CN104490834A - Method for preparing apixaban tablets - Google Patents
Method for preparing apixaban tablets Download PDFInfo
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- CN104490834A CN104490834A CN201410773124.3A CN201410773124A CN104490834A CN 104490834 A CN104490834 A CN 104490834A CN 201410773124 A CN201410773124 A CN 201410773124A CN 104490834 A CN104490834 A CN 104490834A
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Abstract
The invention relates to a method for preparing apixaban tablets. The method comprises the following steps: (1) uniformly mixing apixaban, an excipient, a disintegrating agent, a surfactant and a lubricating agent, performing wet granulation, screening the prepared soft material by using a 20-mesh sieve, granulating, drying and finishing the obtained particles, and collecting the dried particles with the particle size being between 20 meshes and 80 meshes; and (2) mixing the prepared particles with the lubricating agent for 30 minutes and tabletting, wherein the hardness of the tablets is 50-60N. In order to improve the dissolubility, a method for adding the surfactant into the prescription is adopted. According to the method, the dissolubility of the apixaban can be improved, and the problem is well solved, so that the bioavailability of the medicine is improved, and an excellent treatment effect is achieved.
Description
Technical field
The invention belongs to Western medicine preparation technical field, particularly a kind of preparation method of Eliquis tablet.
Background technology
The husky class of Ah croak is the direct Xa factor inhibitor of a kind of new oral, chemical formula is 1-(4 one methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-base) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-first phthalein amine.Molecular formula is C25H25N5O4, and molecular weight is 459.50.Structural formula is as follows:
Atrial fibrillation (atrial fibrillation, AF) be modal types of arrhythmia clinically, it is the important independent hazard factor of apoplexy, the risk that cerebral embolism or transient ischemic attack (transient ischemic attack, TIA) occur AF patient be the 4-5 of non-AF patient doubly.In addition, the apoplexy of AF patient lapses to usually poor, and fatality rate and disability rate are also higher.Case fatality rate in AF patient's Post stroke 1 year is up to 50%.Therefore, formulate the measure of rational AF prevention and therapy and seem particularly important.
Certainly, the AF needs of patients application anticoagulation that apoplexy risk is higher.Although the anticoagulation curative effect taking warfarin as representative is better, onset is slow, impact, inherited metabolic variation by multi-medicament and food, need periodic monitoring and treatment window is narrow etc. that limitation greatly limit its extensive use.Therefore, be starved of novel anticoagulation clinically, can obtain and the equal or better curative effect of warfarin while not increasing or reduce the untoward reaction such as hemorrhage.
Novel anticoagulation through clinical trial checking mainly comprises direct thrombin inhibitor drugs (as dabigatran) or Xa factor depressant (as razaxaban and Eliquis) etc.Eliquis is the direct Xa factor anticoagulation of new oral, and the research after bone surgery in venous thrombosis prevention and therapy completed already, and has got permission to apply in the patient accepting plastic surgery operations.Eliquis also shows good prospect in AF patient's stroke prevention.
Eliquis itself is water insoluble, and the shortcoming that dissolution velocity is slow, dissolution in vitro is low, bioavailability is low, has a certain impact to the absorption of human body.Thus seek a kind of dissolution method increasing Eliquis, the bioavailability method improving Eliquis is extremely urgent.
Through retrieval, find one section of patent documentation relevant to this patent content, specifically, publication number is that the Chinese patent of 102908324A provides a kind of Apixaban tablet, and Apixaban tablet comprises Eliquis 1 part; Water soluble carrier material 10 ~ 20 parts; Excipient 30 ~ 60 parts; Disintegrating agent 5 ~ 10 parts; Fluidizer 5 ~ 10 parts.It is poor that Apixaban tablet of the present invention improves Eliquis dissolution in vitro, the deficiency that bioavailability is low.The invention discloses the preparation method of Apixaban tablet, the method is simple to operate, favorable reproducibility, is easy to realize a large amount of production.Eliquis solid piece is mainly used in antithrombotic.
Summary of the invention
The object of the invention is to overcome prior art weak point, provide a kind of tablet quality stable and hardness is moderate, disintegrate and stripping rapid, the preparation method of the Eliquis tablet of the Selective activation Ⅹ a factor inhibitors that bioavailability is high.
A preparation method for Eliquis tablet, the steps include:
(1) carry out wet granulation, obtained soft material 20 mesh sieves after Eliquis, excipient, disintegrating agent, surfactant and lubricant being mixed, granulate, gained granule drying, granulate, the dry granule between rear collection 20 order-80 order;
(2) by after the granule that makes and mix lubricant 30min, tabletting, tablet hardness is 50-60N.
And described excipient is optionally from the following combination of one or more: starch, Lactis Anhydrous, Icing Sugar, mannitol, dextrin, cyclodextrin, microcrystalline Cellulose and sucrose.
And described disintegrating agent is optionally from the following combination of one or more: carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, crosslinked carboxymethyl fecula sodium, pregelatinized Starch and low-substituted hydroxypropyl cellulose.
And described lubricant is selected for a post and is selected from the following combination of one or more: magnesium stearate, Pulvis Talci and micropowder silica gel.
And described surfactant is optionally from the following combination of one or more: sodium lauryl sulphate, dodecyl sodium sulfate, Polyethylene Glycol.
And the weight ratio of described Eliquis, excipient, disintegrating agent, surfactant and lubricant is: 5-20:0.5-2.5:0.1-0.3:0.1-2.0.
Advantage of the present invention and good effect are:
1, the present invention is in order to improve dissolution, adopts the method adding surfactant in prescription, and the method can increase the dissolution of Eliquis, well solves this problem, and drug bioavailability is improved, and reaches good therapeutic effect.
2, Eliquis tablet stability provided by the invention is high, and by accelerated test study, Apixaban tablet prepared by the present invention is in acceleration after 6 months, and its related substances is no more than 0.70%, and this shows its steady quality, is significantly better than prior art.
3, Eliquis tablet provided by the invention disintegrate and stripping rapid.Investigate experimental study by disintegration and dissolution, Apixaban tablet hardness prepared by the present invention reaches 50-60N, and in 15-25 DEG C of water, in 80s, all disintegrate also passes through No. 2 sieves; And the dissolution in pH 1.2 hydrochloric acid and water and commercially available do not have significant difference.This shows that tablet of the present invention disintegrate and dissolution rate while possessing larger hardness soon, imply that bioavailability is high.
4, Eliquis tablet packing cost provided by the invention is low.The slice, thin piece hardness of Apixaban tablet prepared by the present invention reaches more than 50N, not easily produces fragment, need not adopt extra package material, greatly reduce packing cost.
5, Eliquis tablet preparation method provided by the invention is simple.Direct compression after the prescription employing wet granulation of the Eliquis tablet of the present invention's screening, can obtain steady quality, disintegrate and stripping tablet rapidly, be applicable to industrialized great production.
Through contrast, the present invention and publication number are that the Chinese patent of 102908324A is distinguished and is: the present invention by Surfactant kind, the selection of consumption, thus the bioavailability improving Eliquis, the therapeutical effect of medicine is given full play to, the safety that tool is very high.And be the solubilising material added in the open prescription of medicine Apixaban tablet at surfactant of the present invention, its consumption and safety all have mass data support,
Patent CN102908324A is by solid dispersion technology, in order to reduce Eliquis particle diameter, making the husky class of Ah croak and Polyethylene Glycol form colloidal solution, thus improving dissolution rate and the dissolubility of medicine, increasing drug absorption, improve bioavailability.Its objective is the risk of stability in order to Ah croak husky class prescription and impurity degradation, and solid dispersion technology used in this invention, the Polyethylene Glycol introduced is the import drugs Apixaban tablet openly material that adds outward of prescription, and the research not through clinical trial does not have the safety that this additive supported by human safety test data.
Detailed description of the invention
Below by specific embodiment, the invention will be further described, and following examples are descriptive, is not determinate, can not limit protection scope of the present invention with this.
Embodiment 1
The component of Eliquis tablet
| Component | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) |
| Eliquis | 10 | 20 | 30 |
| Microcrystalline cellulose | 38 | 76 | 114 |
| Lactis Anhydrous | 70 | 140 | 210 |
| Cross-linked cellulose sodium | 2 | 4 | 6 |
| Sodium lauryl sulphate | 2 | 4 | 6 |
| Magnesium stearate | 0.2 | 0.4 | 0.6 |
Preparation method:
(1) take the supplementary material of above-mentioned recipe quantity, except magnesium stearate, carry out wet granulation, obtained soft material 20 mesh sieves by after all supplementary material mixings, granulate, gained granule drying, granulate, the dry granule between rear collection 20 order-80 order.
(2) mix after 30min by the granule made with magnesium stearate, tabletting, slice, thin piece hardness is 50-60N.
Embodiment 2
Eliquis tablet component
| Component | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) |
| Eliquis | 10 | 20 | 40 |
| Icing Sugar | 60 | 120 | 250 |
| Microcrystalline cellulose | 22 | 40 | 88 |
| Polyvinylpolypyrrolidone | 3 | 6 | 16 |
| Dodecyl sodium sulfate | 2 | 4 | 6 |
| Magnesium stearate | 0.2 | 0.4 | 0.6 |
Preparation method:
(1) take the supplementary material of above-mentioned recipe quantity, except magnesium stearate, carry out wet granulation, obtained soft material 20 mesh sieves by after all supplementary material mixings, granulate, gained granule drying, granulate, the dry granule between rear collection 20 order-80 order.
(2) mix after 30min by the granule made with magnesium stearate, tabletting, slice, thin piece hardness is 50-60N.
Embodiment 3
The component of Eliquis tablet
Preparation method:
(1) take the supplementary material of above-mentioned recipe quantity, except magnesium stearate, carry out wet granulation, obtained soft material 20 mesh sieves by after all supplementary material mixings, granulate, gained granule drying, granulate, the dry granule between rear collection 20 order-80 order.
(2) mix after 30min by the granule made with magnesium stearate, tabletting, slice, thin piece hardness is 50-60N.
Data monitoring is tested
The disintegration of Eliquis tablet and dissolution are investigated
(1) mensuration of disintegration
Get Apixaban tablet 6 prepared by embodiment of the present invention 1-3, put in 250m1 beaker, add the water 100m1 of 15-25 DEG C, jolting 3 minutes, measure disintegration.Result of the test is see table 1.
The disintegration of table 1 Apixaban tablet
| Sample | Slice, thin piece hardness (N) | Disintegration (S) |
| Embodiment 1 | 53-58 | 68-74 |
| Embodiment 2 | 55-60 | 68-81 |
| Embodiment 3 | 54-59 | 72-76 |
Result of the test according to table 1 can be found out, Apixaban tablet hardness prepared by the present invention reaches 50-60N, and in 15-25 DEG C of water, in 80s, all disintegrate also passes through No. 2 sieves.This shows that tablet of the present invention disintegrate while possessing larger hardness is rapid.
(2) mensuration of dissolution
Measure according to dissolution method (Chinese Pharmacopoeia 2010 editions two annex XC second methods).Get Apixaban tablet and each 12 of commercially available Apixaban tablet prepared by embodiment of the present invention 1-3, respectively with pH 1.2 hydrochloric acid, water for solvent, rotating speed is 75 revs/min, operates in accordance with the law, respectively at 5,10,15, within 30 minutes, get solution and filter in right amount, as need testing solution; Another precision takes Eliquis reference substance and is about 50mg, puts in 50m1 measuring bottle, adds that second eyeball is ultrasonic in right amount makes dissolving, and is diluted to scale, shakes up.Precision measures 2ml and puts in 200m1 measuring bottle, adds stripping medium to scale, shakes up, in contrast product solution.Get need testing solution and reference substance solution respectively, according to Chinese Pharmacopoeia 2010. editions, (annex IVA ultraviolet visible spectrophotometry, measures absorbance at 272nm place, calculates dissolution.Result of the test in table 2,
The dissolution of table 2 Apixaban tablet in pHl.2 hydrochloric acid
| Group | 5 minutes | 10 minutes | 15 minutes | 30 minutes |
| Commercially available | 10.02％ | 30.85％ | 50.45％ | 60.22％ |
| Embodiment 1 | 11.02％ | 33.34％ | 49.94％ | 69.03％ |
| Embodiment 2 | 11.47％ | 34.73％ | 50.22％ | 64.37％ |
| Embodiment 3 | 10.06％ | 34.89％ | 52.10％ | 65.22％ |
The dissolution of table 3 Apixaban tablet in water
| Group | 5 minutes | 10 minutes | 15 minutes | 30 minutes |
| Commercially available | 90.02％ | 98.85％ | 99.45％ | 100.22％ |
| Embodiment 1 | 91.02％ | 96.34％ | 99.94％ | 99.99％ |
| Embodiment 2 | 91.47％ | 94.73％ | 97.22％ | 99.37％ |
| Embodiment 3 | 89.06％ | 94.89％ | 98.10％ | 99.22％ |
Experimental result according to table 2, table 3 can be found out, the dissolution of Eliquis tablet prepared by the present invention in pHl.2 hydrochloric acid and water and commercially available do not have significant difference.This shows that tablet of the present invention stripping while possessing larger hardness is rapid.
Claims (6)
1. a preparation method for Eliquis tablet, is characterized in that: the steps include:
(1) carry out wet granulation, obtained soft material 20 mesh sieves after Eliquis, excipient, disintegrating agent, surfactant and lubricant being mixed, granulate, gained granule drying, granulate, the dry granule between rear collection 20 order-80 order;
(2) by after the granule that makes and mix lubricant 30min, tabletting, tablet hardness is 50-60N.
2. the preparation method of Eliquis tablet according to claim 1, is characterized in that: described excipient is optionally from the following combination of one or more: starch, Lactis Anhydrous, Icing Sugar, mannitol, dextrin, cyclodextrin, microcrystalline Cellulose and sucrose.
3. the preparation method of Eliquis tablet according to claim 1, is characterized in that: described disintegrating agent is optionally from the following combination of one or more: carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, crosslinked carboxymethyl fecula sodium, pregelatinized Starch and low-substituted hydroxypropyl cellulose.
4. the preparation method of Eliquis tablet according to claim 1, is characterized in that: described lubricant is selected for a post and is selected from the following combination of one or more: magnesium stearate, Pulvis Talci and micropowder silica gel.
5. the preparation method of Eliquis tablet according to claim 1, is characterized in that: described surfactant is optionally from the following combination of one or more: sodium lauryl sulphate, dodecyl sodium sulfate, Polyethylene Glycol.
6. the preparation method of Eliquis tablet according to claim 1, is characterized in that: the weight ratio of described Eliquis, excipient, disintegrating agent, surfactant and lubricant is: 5-20:0.5-2.5:0.1-0.3:0.1-2.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410773124.3A CN104490834A (en) | 2014-12-13 | 2014-12-13 | Method for preparing apixaban tablets |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410773124.3A CN104490834A (en) | 2014-12-13 | 2014-12-13 | Method for preparing apixaban tablets |
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| Publication Number | Publication Date |
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| CN104490834A true CN104490834A (en) | 2015-04-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201410773124.3A Pending CN104490834A (en) | 2014-12-13 | 2014-12-13 | Method for preparing apixaban tablets |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3195860A1 (en) * | 2016-01-22 | 2017-07-26 | STADA Arzneimittel AG | Method for producing an apixaban granulate |
| EP3243505A1 (en) * | 2016-05-13 | 2017-11-15 | Zaklady Farmaceutyczne Polpharma SA | A pharmaceutical composition comprising amorphous apixaban |
| CN107898824A (en) * | 2017-12-28 | 2018-04-13 | 广东伊茗药业有限公司 | A kind of Eliquis tablet |
| US10537524B2 (en) | 2016-01-12 | 2020-01-21 | North & South Brother Pharmacy Investment Company Limited | Apixaban solid composition and preparation method thereof |
| CN110772490A (en) * | 2019-10-31 | 2020-02-11 | 宁波高新区美诺华医药创新研究院有限公司 | Preparation method of apixaban tablets |
| CN111000820A (en) * | 2020-01-09 | 2020-04-14 | 新发药业有限公司 | Apixaban tablet |
-
2014
- 2014-12-13 CN CN201410773124.3A patent/CN104490834A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10537524B2 (en) | 2016-01-12 | 2020-01-21 | North & South Brother Pharmacy Investment Company Limited | Apixaban solid composition and preparation method thereof |
| EP3195860A1 (en) * | 2016-01-22 | 2017-07-26 | STADA Arzneimittel AG | Method for producing an apixaban granulate |
| WO2017125535A1 (en) * | 2016-01-22 | 2017-07-27 | Stada Arzneimittel Ag | Method for producing an apixaban granulate |
| EP3243505A1 (en) * | 2016-05-13 | 2017-11-15 | Zaklady Farmaceutyczne Polpharma SA | A pharmaceutical composition comprising amorphous apixaban |
| CN107898824A (en) * | 2017-12-28 | 2018-04-13 | 广东伊茗药业有限公司 | A kind of Eliquis tablet |
| CN110772490A (en) * | 2019-10-31 | 2020-02-11 | 宁波高新区美诺华医药创新研究院有限公司 | Preparation method of apixaban tablets |
| CN111000820A (en) * | 2020-01-09 | 2020-04-14 | 新发药业有限公司 | Apixaban tablet |
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Application publication date: 20150408 |