CN105982870A

CN105982870A - Apixaban tablet

Info

Publication number: CN105982870A
Application number: CN201510055818.8A
Authority: CN
Inventors: 张贵民; 郝贵周; 高西蒙
Original assignee: Shandong New Time Pharmaceutical Co Ltd
Current assignee: Shandong New Time Pharmaceutical Co Ltd
Priority date: 2015-02-03
Filing date: 2015-02-03
Publication date: 2016-10-05
Anticipated expiration: 2035-02-03
Also published as: CN105982870B

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an apixaban tablet. The apixaban tablet contains apixaban, hydroxy propyl cellulose and fumed silica. A preparation method of the apixaban tablet comprises the following steps: dissolving apixaban and hydroxy propyl cellulose in diethylene glycol monoethyl ether, adding with fumed silica for adsorption, then uniformly mixing with pharmaceutically acceptable auxiliary materials, and carrying out pressing by adopting a direct tableting technology. Compared with the prior art, the apixaban tablet has the advantages that the medicine dissolution speed is high, the process is simple, a surfactant does not need to be added, and the micronization treatment is not needed. The acceleration test result shows that the prepared apixaban tablet is good in stability.

Description

A kind of Eliquis tablet

Technical field

The invention belongs to pharmaceutical preparations technology field, be specifically related to a kind of Eliquis tablet.

Background technology

Eliquis is a kind of new oral direct Xa factor inhibitor, and (its main practical function is to pass through to activate factor Xa The restricted proteolysis of thrombinogen produces thrombin) in the last co-route of blood coagulation, it is in connection endogenous with outer The critical role of source property activation mechanism.Thrombin (the final serine egg in the path being produced fibrin clot by its precursor White enzyme) generation by forming prothrombinase complex (factor Xa, labile factor, Ca²⁺And phospholipid) be amplified. Owing to a factor Xa molecule is computed producing 138 thrombin Inhibitory molecules, factor Xa may be solidifying in interruption In blood system more more effective than the inactivation of thrombin.Therefore, coagulation factor xa inhibitors is that a class effectively treats thromboembolic disorders Compound.

Eliquis is water insoluble, and Eliquis dissolubility in aqueous medium (pH1.2-pH6.8) is 0.04mg/mL.Exist and dissolve The shortcoming that speed is slow, dissolution in vitro is low, bioavailability is low, the absorption to medicine has a certain impact.Husky in order to improve Ah piperazine The dissolution of class, typically uses the method adding exhibiting high surface activating agent in prescription, although the method can increase the molten of Eliquis Out-degree, but exhibiting high surface activating agent brings substantial amounts of toxic and side effects to human body.Thus it is husky to increase Ah piperazine to seek a kind of nontoxic method The dissolution of class is extremely urgent.

Dry granulation process after external employing raw material micronization, although make moderate progress to a certain extent, but dry granulation, work Skill is complicated, and dust-producing amount is big, and granular size heterogeneity, and the unilateral fineness of tablet being pressed into is poor.

CN102908324A discloses a kind of Apixaban tablet, including Eliquis, water soluble carrier material, filler, disintegrate Agent, fluidizer, improve Eliquis dissolution in vitro poor, the deficiency that bioavailability is low.But due to Polyethylene Glycol fusing point Problem that is low, that there is easy sticking in production.

Summary of the invention

In view of the deficiencies in the prior art, the present invention intend providing a kind of In Vitro Dissolution rapidly, good stability, preparation technology simple Ah Piperazine sand class tablet.

Inventors realized that, if it is possible to solving the scattering problem of medicine, direct powder compression is still optimum technology.Invention People, it is considered that jointly pulverized with adjuvant by medicine, although degree of mixing can be improved, but sacrifices the mobility of granule, Ke Nengzao When becoming tabletting, tablet weight is unstable.Further, inventor is little in view of Eliquis tablet specification, if dissolved by Eliquis In organic solvent, adsorb with adjuvant, drug dissolution may be improved.

Inventor has carried out great many of experiments, is found surprisingly that Eliquis is soluble in TC, but enters one Even if step it is demonstrated experimentally that be dissolved in this solvent, after silicon dioxide absorption tabletting, drug-eluting is still slow, inventor In view of when being probably tablet dissolution mensuration, TC is miscible with water, causes solvent to be dispersed in water rapidly, makes Medicine is become to separate out.

Therefore, inventor is it may be further contemplated, prepare solid dispersion soluble drug, and inventor is husky with Ah piperazine by hydroxypropyl cellulose Class dissolves in ethanol, removes ethanol in Rotary Evaporators, and the Dissolution of Tablet of preparation improves a lot, but dispersion is the most viscous Thick, it is difficult to take out, industrialization difficulty.

Unexpectedly, solid dispersions technique is combined by inventor with solubilizing agent and adsorbent, first prepares the molten medicine of solid dispersion Thing, adsorbs the dispersion solution of medicine aerosil, then mixs homogeneously with pharmaceutically acceptable adjuvant, tabletting, Gained tablet dissolution is rapid.

Specifically, the present invention is achieved through the following technical solutions:

A kind of Eliquis tablet, containing Eliquis, hydroxypropyl cellulose, aerosil, TC With other pharmaceutically acceptable adjuvants.

Described Eliquis tablet is prepared from by the following method: Eliquis is dissolved in TC, adds Hydroxypropyl cellulose, is stirred to dissolve, and adds aerosil absorption, then with the mixing of pharmaceutically acceptable adjuvant all Even, use the compacting of direct compression technique to form.

Described Eliquis tablet, Eliquis is 1:2～7 with the weight ratio of TC.Preferably, weight Ratio is 1:5.

Described Eliquis tablet, Eliquis is 1:1～3 with the weight ratio of hydroxypropyl cellulose.Preferably, weight ratio is 1:2。

Described Eliquis tablet, Eliquis is 1:10～30 with the weight ratio of aerosil.Preferably, weight ratio For 1:20.

Described pharmaceutically acceptable adjuvant is filler, disintegrating agent, lubricant.

One or more in microcrystalline Cellulose, lactose, mannitol, starch and dextrin of described filler；Described collapses Solve agent one in carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone and low-substituted hydroxypropyl cellulose Or it is multiple；One or more in magnesium stearate, sodium stearyl fumarate, Pulvis Talci and silicon dioxide of described lubricant. Preferably, described filler is microcrystalline Cellulose；Described disintegrating agent is polyvinylpolypyrrolidone；Described lubricant is magnesium stearate.

Compared with prior art, drug-eluting speed is fast, and technique is simple for the present invention, it is not necessary to adds surfactant, is also not required to Want micronization processes.

Detailed description of the invention

Following example further describe beneficial effects of the present invention, and embodiment is only used for the purpose of illustration, is not intended to the present invention's Scope, those of ordinary skill in the art are made according to the present invention simultaneously obvious change and modification are also contained in model of the present invention Within enclosing.

Embodiment 1

Prescription:

Preparation technology:

Eliquis is dissolved in TC, adds hydroxypropyl cellulose, is stirred to dissolve, adds recipe quantity Aerosil absorption, then with lactose, carboxymethyl starch sodium, magnesium stearate mix homogeneously, use direct compression technique Compacting forms.

Embodiment 2

Prescription:

Preparation technology:

Eliquis is dissolved in TC, adds hydroxypropyl cellulose, is stirred to dissolve, adds recipe quantity Aerosil absorption, then with microcrystalline Cellulose, polyvinylpolypyrrolidone, magnesium stearate mix homogeneously, use direct compression Technique compacting forms.

Embodiment 3

Prescription:

Preparation technology:

Embodiment 4

Prescription:

Preparation technology:

Eliquis is dissolved in TC, adds hydroxypropyl cellulose, is stirred to dissolve, adds recipe quantity Aerosil absorption, then with starch, low-substituted hydroxypropyl cellulose, Pulvis Talci mix homogeneously, use direct compression Technique compacting forms.

Embodiment 5

Prescription:

Preparation technology:

Eliquis comminution by gas stream, particle diameter is D90=10.8, adds the hydroxypropyl cellulose of recipe quantity, aerosil, micro- Crystalline cellulose, polyvinylpolypyrrolidone mix homogeneously, add TC, pelletizes, is subsequently adding magnesium stearate, mixing Uniformly, the compacting of direct compression technique is used to form.

Embodiment 6

Prescription:

Preparation technology:

Embodiment 7

Prescription:

Preparation technology:

Weigh Eliquis and the microcrystalline Cellulose mix homogeneously of recipe quantity.Eliquis microcrystalline cellulose mixt is added and pulverizes Machine pulverizes 3 minutes, then with aerosil, hydroxypropyl cellulose, the crosslinking carboxylic polyvidone of recipe quantity, mix homogeneously, Add TC, pelletize, be subsequently adding magnesium stearate, mix homogeneously, use the compacting of direct compression technique to form. Direct compression obtains Apixaban tablet.

Comparative example 1

Prescription:

Preparation technology:

Then and crystallite Eliquis is dissolved in TC, adds the aerosil absorption of recipe quantity, Cellulose, polyvinylpolypyrrolidone, magnesium stearate mix homogeneously, use the compacting of direct compression technique to form.

Comparative example 2

Prescription:

Preparation technology:

Eliquis comminution by gas stream, D90=10.3 micron, then with microcrystalline Cellulose, polyvinylpolypyrrolidone, magnesium stearate mixing all Even, use the compacting of direct compression technique to form.

Checking embodiment

Dissolution determination.Use high performance liquid chromatography that the content of Ah paisa class sheet is measured chromatographic condition and dissolution determination Method is identical, uses octadecylsilane chemically bonded silica chromatographic column；With 10mM ammonium acetate: acetonitrile (65:35) is for flowing phase；Stream Speed is 1.0ml per minute；Detection wavelength is 280nm；Column temperature is 25 DEG C, by external standard method with in calculated by peak area need testing solution The dissolution of Eliquis.This product stripping quantity of 5 minutes should be not less than 80% (Q) of labelled amount.

Dissolution medium: 0.05% lauryl sulphate acid phosphate buffer pH6.8, medium volume: 900ml, stirring paddle turns Speed 75rpm.

Each embodiment measurement result

Embodiment	0 day result (%)	40 DEG C, 75%RH accelerates result (%) after 6 months
			Embodiment 1	99.1	98.9
Embodiment 2	99.4	99.1
			Embodiment 3	99.9	99.8
Embodiment 4	99.6	99.4
			Embodiment 5	79.9	79.4
Embodiment 6	81.2	80.8
			Embodiment 7	82.3	81.9
Comparative example 1	54.2	53.1
			Comparative example 2	62.3	60.8

As seen from the table, the embodiment of the present invention 1～4 dissolution is rapid, and within 5 minutes, dissolution is all more than 99%, dissolution base after acceleration This is unchanged；Embodiment 5～7, pelletizes by TC, because raw material can not be substantially dissolved in solvent, therefore Dissolution is the slowest；Comparative example 1, does not adds hydroxypropyl cellulose in solvent, and when dissolution measures, medicine separates out, therefore dissolution is not Hurry up；Comparative example 2, raw material micronization processes, and dissolution is slow compared with the present invention.

Claims

1. an Eliquis tablet, it is characterised in that containing Eliquis, hydroxypropyl cellulose, aerosil, two Ethylene glycol monomethyl ether and other pharmaceutically acceptable adjuvants.

Eliquis tablet the most according to claim 1, it is characterised in that it is prepared from by the following method: Eliquis It is dissolved in TC, adds hydroxypropyl cellulose, be stirred to dissolve, add aerosil absorption, Then with pharmaceutically acceptable adjuvant mix homogeneously, the compacting of direct compression technique is used to form.

Eliquis tablet the most according to claim 1, it is characterised in that Eliquis and the weight ratio of hydroxypropyl cellulose For 1:1～3.

Eliquis tablet the most according to claim 1, it is characterised in that Eliquis and the weight ratio of aerosil For 1:10～30.

Eliquis tablet the most according to claim 1, it is characterised in that Eliquis and the weight ratio of aerosil For 1:20.

Eliquis tablet the most according to claim 2, it is characterised in that Eliquis and the weight of TC Amount ratio is 1:2～7.

Eliquis tablet the most according to claim 1, it is characterised in that pharmaceutically acceptable adjuvant is filler, collapses Solve agent, lubricant.

Eliquis tablet the most according to claim 7, it is characterised in that described filler be microcrystalline Cellulose, lactose, One or more in mannitol, starch and dextrin；Described disintegrating agent be carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, One or more in polyvinylpolypyrrolidone and low-substituted hydroxypropyl cellulose；Described lubricant is magnesium stearate, stearic acid richness horse One or more in acid sodium, Pulvis Talci and silicon dioxide.

Razaxaban tablet the most according to claim 7, it is characterised in that described filler is microcrystalline Cellulose；Described collapse Solution agent is polyvinylpolypyrrolidone；Described lubricant is magnesium stearate.