CN103830199A - Medicine preparation containing apixaban and preparation method of medicine preparation - Google Patents
Medicine preparation containing apixaban and preparation method of medicine preparation Download PDFInfo
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- CN103830199A CN103830199A CN201410110926.6A CN201410110926A CN103830199A CN 103830199 A CN103830199 A CN 103830199A CN 201410110926 A CN201410110926 A CN 201410110926A CN 103830199 A CN103830199 A CN 103830199A
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Abstract
The invention discloses a medicine preparation containing apixaban and a preparation method of the medicine preparation, which belong to the technical field of pharmaceutical chemicals. The medicine preparation is prepared from apixaban crystal form R, a water soluble carrier material, a filling agent, a disintegrating agent, a lubricant and a surfactant, wherein the X-powder diffraction pattern of the apixaban crystal form R is shown in the attached drawings in the specification, and compared with an imported product (Eliquis), the medicine preparation is good in dissolution rate and stability. Besides, the invention further provides a method for preparing the medicine preparation. The medicine preparation is simple in preparation process and is particularly applicable to industrial production, the production time is shortened, and the energy consumption and cost are reduced.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to a kind of pharmaceutical formulation containing Eliquis novel crystal forms and preparation method thereof.
Background technology
Eliquis is the direct Xa factor inhibitor of a kind of new oral, chemical formula is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidine-1-yl) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide.Molecular formula is C
25h
25n
5o
4, molecular weight is 459.50.Structural formula is as follows:
Activate the critical role of factor Xa (its main practical function is to produce thrombin by the restricted proteolysis of thrombinogen) in connection endogenous and exogenous activation mechanism in the last co-route of blood coagulation.The generation of thrombin (the final serine protease in the path that is produced fibrin clot by its precursor) is by forming thrombinogen multienzyme complex (factor Xa, labile factor, Ca
2+and phospholipid) be amplified.Because a factor Xa molecule can produce 138 thrombin Inhibitory molecules as calculated, factor Xa may be more effective than the inactivation of thrombin in interruption blood coagulation system.Therefore, coagulation factor xa inhibitors is the compound that a class is effectively treated thromboembolism disease.
Eliquis (apixaban) is the anticoagulant of the common research and development of Bristol Myers Squibb and Pfizer, directly act on factor Xa, be used for the treatment of and comprise deep venous thrombosis (deep venous thrombosis, DVT) and pulmonary infarction (pulmonary embolism, PE) in interior phlebothrombosis disease.In May, 2011, European Union ratifies the direct inhibitor Eliquis of oral Xa factor (trade name Eliquis) listing, for the adult patients of select a time hip joint or replacement knee in arthroplasty, to prevent venous thrombosis (venous thrombembolic events, VTE).
Eliquis is water insoluble, has the shortcoming that dissolution velocity is slow, dissolution in vitro is low, bioavailability is low, and the absorption of medicine is had a certain impact.So it is extremely urgent to seek to improve the method for Eliquis dissolution.
It is the crystal formation of N-1 or H2-2 that patent CN102770126A provides active substance in pharmaceutical composition, and it comprises and has the D that is equal to or less than approximately 89 μ m
90crystalline Eliquis granule and medicinal diluent or carrier, the most preferably D of (measuring through laser scattering method)
90be less than 25 μ m.And the granularity specifying in application and claim refers to and uses the definite granularity of laser scattering technology, adopts the preparation of dry granulation technique.
The problems such as this invention increases stripping by reducing raw material granularity, with the preparation of dry granulation technique, exists length consuming time, energy consumption consumption large in suitability for industrialized production, and production efficiency is low, and product yield is lower.
Patent CN 102908324 A, for solving the problems of the technologies described above, are prepared into solid dispersion by Eliquis, then with the microcrystalline Cellulose of recipe quantity; Polyvinylpolypyrrolidone; Micropowder silica gel mix homogeneously direct compression.Prepare solid dispersion as follows: polyethylene glycol 6000 is heated to 60 DEG C of meltings, and adding Eliquis vigorous stirring is 10000～20000r/min; To the rapid cooling 0 DEG C of curing 2h under the condition of-20 DEG C of the fused mass after stirring; 80 mesh sieves 20 DEG C of drying under reduced pressure 4h are pulverized and crossed to solidfied material, obtains Eliquis solid dispersion.
Although this invention has solved the stripping problem of Eliquis in theory, but its water-solubility carrier surfactant polyethylene 6000 of 10-20 part, in preparation process, need that heating, vigorous stirring, sub-cooled are solidified, room temperature drying under reduced pressure complex steps, and be difficult to operation, be not easy to realize a large amount of production; Main is when patient takes medicine, also to have taken a large amount of polyethylene glycol 6000s, brings larger side effect and untoward reaction to patient.
Summary of the invention
For the problem existing in above two patents, the present invention aims to provide a kind of pharmaceutical preparation containing Eliquis crystal formation.
For realizing above-mentioned technical purpose, the technical solution used in the present invention is as follows:
Containing a pharmaceutical formulation for Eliquis, comprise Eliquis crystal formation R, water-solubility carrier material, filler, disintegrating agent, surfactant and lubricant; Its weight portion is respectively: 1～10 part of Eliquis, and water-solubility carrier material is 5～90 parts, and filler is 5～90 parts, and disintegrating agent is 0.2～4 part, and surfactant is 0.2～3 part, lubricant is 0.1～1 part; The X-powder diagram of wherein said Eliquis crystal formation R is as shown in Figure of description 1.
Preferably, the angle of diffraction of the X-powder diffraction of described Eliquis crystal formation R (2 θ ± 0.2 °) is 5.926,6.997, and 10.958,11.903,12.743,13.499,15.026,15.600,16.127,17.458,19.029,21.412,22.639,24.351,25.900,26.590,27.111,28.708,30.024,30.991,36.615, there is characteristic peak at 38.807,41.633,42.705 places, the collection of illustrative plates that wherein X-powder diagram obtains with Cu-K alpha ray.
Preferably, water-solubility carrier material is selected from one or more of lactose complex, mannitol complex, starch milk saccharide complex, lactose, mannitol, pregelatinized Starch.
Preferably, described filler is selected from one or more in lactose, sucrose, microcrystalline Cellulose, calcium carbonate, pregelatinized Starch.
Preferably, described disintegrating agent is selected one or more in cross-linked carboxymethyl cellulose sodium, carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose.
Preferably, described surfactant is selected from one or more in sodium lauryl sulphate, Polyethylene Glycol, tween, glyceric acid triacetate, poloxamer, lactic acid fatty glyceride.
Preferably, described lubricant is selected from one or more in silicon dioxide, magnesium stearate, Oleum Ricini, calcium hydrogen phosphate, castor oil hydrogenated, silicic acid, Glyceryl Behenate, glyceryl monostearate.
The present invention also provides a kind of method of preparing containing the pharmaceutical formulation of Eliquis, comprises the steps:
(1) pretreatment: by the pretreatment of sieving of Eliquis and other adjuvant thereof;
(2) mix: after Eliquis after treatment is mixed by equivalent incremental manner with water-solubility carrier material, then add suitable filler, disintegrating agent, lubricant and surfactant, after full and uniform mixing, obtain the compositions containing Eliquis;
(3) tabletting: the compositions that obtains in step (2) is carried out to tabletting, and with suitable thin-film material bag sealing coat, obtain product.
Above-mentioned preparation method is through screening, by Eliquis active substance and water-solubility carrier material mixing, add filler, disintegrating agent, lubricant and surfactant, having saved needs active substance micronization, rolls the operation of granulation in patent CN102770126A, easy preparation process, has shortened the production time, has reduced energy consumption and cost, be more suitable for suitability for industrialized production, the sample of preparation has better dissolution and stability.
Brief description of the drawings
Fig. 1 is the X-powder diagram of Eliquis crystal R of the present invention, and wherein the longitudinal axis represents peak intensity, and transverse axis represents the angle of diffraction (2 θ);
Fig. 2 is 2.5mg import drugs and the some embodiment stripping curves of this preparation comparison diagram;
Fig. 3 is 5mg Comparative formulation and the some embodiment stripping curves of this preparation comparison diagram.
Detailed description of the invention
In order to make those skilled in the art, the present invention may be better understood, below in conjunction with drawings and Examples, technical solution of the present invention further illustrated.These embodiment are only for the present invention is described, instead of limitation of the scope of the invention.
A kind of pharmaceutical formulation, comprises Eliquis, water-solubility carrier material, filler, disintegrating agent, surfactant and lubricant; Its weight portion is respectively: 1～10 part of Eliquis, and water-solubility carrier material is 5～90 parts, and filler is 5～90 parts, and disintegrating agent is 0.2～4 part, and surfactant is 0.2～3 part, lubricant is 0.1～1 part.
Wherein, as shown in Figure 1, it at least has the angle of diffraction of being included in (2 θ ± 0.2 °) 5.926 to the X-powder diffraction spectrum of the crystal formation of Eliquis, 6.997,10.958,11.903,12.743,13.499,15.026,15.600,16.127,17.458,19.029,21.412,22.639,24.351,25.900,26.590,27.111,28.708,30.024,30.991,36.615,38.807,41.633, the characteristic peak at 42.705 places, the collection of illustrative plates that described X-powder diagram obtains with Cu-K alpha ray.In the X-ray powder diffraction characteristic peak that 2 θ angles represent, the reasonable measurement error scope that " ± 0.2 ° " representation feature peak position allows.
Described water-solubility carrier material is selected from one or more of lactose complex, mannitol complex, starch milk saccharide complex, lactose, mannitol, pregelatinized Starch, preferably lactose complex, mannitol complex; Described filler is selected from one or more in lactose, sucrose, microcrystalline Cellulose, calcium carbonate, pregelatinized Starch, preferably microcrystalline cellulose; Described disintegrating agent is selected one or more in cross-linked carboxymethyl cellulose sodium, carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, preferably cross-linked carboxymethyl cellulose sodium; Described surfactant is selected from sodium lauryl sulphate, Polyethylene Glycol, tween, one or more in glyceric acid triacetate, poloxamer, lactic acid fatty glyceride, preferably sodium dodecyl sulfate; Described lubricant is selected from one or more in silicon dioxide, magnesium stearate, Oleum Ricini, calcium hydrogen phosphate, castor oil hydrogenated, silicic acid, Glyceryl Behenate, glyceryl monostearate, preferably magnesium stearate.
embodiment 1 ~ 5:
Following embodiment provides proportioning and the preparation method of 10000 Eliquis sheets of preparation (specification is: 2.5mg/ sheet):
Preparation process is as follows:
1) pretreatment: respectively by above-described embodiment by the pretreatment of sieving of Eliquis and other adjuvant thereof;
2) mix: pretreated Eliquis is mixed by equivalent incremental manner with water-solubility carrier material, and then add filler, disintegrating agent, lubricant and the surfactant of proportioning in embodiment, after full and uniform mixing, obtain the compositions containing Eliquis
3) tabletting: with theoretical sheet weight sheet, and with suitable thin-film material bag sealing coat, obtain pharmaceutical formulation sample.
embodiment 6 ~ 9:
Following embodiment provides the proportioning of the different embodiment of preparation 10000 Eliquis sheets (specification is: 2.5mg/ sheet) equally, and its preparation method is identical with embodiment 1 ~ 5.
Following embodiment provides the proportioning of the different embodiment of preparation 10000 Eliquis sheets (specification is: 5mg/ sheet), and its preparation method is identical with embodiment 1 ~ 5.
Following embodiment provides the proportioning of 10000 Eliquis sheets of preparation (specification is: 5mg/ sheet), and its preparation method is identical with embodiment 1～5.
The preparation of preparing with reference to above each embodiment, yield all reaches more than 95%.
test case:
With reference to dissolution method of testing and the sample time of FDA, use USP device 2 (oar) method, with the 0.05M sodium phosphate (pH 6.8) that contains 0.05%SDS solution, as dissolution medium, (SDS (surfactant) is acting as wetting aid to promote hydrophobicity Eliquis to be completed by the stripping of tablet in the dissolution medium of method in the back, instead of the dissolubility of increase Eliquis), in 900mL dissolution medium, carry out stripping test at 37 ° of C in the rotary speed of 75rpm.Test starts to remove sample and analyze Eliquis by HPLC at 280nm after 10,20,30,45,60 minutes.Stripping (external) test is using as quality control tools, and is more preferably used in (in body) performance biology of the described tablet of prediction, wherein established in body-external relation (IVIVR).
Test stripping data are included in the present invention's record and unless otherwise mentioned, the result of report is the meansigma methods from six tablets.
The data that record compare with import drugs (Ai Le is appropriate) and Comparative formulation (CN102770126A) respectively, and result is as following table:
Import drugs information
| Trade name | Specification | Lot number | Date of manufacture | Effect duration | Manufacturer |
| Ai Le appropriate (eliquis) | 2.5mg | 2M52276 | 201301 | 2015.12 | Bristol Myers Squibb |
Stripping curve contrast
remarks:comparative formulation is to manufacture experimently with reference to patent of invention CN102770126A table 3 embodiment.
related substance test:
As depicted in figs. 1 and 2, from testing result, (patent CN102770126A) is similar with import drugs (Ai Le is appropriate), Comparative formulation for the pharmaceutical formulation stripping curve of preparing by the present invention, and related substance is stable under influence factor's condition, and is better than import sample, Comparative formulation.
Known from the preparation process of above-described embodiment, the product yield of preparing by the preparation method of this patent is high, and preparation time is short, favorable reproducibility, and drug regimen of the present invention has good stripping and stability, can be used for suitability for industrialized production.
Claims (8)
1. containing a pharmaceutical formulation for Eliquis, it is characterized in that, comprise Eliquis crystal formation R, water-solubility carrier material, filler, disintegrating agent, surfactant and lubricant; Its weight portion is respectively: 1～10 part of Eliquis, and water-solubility carrier material is 5～90 parts, and filler is 5～90 parts, and disintegrating agent is 0.2～4 part, and surfactant is 0.2～3 part, lubricant is 0.1～1 part; The X-powder diagram of wherein said Eliquis crystal formation R is as shown in Figure of description 1.
2. pharmaceutical formulation according to claim 1, described it is characterized in that, described Eliquis crystal formation R uses Cu-K α radiation, the X-ray powder diffraction representing with 2 θ angles is at 5.926 ± 0.2 °, 6.997 ± 0.2 °, 10.958 ± 0.2 °, 11.903 ± 0.2 °, 12.743 ± 0.2 °, 13.499 ± 0.2 °, 15.026 ± 0.2 °, 15.600 ± 0.2 °, 16.127 ± 0.2 °, 17.458 ± 0.2 °, 19.029 ± 0.2 °, 21.412 ± 0.2 °, 22.639 ± 0.2 °, 24.351 ± 0.2 °, 25.900 ± 0.2 °, 26.590 ± 0.2 °, 27.111 ± 0.2 °, 28.708 ± 0.2 °, 30.024 ± 0.2 °, 30.991 ± 0.2 °, 36.615 ± 0.2 °, 38.807 ± 0.2 °, 41.633 ± 0.2 °, locate characteristic peak for 42.705 ± 0.2 °.
3. pharmaceutical formulation according to claim 1, is characterized in that, described water-solubility carrier material is selected from one or more of lactose complex, mannitol complex, starch milk saccharide complex, lactose, mannitol, pregelatinized Starch.
4. pharmaceutical formulation according to claim 1, is characterized in that, described filler is selected from one or more in lactose, sucrose, microcrystalline Cellulose, calcium carbonate, pregelatinized Starch.
5. pharmaceutical formulation according to claim 1, is characterized in that, described disintegrating agent is selected one or more in cross-linked carboxymethyl cellulose sodium, carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose.
6. pharmaceutical formulation according to claim 1, is characterized in that, described surfactant is selected from one or more in sodium lauryl sulphate, Polyethylene Glycol, tween, glyceric acid triacetate, poloxamer, lactic acid fatty glyceride.
7. pharmaceutical formulation according to claim 1, is characterized in that, described lubricant is selected from one or more in silicon dioxide, magnesium stearate, Oleum Ricini, calcium hydrogen phosphate, castor oil hydrogenated, silicic acid, Glyceryl Behenate, glyceryl monostearate.
8. a method of preparing pharmaceutical formulation described in claim 1 to 7 any one, is characterized in that, comprises the steps:
(1) pretreatment: by the pretreatment of sieving of Eliquis and other adjuvant thereof;
(2) mix: after Eliquis after treatment is mixed by equivalent incremental manner with water-solubility carrier material, then add suitable filler, disintegrating agent, lubricant and surfactant, after full and uniform mixing, obtain the compositions containing Eliquis;
(3) tabletting: to the compositions tabletting that obtains in step (2), and with suitable thin-film material bag sealing coat, obtain formulation samples.
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| CN201410110926.6A CN103830199A (en) | 2014-03-24 | 2014-03-24 | Medicine preparation containing apixaban and preparation method of medicine preparation |
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| CN201410110926.6A CN103830199A (en) | 2014-03-24 | 2014-03-24 | Medicine preparation containing apixaban and preparation method of medicine preparation |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104055743A (en) * | 2014-06-10 | 2014-09-24 | 吉林省博大制药有限责任公司 | Preparation method of oral preparation containing rivaroxaban |
| CN104095823A (en) * | 2014-07-08 | 2014-10-15 | 成都克莱蒙医药科技有限公司 | Method for preparing Apixaban tablets |
| CN104490841A (en) * | 2014-12-19 | 2015-04-08 | 河南润弘制药股份有限公司 | Apixaban tablet and preparation method thereof |
| CN105037349A (en) * | 2015-05-04 | 2015-11-11 | 西安泰科迈医药科技有限公司 | Apixaban in [gamma]-crystal form and preparation method thereof |
| CN106420651A (en) * | 2016-09-28 | 2017-02-22 | 乐普药业股份有限公司 | Method for preparing Apixaban tablet |
| WO2019221488A1 (en) * | 2018-05-14 | 2019-11-21 | Sinil Pharmaceutical Co., Ltd. | Pharmaceutical formulation comprising apixaban and method for preparing the same |
| US10537524B2 (en) | 2016-01-12 | 2020-01-21 | North & South Brother Pharmacy Investment Company Limited | Apixaban solid composition and preparation method thereof |
| CN110934839A (en) * | 2019-12-31 | 2020-03-31 | 常州恒邦药业有限公司 | Apixaban oral tablet and preparation method thereof |
| CN114917196A (en) * | 2022-06-16 | 2022-08-19 | 南京正科医药股份有限公司 | Apixaban tablet and preparation method thereof |
| CN115244046A (en) * | 2021-06-17 | 2022-10-25 | 成都苑东生物制药股份有限公司 | Urea eutectic of Apixaban and preparation method thereof |
| WO2022262244A1 (en) * | 2021-06-17 | 2022-12-22 | 成都苑东生物制药股份有限公司 | Urea co-crystal of apixaban, and preparation method therefor |
| WO2023115593A1 (en) * | 2021-12-26 | 2023-06-29 | 浙江海正药业股份有限公司 | Apixaban tablet and preparation process therefor |
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| CN102770126A (en) * | 2010-02-25 | 2012-11-07 | 百时美施贵宝公司 | Apixaban formulations |
| CN102908324A (en) * | 2012-10-31 | 2013-02-06 | 南京正科制药有限公司 | Apixaban tablet |
| CN103539795A (en) * | 2013-03-18 | 2014-01-29 | 齐鲁制药有限公司 | Apixaban polymorph and preparation method thereof |
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2014
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Patent Citations (3)
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| CN102770126A (en) * | 2010-02-25 | 2012-11-07 | 百时美施贵宝公司 | Apixaban formulations |
| CN102908324A (en) * | 2012-10-31 | 2013-02-06 | 南京正科制药有限公司 | Apixaban tablet |
| CN103539795A (en) * | 2013-03-18 | 2014-01-29 | 齐鲁制药有限公司 | Apixaban polymorph and preparation method thereof |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104055743A (en) * | 2014-06-10 | 2014-09-24 | 吉林省博大制药有限责任公司 | Preparation method of oral preparation containing rivaroxaban |
| CN104095823A (en) * | 2014-07-08 | 2014-10-15 | 成都克莱蒙医药科技有限公司 | Method for preparing Apixaban tablets |
| CN104490841A (en) * | 2014-12-19 | 2015-04-08 | 河南润弘制药股份有限公司 | Apixaban tablet and preparation method thereof |
| CN104490841B (en) * | 2014-12-19 | 2017-06-30 | 河南润弘制药股份有限公司 | A kind of Apixaban tablet and preparation method thereof |
| CN105037349A (en) * | 2015-05-04 | 2015-11-11 | 西安泰科迈医药科技有限公司 | Apixaban in [gamma]-crystal form and preparation method thereof |
| US10537524B2 (en) | 2016-01-12 | 2020-01-21 | North & South Brother Pharmacy Investment Company Limited | Apixaban solid composition and preparation method thereof |
| CN106420651B (en) * | 2016-09-28 | 2019-03-08 | 乐普药业股份有限公司 | A kind of preparation method of Apixaban tablet |
| CN106420651A (en) * | 2016-09-28 | 2017-02-22 | 乐普药业股份有限公司 | Method for preparing Apixaban tablet |
| WO2019221488A1 (en) * | 2018-05-14 | 2019-11-21 | Sinil Pharmaceutical Co., Ltd. | Pharmaceutical formulation comprising apixaban and method for preparing the same |
| CN110934839A (en) * | 2019-12-31 | 2020-03-31 | 常州恒邦药业有限公司 | Apixaban oral tablet and preparation method thereof |
| CN110934839B (en) * | 2019-12-31 | 2022-02-25 | 常州恒邦药业有限公司 | Apixaban oral tablet and preparation method thereof |
| CN115244046A (en) * | 2021-06-17 | 2022-10-25 | 成都苑东生物制药股份有限公司 | Urea eutectic of Apixaban and preparation method thereof |
| WO2022262244A1 (en) * | 2021-06-17 | 2022-12-22 | 成都苑东生物制药股份有限公司 | Urea co-crystal of apixaban, and preparation method therefor |
| WO2023115593A1 (en) * | 2021-12-26 | 2023-06-29 | 浙江海正药业股份有限公司 | Apixaban tablet and preparation process therefor |
| CN114917196A (en) * | 2022-06-16 | 2022-08-19 | 南京正科医药股份有限公司 | Apixaban tablet and preparation method thereof |
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Application publication date: 20140604 |