A kind of razaxaban piece of anti-treatment embolism class diseases and preparation method thereofTechnical field
The invention belongs to technical field of medicine, in particular to a kind of medicine system of anti-treatment embolism class diseasesAgent, more particularly to a kind of tablet containing razaxaban and preparation method thereof.
Background technology
The entitled chloro- nitrogen of 5--((5S) -2- oxygen -3- [- 4- (3- oxygen -4- morpholinyls) of razaxaban (Rivaroxaban) chemistryPhenyl] -1,3- oxazolidine -5- bases -2- thiophene-carboxylic acid amides, structural formula is as follows：
Molecular formula：C19H18ClN3O5S molecular weight：435.89
The medicine is the oral direct Xa factor inhibitor in first, the whole world by Bayer medicine and Johson ＆ Johnson's joint research and development, inSeptember in 2008 obtained listing in Canada and European Union respectively with October 1 on 15th and ratified, trade name Xarelto.RazaxabanIt is a kind of oral anticoagulation with the direct inhibiting factor Xa of high selectivity of low molecule amount, it is various for preventing and/or treatingEmbolism class diseases, particularly prevent and treat Deep vain thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, angina pectoris, bloodIn occlusion and ISR, brain again after Tuboplasty or aortocoronary bypass (aortocoronary bypass)Wind, transient ischemic attack and Peripheral arterial occlusive disease.Razaxaban is used to prevent adult patients hip joint and kneeThe formation of VTE and pulmonary embolism after joint replacement surgery, while secondary prevention, treatment in Chinese patients with deep venous thrombosisThere is certain therapeutic effect in the field such as auricular fibrillation and acute coronary syndrome.
Razaxaban is fat-soluble medicine, is dissolved in dimethyl sulfoxide (DMSO), almost insoluble in methanol or water, in 25 DEG C of barsUnder part, aqueous medium solubility is only 5-7mg/L, causes that its agent in vitro dissolution rate is poor, and vivo biodistribution availability is very low.For insoluble drug, the method for conventional improvement drug-eluting has：Solid dispersions, cyclodextrin encapsulated, drug powderChange, surface active agent solubilization, microemulsified, prepare liposome etc..Wherein, drug micronization is one of most commonly seen method, inState patent CN101128205A, CN103550165A, CN103877060A, CN1886120A, CN104337787A,Although the preparation method difference that CN104173313A is provided, substantially using the method for being micronized razaxaban,And its granularity is controlled.However, because razaxaban raw material has viscosity in itself, knot is easily assembled in crushing processBlock, it is more difficult to reach target grain size, and high energy consumption, dust is big, is unfavorable for production and labour protection.After drug micronization, it is more easy toIn reassembling, raw material particle size is caused to become big, result of extraction is deteriorated；The stronger electrostatic adsorption of micronized medicine also results inThe problems such as mixing uniformity is poor.
CN103705520A discloses a kind of preparation method of rivaroxaban solid composition, and razaxaban is used into wet methodThe method of crushing crushes, and controls razaxaban particle diameter D after wet grinding90Less than 5 μm.The key point of the invention is still micro- for raw materialEfflorescence, due to that using wet pulverizing, relevant material can be caused to significantly increase.
CN104666262A discloses a kind of razaxaban tablet, and razaxaban, hydroxypropyl cellulose are dissolved in into diethylIn glycol list ethylether, aerosil absorption is added, is then pressed into tablet.Due to diethyl containing Auxiliary Liquid Material two in prescriptionAlcohol list ethylether has certain volatility, and content reduces in storing process, causes dissolution to reduce.
CN104055743A is related to a kind of oral tablet containing razaxaban, and the tablet is using the direct mixed pressuring plate of powderPrepared by preparation method, prepared Dissolution of Tablet is poor.
CN101321517A is by being prepared the razaxaban of unformed shape and semi-stability crystal formation II, but medicine stabilityReduce.
CN103550166A provides a kind of rivaroxaban oral microsphere preparation, its complex manufacturing, has used tetrahydrochyseneThe organic solvents such as furans, are unfavorable for labour protection.
The content of the invention
It is that prior art solves the problems, such as the most commonly used technology of the drug-eluting difference to carry out micronization processes to razaxabanMeans, but due to some defects existing for the characteristic and micronization technology of raw material in itself, cause the tablet of preparation and be not up to pre-The effect of phase.
In view of the deficiencies in the prior art, it is an object of the invention to by screening prescription again and carrying out process modification, carryFor a kind of dissolution rate is high, dissolution stability is good, the simple razaxaban tablet of preparation technology.Specifically, the purpose of the present inventionIt is achieved by the following technical solution：
It is a kind of it is anti-treatment embolism class diseases razaxaban tablet, the tablet by medicine-containing particle with it is other pharmaceutically acceptableAuxiliary material mixing after tabletting form, described medicine-containing particle contains razaxaban, sorbester p17, Crodaret, whiteClay.
Preferably, razaxaban tablet as described above, medicine-containing particle therein is by razaxaban, sorbester p17, polyoxy secondAlkene rilanit special and white bole composition.
It is further preferred that razaxaban tablet as described above, the amount ratio of each component of medicine-containing particle therein are：
Still further preferably, razaxaban tablet as described above, the amount ratio of each component of medicine-containing particle thereinFor：
Still further preferably, razaxaban tablet as described above, medicine-containing particle therein be prepared as follows andInto：Razaxaban is added in the mixed liquor of sorbester p17 and Crodaret, under 40 DEG C -50 DEG C of water bath conditionHeat and stir to dissolving, then add white bole, lasting stirring makes mixing, is cooled to room temperature, sieves and produce.
Present invention also offers the preparation method of above-mentioned razaxaban tablet, this method comprises the following steps：
(1) razaxaban is added in the mixed liquor of sorbester p17 and Crodaret, with 40 DEG C of -50 DEG C of water-bathsHeat and stir to dissolving, it is standby；
(2) white bole is added in the mixed liquor of step (1), lasting stirring, is well mixed, is cooled to room temperature, cross 16-40Mesh sieve, it is standby；
(3) medicine-containing particle prepared by step (2) is mixed with other pharmaceutically acceptable auxiliary materials, tabletting.
Preferably, the preparation method of razaxaban tablet as described above, wherein described other pharmaceutically acceptable auxiliaryExpect for filler, disintegrant, lubricant；Wherein, one kind in microcrystalline cellulose, pregelatinized starch and starch of filler orSeveral, disintegrant is selected from PVPP, Ac-Di-Sol, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starchIn one or more, lubricant be selected from magnesium stearate, silica and sodium stearyl fumarate one or more.
Compared with prior art, razaxaban tablet of the present invention has the following advantages that and marked improvement：
(1) dissolution is rapid, 5min dissolutions more than 90%；
(2) medicine, also without the use of organic solvent, is easy to labour protection without micronization processes；
(3) preparation method is simple, easily operated.
Embodiment
Now the preparation process of the present invention and implementation result, but the protection of the present invention are further described by following examplesScope is not limited to following examples.
Embodiment 1
Preparation method：
(1) razaxaban is added in the mixed liquor of sorbester p17 and Crodaret, in 40 DEG C -50 DEG C of waterHeated under the conditions of bath, stirring is standby to dissolving；
(2) white bole is added in the mixed liquor of step (1), lasting stirring, is well mixed, is cooled to room temperature, cross 20 meshSieve standby；
(3) it is the medicine-containing particle and the pregelatinized starch of recipe quantity that prepare step (2), PVPP, silica, hardFatty acid magnesium is well mixed, and with the shallow arc stampings of diameter 9mm, is produced.
Embodiment 2
Preparation method：
(1) razaxaban is added in the mixed liquor of sorbester p17 and Crodaret, in 40 DEG C -50 DEG C of waterHeated under the conditions of bath, stirring is standby to dissolving；
(2) white bole is added in the mixed liquor of step (1), lasting stirring, is well mixed, is cooled to room temperature, cross 20 meshSieve standby；
(3) by the microcrystalline cellulose of the medicine-containing particle of step (2) preparation and recipe quantity, Ac-Di-Sol, twoSilica, magnesium stearate are well mixed, and with the shallow arc stampings of diameter 10mm, are produced.
Embodiment 3
Preparation method：
(1) razaxaban is added in the mixed liquor of sorbester p17 and Crodaret, in 40 DEG C -50 DEG C of waterHeated under the conditions of bath, stirring is standby to dissolving；
(2) white bole is added in the mixed liquor of step (1), lasting stirring, is well mixed, is cooled to room temperature, cross 20 meshSieve standby；
(3) medicine-containing particle and the pregelatinized starch of recipe quantity that prepare step (2), sodium carboxymethyl starch, silica,Sodium stearyl fumarate is well mixed, and with the shallow arc stampings of diameter 11mm, is produced.
The dissolution determination of the razaxaban piece of embodiment 4
Determined according to high performance liquid chromatography (two D of annex V of Chinese Pharmacopoeia version in 2010).It is bonded with octadecylsilaneSilica gel is filler；With acetonitrile-water (40:60) it is mobile phase；Detection wavelength is 250nm；Column temperature is 40 DEG C.Take this product, photograph is moltenOut-degree determination method (the second methods of C of two annex of Chinese Pharmacopoeia version in 2010 Ⅹ), (is taken 2.99g sodium acetates, put with acetate bufferIn 1000ml water, add 1.66ml glacial acetic acid and 20ml 10%SDS solution, adjusted with sodium hydroxide or glacial acetic acid to pH value 4.50± 0.1) 900ml is dissolution medium, and rotating speed is 75 turns per minute, is operated in accordance with the law, during through 5min, takes solution appropriate, filters, take continuousFiltrate is as need testing solution；It is another to take razaxaban reference substance about 27.5mg, it is accurately weighed, put in 50ml measuring bottles, add acetonitrile to fitAmount ultrasound makes dissolving, is cooled to room temperature, is diluted to scale, shakes up, and precision measures in right amount, and every 1ml is made with dissolution medium dilutionIn solution containing about 11 μ g, as reference substance solution.Precision measures need testing solution and each 10 μ l of reference substance solution, is injected separately intoLiquid chromatograph, chromatogram is recorded, by external standard method with the stripping quantity of calculated by peak area every.Measurement result is shown in Table 1.By table 1Test statistics result understands that the razaxaban piece dissolution for preparing of the present invention is rapid, 5min can complete dissolution, and accelerated testDissolution is substantially without significant change afterwards, and this explanation preparation dissolution rate is high, dissolution stability is good.
The razaxaban piece 5min dissolution determinations result (%) of table 1