WO2020078034A1 - 一种利伐沙班药物组合物及其制备方法 - Google Patents

一种利伐沙班药物组合物及其制备方法 Download PDF

Info

Publication number
WO2020078034A1
WO2020078034A1 PCT/CN2019/092744 CN2019092744W WO2020078034A1 WO 2020078034 A1 WO2020078034 A1 WO 2020078034A1 CN 2019092744 W CN2019092744 W CN 2019092744W WO 2020078034 A1 WO2020078034 A1 WO 2020078034A1
Authority
WO
WIPO (PCT)
Prior art keywords
rivaroxaban
preparation
pharmaceutical composition
lubricant
polyethylene glycol
Prior art date
Application number
PCT/CN2019/092744
Other languages
English (en)
French (fr)
Inventor
龙文
张伟明
陶安进
袁建成
Original Assignee
深圳翰宇药业股份有限公司
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 深圳翰宇药业股份有限公司 filed Critical 深圳翰宇药业股份有限公司
Publication of WO2020078034A1 publication Critical patent/WO2020078034A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and particularly relates to a rivaroxaban pharmaceutical composition and a preparation method thereof.
  • Rivaroxaban was jointly developed by Bayer and Johnson & Johnson.
  • the EMA was approved for listing on September 9, 2008, with specifications of 2.5mg, 10mg, 15mg, and 20mg. It was approved for listing in China in 2010.
  • DVD deep vein thrombosis
  • PE pulmonary embolism
  • the rivaroxaban BCS is classified as a class II (low solubility, high permeability) drug.
  • the solubility of the drug substance and the dissolution of the preparation will be absorbed by the drug Restrictive factors.
  • Chinese patent CN104721156A discloses a tablet containing rivaroxaban.
  • the micronized rivaroxaban and hydrophilic excipients are mixed and then crushed to improve the dissolution of rivaroxaban.
  • this crushing method has limited improvement in dissolution.
  • Patent CN200680045548.1 discloses the preparation of rivaroxaban in amorphous form and crystal form II by dissolution method, melting method and melt extrusion method, and then applying it to oral solid pharmaceutical preparations to improve the dissolution rate and biological Utilization.
  • amorphous or metastable rivaroxaban used it will be affected by the stability problem, and the solubility of the rivaroxaban raw material is poor.
  • the dissolution method requires a large amount of solvent and is difficult to industrialize.
  • Patent CN104055743B discloses the preparation of rivaroxaban tablets by powder direct pressure method, but rivaroxaban is a poorly soluble drug, and the use of powder direct pressure method is not conducive to improving the dissolution of poorly soluble drugs.
  • the original patent CN1886120B adopts micronization of the raw material drug, and disperses the micronized active ingredient in the granulation solution prepared by the hydrophilic binder, solvent, and wetting agent, and then obtains the drug-containing by wet granulation in the fluidized bed Granules, then mix and tablet.
  • hypromellose is used as the hydrophilic binder
  • sodium lauryl sulfate is used as the wetting agent to prepare a granulation solution
  • the micronized rivaroxaban is added to the above granulation liquid to make a profit Varshaban suspension to hydrophilize rivaroxaban.
  • the addition of the hydrophilic binder to the granulation solution requires a large amount of solvent treatment, and the hydrophilic binder is relatively viscous. It takes a long time to prepare a uniform rivaroxaban suspension, and the time from spraying to material granulation is relatively large. Longer, the granulation end point control also has greater technical difficulty, such as particles easy to clump.
  • the object of the present invention is to provide a rivaroxaban pharmaceutical composition with high drug dissolution in view of the defects of the prior art.
  • the present invention adopts the following technical solutions:
  • a rivaroxaban pharmaceutical composition is composed of the following components:
  • the sum of the components is 100% by weight.
  • the weight ratio of the rivaroxaban to the polyethylene glycol in the rivaroxaban pharmaceutical composition is 1: 0.5 to 1: 5. More preferably, it is 1: 1 to 1: 2.5.
  • the molecular weight of the polyethylene glycol is 1000-10000. It is more preferably one or both of polyethylene glycol 4000 and polyethylene glycol 6000.
  • the filler is selected from one or more of lactose, microcrystalline cellulose, starch, and mannitol.
  • the filler is microcrystalline cellulose PH101.
  • the filler is a mixture of corn starch, lactose, and microcrystalline cellulose PH101.
  • the filler is a mixture of corn starch and microcrystalline cellulose PH101.
  • the binder is selected from one or more of polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, and hypromellose.
  • the binder is polyvinylpyrrolidone K29 / 32.
  • the binder is sodium carboxymethyl cellulose.
  • the binder is hypromellose (6cP).
  • the disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, pregelatinized starch .
  • the disintegrant is croscarmellose.
  • the disintegrant is cross-linked polyvinylpyrrolidone.
  • the lubricant is selected from one or more of talc, magnesium stearate, sodium stearyl fumarate, and colloidal silica.
  • the lubricant is magnesium stearate.
  • the surfactant is selected from one or two of poloxamer and sodium lauryl sulfate. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, no surfactant may be added.
  • the above pharmaceutical composition has a preparation specification ranging from 2.5 mg to 20 mg, such as 2.5 mg or 10 mg or 15 mg or 20 mg.
  • the invention also provides a preparation method of the rivaroxaban pharmaceutical composition. After crushing, the rivaroxaban is dispersed in an aqueous solution of polyethylene glycol to make a rivaroxaban suspension dispersion, which is sprayed to the lubricant Granulated in the mixture of other components, dried and sized, mixed with lubricant.
  • the crushing is airflow crushing.
  • the rivaroxaban is crushed to a D 90 of less than 50 microns and a D 50 of less than 25 microns. More preferably, the rivaroxaban is crushed to a D 90 of less than 30 microns and a D 50 of less than 15 microns.
  • the solid content of the rivaroxaban suspension dispersion is 5 wt% to 12 wt%.
  • the granulation is specifically mixing and transferring other components except the lubricant to the mixing granulator, and evenly spraying the rivaroxaban suspension dispersion Mix the mixture in the granulator.
  • the other components besides the lubricant include binder, filler, disintegrant and surfactant.
  • the surfactant may not be added.
  • the disintegrant may be added in an additional manner, that is, the disintegrant is not included in other components except the lubricant, and the disintegrant is added after mixing with the lubricant after spray granulation and drying .
  • the mixing granulator is a fluidized bed granulator or a high-shear mixing granulator. More preferably, it is a fluidized bed granulator.
  • the spray is a top spray method or a bottom spray method, that is, the top spray method or the bottom spray method is used to uniformly spray the rivaroxaban suspension dispersion in the mixture material in the mixing granulator.
  • the temperature of the mixture is controlled below 50 ° C.
  • the drying after granulation is drying until the moisture content of the granules is 1.5-2.5%.
  • the present invention also provides a rivaroxaban tablet, comprising the above rivaroxaban pharmaceutical composition and a water-soluble film coating.
  • the water-soluble film coating is Opadry A powder mixture formulated by Calcon.
  • the weight gain of film coating is 2.0% ⁇ 4.0%.
  • the present invention provides a rivaroxaban pharmaceutical composition and a preparation method thereof.
  • the components of the rivaroxaban pharmaceutical composition of the present invention are rivaroxaban 4wt% -30wt%, polyethylene glycol 2wt% -60wt%, binder 2wt% -10wt%, filler 5wt% -85wt %, Disintegrant 2wt% -10wt%, surfactant 0wt% -1wt%, lubricant 0.1wt% -3wt%, the sum of the above components is 100wt%.
  • the raw material medicine crushed by the air flow is dispersed in the polyethylene glycol carrier solution, and the solid dispersion technology is adopted.
  • Polyethylene glycol is a hydrophilic polymer with low viscosity and good water solubility.
  • the preparation of rivaroxaban polyethylene glycol dispersion solution requires relatively few solvents, simple preparation and short time.
  • the required binder is mixed in powder form with filler, disintegrant, and a small amount of surfactant if necessary in a fluidized bed or high shear granulator, and then the rivaroxaban is polymerized.
  • the ethylene glycol dispersion is evenly sprayed in the mixed motion materials for granulation and drying.
  • the prepared granules have good fluidity and compressibility, the granulation end point is easy to control, and the granules have no large agglomeration phenomenon.
  • the prepared granules are further mixed with a lubricant and compressed into tablets, namely rivaroxaban tablets, which can be further coated.
  • the rivaroxaban tablet prepared by the invention can achieve good in vitro dissolution without adding a surfactant or a small amount of surfactant in the components.
  • the rivaroxaban tablets prepared by the present invention have better compressibility, tablet weight stability, less brittleness, good dissolution in vitro, and the dissolution rate can reach more than 80% in 30 minutes.
  • the invention discloses a rivaroxaban pharmaceutical composition and a preparation method thereof. Those skilled in the art can learn from this article and appropriately improve the process parameters to achieve. In particular, it should be noted that all similar substitutions and modifications will be obvious to those skilled in the art, and they are all considered to be included in the present invention.
  • the methods and products of the present invention have been described through preferred embodiments, and it is obvious that relevant personnel can modify or appropriately modify and combine the methods described herein without departing from the content, spirit, and scope of the present invention to implement and apply this method. Invention technology.
  • the reagents involved in the embodiments of the present invention are all commercially available products and can be purchased through commercial channels.
  • Material pre-treatment rivaroxaban jet mill is crushed to D 90 less than 30 microns, D 50 less than 15 microns.
  • step 4 After the dried granules prepared in step 3 are dried and granulated through a 40 mesh screen, magnesium stearate is added according to the prescription ratio for total mixing to obtain the total blend.
  • Material pre-treatment rivaroxaban jet mill is crushed to D 90 less than 30 microns, D 50 less than 15 microns.
  • step 4 After the dried granules prepared in step 3 are dried and granulated through a 40 mesh screen, magnesium stearate is added according to the prescription ratio for total mixing to obtain the total blend.
  • Material pre-treatment rivaroxaban jet mill is crushed to D 90 less than 30 microns, D 50 less than 15 microns.
  • step 4 After the dried granules prepared in step 3 are dried and granulated through a 40 mesh screen, magnesium stearate is added according to the prescription ratio for total mixing to obtain the total blend.
  • micronized rivaroxaban (D 90 less than 30 microns, D 50 less than 15 microns), sodium carboxymethyl cellulose, corn starch, lactose, microcrystalline cellulose PH102, cross-linked polymer Vinylpyrrolidone is initially mixed into the mixing hopper, the mixing time is 10 minutes, and the mixing speed is 15 rpm. After preliminary mixing, magnesium stearate was added for total mixing, with a total mixing time of 5 min and a mixing speed of 15 rpm. The total blend was then compressed to obtain rivaroxaban tablets. The rivaroxaban tablets are further film coated, and the film coating powder adopts Opadry The weight gain of the coating is 2% to 4%.
  • Material pre-treatment rivaroxaban jet mill is crushed to D 90 less than 30 microns, D 50 less than 15 microns.
  • step 4 After the dried granules prepared in step 3 are dried and granulated through a 40 mesh screen, magnesium stearate is added according to the prescription ratio for total mixing to obtain the total blend.
  • Rivaroxaban is crushed by a jet mill to a D 90 of approximately 106.1 microns and a D 50 of approximately 30.3 microns.
  • step 4 After the dried granules prepared in step 3 are dried and granulated through a 40 mesh screen, magnesium stearate is added according to the prescription ratio for total mixing to obtain the total blend.
  • Material pre-treatment rivaroxaban jet mill is crushed to D 90 less than 30 microns, D 50 less than 15 microns.
  • step 4 After the dried granules prepared in step 3 are dried and granulated through a 40 mesh screen, magnesium stearate is added according to the prescription ratio for total mixing to obtain the total blend.
  • Material pre-treatment rivaroxaban jet mill is crushed to D 90 less than 30 microns, D 50 less than 15 microns.
  • step 4 After the dried granules prepared in step 3 are dried and granulated through a 40 mesh screen, magnesium stearate is added according to the prescription ratio for total mixing to obtain the total blend.
  • the rivaroxaban tablets prepared in the above examples and comparative examples were investigated according to the following methods. The results are shown in Table 1. Among them, the average hardness test method of plain tablets: the average hardness of 10 consecutive plain tablets compressed by the tablet press under the same compression force; the method of investigating the difference in tablet weight: the use of the Chinese Pharmacopoeia 2015 version of four preparations general principles 0101 tablet weight difference inspection ; Method of investigation of friability: the Chinese Pharmacopoeia 2015 edition of four 0923 tablets friability inspection method.
  • Comparative Example 1 48N ⁇ 4.9% 0.36 Comparative Example 2 53N ⁇ 4.2% 0.26 Comparative Example 3 38N ⁇ 3.5% 0.43 Comparative Example 4 51N ⁇ 3.1% 0.23 Comparative Example 5 43N ⁇ 3.8% 0.37
  • Example 1 75.7% 87.3% 93.0% 96.2%
  • Example 2 79.6% 93.5% 98.2% 99.8%
  • Example 3 77.8% 90.4% 95.1% 97.6% Comparative Example 1 69.7% 79.8% 88.7% 92.8% Comparative Example 2 63.5% 78.3% 89.6% 92.3% Comparative Example 3 43.3% 62.8% 73.6% 85.1% Comparative Example 4 58.6% 72.1% 83.8% 90.2% Comparative Example 5 67.3% 78.2% 86.9% 93.6%
  • Table 2 show that the samples prepared in Examples 1 to 3 of the present invention have a dissolution rate of more than 80% in 30 minutes, and all are close to the dissolution platform.
  • the samples prepared in Comparative Examples 1 to 5 had a dissolution rate of less than 80% in 30 minutes, which was far from the dissolution platform.
  • Comparative Example 2 Polyvinylpyrrolidone K29 / 32 and micronized API were used as a suspension solution, and the sample was prepared by fluidized bed granulation. The sample did not reach 80% after 30 minutes of dissolution.
  • the particle size of the drug used in Comparative Example 3 exceeds the size range less than 50 microns D 90, D 50 of less than 25 microns, more coarse particle size, D 90 of about 106.1 microns, D 50 of about 30.3 microns.
  • Comparative Example 3 has poor compressibility and friability.
  • Comparative Example 4 uses rivaroxaban raw material within the particle size range, but the sample with only 1.5% disintegrant dissolves only 72.1% in 30 minutes.
  • the process of Example 3 is the same as that of Comparative Example 5, except that the lubricant amount of Comparative Example 5 exceeds 3% and reaches 3.5% only on the prescription.
  • the dissolution of Comparative Example 5 was slower than that of Example 3, and the dissolution rate was only 78.2% in 30 minutes.
  • the samples prepared by the present invention have better compressibility, tablet weight stability, less brittleness, good in vitro dissolution, and the dissolution rate can reach more than 80% in 30 minutes.

Landscapes

  • 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)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

一种利伐沙班药物组合物及其制备方法，所述利伐沙班药物组合物由利伐沙班、聚乙二醇、粘合剂、填充剂、崩解剂、表面活性剂、润滑剂按一定配比组成。所述制备方法为：将利伐沙班粉碎后分散在聚乙二醇的水溶液中制成利伐沙班悬浮分散液，喷雾至除润滑剂外的其它组分的混合物料中制粒，干燥后与润滑剂混合、压片，即得。

Description

一种利伐沙班药物组合物及其制备方法
本申请要求于2018年10月16日提交中国专利局、申请号为201811203606.X、发明名称为“一种利伐沙班药物组合物及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于药物制剂领域，具体涉及一种利伐沙班药物组合物及其制备方法。
背景技术
利伐沙班由拜耳和强生公司联合开发，EMA于2008年9批准上市，规格为2.5mg、10mg、15mg、20mg。2010年在中国获批上市。于2011年7月在美国获得FDA批准上市，商品名为“Xartelto”，规格有10mg、15mg、20mg，获准用于膝或髋部置换手术病人预防深静脉血栓和肺栓塞；2011年11月又获准用于非瓣膜性房颤患者预防中风；2012年11月FDA批准扩大适应症，新增用于治疗深静脉血栓(DVT)或肺栓塞(PE)以及预防DVT和PE复发。
据欧洲药品管理局EMA对拜瑞妥的药物评估报告中可知，利伐沙班的BCS分类为II类(低溶解、高渗透)药物，原料药的溶解度和制剂的溶出将是该药物体内吸收的限制性因素。
中国专利CN104721156A公开了一种含利伐沙班的片剂，其通过将微粉化的利伐沙班和亲水性辅料混合后，再进行粉碎处理，以提高利伐沙班的溶出。但这种粉碎方法对溶出的改善有限。
专利CN200680045548.1中公开了通过溶解法、熔化法、熔融挤出法制备得到无定形态与晶型Ⅱ的利伐沙班，再将其应用于口服固体药物制剂中，以提高溶出速率和生物利用度。但由于其用到的无定形或亚稳定型的利伐沙班，会受到稳定性问题的影响，而且利伐沙班原料药溶解性差，采用溶解法需要大量溶剂，难以工业化生产。
专利CN104055743B公开了采用粉末直压法制备利伐沙班片，但利伐沙班为难溶性药物，采用粉末直压法不利于提高难溶性药物的溶出。
原研专利CN1886120B采用将原料药微粉化，且将微粉化的活性成分散在由亲水性粘合剂、溶剂、润湿剂制备的造粒溶液中，然后通过流化床湿法制粒制得含药颗粒，再总混、压片。其中选用羟丙甲纤维素作为亲水性粘合剂、以十二烷基硫酸钠为润湿剂配制成造粒溶液，并将微粉化的利伐沙班加入上述造粒液中制成利伐沙班悬浮液，以对利伐沙班进行亲水化处理。然而所述的亲水粘合剂加在造粒溶液中需要大量的溶剂处理，且亲水粘合剂粘性较大，配制均一利伐沙班悬浮液时间长，且喷雾至物料制粒时间相对较长，制粒终点控制也有较大的技术难度，如颗粒易成团等。
发明内容
有鉴于此，本发明的目的在于针对现有技术的缺陷，提供一种药物溶出度高的利伐沙班药物组合物。
为实现本发明的目的，本发明采用如下技术方案：
一种利伐沙班药物组合物，由如下组分组成：
Figure PCTCN2019092744-appb-000001
各组分总和为100wt％。
其中，作为优选，所述利伐沙班药物组合物中所述利伐沙班与聚乙二醇的重量比为1:0.5～1:5。更优选为1:1～1:2.5。
作为优选，所述聚乙二醇分子量为1000～10000。更优选为聚乙二醇4000、聚乙二醇6000中的一种或两种。
作为优选，所述填充剂选自乳糖、微晶纤维素、淀粉、甘露醇中的一种或几种。在一些实施方案中，所述填充剂为微晶纤维素PH101。在一些实施方案中，所述填充剂为玉米淀粉、乳糖和微晶纤维素PH101的混合物。在一些实施方案中，所述填充剂为玉米淀粉和微晶纤维素PH101的混合物。
作为优选，所述粘合剂选自聚乙烯吡咯烷酮、羧甲基纤维素钠、羟丙基纤维素、聚乙烯醇、羟丙甲纤维素中的一种或几种。在一些实施方案中，所述粘合剂为聚乙烯吡咯烷酮K29/32。在一些实施方案中，所述粘合剂为羧甲基纤维素钠。在一些实施方案中，所述粘合剂为羟丙甲纤维素(6cP)。
作为优选，所述崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、预胶化淀粉中的一种或几种。在一些实施方案中，所述崩解剂为交联羧甲基纤维素。在一些实施方案中，所述崩解剂为交联聚乙烯吡咯烷酮。
作为优选，所述润滑剂选自滑石粉、硬脂酸镁、硬脂富马酸钠、胶态二氧化硅中的一种或几种。在一些实施方案中，所述润滑剂为硬脂酸镁。
作为优选，所述表面活性剂选自泊洛沙姆、十二烷基硫酸钠中的一种或两种。在一些实施方案中，所述表面活性剂为十二烷基硫酸钠。在一些实施方案中，可不加入表面活性剂。
上述药物组合物，制剂规格范围2.5mg～20mg，如2.5mg或10mg或15mg或20mg。
本发明还提供了所述的利伐沙班药物组合物的制备方法，利伐沙班粉碎后分散在聚乙二醇的水溶液中制成利伐沙班悬浮分散液，喷雾至除润滑剂外的其它组分的混合物料中制粒，干燥后整粒，与润滑剂混合。
其中，所述粉碎为气流粉碎。
作为优选，所述利伐沙班粉碎至D 90小于50微米，D 50小于25微米。更优选为利伐沙班粉碎至D 90小于30微米，D 50小于15微米。
作为优选，所述利伐沙班悬浮分散液中固含量为5wt％～12wt％。
进一步的，所述的利伐沙班药物组合物的制备方法中所述制粒具体为除润滑剂外的其它组分混合转移至混合制粒器中，将利伐沙班悬浮分散液均匀喷雾混合制粒器中的混合物料中。
其中，所述除润滑剂外的其它组分包括粘合剂、填充剂、崩解剂和表面活性剂。在一些实施方案中，所述表面活性剂可不加入。在一些实施方案中，所述崩解剂可以以外加的方式加入，即除润滑剂外的其它组分中不包括崩解剂，待喷雾制粒干燥后与润滑剂混合时再加入崩解剂。
作为优选，所述混合制粒器为流化床制粒机或高剪切混合制粒机.更优选为流化床制粒机。
作为优选，所述喷雾为顶喷法喷雾或底喷法喷雾，即采用顶喷法或底喷法将利伐沙班悬浮分散液均匀喷雾在混合制粒器中的混合物料中。
作为优选，所述制粒过程中，所述混合物料的温度控制在50℃以下。
作为优选，所述的利伐沙班药物组合物的制备方法中所述制粒后的干燥为干燥至颗粒含水量在1.5～2.5％。
本发明还提供了一种利伐沙班片剂，包括上述利伐沙班药物组合物和水溶性薄膜衣。
在一些实施方案中，所述水溶性薄膜衣为欧巴代
Figure PCTCN2019092744-appb-000002
由卡乐康提供配制的粉末混合物。薄膜包衣增重2.0％～4.0％。
由上述技术方案可知，本发明提供了一种利伐沙班药物组合物及其制备方法。本发明所述利伐沙班药物组合物各组分组成为利伐沙班4wt％～30wt％、聚乙二醇2wt％～60wt％、粘合剂2wt％～10wt％、 填充剂5wt％～85wt％、崩解剂2wt％～10wt％、表面活性剂0wt％～1wt％、润滑剂0.1wt％～3wt％，以上各组分总和为100wt％。本发明采用将经气流粉碎后的原料药分散在聚乙二醇载体溶液中，采用固体分散技术。聚乙二醇为亲水性聚合物，粘性低，具有良好的水溶性，利伐沙班聚乙二醇分散溶液配制所需溶剂相对较少，配制简单，所需时间短。另所需的粘合剂以粉末形式与填充剂、崩解剂、视需要存在的少量表面活性剂在流化床中流化混合或高剪切制粒机中混合，而后将利伐沙班聚乙二醇分散液均匀喷雾在混合运动状态物料中进行制粒，干燥。制得的颗粒流动性和可压性均良好，制粒终点易控制，颗粒无较大成团结块现象。制得的颗粒进一步与润滑剂混合，压片，即得利伐沙班片，可进一步包衣。采用本发明制备的利伐沙班片，在组分中不加表面活性剂或加很少量的表面活性剂即可达到良好体外溶出。实验表明，本发明制得的利伐沙班片具备较优的可压性、片重稳定性、较小的脆碎度，良好的体外溶出，30分钟溶出度可达80％以上。
具体实施方式
本发明公开了一种利伐沙班药物组合物及其制备方法。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及产品已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法进行改动或适当变更与组合，来实现和应用本发明技术。
为了进一步理解本发明，下面将结合本发明实施例，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所 有其他实施例，都属于本发明保护的范围。
如无特殊说明，本发明实施例中所涉及的试剂均为市售产品，均可以通过商业渠道购买获得。
实施例1
配方：
组分 比例(wt％)
利伐沙班 11.8
聚乙二醇4000 14.1
聚乙烯吡咯烷酮K29/32 5.8
微晶纤维素PH101 63.2
交联羧甲基纤维素钠 4.2
十二烷基硫酸钠 0.3
硬脂酸镁 0.6
合计 100
制备方法：
1：物料前处理：利伐沙班气流粉碎机粉碎至D 90小于30微米，D 50小于15微米。
2：将处方量的粉碎后的利伐沙班与聚乙二醇4000加入纯水中配制成悬浮分散液，利伐沙班悬浮分散液配制好后一直处于搅拌状态。
3：将处方量的微晶纤维素PH101、聚乙烯吡咯烷酮K29/32、交联羧甲基纤维素钠、十二烷基硫酸钠转移至流化床中，采用顶喷法将利伐沙班悬浮分散液均匀喷雾在流化床状态的混合物料中，流化床制粒的物料温度控制在50℃以下，干燥颗粒含水量在1.5～2.5％即可停止干燥。
4：将步骤3制得干燥颗粒过40目筛网干整粒后，按处方比加入硬脂酸镁进行总混，即得总混物。
5：将上述总混合物进一步压片，得利伐沙班素片。
6：将利伐沙班素片进一步薄膜包衣，薄膜包衣粉采用欧巴 代
Figure PCTCN2019092744-appb-000003
包衣增重2％～4％。
实施例2
配方：
组分 比例(wt％)
利伐沙班 11.8
聚乙二醇6000 17.6
羧甲基纤维素钠 3.5
玉米淀粉 15.9
乳糖 11.8
微晶纤维素PH101 35.3
交联聚乙烯吡咯烷酮 3.5
硬脂酸镁 0.6
合计 100
制备方法：
1：物料前处理：利伐沙班气流粉碎机粉碎至D 90小于30微米，D 50小于15微米。
2：将处方量的粉碎后的利伐沙班与聚乙二醇6000加入纯水中配制成悬浮分散液，利伐沙班悬浮分散液配制好后一直处于搅拌状态。
3：将处方量的微晶纤维素PH101、乳糖、玉米淀粉、羧甲基纤维素钠、交联聚乙烯吡咯烷酮转移至流化床中，采用顶喷法将利伐沙班悬浮分散液均匀喷雾在流化床状态的混合物料中，流化床制粒的物料温度控制在50℃以下，干燥颗粒含水量在1.5～2.5％即可停止干燥。
4：将步骤3制得干燥颗粒过40目筛网干整粒后，按处方比加入硬脂酸镁进行总混，即得总混物。
5：将上述总混合物进一步压片，得利伐沙班素片。
6：将利伐沙班素片进一步薄膜包衣，薄膜包衣粉采用欧巴代
Figure PCTCN2019092744-appb-000004
包衣增重2％～4％。
实施例3
配方：
组分 比例(wt％)
利伐沙班 23.5
聚乙二醇6000 23.5
羟丙甲纤维素(6cP) 3.5
玉米淀粉 12.1
微晶纤维素PH101 33.0
交联羧甲基纤维素钠 3.5
十二烷基硫酸钠 0.2
硬脂酸镁 0.7
合计 100
制备方法：
1：物料前处理：利伐沙班气流粉碎机粉碎至D 90小于30微米，D 50小于15微米。
2：将处方量的粉碎后的利伐沙班与聚乙二醇6000加入纯水中配制成悬浮分散液，利伐沙班悬浮分散液配制好后一直处于搅拌状态。
3：将处方量的微晶纤维素PH101、玉米淀粉、羟丙甲纤维素(6cP)、交联羧甲基纤维素钠、十二烷基硫酸钠转移至流化床中，采用顶喷法将利伐沙班悬浮分散液均匀喷雾在流化床状态的混合物料中，流化床制粒的物料温度控制在50℃以下，干燥颗粒含水量在1.5～2.5％即可停止干燥。
4：将步骤3制得干燥颗粒过40目筛网干整粒后，按处方比加入硬脂酸镁进行总混，即得总混物。
5：将上述总混合物进一步压片，得利伐沙班素片。
6：将利伐沙班素片进一步薄膜包衣，薄膜包衣粉采用欧巴代
Figure PCTCN2019092744-appb-000005
包衣增重2％～4％。
对比例1
配方：
组分 比例(wt％)
利伐沙班 11.8
羧甲基纤维素钠 3.5
玉米淀粉 15.9
乳糖 11.8
微晶纤维素PH102 52.9
交联聚乙烯吡咯烷酮 3.5
硬脂酸镁 0.6
合计 100
采用粉末直压法制备：将微粉化的利伐沙班(D 90小于30微米，D 50小于15微米)、羧甲基纤维素钠、玉米淀粉、乳糖、微晶纤维素PH102、交联聚乙烯吡咯烷酮至混合料斗中进行初步混合，混合时间10min，混合转速15rpm。初步混合后再加入硬脂酸镁进行总混，总混时间5min，混合转速15rpm。然后将总混物进行压片，得利伐沙班素片。将利伐沙班素片进一步薄膜包衣，薄膜包衣粉采用欧巴代
Figure PCTCN2019092744-appb-000006
包衣增重2％～4％。
对比例2
配方：
组分 比例(wt％)
利伐沙班 11.8
聚乙烯吡咯烷酮K29/32 10.0
微晶纤维素PH101 63.2
交联羧甲基纤维素钠 4.2
乳糖 10.2
硬脂酸镁 0.6
合计 100
制备方法：
1：物料前处理：利伐沙班气流粉碎机粉碎至D 90小于30微米，D 50小于15微米。
2：将处方量的粉碎后的利伐沙班与聚乙烯吡咯烷酮K29/32加入纯水中配制成悬浮分散液，利伐沙班悬浮分散液配制好后一直处于搅拌状态。
3：将处方量的微晶纤维素PH101、交联羧甲基纤维素钠、乳糖转移至流化床中，采用顶喷法将利伐沙班悬浮分散液均匀喷雾在流化床状态的混合物料中，流化床制粒的物料温度控制在50℃以下，干燥颗粒含水量在1.5～2.5％即可停止干燥。
4：将步骤3制得干燥颗粒过40目筛网干整粒后，按处方比加入硬脂酸镁进行总混，即得总混物。
5：将上述总混合物进一步压片，得利伐沙班素片。
6：将利伐沙班素片进一步薄膜包衣，薄膜包衣粉采用欧巴代
Figure PCTCN2019092744-appb-000007
包衣增重2％～4％。
对比例3
配方：
组分 比例(wt％)
利伐沙班(D 90＝106.1微米；D 50＝30.3微米) 11.8
聚乙二醇4000 60.2
聚乙烯吡咯烷酮K29/32 5.8
微晶纤维素PH101 10.6
交联羧甲基纤维素钠 10.0
十二烷基硫酸钠 1.0
硬脂酸镁 0.6
合计 100
制备方法：
1：物料前处理：利伐沙班经气流粉碎机粉碎至D 90约为106.1微米，D 50约为30.3微米。
2：将处方量的粉碎后的原料药与聚乙二醇4000加入纯水中配制成悬浮分散液，利伐沙班悬浮分散液配制好后一直处于搅拌状态。
3：将处方量的聚乙烯吡咯烷酮K29/32、微晶纤维素PH101、交联羧甲基纤维素钠、十二烷基硫酸钠转移至流化床中，采用顶喷法将利伐沙班悬浮分散液均匀喷雾在流化床状态的混合物料中。流化床制粒的物料温度控制在50℃以下；干燥颗粒含水量在1.5～2.5％即可停止干燥。
4：将步骤3制得干燥颗粒过40目筛网干整粒后，按处方比加入硬脂酸镁进行总混，即得总混物。
5：将上述总混合物进一步压片，得利伐沙班素片。
6：将利伐沙班素片进一步薄膜包衣，薄膜包衣粉采用欧巴代
Figure PCTCN2019092744-appb-000008
包衣增重2％～4％。
对比例4
配方：
组分 比例(wt％)
利伐沙班 11.8
聚乙二醇6000 17.6
羧甲基纤维素钠 3.5
玉米淀粉 15.9
乳糖 12.8
微晶纤维素PH101 36.3
交联聚乙烯吡咯烷酮 1.5
硬脂酸镁 0.6
合计 100
制备方法：
1：物料前处理：利伐沙班气流粉碎机粉碎至D 90小于30微米，D 50小于15微米。
2：将处方量的粉碎后的利伐沙班与聚乙二醇6000加入纯水中配制成悬浮分散液，利伐沙班悬浮分散液配制好后一直处于搅拌状态。
3：将处方量的微晶纤维素PH101、乳糖、玉米淀粉、羧甲基纤维素钠、交联聚乙烯吡咯烷酮转移至流化床中，采用顶喷法将利伐沙班悬浮分散液均匀喷雾在流化床状态的混合物料中，流化床制粒的物料温度控制在50℃以下，干燥颗粒含水量在1.5～2.5％即可停止干燥。
4：将步骤3制得干燥颗粒过40目筛网干整粒后，按处方比加入硬脂酸镁进行总混，即得总混物。
5：将上述总混合物进一步压片，得利伐沙班素片。
6：将利伐沙班素片进一步薄膜包衣，薄膜包衣粉采用欧巴代
Figure PCTCN2019092744-appb-000009
包衣增重2％～4％。
对比例5
配方：
组分 比例(wt％)
利伐沙班 23.5
聚乙二醇6000 23.5
羟丙甲纤维素(6cP) 3.5
玉米淀粉 12.1
微晶纤维素PH101 30.2
交联羧甲基纤维素钠 3.5
十二烷基硫酸钠 0.2
硬脂酸镁 3.5
合计 100
制备方法：
1：物料前处理：利伐沙班气流粉碎机粉碎至D 90小于30微米，D 50小于15微米。
2：将处方量的粉碎后的利伐沙班与聚乙二醇6000加入纯水中配制成悬浮分散液，利伐沙班悬浮分散液配制好后一直处于搅拌状态。
3：将处方量的微晶纤维素PH101、玉米淀粉、羟丙甲纤维素(6cP)、交联羧甲基纤维素钠、十二烷基硫酸钠转移至流化床中，采用顶喷法将利伐沙班悬浮分散液均匀喷雾在流化床状态的混合物料中，流化床制粒的物料温度控制在50℃以下，干燥颗粒含水量在1.5～2.5％即可停止干燥。
4：将步骤3制得干燥颗粒过40目筛网干整粒后，按处方比加入硬脂酸镁进行总混，即得总混物。
5：将上述总混合物进一步压片，得利伐沙班素片。
6：将利伐沙班素片进一步薄膜包衣，薄膜包衣粉采用欧巴代
Figure PCTCN2019092744-appb-000010
包衣增重2％～4％。
试验例：
1、片剂质量的考察
按照下述方法对上述各实施例及对比例制得的利伐沙班素片进行考察，结果见表1。其中，素片平均硬度考察方法：采用相同压片力下压片机压制的连续10片素片的平均硬度；片重差异考察方法：采用中国药典2015版四部制剂通则0101片剂重量差异检查法；脆碎度考察方法：采用中国药典2015版四部0923片剂脆碎度检查法。
表1压片的试验结果
样品 素片平均硬度(n＝10) 片重差异 脆碎度(％)
实施例1 63N ±3.2％ 0.24
实施例2 68N ±2.5％ 0.15
实施例3 56N ±3.6％ 0.21
对比例1 48N ±4.9％ 0.36
对比例2 53N ±4.2％ 0.26
对比例3 38N ±3.5％ 0.43
对比例4 51N ±3.1％ 0.23
对比例5 43N ±3.8％ 0.37
结果显示，本发明实施例1～3制备的素片样品，平均硬度均在55N以上，片重稳定，脆碎度良好。相比而言，对比例1～5制备的素片样品，平均硬度均在55N以下。另外对比例1与对比例2的片重差异也相对较大。表明本发明实施例1～3样品相比其他对比例样品可压性更优，片重更稳定，且脆碎度较小。
2、体外溶出度考察
取实施例1～3、对比例1～5样品各6片，采用溶出度测定法Ⅱ法：桨法(75rpm)进行体外溶出度检测，介质为900mL 0.2％SDS的pH4.5醋酸盐缓冲溶液，考察在15分钟，30分钟，45分钟，60分钟样品溶出度，结果见表2。
表2体外溶出度考察结果
时间 15分钟 30分钟 45分钟 60分钟
实施例1 75.7％ 87.3％ 93.0％ 96.2％
实施例2 79.6％ 93.5％ 98.2％ 99.8％
实施例3 77.8％ 90.4％ 95.1％ 97.6％
对比例1 69.7％ 79.8％ 88.7％ 92.8％
对比例2 63.5％ 78.3％ 89.6％ 92.3％
对比例3 43.3％ 62.8％ 73.6％ 85.1％
对比例4 58.6％ 72.1％ 83.8％ 90.2％
对比例5 67.3％ 78.2％ 86.9％ 93.6％
表2结果显示，本发明实施例1～3制备的样品30分钟溶出度均在80％以上，均接近溶出平台。而对比例1～5制备的样品30分钟溶 出度均在80％以下，远未达溶出平台。
采用粉末直压工艺的对比例1制得的样品体外溶出30分钟溶出低于80％，且对比例1样品的片重稳定性较差。对比例2采用聚乙烯吡咯烷酮K29/32与微粉化原料药制成混悬溶液，经流化床制粒制备样品，样品溶出30分钟也未达80％。对比例3采用的原料药粒径超出D 90小于50微米，D 50小于25微米的粒径范围，其粒径更粗，D 90约为106.1微米，D 50约为30.3微米。采用这种更粗粒径的利伐沙班原料制备处方样品，即使聚乙二醇用量达60.2％，崩解剂用量达10.0％，表面活性剂十二烷基硫酸钠的用量达1.0％，其30分钟溶出仅62.8％，且对比例3的可压性和脆碎度较差。对比例4采用粒径范围内的利伐沙班原料，但崩解剂用量仅1.5％的样品30分钟溶出仅72.1％。实施例3与对比例5工艺一样，仅在处方上对比例5的润滑剂用量超3％，达3.5％。对比例5的溶出比实施例3偏慢，30分钟溶出仅78.2％。
综上所述，本发明制得的样品具备较优的可压性、片重稳定性、较小的脆碎度，良好的体外溶出，30分钟溶出度可达80％以上。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (10)

  1. 一种利伐沙班药物组合物，由如下组分组成：
    Figure PCTCN2019092744-appb-100001
  2. 根据权利要求1所述的利伐沙班药物组合物，所述利伐沙班与聚乙二醇的重量比为1:0.5～1:5。
  3. 根据权利要求1或2所述的利伐沙班药物组合物，所述聚乙二醇分子量为1000～10000；所述填充剂选自乳糖、微晶纤维素、淀粉、甘露醇中的一种或几种；所述粘合剂选自聚乙烯吡咯烷酮、羧甲基纤维素钠、羟丙基纤维素、聚乙烯醇、羟丙甲纤维素中的一种或几种；所述崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、预胶化淀粉中的一种或几种；所述润滑剂选自滑石粉、硬脂酸镁、硬脂富马酸钠、胶态二氧化硅中的一种或几种；所述表面活性剂选自泊洛沙姆、十二烷基硫酸钠中的一种或两种。
  4. 权利要求1-3任意一项所述的利伐沙班药物组合物的制备方法，利伐沙班粉碎后分散在聚乙二醇的水溶液中制成利伐沙班悬浮分散液，喷雾至除润滑剂外的其它组分的混合物料中制粒，干燥后与润滑剂混合。
  5. 根据权利要求4所述的制备方法，所述粉碎为气流粉碎；所述利伐沙班粉碎至D 90小于50微米，D 50小于25微米。
  6. 根据权利要求4所述的制备方法，所述利伐沙班悬浮分散液 中固含量为5wt％～12wt％。
  7. 根据权利要求4所述的制备方法，所述制粒具体为除润滑剂外的其它组分混合转移至混合制粒器中，将利伐沙班悬浮分散液均匀喷雾混合制粒器中的混合物料中。
  8. 根据权利要求7所述的制备方法，所述混合制粒器为流化床制粒机或高剪切混合制粒机；所述喷雾为顶喷法喷雾或底喷法喷雾；所述混合物料的温度控制在50℃以下。
  9. 根据权利要求4所述的制备方法，所述干燥为干燥至颗粒含水量在1.5～2.5％。
  10. 一种利伐沙班片剂，包括权利要求1-3任意一项所述利伐沙班药物组合物和包衣膜。
PCT/CN2019/092744 2018-10-16 2019-06-25 一种利伐沙班药物组合物及其制备方法 WO2020078034A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811203606.XA CN111053753A (zh) 2018-10-16 2018-10-16 一种利伐沙班药物组合物及其制备方法
CN201811203606.X 2018-10-16

Publications (1)

Publication Number Publication Date
WO2020078034A1 true WO2020078034A1 (zh) 2020-04-23

Family

ID=70283707

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/092744 WO2020078034A1 (zh) 2018-10-16 2019-06-25 一种利伐沙班药物组合物及其制备方法

Country Status (2)

Country Link
CN (1) CN111053753A (zh)
WO (1) WO2020078034A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104173313A (zh) * 2014-08-25 2014-12-03 杭州朱养心药业有限公司 利伐沙班片剂药物组合物
CN104721142A (zh) * 2013-12-18 2015-06-24 山东新时代药业有限公司 一种利伐沙班固体分散体及其制备方法
CN107823166A (zh) * 2016-09-21 2018-03-23 齐鲁制药有限公司 一种利伐沙班片的制备方法
CN108186577A (zh) * 2018-03-09 2018-06-22 武汉工程大学 一种利伐沙班固体分散体及其制备方法和制剂
CN108371655A (zh) * 2018-03-29 2018-08-07 重庆华邦制药有限公司 包含利伐沙班的固体药物及其制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103705520A (zh) * 2013-12-27 2014-04-09 华润赛科药业有限责任公司 一种利伐沙班固体组合物的制备方法
CN103877060A (zh) * 2014-03-25 2014-06-25 江苏正大清江制药有限公司 一种利伐沙班组合物及其制备方法
CN107582531B (zh) * 2016-07-06 2020-12-29 四川科伦药物研究院有限公司 一种利伐沙班固体制剂及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104721142A (zh) * 2013-12-18 2015-06-24 山东新时代药业有限公司 一种利伐沙班固体分散体及其制备方法
CN104173313A (zh) * 2014-08-25 2014-12-03 杭州朱养心药业有限公司 利伐沙班片剂药物组合物
CN107823166A (zh) * 2016-09-21 2018-03-23 齐鲁制药有限公司 一种利伐沙班片的制备方法
CN108186577A (zh) * 2018-03-09 2018-06-22 武汉工程大学 一种利伐沙班固体分散体及其制备方法和制剂
CN108371655A (zh) * 2018-03-29 2018-08-07 重庆华邦制药有限公司 包含利伐沙班的固体药物及其制备方法

Also Published As

Publication number Publication date
CN111053753A (zh) 2020-04-24

Similar Documents

Publication Publication Date Title
JP2021100968A (ja) 新たな医薬組成物
JP5714600B2 (ja) 共加工された錠用賦形剤混合物、その調製及び使用
KR20080012306A (ko) 약학 조성물
JP2556623B2 (ja) 高いイブプロフェン含有量を示す顆粒状物
JP2007308480A (ja) 腸溶性固体分散体を含んでなる固形製剤
US20040170695A1 (en) Melt granulated composition and modified release dosage form prepared from said composition
JP2007308479A (ja) 固体分散体製剤
TW570798B (en) Pharmaceutical compositions
AU2014295100B2 (en) Antitubercular composition comprising rifampicin, isoniazid, ethambutol and pyrazinamide and its process of preparation.
US20030104059A1 (en) Controlled release tablets of metformin
CN102292075B (zh) 包含hcv聚合酶抑制剂前药的药物组合物
WO2018095403A1 (zh) 一种吡啶酮类衍生物药物组合物及其制备方法
EP2913048A1 (en) Pharmaceutical composition comprising trametinib
CN109498587A (zh) 盐酸鲁拉西酮片的制备方法
CN103083326A (zh) 一种醋酸优力司特药物组合物
WO2020078034A1 (zh) 一种利伐沙班药物组合物及其制备方法
JP5576922B2 (ja) 腸溶性固体分散体を含んでなる固形製剤
CN102755300A (zh) 一种伏立康唑组合物及其制备方法
WO2019080830A1 (zh) 一种含有喹啉衍生物的药物组合物
CN109700773B (zh) 一种替格瑞洛制剂组合物及其制备方法
US20190167592A1 (en) Process for directly compressible co-processed excipient for modified release application
JP5576963B2 (ja) 固体分散体製剤
CN114306264B (zh) 一种他达拉非片剂及其制备方法
AU2018454263B2 (en) Dosage form containing abiraterone acetate
JPH11130663A (ja) 水難溶性成分を配合した固形剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19874005

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19874005

Country of ref document: EP

Kind code of ref document: A1