WO2020101587A1 - Formulations orales comprenant du rivaroxaban - Google Patents

Formulations orales comprenant du rivaroxaban Download PDF

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Publication number
WO2020101587A1
WO2020101587A1 PCT/TR2018/050699 TR2018050699W WO2020101587A1 WO 2020101587 A1 WO2020101587 A1 WO 2020101587A1 TR 2018050699 W TR2018050699 W TR 2018050699W WO 2020101587 A1 WO2020101587 A1 WO 2020101587A1
Authority
WO
WIPO (PCT)
Prior art keywords
rivaroxaban
pharmaceutical composition
composition according
oral pharmaceutical
group
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.)
Ceased
Application number
PCT/TR2018/050699
Other languages
English (en)
Inventor
Ersin Yildirim
Bayram Kanik
Tansel AKTAŞ
Fatma ÖZTÜRK
Tuncay Gül
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.)
Santa Farma Ilac Sanayi AS
Original Assignee
Santa Farma Ilac Sanayi 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 Santa Farma Ilac Sanayi AS filed Critical Santa Farma Ilac Sanayi AS
Priority to PCT/TR2018/050699 priority Critical patent/WO2020101587A1/fr
Priority to EP18940435.3A priority patent/EP3796915A4/fr
Publication of WO2020101587A1 publication Critical patent/WO2020101587A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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 a pharmaceutical composition, comprising rivaroxaban or a pharmaceutically acceptable salt thereof.
  • Rivaroxaban (5-chloro-N- ⁇ [(5S )-2-oxo-3 - [4-(3 -oxomorpholin-4-yl)phenyl] oxazolidin-5- yl] methyl ⁇ thiophene-2-carboxamide) is a low molecular weight, orally administrable anticoagulant drug. Rivaroxaban is an anticoagulant and the first orally active direct factor Xa inhibitor. The pharmaceutical directly inhibits the active form of serine protease Factor Xa (FXa).
  • Rivaroxaban can be used for the prevention and treatment of various thromboembolic diseases, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract, angina pectoris, reocclusions and restenoses after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases.
  • DVT deep vein thrombosis
  • PE pulmonary embolism
  • myocardial infract myocardial infract
  • angina pectoris reocclusions and restenoses after angioplasty or aortocoronary bypass
  • cerebral stroke CAD
  • transitory ischemic attacks and peripheral arterial occlusive diseases.
  • Rivaroxaban was first disclosed in WO0147919, has the systematic name 5-chloro-N-( ⁇ (5S)- 2-OXO-3- [4-(3-oxomorpholin-4-yl)phenyl]-l , 3 -oxazolidin-5-yl ⁇ methyl) thiophene-2- carboxamide and the following chemical structure:
  • W02009023233 relates to novel compounds that are substituted oxazolidinones derivatives and pharmaceutically acceptable salts thereof. More specifically, this invention relates to novel oxazolidinone compounds that are derivatives of Rivaroxaban.
  • the invention also provides pyrogen-free compositions comprising one or more compounds of the invention and a carrier, along with the use of the disclosed compounds and compositions in methods of treating diseases and condition that are beneficially treated by administering a selective inhibitor of factor Xa, such as Rivaroxaban.
  • WO2015155307 relates to a novel pharmaceutical composition
  • a novel pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof in combination with a proton pump inhibitor for use in the anticoagulant treatment with preventing or reducing the risk of a gastrointestinal disorder.
  • WO2015169957 relates to a novel pharmaceutical composition
  • a novel pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof in combination with a proton pump inhibitor for use in the anticoagulant treatment with preventing or reducing the risk of a gastrointestinal disorder.
  • WO2016131896 relates to a pharmaceutical combination comprising dronedarone or a pharmaceutically acceptable salt thereof in combination with rivaroxaban and at least one pharmaceutically acceptable excipient.
  • W007039122 relates to rivaroxaban formulations comprising rivaroxaban in amorphous form or thermodynamically metastable crystal modification.
  • W009049820 relates to rivaroxaban formulations comprising at least one solid substance at room temperature, the thermodynamically preferred crystalline form of rivaroxaban, cellulose and/or cellulose derivatives, as well as optionally a surface-active substance, wherein more than 50% of rivaroxaban in the formulation is in amorphous mixed phase as determined by X- ray diffractometry.
  • W02005060940 relates to a method for production of a solid, orally administrable pharmaceutical composition comprising rivaroxaban in hydrophilized form.
  • the wet granulation manufacturing method is disclosed by using fluidized-bed granulation. In the manufacturing method, first rivaroxaban is introduced into the wet granulation suspended in the granulation liquid.
  • rivaroxaban is a poor-water soluble drug, it should be dissolved in a suitable solvent for further processing and get a dosage form with good pharmaceutical properties.
  • WO2017021482 relates to an immediate release tablet comprising; rivaroxaban, a non-ionic surfactant and optionally one or more pharmaceutically acceptable excipients obtainable by using a dry process.
  • W010146179 or W011042156 disclose hot melt rivaroxaban formulations.
  • the use of hot melt process, coated granules, milling with excipients or microspheres formulations imply complex, lengthy and costly processes; therefore, they are not desirable.
  • Rivaroxaban is a pharmaceutical agent that is used to reduce stroke risk in nonvalvular atrial fibrillation. It helps reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It is also indicated for treating deep vein thrombosis and pulmonary embolism. It also reduces in the risk of recurrence of the same. Specifically, rivaroxaban is used for the prophylaxis of deep vein thrombosis after knee or hip replacement surgery which may lead to pulmonary embolism.
  • Rivaroxaban is an orally active factor Xa inhibitor marketed for the treatment or prevention of atherothrombotic events, prevention of venous thromboembolism, prevention of stroke and systemic embolism, treatment and prevention of deep vein thrombosis or treatment and prevention of pulmonary embolism.
  • Rivaroxaban is marketed in 2.5, 10, 15 and 20 mg strengths immediate release tablets.
  • Rivaroxaban has poor water solubility (7 mg/L) and is thus difficult to incorporate into oral dosage forms that provide sufficient bioavailability of rivaroxaban following oral administration. There is thus a need to provide an improved process for the preparation of dosage forms of rivaroxaban with improved bioavailability of the rivaroxaban active ingredient. Based on the information about the solubility of rivaroxaban wet granulation method is the preferred manufacturing method to achieve a solid dosage form with good pharmaceutical characteristics.
  • a high-shear granulator consists of a cylindrical or conical mixing bowl, a three bladed impeller, a chopper, an auxiliary chopper, a motor to drive the blades and a discharge pot.
  • the mixing bowl is jacketed for heating or cooling the contents of the bowl as the case may be.
  • the present invention is an oral dosage form non-hydrophilized rivaroxaban with improved pharmaceutical characteristics by using high-shear granulation process as a part of wet granulation method.
  • the present invention relates to an immediate release solid oral composition
  • an immediate release solid oral composition comprising rivaroxaban and one or more acceptable excipients manufactured by using optimised high- shear granulation process.
  • Another object of the invention is the oral dosage form of the present invention for the treatment or prevention of atherothrombotic events, prevention of venous thromboembolism, prevention of stroke and systemic embolism, treatment and prevention of deep vein thrombosis or treatment and prevention of pulmonary embolism.
  • Another object of the invention is the oral dosage form comprising rivaroxaban in non- hydrophilized form which means rivaroxaban does not introduce into a solvent prior to further manufacturing processes. Manufacturing process without solvent has many challenges regarding rivaroxaban is poorly water-soluble drug. To overcome these problems some additional excipients should be used. In the present invention the excipients are selected according to conventional manufacturing methods. Thus, critical manufacturing processes are improved.
  • Another object of the invention is to develop an oral dosage form with improved pharmaceutical properties.
  • the water-solubility of rivaroxaban is very low it is difficult to have an oral dosage form with improved bioavailability.Thus, critical manufacturing processes are improved.
  • the pharmaceutically acceptable inert excipients comprise diluents, disintegrants, binders and solubilizers, lubricants, surfactants etc.
  • the granulation is wet granulation. In yet another aspect of the embodiment, the granulation is high-shear granulation process.
  • the high-shear wet granulation process using high-shear granulator can be divided into 5 main stages includes;
  • An advantage of high-shear granulation is that the process is completed within a short period of time. It does, however, need to be carefully controlled as the formulation can quickly progress from under- to overgranulated.
  • Kneading process is the part of granulation process after the completion of the addition of the binder solution. Kneading time is the critical parameter in wet granulation processes which determines the physical and chemical properties of the granule. It is surprisingly found that solid oral dosage forms comprising non-hydrophilized rivaroxaban manufactured by using wet granulation especially high-shear granulation processhas improved pharmaceutical properties through a specified kneading time in granulation step.
  • the present invention provides a solid oral dosage form comprising non-hydrophilized rivaroxaban and pharmaceutically acceptable excipients manufactured by using a high-shear granulation process with a specified kneading time in granulation step.
  • the rivaroxaban- containing particles of the present invention is easily incorporated into pharmaceutical dosage forms for oral administration to patients in need thereof.
  • the manufacturing methods are investigated by using direct compression and slugging compression as the short and financially advantageous processes.
  • the solid oral dosage forms are obtained and analysed for in-vitro dissolution.
  • the parameters of dissolution analysis are defined as 900 ml pH 4.5 with 0.4% SLS, Pedal (USP App. II), 75 rpm. Table 1: Dissolution results of drug products with dry manufacturing methods
  • Solid oral pharmaceutical dosage forms comprising rivaroxaban and pharmaceutically acceptable excipients manufactured by using the methods without a solvent is not convenient based on the dissolution results presented in the table 1.
  • Manufacturing method is determined as wet granulation method considering the dissolution results above. Particularly wetting stage is important as the rivaroxaban is a poor water- soluble drug. More particularly, granulation parameters should be optimized sensitively.
  • the granulation process may result in enhanced granule consistency, improved workability of the final blend prior to solid oral dosage form.
  • rivaroxaban is dissolved in a solvent (hydrophilized) which means dosage form is expected to have improved dissolution results.
  • manufacturing steps are:
  • Rivaroxaban, surfactant and a specified amount of binder are dissolved in deionised water and mixed to obtain uniform solution.
  • step 3 The granulation solution prepared in step 1 is added on the powder mixture obtained in step 2 and granulation process is performed by using high-shear granulator.
  • Granules are used to get a pharmaceutically acceptable solid oral dosage forms.
  • rivaroxaban is dissolved in deionized water with the pharmaceutically acceptable excipients.
  • This process has various disadvantageous like, loss of solution comprising rivaroxaban, difficult to obtain a uniform blend.
  • the blend obtained with wet granulation method was not uniform and its appearance was opaque which is not clear.
  • dissolving rivaroxaban in binder solution makes a strong bound between rivaroxaban and binder which inhibits the release of rivaroxaban.
  • Rivaroxaban is considered to be mixed with pharmaceutically acceptable excipients without a solvent which means it is in non-hydrophilized form.
  • manufacturing steps are: 1. Surfactant and a specified amount of binder are dissolved in deionised water and mixed to obtain uniform solution.
  • Specified amount of rivaroxaban, filer, glidant, diluent and the remaining part of binder is mixed in a separate bowl.
  • step 3 The granulation solution prepared in step 1 is added on the powder mixture obtained in step
  • Granules are used to get a pharmaceutically acceptable solid oral dosage forms.
  • a binder solution is added to the powder mixture of rivaroxaban and one or more pharmaceutically acceptable excipients, resulting in a granulation mixture.
  • the binder solution is added to the blend with an optimized rate while the blend is subjected to high- shear granulation.
  • the binder may be, for example, hypromellose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof.
  • the binder is dissolved in a solvent, for instance, water, an alcohol, or mixtures thereof.
  • the binder solution is hypromellose dissolved in water.
  • the filler is selected from the group consisting of lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and / or tribasic), calcium sulphate trihydrate or dihydrate, calcium carbonate, kaolin, cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, glucose, mannitol, maltol, sorbitol, xylitol, titanium dioxide (T1O 2 ) or the mixture thereof.
  • the disintegrant is selected from the group consisting of calcium phosphate (dibasic and / or tribasic), sodium starch glycolate, crospovidone, croscarmellose sodium and the mixture thereof.
  • the surfactant is selected from the group consisting of alkylbenzene sulfonates, sodium lauryl sulphate, dialkyl sulfosuccinate, polyethylene glycol, sorbitan monoester, glycerol diester and the mixture thereof.
  • the lubricant is selected from the group consisting of magnesium stearate, stearic acid, polyethylene glycol, sodium stearyl fumarate and the mixture thereof.
  • the critical step in the process of the present invention is the step 3, granulation step. Granulating the powder mixture with granulation or binder solution. In this step, kneading time after the completion of binder solution addition directly affects the physical and chemical properties of the granule. In the manufacturing methods of Formulation I and II, average kneading time in granulation was selected. However; granulation parameters should be optimised.
  • granulation method, kneading time in granulation step is optimised with multiple experiments.
  • composition and manufacturing method for Formulation II are constant as defining the most proper granulation parameter; kneading time in granulation step.
  • Table 4 Optimization of Kneading Timethrough Formulation II by In-vitro Analysis
  • Formulation II with optimized kneading time is subjected to bioequivalence study.
  • PK parameters (AU and C max ) are in line with the specifications based on Guideline on the Investigation on Bioequivalence.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne une composition orale solide à libération immédiate comprenant du rivaroxaban et un ou plusieurs excipients acceptables, fabriquée en utilisant un procédé de granulation à cisaillement élevé optimisé. Plus spécifiquement, l'invention concerne la formulation pharmaceutique orale comprenant du rivaroxaban et des excipients pharmaceutiquement acceptables, fabriquée en utilisant une méthode de granulation par voie humide dans laquelle le rivaroxaban est sous une forme non hydrophilisée avec un temps de malaxage optimisé de 30 secondes à 3 minutes.
PCT/TR2018/050699 2018-11-16 2018-11-16 Formulations orales comprenant du rivaroxaban Ceased WO2020101587A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/TR2018/050699 WO2020101587A1 (fr) 2018-11-16 2018-11-16 Formulations orales comprenant du rivaroxaban
EP18940435.3A EP3796915A4 (fr) 2018-11-16 2018-11-16 Formulations orales comprenant du rivaroxaban

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2018/050699 WO2020101587A1 (fr) 2018-11-16 2018-11-16 Formulations orales comprenant du rivaroxaban

Publications (1)

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WO2020101587A1 true WO2020101587A1 (fr) 2020-05-22

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PCT/TR2018/050699 Ceased WO2020101587A1 (fr) 2018-11-16 2018-11-16 Formulations orales comprenant du rivaroxaban

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EP (1) EP3796915A4 (fr)
WO (1) WO2020101587A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114886867A (zh) * 2022-06-16 2022-08-12 北京四环制药有限公司 一种高稳定性的利伐沙班药物组合物及其制备方法
WO2023067620A1 (fr) * 2021-10-18 2023-04-27 Unison Pharmaceuticals Pvt. Ltd. Compositions pharmaceutiques de rivaroxaban à désintégration orale
US20230190499A1 (en) * 2020-05-26 2023-06-22 Elixir Medical Corporation Anticoagulant compounds and methods and devices for their use

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WO2007039122A2 (fr) 2005-10-04 2007-04-12 Bayer Healthcare Ag Formulations de presentation pharmaceutiques, solides et administrees par voie orale presentant une liberation d'agents actifs rapide
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WO2009023233A1 (fr) 2007-08-14 2009-02-19 Concert Pharmaceuticals, Inc. Dérivés d'oxazolidinones substituées
WO2009049820A2 (fr) 2007-10-11 2009-04-23 Bayer Schering Pharma Aktiengesellschaft Formulation amorphe
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IN2014MU00781A (fr) * 2014-03-07 2015-09-25 Torrent Pharmaceuticals Ltd
WO2015155307A1 (fr) 2014-04-11 2015-10-15 Sanovel Ilac Sanayi Ve Ticaret A.S. Combinaisons pharmaceutiques de rivaroxaban et d'inhibiteurs de pompe à protons
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WO2016131896A1 (fr) 2015-02-19 2016-08-25 Sanovel Ilac Sanayi Ve Ticaret A.S. Combinaisons pharmaceutiques de dronédarone et de rivaroxaban
WO2017021482A1 (fr) 2015-08-05 2017-02-09 Interquim, S.A. Compositions pharmaceutiques de rivaroxaban
WO2017146709A1 (fr) * 2016-02-25 2017-08-31 Mylan Inc. Procédé unique de granulation sous fort cisaillement améliorant la biodisponibilité du rivaroxaban

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CN103550165B (zh) * 2013-10-19 2019-07-16 浙江华海药业股份有限公司 一种含有利伐沙班的药物组合物及其制备方法
WO2016166733A1 (fr) * 2015-04-17 2016-10-20 Micro Labs Limited Procédé de préparation d'une composition pharmaceutique comprenant du rivaroxaban
CN106491514B (zh) * 2015-09-08 2019-04-23 凯望药业有限公司 利伐沙班的固体制剂及其制备方法
CN105267169B (zh) * 2015-12-07 2018-03-30 石家庄康贺威药业有限公司 一种利伐沙班片剂及其制备方法

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WO2001047919A1 (fr) 1999-12-24 2001-07-05 Bayer Aktiengesellschaft Oxazolidinones substituees et leur utilisation dans le domaine de la coagulation sanguine
US20070149522A1 (en) 2003-01-07 2007-06-28 Bayer Healthcare Ag Method for producing 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
WO2005060940A2 (fr) 2003-11-27 2005-07-07 Bayer Healthcare Ag Procede pour produire une composition pharmaceutique solide a application orale
WO2007039132A1 (fr) 2005-10-04 2007-04-12 Bayer Healthcare Ag Nouvelle forme polymorphe et forme amorphe de 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide
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WO2009023233A1 (fr) 2007-08-14 2009-02-19 Concert Pharmaceuticals, Inc. Dérivés d'oxazolidinones substituées
WO2009049820A2 (fr) 2007-10-11 2009-04-23 Bayer Schering Pharma Aktiengesellschaft Formulation amorphe
WO2010146179A2 (fr) 2009-06-18 2010-12-23 Krka, Tovarna Zdravil, D.D., Novo Mesto Composition pharmaceutique solide comprenant du rivaroxaban
WO2011042156A1 (fr) 2009-10-06 2011-04-14 Ratiopharm Gmbh Compositions pharmaceutiques contenant du rivaroxaban
IN2014MU00781A (fr) * 2014-03-07 2015-09-25 Torrent Pharmaceuticals Ltd
WO2015155307A1 (fr) 2014-04-11 2015-10-15 Sanovel Ilac Sanayi Ve Ticaret A.S. Combinaisons pharmaceutiques de rivaroxaban et d'inhibiteurs de pompe à protons
WO2015169957A1 (fr) 2014-05-09 2015-11-12 Sanovel Ilac Sanayi Ve Ticaret A.S. Combinaisons pharmaceutiques de rivaroxaban et d'antagonistes du récepteur h2
WO2016131896A1 (fr) 2015-02-19 2016-08-25 Sanovel Ilac Sanayi Ve Ticaret A.S. Combinaisons pharmaceutiques de dronédarone et de rivaroxaban
WO2017021482A1 (fr) 2015-08-05 2017-02-09 Interquim, S.A. Compositions pharmaceutiques de rivaroxaban
WO2017146709A1 (fr) * 2016-02-25 2017-08-31 Mylan Inc. Procédé unique de granulation sous fort cisaillement améliorant la biodisponibilité du rivaroxaban

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Title
See also references of EP3796915A4

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230190499A1 (en) * 2020-05-26 2023-06-22 Elixir Medical Corporation Anticoagulant compounds and methods and devices for their use
US12521258B2 (en) * 2020-05-26 2026-01-13 Elixir Medical Corporation Anticoagulant compounds and methods and devices for their use
WO2023067620A1 (fr) * 2021-10-18 2023-04-27 Unison Pharmaceuticals Pvt. Ltd. Compositions pharmaceutiques de rivaroxaban à désintégration orale
CN114886867A (zh) * 2022-06-16 2022-08-12 北京四环制药有限公司 一种高稳定性的利伐沙班药物组合物及其制备方法

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EP3796915A1 (fr) 2021-03-31
EP3796915A4 (fr) 2022-01-26

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