryl sulphate (SLS) solution has been used as dissolution medium
  • SLS sodium lauryl sulphate
  • the pharmaceuti cal compositi ons are prepared by a dry granulation process comprising the steps of blending apixaban particles of a predetermined size with one or more excipients, granulati ng the blend using a dry granulation process, adding one or more extragranular excipients, compressing the blend i nto tabl ets and opti onal ly f i I m coati ng the tabl et
  • the pharmaceutical compositions are prepared by a wet granulation process comprising the steps of blending apixaban particles of a predetermined size with one or more excipients, adding a binder, disintegrant, and other fillers, and carrying out wet granulation using a solution comprising the bi nder in a suitable solvent followed by sizing the granules by passing them through a mill such as a screen mill.
  • the granules are then dried using a convection oven or a fluid- bed dryer, and optionally sized by passing them through a mill such as a screen mill.
  • a suitable disintegrant is then added as an extragranular material and mixed.
  • the blend is then compressed i nto tabl ets.
  • compositions of the present invention including fillers or diluents, binders, disintegrants, lubricants, glidants, and colorants.
  • Fil lers or diluents may be selected from the group comprising carbohydrates, confectioners sugar, compressible sugars, dextrose, dextrates, dextrin, fructose, lactitol, xylitol, sorbitol, microcrystalline cellulose, mannitol, lactose, sucrose, maltose, starch, calcium carbonate, calcium sulfate, calcium hydrogen phosphate, or combinations thereof.
  • Fillers or diluents may be used in the range of 10-90% w/w of the total weight of the oral pharmaceutical composition.
  • Binders may be selected from the group comprisi ng potato starch, wheat starch, corn starch, microcrystall ine cellulose, cellulose, including hydroxy propyl cellulose, hydroxy propyl methyl cellulose, povidone, hydroxy ethyl cellulose, sodium carboxy methyl cellulose, natural gums including acacia, alginic acid, guar gum, liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth; or combinations thereof. Binders may be used in the range of 1-15% w/w of the total weight of the oral pharmaceutical composition.
  • Disintegrants may be selected from the group comprising alginic acid, carboxymethyl cellulose calcium, carboxy methyl eel I ulose sodium, croscarmel lose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium algi nate, sodium starch glycolate, starches or combi nations thereof. Disintegrants may be used in the range of 1- 20% w/W of the total weight of the oral pharmaceuti cal composition.
  • L ubri cants_ may be sel ected from the group comprisi ng al umi ni um stearate, zi nc stearate, calcium stearate, magnesium stearate, polyethylene glycol, mineral oil, talc, hydrogenated vegetabl e oi I , steari c aci d, magnesi um al umi num si I i cate, sodi um stearyl f umarate, glyceryl behenate, sodium benzoate or mixtures thereof.
  • Lubricants may be used in the range of 0.1 - 5 % w/W of the total weight of the oral pharmaceutical composition.
  • Glidants may be selected from the group comprising silicon dioxide, magnesium tri si licate, powdered cellulose, starch, talc, tri basic calcium phosphate, calcium silicate, magnesi um si I i cate, col I oi dal si I i con di oxi de, si I i con hydrogel or mixtures thereof.
  • G I i dants may be used in the range of 0.01 " 4% w/W of the total weight of the oral pharmaceutical composition.
  • Colorants may be selected from the group comprising iron oxide yellow, iron oxide red, titanium dioxide or mixtures thereof. Colorants may be used in the range of 0.01 " 1.5% w/W of the total weight of the oral pharmaceutical composition.
  • the pharmaceutical compositions of the present invention may have one or more coati ngs such as f i I m coati ngs and/or sugar coati ngs.
  • T he coati ng may compri se from about 1 - 4.5% w/W of the total weight of the pharmaceutical composition.
  • Coating agents which are useful in the coating process, may be selected from the group comprising water sol uble polymers including, polyvinylpyrrolidone or water soluble cellulose including, hydroxy propyl methyl cellulose or hydroxy propyl cellulose.
  • Coating agents may be selected from the group comprising soluble agents such as polysorbate 80, polysaccharides such as, acacia, corn, sucrose, gelatin, shel lac, cellulose acetate phthalate, lipids, synthetic resins, acrylic polymers, opadry, polyvinyl alcohol, copolymers of vinyl pyrrol idone, vinyl acetate or combinations thereof. These may be applied from aqueous or non- aqueous systems or combi nations of aqueous and non-aqueous system as appropriate.
  • soluble agents such as polysorbate 80, polysaccharides such as, acacia, corn, sucrose, gelatin, shel lac, cellulose acetate phthalate, lipids, synthetic resins, acrylic polymers, opadry, polyvinyl alcohol, copolymers of vinyl pyrrol idone, vinyl acetate or combinations thereof.
  • additives may be selected along with film formers to obtain satisfactory films. These additives may be selected from the group comprising plasticizers such as di butyl phthalate, tri ethyl citrate, polyethylene glycol, or the I ike; antitacking agents such as, talc, stearic acid, magnesi um stearate, col I oi dal si I i con di oxi de or the I i ke; f i 11 ers such as tal c or preci pitated calcium carbonate; polishing agents such as beeswax, carnauba wax or synthetic chlorinated wax; opacifying agents such as titanium dioxide; or colorants, etc. Antitacking agents may be used in the range of 0.1 - 15% w/w of the total weight of the oral pharmaceutical composition.
  • plasticizers such as di butyl phthalate, tri ethyl citrate, polyethylene glycol, or the I ike
  • antitacking agents such as, talc,
  • Solvents may be any pharmaceutical ly acceptable, non-toxic agent or a mixture of agents i n the form of a I i qui d, whi ch i s used for di ssol vi ng another sol i d or I i qui d, or as a di spersi ng or granulating media.
  • Solvents employed in the present invention may be aqueous, alcoholic, hydroalcohol ic or organic in nature with varying polarity. Representative examples of solvents employed i ncl ude acetone, dichloromethane, ethyl alcohol, isopropyl alcohol, water, and mixtures thereof.
  • apixaban contained in a tablet, capsule, or other dosage form containing a composition of this invention will contain therapeutically effective amount of apixaban.
  • Therapeutically effective amount refers to amount of the active agent which halts or reduces the progress of the condition being treated or which otherwise partly, cures or acts palliatively on the condition. A person skilled in the art can easily determine such an amount by routi ne experimentation and with an undue burden.
  • Therapeutically effective amount of apixaban in the respect of this invention is usually between 2.5 and 5 mg, usually administered orally twice a day, although amounts outside thi s range and different f requenci es of admi ni strati on are f easi bl e for use i n therapy under prescribed medical conditions.
  • the pharmaceutical compositions of the present invention are useful, inter alia, in the prevention and/or treatment of thromboembolic disorders, for example, deep vei n thrombosis, acute coronary syndrome, stroke, and pulmonary embolism
  • step- 1 blend in suitable blender for 25 minutes.
  • step-3 blend on roller compactor and compact the material of step-3 on roller compactor to get desi red compacted flakes and milled through oscillating granulator.
  • step 9 Sift magnesium stearate through 60# AST M S.S. seive and add to step 9 blend and I ubricate the blend for 5 mi nutes.
  • step- 10 Compress the tablet with step- 10 blend using 6.0 mm round shaped bevel concave punches on a compression machine with suitable parameter.
  • step-11 Load the tablets of step-11 into perforated coating pan and coat the tablet with an inlet ai r temperature 55 e 5°C till 3.5% w/w e 0.25% weight build up is attained.
  • step- 10 Dry the tablet of step- 10 for 60 minutes at inlet air temperature 55 e 5°C with intermittent jogging.
  • Co-sift apixaban, lactose, microcrystalline cellulose, croscarmel lose sodium through 40 #AST M S.S. sieve.
  • step- 1 blend in suitable blender for 25 minutes.
  • step-3 blend on roller compactor and compact the material of step-3 on roller compactor to get desi red compacted flakes and milled through oscillating granulator.
  • step 9 Sift magnesium stearate through 60# AST M S.S. seive and add to step 9 blend and I ubricate the blend for 5 mi nutes.
  • step-11 Add and disperse quantity of opadry pink under continuous stirring in purified water and sti r for 45 mi nutes to get 10% w/w dispersi on. 13.
  • step- 10 Dry the tablet of step- 10 for 60 minutes at inlet air temperature 50 e 5°C with intermittent jogging.
  • T able 1 Dissolution data of the formulations of Example 1 and Example 2:
  • Poloxamer 4.0 Sodium lauryl sulfate 6.0
  • step- 1 blend in suitable blender for 25 minutes.
  • step-3 blend on roller compactor and compact the material of step-3 on roller compactor to get desi red compacted flakes and milled through oscillating granulator.
  • step 9 Sift magnesium stearate through 60# AST M S.S. seive and add to step 9 blend and I ubricate the blend for 5 mi nutes.
  • step- 10 Compress the tablet with step- 10 blend using 9.8 B 5.2 mm oval shaped bevel concave punches on a compression machine with suitable parameter.
  • step-10 Dry the tablet of step-10 for 60 minutes at inlet air temperature 50 e 5°C with intermittent jogging.
  • T able 2 Dissolution data of the formulation of E xample 3:
  • step 2 blend with using step 5 solution i n fluidised bed process with suitable parameters.
  • D ry the granul es after granul ati on for 15 mi nutes at bed temperature of 35-40eC .
  • step 9 Sift magnesium stearate through 60# AST M S.S. sieve and add to step 9 blend and I ubricate the blend for 5 mi nutes.
  • step- 10 Compress the tablet with step- 10 blend using 6.0 mm round shaped bevel concave punches on a compression machine with suitable parameter.
  • step-11 Load the tablets of step-11 into perforated coating pan and coat the tablet with an inlet ai r temperature 55e 5eC till 3.5% w/w e 0.25% weight build up is attained.
  • step- 10 Dry the tablet of step- 10 for 60 minutes at i nlet air temperature 55e 5eC with intermittent jogging.
  • T able 3 Dissolution data of the formulation of E xample 4:
  • step 1 blend in rapid mixer granulator and mix the blend for 15 minutes at slow i mpel I or speed and chopper off.
  • step 2 blend with addition of step 3 binder solution under slow impel I or and chopper speed.
  • step-6 Pass the dried granules of step-5 through 25#and load to the suitable blender.
  • step 7 Sift magnesium stearate through 60# ASTM S.S. seive and add to step 7 blend and I ubricate the blend for 5 mi nutes.
  • step- 11 Dry the tablet of step- 11 for 60 minutes at inlet air temperature 50 e 5°C with intermittent jogging.
  • T able 4 Dissolution data of the formulation of E xample 5:
  • Dissolution (Dissolution media volume: 900 mL, Paddle, 75 R PM) pH 6.8 Phosphate buffer with 0.05% SLS

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Abstract

L'invention porte également sur des compositions comprenant des particules d'apixaban cristallin ayant un D90 de plus de 89 I m, et un support pharmaceutiquement acceptable qui peut être utilisé pour le traitement et/ou la prophylaxie de troubles thromboemboliques.
PCT/IB2017/053761 2016-06-23 2017-06-23 Formulations pharmaceutiques d'apixaban Ceased WO2017221209A1 (fr)

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IN201621021634 2016-06-23

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Cited By (6)

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Publication number Priority date Publication date Assignee Title
US10537524B2 (en) * 2016-01-12 2020-01-21 North & South Brother Pharmacy Investment Company Limited Apixaban solid composition and preparation method thereof
EP3669866A1 (fr) 2018-12-19 2020-06-24 KRKA, d.d., Novo mesto Composition pharmaceutique comprenant de l'apixaban
CN113891705A (zh) * 2019-03-27 2022-01-04 Hlb制药有限责任公司 用于制备负载阿哌沙班的微球的分散相的组合物和由其制备的基于生物相容性聚合物的负载阿哌沙班的微球
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
US12508254B2 (en) 2019-11-13 2025-12-30 Unison Pharmaceuticals Pvt. Ltd. Orally disintegrating pharmaceutical compositions of apixaban

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WO2014108919A2 (fr) * 2013-01-09 2014-07-17 Msn Laboratories Limited Nouvel intermédiaire et nouveaux polymorphes du 1-(4-méthoxyphényl)-7-oxo-6-[4-(2-oxopipéridin-1-yl)phényl]-4,5,6,7-tétrahydro-1h-pyrazolo[3,4-c]pyridine-3-carboxamide et procédé s'y rapportant
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US10537524B2 (en) * 2016-01-12 2020-01-21 North & South Brother Pharmacy Investment Company Limited Apixaban solid composition and preparation method thereof
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
CN113891705A (zh) * 2019-03-27 2022-01-04 Hlb制药有限责任公司 用于制备负载阿哌沙班的微球的分散相的组合物和由其制备的基于生物相容性聚合物的负载阿哌沙班的微球
CN113891705B (zh) * 2019-03-27 2024-04-09 Hlb制药有限责任公司 用于制备负载阿哌沙班的微球的分散相的组合物和由其制备的基于生物相容性聚合物的负载阿哌沙班的微球
US12508254B2 (en) 2019-11-13 2025-12-30 Unison Pharmaceuticals Pvt. Ltd. Orally disintegrating pharmaceutical compositions of 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
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

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