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WO2018120777A1 - Préparation auto-émulsifiante de rivaroxaban et son procédé de préparation - Google Patents

Préparation auto-émulsifiante de rivaroxaban et son procédé de préparation Download PDF

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Publication number
WO2018120777A1
WO2018120777A1 PCT/CN2017/093298 CN2017093298W WO2018120777A1 WO 2018120777 A1 WO2018120777 A1 WO 2018120777A1 CN 2017093298 W CN2017093298 W CN 2017093298W WO 2018120777 A1 WO2018120777 A1 WO 2018120777A1
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WIPO (PCT)
Prior art keywords
rivaroxaban
self
preparation
emulsifying
emulsified
Prior art date
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Ceased
Application number
PCT/CN2017/093298
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English (en)
Chinese (zh)
Inventor
颜携国
张伟明
陶安进
袁建成
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Hybio Pharmaceutical Co Ltd
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Hybio Pharmaceutical Co Ltd
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Publication of WO2018120777A1 publication Critical patent/WO2018120777A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • 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
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a rivaroxaban self-emulsification preparation and a preparation method thereof.
  • Rivaroxaban is a drug for the prevention and treatment of venous thrombosis. It is also the world's first oral direct inhibitor of factor Xa. It was developed by Bayer/Johnson and is clinically used to prevent patients after hip and knee joint replacement. The formation of deep vein thrombosis (DVT) and pulmonary embolism (PE) can also be used to prevent stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation, and to reduce the risk of recurrence of coronary syndrome. At present, rivaroxaban has been registered and approved in Canada, the European Union, South America, China, Australia and other countries and regions. The trade name is Xarelto.
  • Rivaroxaban molecular formula C 19 H 18 C l N 3 O 5 S, chemical name 5-chloro-nitrogen-((5s)-2-oxo-3-[-4-(3-oxo-4-) Polinyl)phenyl]-1,3-oxazolidin-5-yl-2-thiophene-carboxamide, the structural formula is as follows:
  • Rivaroxaban belongs to class II (low solubility hypertonicity) in the classification of biopharmaceutics classification system (BCS).
  • BCS biopharmaceutics classification system
  • rivaroxaban greatly limits its application in the medical field due to its low solubility and low bioavailability. Therefore, finding a preparation which can improve the solubility and bioavailability of rivaroxaban is a technical problem to be solved by those skilled in the art.
  • the present invention adopts the following technical solutions:
  • the invention discloses a rivaroxaban self-emulsification preparation, which comprises the following components in terms of mass percentage:
  • the rivaroxaban self-emulsified preparation of the invention is a thermodynamically stable uniform system composed of rivaroxaban, an oil phase, an emulsifier and a co-emulsifier, and can spontaneously form a particle size smaller than stirring at an ambient temperature and a small amount of water.
  • the 100nm O/W microemulsion due to the small microemulsion particles and large surface area, greatly increases the contact area of rivaroxaban with the medium and mucous membrane, and can promote the oral absorption of refractory rivaroxaban.
  • the rivaroxaban self-emulsifying formulation comprises, by mass percent, the following components:
  • the oil phase is oleic acid, soybean oil, ethyl oleate, isopropyl myristate, isopropyl palmitate, corn oil, castor oil, caprylic/capric triglyceride, glycerol monooleate At least one of ester, linoleic acid glyceride, oleic acid, olive oil, sesame oil, peanut oil, almond oil.
  • the oil phase is oleic acid, soybean oil, ethyl oleate, nutmeg One of isopropyl citrate.
  • the emulsifier is polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyethylene glycol stearate-15, oleic acid polyethylene glycol glyceride, polyethylene glycol octyl phenyl ether , octanoic acid polyethylene glycol glyceride, poloxamer 188, Tween-80, phospholipids, liquid lecithin, sucrose laurate, sucrose palmitate, sucrose stearate, lauric acid polyethylene glycol At least one of a glyceride, glycerol polyethylene glycol-75-stearate.
  • the emulsifier is one of polyoxyethylene castor oil, poloxamer 188, Tween-80.
  • the co-emulsifier is glycerin, ethanol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, isopropanol, 1,2-propanediol, n-butanol, diethylene glycol monoethyl ether, and propylene carbonate. At least one of the diesters.
  • the co-emulsifier is one of glycerin, ethanol.
  • the invention also provides a preparation method of the rivaroxaban self-emulsified preparation, comprising the steps of: uniformly mixing an oil phase, an emulsifier and a co-emulsifier, and then uniformly mixing with rivaroxaban to obtain rivaroxaban self-emulsification preparation.
  • the present invention also provides a pharmaceutical preparation comprising the rivaroxaban self-emulsifying preparation and a pharmaceutically acceptable excipient.
  • it is an oral preparation or an injection preparation.
  • the oral preparation may be a granule, a tablet, a dispersant, or a capsule.
  • the rivaroxaban self-emulsifying formulation is filled orally in a soft capsule, and in some embodiments, the rivaroxaban self-emulsifying formulation is dispersed for use in physiological saline or 5% dextrose for injection.
  • the rivaroxaban self-emulsifying formulation is a rivaroxaban self-emulsifying dispersible tablet.
  • the auxiliary material is at least one of an adsorbent, a diluent, a disintegrant, a flavor, and a lubricant.
  • the adsorbent is selected from the group consisting of anhydrous calcium hydrogen phosphate, calcium phosphate, calcium carbonate, magnesium carbonate, magnesium oxide micropowder silica gel, microcrystalline cellulose, lactose, aluminum hydroxide gel powder, and chlorination.
  • anhydrous calcium hydrogen phosphate, calcium phosphate, calcium carbonate, magnesium carbonate, magnesium oxide micropowder silica gel, microcrystalline cellulose, lactose, aluminum hydroxide gel powder, and chlorination Sodium, pregelatinized starch, sucrose powder, glucose powder, mannitol, sorbitol starch, cyclodextrin, sodium carbonate, sodium hydrogencarbonate, calcium sulfate, povidone, polyethylene glycol 4000, polyethylene glycol 6000 At least one of them.
  • the adsorbent is one of lactose, anhydrous calcium hydrogen phosphate.
  • the diluent is at least one selected from the group consisting of microcrystalline cellulose, calcium hydrogen phosphate, lactose, starch, dextrin, pregelatinized starch, mannitol, glucose powder, sucrose powder, and sorbitol.
  • the diluent is microcrystalline cellulose.
  • the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, partially pregelatinized starch At least one of them.
  • the disintegrant is one of crospovidone, croscarmellose sodium.
  • the flavoring agent is selected from at least one of stevioside, aspartame, citric acid, food flavor, lactose, glucose, sucrose, and mannitol.
  • the flavoring agent is citric acid.
  • the lubricant is selected from at least one of micronized silica gel, magnesium stearate, talc, and sodium stearyl fumarate.
  • the lubricant is one of micronized silica gel, magnesium stearate, sodium stearyl fumarate.
  • the pharmaceutical formulation is a rivaroxaban self-emulsifying dispersible tablet, the mass of each component being:
  • the absorbent is anhydrous calcium hydrogen phosphate or lactose; the diluent is microcrystalline cellulose;
  • the disintegrant is crospovidone or croscarmellose sodium; the flavoring agent is citric acid; the lubricant is micronized silica gel, magnesium stearate or sodium stearyl fumarate .
  • the invention also provides a preparation method of a rivaroxaban self-emulsifying dispersible tablet, which is mixed with a rivaroxaban self-emulsifying preparation, and then mixed with a diluent, a disintegrant, a flavoring agent and a lubricant, Tableting.
  • the present invention provides a rivaroxaban self-emulsifying preparation and a preparation method thereof.
  • the rivaroxaban self-emulsified preparation of the present invention comprises 1-1% by weight of rivaroxaban, 5-50% of oil phase, 20-70% of emulsifier, and 0-50% of co-emulsifier.
  • the rivaroxaban self-emulsified preparation of the invention has a particle size distribution of less than 1 ⁇ m, and can spontaneously emulsify in the body to form microemulsions having a particle diameter of 20 to 1000 nm, thereby improving the solubility and bioavailability of rivaroxaban.
  • the rivaroxaban self-emulsifiable preparation can be mixed with a suitable solid auxiliary material to achieve solidification, and the obtained rivaroxaban self-emulsifying dispersible tablet improves the low permeability problem of rivaroxaban and dissolves more rapidly.
  • the preparation method of the rivaroxaban self-emulsified preparation of the invention has the advantages of simple process and low cost.
  • the invention provides a rivaroxaban self-emulsifying preparation and a preparation method thereof for solving the technical defects in the prior art.
  • the raw materials are all commercially available.
  • the prescribed amount of castor oil, glycerol monooleate, lauric acid polyethylene glycol glyceride and glycerin were weighed, mixed, and magnetically stirred for 20 min to form a uniform liquid, and then a prescribed amount of rivaroxaban was added, and stirring was continued for 30 minutes.
  • the rivaroxaban self-emulsified preparation is obtained after being sufficiently dissolved.
  • the rivaroxaban self-emulsified formulations of Examples 1-5 were separately added to a Malvern laser particle size analyzer to measure the particle size distribution.
  • the anhydrous calcium hydrogen phosphate was weighed according to the above prescription, and the prescribed amount of rivaroxaban self-emulsified preparation was added to make the rivaroxaban self-emulsified preparation fully adsorbed, and the wet granules were prepared, transferred to a fluidized bed to be dried, and the moisture was controlled. Dry granules are obtained within 3%, and the dry granules are further granulated (the No. 1 sieve removes the large particles, and the No. 5 sieve removes the fine powder) to obtain rivaroxaban self-emulsified granules;
  • the rivaroxaban self-emulsified oral granules were added to the mixing hopper, microcrystalline cellulose, croscarmellose sodium, and citric acid were added, premixed for 10 min, then magnesium stearate and breeze silica gel were added and mixed for 4 min. Tableting, that is, rivaroxaban self-emulsifying dispersible tablets.
  • the anhydrous calcium hydrogen phosphate was weighed according to the above prescription, and the prescribed amount of rivaroxaban self-emulsified preparation was added to make the rivaroxaban self-emulsified preparation fully adsorbed, and the wet granules were prepared, transferred to a fluidized bed to be dried, and the moisture was controlled. Dry granules are obtained within 3%, and the dry granules are further granulated (the No. 1 sieve removes the large particles, and the No. 5 sieve removes the fine powder) to obtain rivaroxaban self-emulsified granules;
  • the anhydrous calcium hydrogen phosphate was weighed according to the above prescription, and the prescribed amount of rivaroxaban self-emulsified preparation was added to make the rivaroxaban self-emulsified preparation fully adsorbed, and the wet granules were prepared, transferred to a fluidized bed to be dried, and the moisture was controlled. Dry granules are obtained within 3%, and the dry granules are further granulated (the No. 1 sieve removes the large particles, and the No. 5 sieve removes the fine powder) to obtain rivaroxaban self-emulsified granules;
  • the rivaroxaban self-emulsified oral granules were added to the mixing hopper, microcrystalline cellulose, croscarmellose sodium, and citric acid were added, premixed for 10 min, then magnesium stearate and breeze silica gel were added and mixed for 4 min. Tableting, that is, rivaroxaban self-emulsifying dispersible tablets.
  • the anhydrous calcium hydrogen phosphate was weighed according to the above prescription, and the prescribed amount of rivaroxaban self-emulsified preparation was added to make the rivaroxaban self-emulsified preparation fully adsorbed, and the wet granules were prepared, transferred to a fluidized bed to be dried, and the moisture was controlled. Dry granules are obtained within 3%, and the dry granules are further granulated (the No. 1 sieve removes the large particles, and the No. 5 sieve removes the fine powder) to obtain rivaroxaban self-emulsified granules;
  • the lactose is weighed according to the above prescription, and the prescribed amount of rivaroxaban self-emulsified preparation is added to make the rivaroxaban self-emulsified preparation fully adsorbed, and the wet granules are prepared, transferred to a fluidized bed for drying, and the controlled moisture is obtained within 3%. Dry granules, dry granules are further granulated (No. 1 sieve removes large granules, No. 5 sieve removes fine powder), and rivaroxaban self-emulsified granules are obtained;
  • the rivaroxaban self-emulsified oral granules were added to the mixing hopper, microcrystalline cellulose and crospovidone were added, premixed for 15 min, then sodium stearyl fumarate and breeze silica gel were added, mixed for 4 min, and compressed. Rivaroxaban self-emulsifying dispersible tablets.
  • microcrystalline cellulose was weighed according to the above prescription, and the prescribed amount of rivaroxaban self-emulsified preparation was added to make the rivaroxaban self-emulsified preparation fully adsorbed, and the wet granules were prepared, transferred to a fluidized bed to be dried, and the moisture was controlled at 3 Dry granules are obtained within %, and the dry granules are further granulated (the No. 1 sieve removes the large granules, and the No. 5 sieve removes the fine powder) to obtain rivaroxaban self-emulsified granules;
  • rivaroxaban self-emulsified oral granules to the mixing hopper, add lactose, croscarmellose sodium, premix for 15min, then add sodium stearyl fumarate and breeze silica gel, mix for 4min, and compress. Rivaroxaban self-emulsifying dispersible tablets.
  • the anhydrous calcium hydrogen phosphate was weighed according to the above prescription, and the prescribed amount of rivaroxaban self-emulsified preparation was added to make the rivaroxaban self-emulsified preparation fully adsorbed, and the wet granules were prepared, transferred to a fluidized bed to be dried, and the moisture was controlled. Dry granules are obtained within 3%, and the dry granules are further granulated (the No. 1 sieve removes the large particles, and the No. 5 sieve removes the fine powder) to obtain rivaroxaban self-emulsified granules;
  • rivaroxaban self-emulsified oral granules to the mixing hopper, add lactose, croscarmellose sodium, premix for 15 minutes, then add magnesium stearate and breeze silica gel, mix 4 min, tableting, that is, rivaroxaban self-emulsifying dispersible tablets.
  • the detection wavelength was 250 nm, the column temperature was 45 ° C, and the injection amount was 5 ⁇ l.
  • a small-tailed Han sheep model was established, and 18 male small-tailed Han sheep were taken, weighing 45-55 kg, with an average of 47 kg. Captive for 7 to 10 days before surgery, parallel pest control, fasting 24 hours before surgery, banned drink for 8 hours, left chest and limbs skin preparation. Another 9 small-tailed Han sheep were taken, male or female, and the rats were sacrificed under sterile conditions for about 2000 ml of blood through the femoral artery. Fresh blood was used. 12 domestic double-leaf mechanical valves were sterilized by autoclaving at 121 °C for 20 minutes.
  • Ketamine 20 ⁇ 30mg / kg, diazepam 2 ⁇ 2.5mg / kg intramuscular injection induction, Ato 1mg intramuscular injection, endotracheal intubation, anesthesia machine; limb conduction ECG, continuous monitoring of percutaneous oxygen saturation; right venous puncture to establish venous access for venous pressure, transfusion and medication; right radial artery catheterization Continuous monitoring of arterial pressure, parallel blood gas, blood potassium and whole blood activated clotting time (ACT) detection; monitoring of rectal temperature, homemade urine bag to measure urine output.
  • ACT blood activated clotting time
  • the flaps were normally opened and closed, and the 4-0 Prolene line was used to suture the pulmonary incision continuously. Adjust the flow rate, measure blood pressure, heart rate, blood gas, blood potassium and hemoglobin in the normal range, stop, give anticoagulant, withdraw from extracorporeal circulation.
  • the left 6th intercostal space near the sternum was 2cm.
  • the chest drainage tube was treated with a water-sealed bottle, and the chest was closed layer by layer. Preoperative and intraoperative injection of penicillin was 3.2 million units, so a good model was established.
  • Eighteen small-tailed Han sheep undergoing heart valve replacement were randomly divided into three groups.
  • Six of the control group started taking rivaroxaban tablets (commercially available) on the first day after surgery for anticoagulant therapy.
  • the rivaroxaban self-emulsifying dispersible tablets prepared in Example 6 were used for bridging anticoagulation; the first two groups of the experimental group began to take rivaroxaban self-emulsifying dispersion on the first day after surgery.
  • the tablets were bridged for anticoagulation, and the INR values of the three groups of small-tailed Han sheep were compared.
  • Table 2 shows that the INR of the experimental group was significantly different from the control group and the experimental group.
  • the rivaroxaban self-emulsifying dispersible tablet prepared in Examples 7-10 and the benefit prepared in Example 1 The results of the venezuela self-emulsifying dispersible tablets are comparable. It is indicated that the rivaroxaban self-emulsifying dispersible tablet prepared by the invention can effectively exert a good anticoagulant effect on the small-tailed Han sheep undergoing heart valve replacement.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dispersion Chemistry (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une préparation auto-émulsifiante de rivaroxaban et son procédé de préparation, la préparation comprenant en pourcentage en masse, 1 à 13 % de rivaroxaban, 5 à 50 % de phase huileuse, 20 à 70 % d'émulsifiant, 0 à 50 % du co-émulsifiant; le procédé de préparation de celle-ci comprend le mélange de la phase huileuse, de l'émulsifiant et du co-émulsifiant de manière uniforme, et ensuite le mélange du mélange avec du rivaroxaban pour obtenir la préparation auto-émulsifiante de rivaroxaban.
PCT/CN2017/093298 2016-12-26 2017-07-18 Préparation auto-émulsifiante de rivaroxaban et son procédé de préparation Ceased WO2018120777A1 (fr)

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CN201611220383.9A CN108236602B (zh) 2016-12-26 2016-12-26 一种利伐沙班自乳化制剂及其制备方法
CN201611220383.9 2016-12-26

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KR20210085317A (ko) * 2019-12-30 2021-07-08 단국대학교 천안캠퍼스 산학협력단 자가나노유화 약물전달시스템을 이용한 리바록사반의 경구용 고형제 조성물 및 이의 제조방법
KR102290670B1 (ko) * 2019-12-30 2021-08-18 단국대학교 천안캠퍼스 산학협력단 자가나노유화 약물전달시스템을 이용한 리바록사반의 경구용 고형제 조성물 및 이의 제조방법

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