CN104173313B - Rivaroxaban troche pharmaceutical composition - Google Patents
Rivaroxaban troche pharmaceutical composition Download PDFInfo
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- CN104173313B CN104173313B CN201410420048.8A CN201410420048A CN104173313B CN 104173313 B CN104173313 B CN 104173313B CN 201410420048 A CN201410420048 A CN 201410420048A CN 104173313 B CN104173313 B CN 104173313B
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Abstract
The invention belongs to the technical field of medicines, relates to a rivaroxaban troche pharmaceutical composition, and particularly relates to a pharmaceutical composition in form of a troche. The pharmaceutical composition includes rivaroxaban, a diluent, a disintegrant, an adhesive, a wetting agent and a lubricant. Each troche comprises 1-100mg of rivaroxaban. The troche can be further coated, for example, a film coated troche. The troche provided by the invention has the advantages described in specification. The rivaroxaban troche pharmaceutical composition has excellent dissolving-out performance, stability and other preparation performances.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of composition of anticoagulation medicine, more particularly to a kind of FXa suppressions
The pharmaceutical composition of preparation razaxaban is particularly its tablet, further relates to the preparation method of the pharmaceutical composition.
Background technology
Most early in WO01/47919, it has having structure to razaxaban
Molecular formula C19H18ClN3O5S, molecular weight 435.89, English name rivaroxaban researches and develops code name BAY5927939,
Trade name Xarelto, CAS366789-02-8, domestic nomenclature of drug for visit it is auspicious appropriate, Chinese chemical name be the chloro- N- of 5- ((5S)-
2- oxos -3- [4- (3- oxo -4- morpholinyls) phenyl] -1,3- oxazolidine -5- bases } methyl) -2- thenoyl amines, Englishization
Scientific name is 5-Chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -1,3-
oxazolidin-5-yl}methyl)-2-thiophenecarboxamide.The razaxaban for clinically using is a kind of pure
(S)-enantiomter, it is a kind of tasteless, non-hygroscopic, white to micro-yellow powder.Razaxaban is slightly soluble in organic solvent
(such as acetone, PEG400), is practically insoluble in water and water-bearing media.The product of clinic listing is oral tablet, and every contains
Razaxaban 10mg, 15mg or 20mg.
Razaxaban is low-molecular-weight, the anticoagulation medicine being administered orally.The medicine directly suppresses serine protease
The activity form of factor Xa (FXa).Razaxaban can be used to prevent and treat various thrombotic diseases, particularly prevention and
Treatment Deep vain thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, angina pectoris, angioplasty or aortocoronary
Inaccessible again and ISR, headstroke, transient ischemic attack after bypass (aortocoronary bypass) and outer
PAOD.Razaxaban is used to prevent the phlebothrombosis bolt after adult patients hip joint and replacement knee in arthroplasty
The formation of plug and pulmonary embolism.Secondary prevention simultaneously in Chinese patients with deep venous thrombosis, treatment auricular fibrillation and acute coronary syndromes
There is certain therapeutic effect in the fields such as disease.
Clinically usable anticoagulant includes unfractionated heparin (unfractionated heparin, UFH), low at present
Molecular weight heparin (low molecular weight heparin, LMWH), vitamin K antagon warfarin (warfarin) with
And pentasaccharide fondaparinux sodium (fondaparinux, Arixtra).
Heparin class material produces anticoagulation effect by cascading correlation factor interaction with various blood clottings, clinically mainly
Also often limited the use of in inpatient or short-term (≤2wk) prevention phlebothrombosis bolt for short-term antithrombotic heparin class material
Plug sexual behavior part).In view of the larger and existing medicine of the market opportunity is each defective, drugmaker to novel anticoagulation medicine research with open
The concern of hair and throwing people substantially increase.Certainly, the curative effect of these anticoagulation new drugs should at least correspond to existing medicine, but safety
Property must be improved, need to particularly reduce bleeding risk, be administered simultaneously scheme easy (if oral etc.).
Because Xa factor is that a kind of fibrin ferment forms necessary clotting factor direct thrombin inhibitor, Xa factor is studied
Inhibitor plays key effect to research anticoagulant.Receive much concern member in oral Selective activation Xa factor inhibitor
It is Eliquis (Apixaban, trade name Eliquis), dabigatran, three new oral anti-coagulants of razaxaban.In Europe
Approval these three oral anticoagulants in, with current bone surgery after prevent venous thromboembolism standard regimens according to promise
Heparin is compared, and razaxaban and Eliquis highlight advantage in RECORD experiments and ADVANCE experiments respectively.Expert represents,
The result that these are tested side by side from the point of view of, the curative effect of razaxaban seems more preferable.
Razaxaban is by Bayer and Johson ＆ Johnson's cooperative research and development.The medicine is the efficient oxazolidone obtained by high flux screening
Class FXa inhibitor is screened as lead compound, then in a series of oxazolidinones obtained from derivative optimization, is most passed through afterwards
Pharmacodynamics, pharmacokinetics etc. are investigated and turn into clinical candidate.It is clinical pass through for III phase at present, in September in 2008 15 days and October 1
Day obtains listing approval in Canada and European Union respectively.29 countries including including China are approved listing, for pre-
The formation of VTE and pulmonary embolism after anti-adult patients hip joint and replacement knee in arthroplasty.In theory, security
Better than conventional all of anti-coagulants.In July, 2011 is ratified to list by U.S. FDA, while two grades in Chinese patients with deep venous thrombosis pre-
There is certain therapeutic effect in the fields such as anti-, treatment auricular fibrillation and acute coronary syndrome.Razaxaban passes through high selection
Property directly suppress Xa factor and reach blood coagulation resisting function, compared with traditional anticoagulation medicine, with it is convenient to take, work rapid, peace
The features such as property is high entirely.
Existing numerous documents and materials disclose pharmaceutical composition particularly its tablet of razaxaban.
CN200680045548.1 prepares unformed shape and semi-stability by dissolution method, fusion method, extrusion by melting
The razaxaban of crystal formation II, then be applied in oral solid pharmaceutical dosage, can significantly improve its dissolution rate and oral
Bioavilability.But due to using amorphous or meta-stable form razaxaban, can be pind down by stability problem, it is another
Aspect has the solubility of extreme difference due to razaxaban, the also indissoluble in pharmaceutically acceptable solvent such as ethanol or acetone, leads to
Cross dissolution method prepare it is amorphous need substantial amounts of solvent, the problem of solvent recovery and environmental protection causes its industrialization difficult to realize
Production, adds that its fusing point is high, and being prepared by fusion method amorphous can also produce unfavorable degradable component.
WO2010/146179A2 is using micronizing main ingredient and auxiliary material is co-mulled and made into, hot-melt extruded, dry granulation technology prepare mouth
Oral solid drug combination preparation, its dissolution rate can reach 30min at least dissolutions 70%.
CN103550165A (201310504757.X, Zhejiang Huahai) is related to a kind of quick release containing razaxaban
Oral solid drug composition and preparation method thereof, it passes through wet granulation technology and suitable pharmaceutic adjuvant is processed, then
Mix with razaxaban active component, obtain the pharmaceutical composition that dissolution is significantly improved, particularly first will be pharmaceutically acceptable
Auxiliary material obtains the blank granules without active component by wet granulation, then by razaxaban and above-mentioned blank granules and extra
Pharmaceutically acceptable additive mixing, be made oral solid drug composition.It is believed that the preparation method of the invention has work
Skill is simple, the characteristics of suitable industrialized production, solves the problems, such as that the preparation technology of prior art is more complicated.
CN103877060A (201410113352.8, the honest Qingjian River) discloses composition and its system comprising razaxaban
Preparation Method.The invention makes its particle diameter reach less than 10 μm with razaxaban as active component by pretreatment, and use with it is hydrophilic
Property auxiliary material, disintegrant, surfactant mix after wet granulation technique, effectively raise the dissolution rate of razaxaban and molten
Go out speed.
CN1886120B (200480035106.x) proposes to be suspended in razaxaban to make its hydrophiling in binder solution,
So as to the razaxaban preparation for obtaining quick release He significantly improve bioavilability.
CN103705520A (201310732239.3, China Resources match section) discloses a kind of system of rivaroxaban solid composition
Preparation Method.Razaxaban is crushed using the method for wet pulverizing, while being prepared into suspension solution；Suspension solution is sprayed into other
Suitable particle is made in auxiliary material；It is being further prepared into minimum pharmaceutical dosage unit.The specific method of the invention includes following
Step：Razaxaban bulk drug (micronizing), adhesive, wetting agent are mixed with water, suspension solution I is obtained；To be suspended
Solution I carries out wet pulverizing, obtains suspension solution II；Suspension solution II is added to the dilute of pharmaceutical composition by the way of spraying into
In releasing agent, and drying is prepared into the particle and powder of razaxaban pharmaceutical composition；And particle and powder are prepared into profit cut down
The husky medicinal minimum dose unit of class.It is believed that the invention beneficial effect includes：Solve and adopt conventional comminution processes and prepare razaxaban
During particulate, particle diameter can not be reduced to 5 μm of problem, be conducive to increasing the dissolution rate of razaxaban preparation.
Tablet coating is in many cases that the tablet of beneficial, such as different dosage uses different colours to be coated with profit
The moisture and air that can also contribute to making active component and the external world are coated to improve the stability of medicine in differentiation, tablet.
However, it has been found by the present inventors that the tablet prepared using art methods, its friability performance be it is not enough, this
To have a strong impact on and tablet will further be wrapped up in into film-coating.
Therefore, this area is still expected to have and new prepares razaxaban solid composite medicament particularly its tablet particularly
Ground is the method for its film coating tablet, and the composition that expectation the method is prepared has the excellent of one or more aspects
Pharmaceutical properties.
The content of the invention
New razaxaban solid composite medicament particularly its tablet is prepared it is an object of the invention to provide a kind of more
The method of its film coating tablet in particular, the composition that expectation the method is prepared has one or more aspects
Excellent pharmaceutical properties.It has been found, unexpectedly, being presented at least one using the film coating tablet of inventive formulation
The beneficial pharmaceutical properties of aspect.The present invention is accomplished based on this discovery.
Therefore, first aspect present invention is related to a kind of pharmaceutical composition in tablet form, wherein including：Razaxaban,
Diluent, disintegrant, adhesive, wetting agent, lubricant.
The pharmaceutical composition of any one according to a first aspect of the present invention, wherein the razaxaban is made with Micronised form
.In one embodiment, razaxaban has less than 10 μm, preferably with 1-8 μm of particle mean size X50And be less than
20 μm, preferably shorter than 15 μm of X90(90% ratio).
The pharmaceutical composition of any one according to a first aspect of the present invention, wherein being comprising razaxaban in every, the tablet
Such as 1-100mg, such as it is 2-50mg that razaxaban is included in every, and it is 5-40mg that razaxaban is included in every, for example often
It is 5mg, 10mg, 15mg, 20mg, 30mg, 40mg that razaxaban is included in piece.
The pharmaceutical composition of any one according to a first aspect of the present invention, wherein the diluent be selected from following one kind or
It is various：Cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, Dicalcium Phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, wheat
Bud sugar alcohol, D-sorbite, xylitol, lactose (such as Lactis Anhydrous or lactose monohydrate), D-glucose, maltose, sugarcane
Sugar, glucose, fructose or maltodextrin.In one embodiment, the diluent is microcrystalline cellulose and lactose
Combination.In one embodiment, the diluent is the combination of microcrystalline cellulose and lactose, microcrystalline cellulose and both lactose
Weight ratio be 0.1~10：1, such as 0.2~5：1.
The pharmaceutical composition of any one according to a first aspect of the present invention, wherein in terms of the razaxaban of every 10 weight portion, institute
The consumption of diluent is stated for 20-200 weight portions, such as 20-150 weight portions.
The pharmaceutical composition of any one according to a first aspect of the present invention, wherein the disintegrant be selected from following one kind or
It is various：Carboxymethylcellulose calcium, cross-linked carboxymethyl cellulose, Ac-Di-Sol, Crospovidone, low substituted hydroxy-propyl are fine
Dimension plain (L-HPC), sodium carboxymethyl starch, primojel, boiling starch, wheaten starch, cornstarch, rice starch
Or potato starch.
The pharmaceutical composition of any one according to a first aspect of the present invention, wherein in terms of the razaxaban of every 10 weight portion, institute
The consumption of disintegrant is stated for 1-20 weight portions, such as 1.5-7.5 weight portions.
The pharmaceutical composition of any one according to a first aspect of the present invention, wherein described adhesive be selected from following one kind or
It is various：Hydroxypropyl methyl cellulose (HPMC), carboxymethylcellulose calcium (sodium salt or calcium salt), ethyl cellulose, methylcellulose, hydroxyl
Ethyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl fiber element (HPC), L-HPC, PVP, polyethylene
Alcohol, acrylic acid polymer and its salt, vinylpyrrolidone/vinyl acetate copolymer (such as Kollidon@VA64,
BASF), gelatin, guar gum, boiling starch, alginates or xanthans.In one embodiment, described adhesive is
HPMC。
The pharmaceutical composition of any one according to a first aspect of the present invention, wherein in terms of the razaxaban of every 10 weight portion, institute
The consumption of adhesive is stated for 1-10 weight portions, such as 1.5-5 weight portions.In one embodiment, described adhesive is matched somebody with somebody with water
Concentration 1-20% is made, the solution of such as 1-10% is used as the adhesive of wet granulation.
The pharmaceutical composition of any one according to a first aspect of the present invention, wherein the wetting agent be selected from following one kind or
It is various：The sodium salt of sulfated fatty alcohol ester such as NaLS, lauryl sodium sulfate, sulfosuccinate such as dioctyl
Sodium sulfosuccinate, the fatty acid partial ester such as glyceryl monostearate of polyalcohol, the fatty acid partial ester example of sorbitan
Such as sorbitan monolaurate, for example many ethylene glycol of fatty acid partial ester of polyhydroxy ethylidene sorbitan-de-
Water D-sorbite monolaurate, polyethylene glycol-sorbitan monostearate or polyethylene glycol-Sorbitan
Alcohol monoleate, polyhydroxy ethylidene fatty alcohol ether, polyhydroxy ethylidene fatty acid ester, epoxy ethane-epoxy propane block is total to
Polymers (such as Pluronic) or the triglycerides of ethoxylation.Preferably use NaLS or lauryl sodium sulfate
As wetting agent.
The pharmaceutical composition of any one according to a first aspect of the present invention, wherein in terms of the razaxaban of every 10 weight portion, institute
The consumption of wetting agent is stated for 0.2-5 weight portions, such as 0.3-3 weight portions.In one embodiment, the wetting agent is dissolving
Used in described adhesive solution.
The pharmaceutical composition of any one according to a first aspect of the present invention, wherein the lubricant be selected from following one kind or
It is various：Fumaric acid, stearic acid, magnesium stearate, calcium stearate, stearyl fumarate, high molecular weight fatty alcohol, polyethylene glycol,
Starch (for example, wheaten starch, rice starch, cornstarch or potato starch), talcum powder, polymolecularity (colloid) titanium dioxide
Silicon, Compritol 888 ATO, magnesia, magnesium carbonate, calcium silicates.In one embodiment, it is preferred to using Compritol 888 ATO and/
Or magnesium stearate is used as lubricant.
The pharmaceutical composition of any one according to a first aspect of the present invention, wherein in terms of the razaxaban of every 10 weight portion, institute
The consumption of magnesium stearate is stated for 0.1-10 weight portions, such as 0.2-5 weight portions, such as 0.5-2 weight portions.According to the present invention first
The pharmaceutical composition of any one of aspect, wherein in terms of the razaxaban of every 10 weight portion, the consumption of the Compritol 888 ATO is
0.1-10 weight portions, such as 0.2-5 weight portions, such as 0.5-2 weight portions.The medicine group of any one according to a first aspect of the present invention
Compound, wherein Compritol 888 ATO are 0.5~2 with the weight ratio of magnesium stearate：1.Any one according to a first aspect of the present invention
Pharmaceutical composition, wherein in terms of the razaxaban of every 10 weight portion, the consumption of the lubricant is 0.1-10 weight portions, such as
0.2-5 weight portions, such as 0.5-2 weight portions.
The pharmaceutical composition of any one according to a first aspect of the present invention, it is tablet, and it is further coated.For example its
It is film coating tablet.Therefore, as tablet, wherein above-mentioned razaxaban, diluent, disintegrant, adhesive, wetting agent, profit
Lubrication prescription constitutes the label of tablet, and the label is generally also known as plain piece；And be coated and be generally also known as clothing layer etc..
The pharmaceutical composition of any one according to a first aspect of the present invention, the coating is ripe in addition those skilled in the art
Know it is conventional be coated under conditions of medium and film forming agent (they are commonly refereed to as coating material) carry out, these coating materials can be with
It is selected from following one or more：Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, polyvinylpyrrolidine
Alkanone, vinylpyrrolidone/vinyl acetate copolymer are (for exampleVA64, BASF), shellac, acrylate and/
Or the copolymer of methacrylate and methacrylic acid trimethyl ammonium, dimethylaminomethacrylic acid and neutral methyl propylene
The copolymer of acid esters, the polymer of methacrylic acid or methacrylate, ethyl acrylate-methyl methacrylate copolymer
Thing, methacrylic acid-acrylic acid methyl terpolymer, propane diols, polyethylene glycol, glyceryl triacetate, triethyl citrate and/or
Dye additive/pigment such as titanium dioxide, iron oxide, indigo or suitable color lake.This area have many can from business way
The thin film coating material that footpath obtains, the thin film coating material that directly can be for example bought from the happy Kanggong department of card, such as various models
OpadryProduct, such as Opadry295F640021。
The pharmaceutical composition in tablet form of any one according to a first aspect of the present invention, if it is coated, the bag
The coating layer weight being rolled in outside label accounts for the 1-6% of whole total weight of tablet, such as 1-4%.
The pharmaceutical composition of any one according to a first aspect of the present invention, it is in tablet form, and it uses Chinese Pharmacopoeia 2010
Version annex XC dissolution method the second method (paddle method) 75rpm, is delayed with the pH4.5 acetate containing 0.2% lauryl sodium sulfate
Fliud flushing 900mL detects that 30min dissolution rates are not less than 85% as dissolution medium.
The pharmaceutical composition of any one according to a first aspect of the present invention, it is in tablet form, and its have it is hereafter any
Formula composition described in embodiment.The pharmaceutical composition of any one according to a first aspect of the present invention, it is in tablet form, and its
It is made with the formula composition described in hereafter any embodiment and by its corresponding preparation method.
The pharmaceutical composition of any one according to a first aspect of the present invention, it is appointed by second aspect present invention or the third aspect
What one methods described was prepared.
Further, second aspect present invention is provided and prepares first aspect present invention any one described pharmaceutical composition
Method, it is comprised the following steps：
A () makes adhesive and wetting agent be dissolved in suitable quantity of water, make concentration of the adhesive in the solution up to 1-10%, connects
And add through the material medicine razaxaban of micronization processes, fully homogenizing makes medicine be suspended in mixed liquor, obtains suspension；
B () makes diluent and disintegrant are sufficiently mixed in fluidized bed pelletizer, then by step (a) gained suspension spray
To carry out wet granulation in the hybrid particles of fluidized bed comminutor, wet granular is dried in fluid bed, obtains dry particle；
C () makes step (b) gained dry particle uniform with mix lubricant, tabletted；Optionally,
D () obtains in the pharmaceutical composition of film coated tablet form step (c) gained tablet wrap film clothing.
Further, third aspect present invention provides the method prepared in the pharmaceutical composition of tablet form, the medicine
Included in compositions：Razaxaban, diluent, disintegrant, adhesive, wetting agent, lubricant, the method include following step
Suddenly：
A () makes adhesive and wetting agent be dissolved in suitable quantity of water, make concentration of the adhesive in the solution up to 1-10%, connects
And add through the material medicine razaxaban of micronization processes, fully homogenizing makes medicine be suspended in mixed liquor, obtains suspension；
B () makes diluent and disintegrant are sufficiently mixed in fluidized bed pelletizer, then by step (a) gained suspension spray
To carry out wet granulation in the hybrid particles of fluidized bed comminutor, wet granular is dried in fluid bed, obtains dry particle；
C () makes step (b) gained dry particle uniform with mix lubricant, tabletted；Optionally,
D () obtains in the pharmaceutical composition of film coated tablet form step (c) gained tablet wrap film clothing.
The method of any one according to a third aspect of the present invention, wherein the razaxaban is used with Micronised form.
In one embodiment, razaxaban has less than 10 μm, preferably with 1-8 μm of particle mean size X50And less than 20 μm,
Preferably shorter than 15 μm of X90(90% ratio).
The method of any one according to a third aspect of the present invention, wherein comprising razaxaban being 1- in every, the tablet
Such as 100mg, such as it is 2-50mg that razaxaban is included in every, and it is 5-40mg, such as every that razaxaban is included in every
In comprising razaxaban be 5mg, 10mg, 15mg, 20mg, 30mg, 40mg.
The method of any one according to a third aspect of the present invention, wherein the diluent is selected from following one or more：
Cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, Dicalcium Phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltose
Alcohol, D-sorbite, xylitol, lactose (such as Lactis Anhydrous or lactose monohydrate), D-glucose, maltose, sucrose, Portugal
Grape sugar, fructose or maltodextrin.In one embodiment, the diluent is the combination of microcrystalline cellulose and lactose.
In one embodiment, the diluent is the weight of the combination of microcrystalline cellulose and lactose, microcrystalline cellulose and both lactose
Amount is than being 0.1~10：1, such as 0.2~5：1.
The method of any one according to a third aspect of the present invention, wherein in terms of the razaxaban of every 10 weight portion, the dilution
The consumption of agent is 20-200 weight portions, such as 20-150 weight portions.
The method of any one according to a third aspect of the present invention, wherein the disintegrant is selected from following one or more：
Carboxymethylcellulose calcium, cross-linked carboxymethyl cellulose, Ac-Di-Sol, Crospovidone, low-substituted hydroxypropyl cellulose
(L-HPC), sodium carboxymethyl starch, primojel, boiling starch, wheaten starch, cornstarch, rice starch or
Potato starch.
The method of any one according to a third aspect of the present invention, wherein in terms of the razaxaban of every 10 weight portion, the disintegration
The consumption of agent is 1-20 weight portions, such as 1.5-7.5 weight portions.
The method of any one according to a third aspect of the present invention, wherein described adhesive are selected from following one or more：
Hydroxypropyl methyl cellulose (HPMC), carboxymethylcellulose calcium (sodium salt or calcium salt), ethyl cellulose, methylcellulose, ethoxy
Cellulose, ethylhydroxyethylcellulose, hydroxypropyl fiber element (HPC), L-HPC, PVP, polyvinyl alcohol, third
It is the polymer and its salt of olefin(e) acid, vinylpyrrolidone/vinyl acetate copolymer (such as Kollidon@VA64, BASF), bright
Glue, guar gum, boiling starch, alginates or xanthans.In one embodiment, described adhesive is HPMC.
The method of any one according to a third aspect of the present invention, wherein in terms of the razaxaban of every 10 weight portion, the bonding
The consumption of agent is 1-10 weight portions, such as 1.5-5 weight portions.In one embodiment, described adhesive water is configured to dense
Degree 1-20%, the solution of such as 1-10% is used as the adhesive of wet granulation.
The method of any one according to a third aspect of the present invention, wherein the wetting agent is selected from following one or more：
The sodium salt of sulfated fatty alcohol ester such as NaLS, lauryl sodium sulfate, sulfosuccinate such as dioctyl sulfo group
Sodium succinate, the fatty acid partial ester such as glyceryl monostearate of polyalcohol, the fatty acid partial ester of sorbitan for example takes off
Water D-sorbite monolaurate, for example many ethylene glycol-dehydration mountains of fatty acid partial ester of polyhydroxy ethylidene sorbitan
Pears sugar alcohol monolaurate, polyethylene glycol-sorbitan monostearate or polyethylene glycol-sorbitan list
Oleate, polyhydroxy ethylidene fatty alcohol ether, polyhydroxy ethylidene fatty acid ester, ethylene oxide-propylene oxide block copolymer
(such as Pluronic) or the triglycerides of ethoxylation.Preferably use NaLS or lauryl sodium sulfate conduct
Wetting agent.
The method of any one according to a third aspect of the present invention, wherein in terms of the razaxaban of every 10 weight portion, the wetting
The consumption of agent is 0.2-5 weight portions, such as 0.3-3 weight portions.In one embodiment, the wetting agent is dissolved in described
Used in binder solution.
The method of any one according to a third aspect of the present invention, wherein the lubricant is selected from following one or more：
Fumaric acid, stearic acid, magnesium stearate, calcium stearate, stearyl fumarate, high molecular weight fatty alcohol, polyethylene glycol, starch
(for example, wheaten starch, rice starch, cornstarch or potato starch), talcum powder, polymolecularity (colloid) silica,
Compritol 888 ATO, magnesia, magnesium carbonate, calcium silicates.In one embodiment, it is preferred to using Compritol 888 ATO and/or
Magnesium stearate is used as lubricant.
The method of any one according to a third aspect of the present invention, wherein in terms of the razaxaban of every 10 weight portion, the tristearin
The consumption of sour magnesium is 0.1-10 weight portions, such as such as 0.2-5 weight portions, 0.5-2 weight portions.Appoint according to a first aspect of the present invention
The pharmaceutical composition of one, wherein in terms of the razaxaban of every 10 weight portion, the consumption of the Compritol 888 ATO is 0.1-10
Weight portion, such as 0.2-5 weight portions, such as 0.5-2 weight portions.The pharmaceutical composition of any one according to a first aspect of the present invention,
Wherein in terms of the razaxaban of every 10 weight portion, the consumption of the lubricant is 0.1-10 weight portions, such as 0.2-5 weight portions,
Such as 0.5-2 weight portions.
The method of any one according to a third aspect of the present invention, wherein institute's den of monsters pharmaceutical composition are tablet, and it is further
It is coated.For example it is film coating tablet.Therefore, as tablet, wherein above-mentioned razaxaban, diluent, disintegrant, bonding
Agent, wetting agent, the label of lubricant composition tablet, the label are generally also known as plain piece；And be coated and be generally also known as clothing layer etc..
The method of any one according to a third aspect of the present invention, the coating is to add familiar to the person skilled in the art normal
Rule are carried out under conditions of being coated medium and film forming agent (they are commonly refereed to as coating material), and these coating materials can be selected from
Following one or more：Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, PVP, second
Vinyl pyrrolidone-vinyl acetate copolymer is (for exampleVA64, BASF), shellac, acrylate and/or methyl
The copolymer of acrylate and methacrylic acid trimethyl ammonium, dimethylaminomethacrylic acid and neutral methacrylic acid esters
The polymer of copolymer, methacrylic acid or methacrylate, EUDRAGIT NE 30 D, methyl
Copolymer of acrylic acid and methyl acrylate, propane diols, polyethylene glycol, glyceryl triacetate, triethyl citrate and/or dyestuff add
Plus agent/pigment such as titanium dioxide, iron oxide, indigo or suitable color lake.
The method of any one according to a third aspect of the present invention, if wherein the pharmaceutical composition in tablet form is wrapped
Clothing, the coating layer weight being wrapped in outside label accounts for the 1-6% of whole total weight of tablet, such as 1-4%.
The method of any one according to a third aspect of the present invention, wherein described pharmaceutical composition are in tablet form, during it is used
2010 editions annex XC dissolution method the second method (paddle method) 75rpm of state's pharmacopeia, with containing 0.2% lauryl sodium sulfate
PH4.5 acetate buffers 900mL detects that 30min dissolution rates are not less than 85% as dissolution medium.
Further, fourth aspect present invention provides pharmaceutical composition of the invention and is used to prevent and/or treat disease
Purposes, the disease especially thromboembolic disorders such as miocardial infarction, angina pectoris (including irregular angina), blood vessel into
After shape art or aortocoronary bypass block again with ISR, cerebrum block, transient ischemic attack,
Peripheral arterial closure disease, pulmonary embolism or DVT.
Any technical characteristic that any embodiment of either side of the present invention or the either side has is equally applicable
Any embodiment of other any embodiments or other either sides, as long as they will not be conflicting, certainly mutual
Between where applicable, if necessary can individual features be made with appropriate modification.Make into one with feature to various aspects of the present invention below
The description of step.
All documents recited in the present invention, their full content is incorporated herein by reference, and if these are literary
Offer expressed implication with it is of the invention inconsistent when, be defined by statement of the invention.Additionally, the various terms that use of the present invention and
Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and
Phrase is described in more detail and explains, the term and phrase for referring to if any inconsistent with common art-recognized meanings, with institute's table of the present invention
The implication stated is defined.
In the present invention if not otherwise indicated, the % being related to is w/w percentage.
It is known in the art that NaLS is also known as lauryl sodium sulfate etc., their title is generally applicable.
Razaxaban (Rivaroxaban) is by Bayer Bitterfeld GmbH medicine and Johnson Co. after the new of 10 years cooperative research and development
Type anticoagulant, is the directly oral Xa factor inhibitor in first, the whole world.It can high selectivity and contestable suppression trip
From Xa factor and prothrombin activity with combination, activated partial thromboplastin time plate is extended with dose-dependent fashion
(APTT) and prothrombin time (PT), so as to extend the clotting time, reduce fibrin ferment and formed.It has bioavilability high,
Treatment spectrum of disease is wide, dose-effect relationship stabilization, convenient oral, the characteristics of bleeding risk is low.In October, 2008, in Canada and European Union
Get the Green Light listing, trade name Xarelto.In U.S.'s listing, listed in more than 50, whole world country so far within 2011.2009
June in year is listed in the Chinese approval of import, and trade name is visitd auspicious appropriate.The domestic existing specification 10mg of China, my company copies specification and is
10mg。
Razaxaban is also the medicine for preventing and treating phlebothrombosis.After Orthopaedics Major Operation, venous thromboembolism (VTE) incidence
It is higher, it is one of patients'perioperative main causes of death, it is also unexpected dead major reason in hospital, it is big to orthopaedics
The prevention of operation VTE, it is possible to decrease risk of venous thrombosis, mitigates patient suffering, reduces medical expense.Clinically it is mainly used in prevention
The formation of hip joint and knee prosthesis postoperative patient person DVT (DVT) and pulmonary embolism (PE).Can also be used for preventing non-valve
Film Patients With Atrial Fibrillation cerebral apoplexy and non-central nervous system embolism, reduce risk of coronary syndrome recurrence etc..
According to Amy bodyguard market research agency (IMS Health) data display, global antithrombotic reagent market sale in 2008
Volume is 18,000,000,000 dollars, increases by 16% on a year-on-year basis, and 2009 annual growths are 7.95%, up to 19,500,000,000 dollars, global seven big drug markets
Antithrombotic growth rate is 7.13%, wide market.Razaxaban global marketing volume in 2012 is 6.67 hundred million dollars, 2013
Year global marketing volume reaches 21.24 hundred million dollars.It is the oral new drug of anticoagulation of the first listing over 50 years after warfarin, is anti-
Anticoagulation treatment field and another milestone in potential lethal thrombus prevention field.
Specific embodiment
The present invention can be conducted further description by the following examples, however, the scope of the present invention is not limited
In following embodiments.One of skill in the art, can be with it is understood that on the premise of without departing substantially from the spirit and scope of the present invention
Various change and modification are carried out to the present invention.The present invention to used in experiment to material and test method carry out generality
And/or specific description.Although for realize many materials that the object of the invention used and operating method be it is known in the art that
But the present invention is still described in detail as far as possible herein.
In EXAMPLEPART in detail below, be such as not otherwise mentioned, there is provided tablet be to provide formula with every consumption；
During actual preparation, fed intake with the amount of 10000/batches.Material medicine razaxaban used below if not otherwise indicated is with micro mist
Change form is used, with 1-8 μm of particle mean size X50And the X less than 15 μm90(90% ratio).Pressed below
During piece, if not otherwise indicated, flat using proper diameter rushes in row compressing tablet, makes the hardness of plain piece in the range of 60-80N.
Embodiment 1：Prepare razaxaban tablet
Prescription constitutes (mg/ pieces)：
Label：
Razaxaban (micronizing) 20.0mg
Microcrystalline cellulose 35.0mg
Lactose monohydrate 22.9mg
Cross-linked carboxymethyl cellulose (Ac-Di-FMC)3.0mg
Hydroxypropyl methyl cellulose (5cp) 3.0mg
NaLS 0.5mg
Magnesium stearate 0.6mg；
It is coated：
Hydroxypropyl methyl cellulose (15cp) 1.5mg
The polyethylene glycol 0.5mg of molecular weight 3350
Titanium dioxide 0.5mg；
Amount to 87.5mg.
Preparation method：Hydroxypropyl methyl cellulose and NaLS is soluble in water.The razaxaban that will be micronized suspends
To in the solution.Thus the suspension for preparing is in the fluidized bed prilling stage as wet granulation liquid spray to by microcrystalline cellulose
On the mixed-powder material of the fluidized state of element, lactose monohydrate and cross-linked carboxymethyl cellulose composition.In dried and screened
Added after particle obtained by (0.8mm mesh widths) and mix magnesium stearate.The mixture of compressing tablet is pressed by thus obtained
It is made the tablet (tablet can be described as label or plain piece) of 6mm diameters and hardness 60-80N.By coating material with appropriate water dissolves/
It is suspended as coating solution, above-mentioned plain piece is coated using the coating solution, obtains final product film coating tablet.
Embodiment 2：Prepare razaxaban tablet
Prescription constitutes (mg/ pieces)：
Label：
Razaxaban (micronizing) 5mg
Microcrystalline cellulose 40mg
Lactose monohydrate 33.9mg
Cross-linked carboxymethyl cellulose (Ac-Di-FMC)3mg
Hydroxypropyl methyl cellulose (3cp) 2mg
NaLS 0.5mg
Magnesium stearate 0.6mg；
It is coated：
Hydroxypropyl methyl cellulose (15cp) 1.5mg
The polyethylene glycol 0.5mg of molecular weight 400
Iron oxide yellow 0.1mg
Titanium dioxide 0.4mg；
Amount to 87.5mg.
Preparation method：Preparation method according to embodiment 1 is carried out.
Embodiment 3：Prepare razaxaban tablet
, with reference to embodiment 1, different is only that cross-linked carboxymethyl cellulose therein is replaced with into equivalent for prescription and preparation method
Ac-Di-Sol.
Embodiment 4：Prepare razaxaban tablet
, with reference to embodiment 2, different is only that cross-linked carboxymethyl cellulose therein is replaced with into equivalent for prescription and preparation method
Ac-Di-Sol.
Embodiment 5：Prepare razaxaban tablet
Prescription constitutes (mg/ pieces)：
Razaxaban 10mg
Microcrystalline cellulose (PH101) 40mg
Lactose monohydrate 27.9mg
Hydroxypropyl methyl cellulose 3mg
Ac-Di-Sol 3mg
Lauryl sodium sulfate 0.5mg
Magnesium stearate 0.6mg
Opadry (295F640021) 2mg.
1) add about 5ml water to be well mixed razaxaban (micronizing), HPMC (E5), lauryl sodium sulfate, obtain mixed
Outstanding solution I；
2) suspension solution I high-speed stirreds ball mill is carried out into wet grinding crushing, obtains suspension solution II and (swash through with Malvern
Light granularity analysis-e/or determining its granularity, the d (0.5) of wherein razaxaban is that 1.73, d (0.9) is 4.24)；
3) by microcrystalline cellulose PH101, lactose monohydrate, Ac-Di-Sol addition fluid bed, fluidize
It is well mixed；
4) suspension solution II is injected to step 3 using fluid bed) composition diluent in, and drying be prepared into profit
Cut down the particle I of husky class's pharmaceutical composition；
5) particle I addition magnesium stearates are well mixed, obtain particle II；And
6) particle II compressing tablets, piece weight 85mg, is plain piece.
Then plain piece obtained as above is used into Opadry295F640021 is coated, and obtains coating tablet.
Embodiment 6：Prepare razaxaban tablet
The present embodiment carries out 5 experiments, is expressed as embodiment 61, embodiment 62, embodiment 63, embodiment 64, reality
Apply example 65.In being tested at above-mentioned 5 times, the formula and method of embodiment 1-5 are respectively referred to, unlike, by stearic acid therein
Magnesium replaces with the Compritol 888 ATO of equivalent and is added in corresponding process.Obtain five batches of plain pieces respectively embodiment
61st, embodiment 62, embodiment 63, embodiment 64, embodiment 65, and corresponding 5 batches of coated tablets.
Embodiment 7：Prepare razaxaban tablet
The present embodiment carries out 5 experiments, is expressed as embodiment 71, embodiment 72, embodiment 73, embodiment 74, reality
Apply example 75.In being tested at above-mentioned 5 times, the formula and method of embodiment 1-5 are respectively referred to, unlike, in addition magnesium stearate
While, also add the Compritol 888 ATO with the magnesium stearate equivalent.Obtain five batches of plain pieces respectively embodiment 71, embodiment
72nd, embodiment 73, embodiment 74, embodiment 75, and corresponding 5 batches of coated tablets.
Embodiment 8：Prepare razaxaban tablet
Prescription constitutes (mg/ pieces)：
Razaxaban (micronizing) 10.0mg
Microcrystalline cellulose 25mg
Lactose monohydrate 125mg
Ac-Di-Sol 7.5mg
Hydroxypropyl methyl cellulose (5cp) 5mg
NaLS 0.3mg
Compritol 888 ATO 1.33mg
Magnesium stearate 0.67mg；
Preparation method：Carried out with reference to embodiment 1, Compritol 888 ATO is added together with magnesium stearate, obtain plain piece；The plain piece makes
It is coated with the coating material of embodiment 1, clothing layer accounts for the 2.2% of final tablet total weight, obtains coating tablet.
Embodiment 9：Prepare razaxaban tablet
Prescription is constituted：
Razaxaban (micronizing) 10mg
Microcrystalline cellulose 20mg
Lactose monohydrate 4mg
Ac-Di-Sol 1.5mg
Hydroxypropyl methyl cellulose (5cp) 1.5mg
NaLS 3mg
Compritol 888 ATO 0.17mg
Magnesium stearate 0.33mg；
Preparation method：Carried out with reference to embodiment 1, Compritol 888 ATO is added together with magnesium stearate, active component is contained with every
40mg is tabletted, obtains plain piece；The plain piece is coated using the coating material of embodiment 1, and it is total that clothing layer accounts for final tablet
The 2.2% of weight, obtains coating tablet.
Test example 1：Friability is detected
The plain piece of the whole batches of above example 1-9 gained, every batch takes 10g measure, with reference to Chinese Pharmacopoeia version two in 2010
Portion's annex XG " tablet friability inspection technique ", detects less loss weight of these tablets after rotating 250 times under shining pharmacopeia appointed condition
Amount (less loss weight should be less than 1.0% when States Pharmacopoeia specifications are rotated 100 times, otherwise it is assumed that this kind of tablet is unqualified, in long-term storage fortune
Abrasion is had during defeated.The present invention is the facility investigated, and number of revolutions is changed to 250 times, and tabletting properties are evaluated with less loss weight,
If less loss weight is excessive, it is unfavorable for the coating of tablet, because stronger Tab attrition occurs in coating process).
As a result：The plain piece of the whole batches of gained in embodiment 1-6, less loss weight in the range of 1.21~1.76%, example
Plain piece less loss weight such as embodiment 61 is 1.53%；The plain piece of the whole batches of gained in embodiment 7-9, less loss weight exists
In the range of 0.12~0.29%, the plain piece less loss weight of such as embodiment 71 is 0.18%.Above example 7-9 is to use stream
Change tablet prepared by bed marumerization.In the experiment of supplement, by embodiment 7-9, these are formulated the mixing of more solitos to inventor
The tablet making technology (preparation technology with reference to described in CN103877060A embodiments 1) of wet granulation obtains 7 batches of tablets.This 7 batches
The plain piece of tablet is detected that as a result less loss weight shows in the range of 1.13~1.56% according to above-mentioned friability detection method
Display is difficult to obtain above-mentioned technique effect of the invention without the tablet producing technology of fluid-bed marumerization method of the present invention.
Test example 2：Study on the stability
They are used aluminum-plastic composite membrane bag hermetic package by the plain piece of the whole batches of above example 1-9 gained, put 42 DEG C of temperature
Degree is lower to be placed May (this disposal is also referred to as high-temperature treatment in the present invention).According to following HPLC methods each tablet of measure at high temperature
Put forward and backward relevant material.
【HPLC】：
Determined according to high performance liquid chromatography (two D of annex V of Chinese Pharmacopoeia version in 2010)；
Chromatographic condition and system suitability：It is that filler (is used in this experiment with octadecylsilane chemically bonded silica
Purospher Star RP-18 posts, 55mm × 4.0mm, 3 μm)；Phosphoric acid solution with 0.01mol/L as mobile phase A, by acetonitrile
It is Mobile phase B, following table carries out gradient elution：
| Time (minute) | A (%) | B (%) |
| 0 | 90 | 10 |
| 18 | 50 | 50 |
Detection wavelength is 250nm, and column temperature is 45 DEG C, flow velocity 1ml/min；
The preparation of need testing solution：20, test sample tablet is taken, accurately weighed, finely ground, precision is weighed and (is approximately equivalent in right amount
Razaxaban 20mg), in putting 100ml measuring bottles, plus mixed solvent (phosphoric acid solution=3 of acetonitrile -0.01mol/L: 2) about 60ml,
Dissolve razaxaban within ultrasonically treated about 15 minutes, let cool to room temperature, scale is diluted to mixed solvent, shake up, filter, take continuous
Filtrate is used as need testing solution；
Determination method：Precision measures the μ l of need testing solution 10, injects liquid chromatograph, records chromatogram, calculates each impurity peaks
Relative to the area percent (also referred to as content (%)) of main peak, the identification of each impurity peaks is with the impurity peaks relative to main peak
Relative retention time (RRT) determines.RRT<0.3 scope is the peaks such as solvent, auxiliary material, is ignored, and only investigates RRT>0.3 scope
Impurity peaks situation of change.
It has been found that each tablet sample is after high-temperature treatment, and in the range of RRT=0.84 ± 0.10, the piece of different batches
There are a different size of impurity peaks in agent, and when each batch of tablet does not carry out high-temperature treatment, in this RRT=0.84 ± 0.10 model
Impurity (impurity can be described as RRT0.84 in the present invention) peak in enclosing is substantially less than quantitative limit (it is considered that now their phases
0%) area percent for main peak is.Specifically：The plain piece of the whole batches of gained in embodiment 1-6, RRT0.84 contains
Up in the range of 0.43~0.76%, the RRT0.84 contents of such as plain piece of embodiment 61 are 0.58% to amount；In embodiment 7-9
The plain piece of gained whole batches, RRT0.84 contents up in the range of 0.07~0.19%, such as plain piece of embodiment 71
RRT0.84 contents are 0.11%.
Test example 3：Determine the dissolution rate of tablet
Take the above example 1-9 whole batches of gained plain piece and coating tablet and commercially available razaxaban piece (it is visit auspicious appropriate,
10mg), using 2010 editions annex XC dissolution method the second method (paddle method) 75rpm of Chinese Pharmacopoeia, with containing 0.2% dodecyl
The pH4.5 acetate buffers 900mL of sodium sulphate determines their dissolution rates in 30min as dissolution medium detection.
As a result, the plain piece and coating tablet of the whole batches of embodiment 1-9 gained and commercially available razaxaban piece (it is visit auspicious appropriate,
10mg), their dissolution rate is in the range of 91~97%.For the tablet of each embodiment, to be coated and have no bright with being uncoated
Aobvious dissolution rate difference (difference is within 2 percentage points).For the five batches of plain pieces obtained in embodiment 6, they and its phase
Also obvious dissolution rate difference is had no between the plain piece of the embodiment 1-5 for answering (difference is within 3 percentage points).For implementing
The five batches of plain pieces obtained in example 7, obvious dissolution rate difference is also had no between the plain piece of their its corresponding embodiment 1-5
(difference is within 2.5 percentage points).In addition, commercially available razaxaban piece (visiing auspicious appropriate, 10mg) is determined using the above method.
It can be seen that Tablets have no notable difference with prior art tablet in terms of dissolution rate.
Claims (11)
1. a kind of pharmaceutical composition in tablet form, consisting of：The weight portion of razaxaban 10, diluent 20-200 weight
Part, disintegrant 1-20 weight portions, adhesive 1-10 weight portions, wetting agent 0.2-5 weight portions and lubricant；
The diluent is selected from following one or more：Microcrystalline cellulose, silicified microcrystalline cellulose, Dicalcium Phosphate, phosphoric acid
DFP, magnesium trisilicate, mannitol, maltitol, D-sorbite, xylitol, lactose, maltose, sucrose, glucose, fructose
Or maltodextrin；
The disintegrant is selected from following one or more：Carboxymethylcellulose calcium, cross-linked carboxymethyl cellulose, cross-linked carboxymethyl
Sodium cellulosate, Crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, primojel, boiling starch,
Wheaten starch, cornstarch, rice starch, potato starch；
Described adhesive is selected from following one or more：Hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose
It is element, methylcellulose, hydroxyethyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl fiber element, PVP, poly-
Vinyl alcohol, acrylic acid polymer and its salt, vinylpyrrolidone/vinyl acetate copolymer, gelatin, guar gum, part
Hydrolysis starch；
The wetting agent is selected from following one or more：NaLS, dioctyl sodium sulphosuccinate, glycerine list are hard
Resin acid ester, sorbitan monolaurate, polyethylene glycol-sorbitan monostearate, polyethylene glycol-dehydration mountain
Pears Sorbitane monooleate；
The lubricant is magnesium stearate and Compritol 888 ATO, in terms of the razaxaban of every 10 weight portion, the use of magnesium stearate
It is 0.5-2 weight portions to measure, and the consumption of Compritol 888 ATO is 0.5-2 weight portions；
The pharmaceutical composition of the tablet form is prepared according to following method：
A () makes adhesive and wetting agent be dissolved in suitable quantity of water, make concentration of the adhesive in the solution up to 1-10%, then adds
Enter through the material medicine razaxaban of micronization processes, fully homogenizing makes medicine be suspended in mixed liquor, obtains suspension；
B () makes diluent and disintegrant are sufficiently mixed in fluidized bed pelletizer, step (a) gained suspension then is sprayed into stream
To carry out wet granulation in the hybrid particles of change bed comminutor, wet granular is dried in fluid bed, obtains dry particle；
C () makes step (b) gained dry particle uniform with mix lubricant, tabletted；Optionally,
D () obtains in the pharmaceutical composition of film coated tablet form step (c) gained tablet wrap film clothing.
2. pharmaceutical composition according to claim 1, wherein comprising razaxaban being 1-100mg in every, the tablet.
3. pharmaceutical composition according to claim 1, in terms of the razaxaban of every 10 weight portion, the consumption of the diluent is
20-150 weight portions.
4. pharmaceutical composition according to claim 1, in terms of the razaxaban of every 10 weight portion, the consumption of the disintegrant is
1.5-7.5 weight portion.
5. pharmaceutical composition according to claim 1, in terms of the razaxaban of every 10 weight portion, the consumption of described adhesive is
1.5-5 weight portion.
6. pharmaceutical composition according to claim 1, in terms of the razaxaban of every 10 weight portion, the consumption of the wetting agent is
0.3-3 weight portions.
7. pharmaceutical composition according to claim 1, the coating material used by wrap film clothing is selected from following one kind or many
Kind：Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, PVP, vinyl pyrrolidone-
The copolymer of vinyl acetate copolymer, shellac, acrylate and/or methacrylate and methacrylic acid trimethyl ammonium,
The polymerization of the copolymer, methacrylic acid or methacrylate of dimethylaminomethacrylic acid and neutral methacrylic acid esters
Thing, EUDRAGIT NE 30 D, methacrylic acid-acrylic acid methyl terpolymer, propane diols, poly- second two
It is alcohol, glyceryl triacetate, triethyl citrate, titanium dioxide, iron oxide, indigo.
8. pharmaceutical composition according to claim 7, the coating layer weight being wrapped in outside label accounts for the 1- of whole total weight of tablet
6%。
9. pharmaceutical composition according to claim 7, the coating layer weight being wrapped in outside label accounts for the 1- of whole total weight of tablet
4%。
10. pharmaceutical composition according to claim 1, it uses 2010 editions annex XC the second methods of dissolution method of Chinese Pharmacopoeia
That is paddle method detects with 75rpm using the pH4.5 acetate buffers 900mL containing 0.2% lauryl sodium sulfate as dissolution medium,
30min dissolution rates are not less than 85%.
The method of 11. pharmaceutical compositions for preparing claim any one of 1-10, it is comprised the following steps：
A () makes adhesive and wetting agent be dissolved in suitable quantity of water, make concentration of the adhesive in the solution up to 1-10%, then adds
Enter through the material medicine razaxaban of micronization processes, fully homogenizing makes medicine be suspended in mixed liquor, obtains suspension；
B () makes diluent and disintegrant are sufficiently mixed in fluidized bed pelletizer, step (a) gained suspension then is sprayed into stream
To carry out wet granulation in the hybrid particles of change bed comminutor, wet granular is dried in fluid bed, obtains dry particle；
C () makes step (b) gained dry particle uniform with mix lubricant, tabletted；Optionally,
D () obtains in the pharmaceutical composition of film coated tablet form step (c) gained tablet wrap film clothing.
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| EA201792205A1 (en) | 2015-04-03 | 2018-02-28 | Инсайт Корпорейшн | HETEROCYCLIC COMPOUNDS AS LSD1 INHIBITORS |
| WO2017027678A1 (en) | 2015-08-12 | 2017-02-16 | Incyte Corporation | Salts of an lsd1 inhibitor |
| CN105078915A (en) * | 2015-08-27 | 2015-11-25 | 江苏中邦制药有限公司 | Rivaroxaban tablets and preparation method for same |
| CN106491514B (en) * | 2015-09-08 | 2019-04-23 | 凯望药业有限公司 | Solid pharmaceutical preparation of razaxaban and preparation method thereof |
| CN105232488B (en) * | 2015-10-15 | 2021-05-04 | 上海凌凯医药科技有限公司 | Solid pharmaceutical composition containing rivaroxaban |
| CN105726499B (en) * | 2016-02-01 | 2020-09-08 | 深圳信立泰药业股份有限公司 | Rivaroxaban pharmaceutical composition and preparation method thereof |
| CN107582531B (en) * | 2016-07-06 | 2020-12-29 | 四川科伦药物研究院有限公司 | Rivaroxaban solid preparation and preparation method thereof |
| WO2020047198A1 (en) | 2018-08-31 | 2020-03-05 | Incyte Corporation | Salts of an lsd1 inhibitor and processes for preparing the same |
| CN111053753A (en) * | 2018-10-16 | 2020-04-24 | 深圳翰宇药业股份有限公司 | Rivaroxaban pharmaceutical composition and preparation method thereof |
| CN111265654B (en) * | 2018-12-05 | 2023-05-16 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition of GLP-1 analogue and preparation method thereof |
| CN110693847B (en) * | 2019-12-07 | 2020-11-06 | 邹金林 | Film-coated tablet for preventing and treating polycystic ovarian syndrome and preparation method thereof |
| CN116850173A (en) * | 2023-06-06 | 2023-10-10 | 上海泰楚生物技术有限公司 | Application of dihydromyricetin in preparation of medicine of blood coagulation X factor FXa inhibitor |
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