CN101590023A - Clopidogrel hydrogen sulfate tablet and preparation method thereof - Google Patents
Clopidogrel hydrogen sulfate tablet and preparation method thereof Download PDFInfo
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- CN101590023A CN101590023A CNA2008100619548A CN200810061954A CN101590023A CN 101590023 A CN101590023 A CN 101590023A CN A2008100619548 A CNA2008100619548 A CN A2008100619548A CN 200810061954 A CN200810061954 A CN 200810061954A CN 101590023 A CN101590023 A CN 101590023A
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- clopidogrel
- hydrogen sulfate
- vitamin
- bha
- sulfate tablet
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Abstract
The invention discloses a kind of clopidogrel hydrogen sulfate tablet and preparation method thereof.Clopidogrel in the existing clopidogrel hydrogen sulfate tablet more easily is converted into clopidogrel acid, and the clopidogrel dextroisomer more easily is converted into laevoisomer.The present invention is a principal agent with the bisulfate clopidogrel, is equipped with filler, disintegrating agent, fluidizer and lubricant, it is characterized in that it has added one or both mixture in vitamin C, the BHA, and its percentage by weight is 0.05～5%.Vitamin C of the present invention is or/and BHA energy good restraining clopidogrel is converted into clopidogrel acid and the clopidogrel dextroisomer is converted into laevoisomer, improve the stability of clopidogrel hydrogen sulfate tablet, improved clinical application safety and effectiveness.
Description
Technical field
The present invention relates to field of medicaments, specifically a kind of clopidogrel hydrogen sulfate tablet and preparation method thereof.
Background technology
Clopidogrel is a kind of anticoagulant, suppresses adenosine diphosphate (ADP) (ADP) and its combining and the activation of the glycoprotein GPIIb/IIIa complex that the ADP of secondary mediates of platelet receptor by selectivity, thereby reaches the effect of anticoagulant.Clopidogrel is a kind of prodrug, forms 2-oxygen base-clopidogrel by Oxidation, and then forms active metabolite (a kind of thiol derivative) through hydrolysis; Oxidation is mainly regulated by Cytochrome P450 isozyme 2B6 and 3A4, and 1A1,1A2 and 2C19 also have certain regulating action.This active metabolite of in-vitro separation shows that it can irreversiblely rapidly combine with platelet receptor, thus anticoagulant.Clopidogrel reaches the curative effect of prevention of stroke and heart attack by suppressing the chance that platelet aggregation has reduced obstruction of artery, and effectively smelting treatment and prevention of arterial are atherosis.But there is following problem in present clopidogrel hydrogen sulfate tablet: the clopidogrel in the clopidogrel hydrogen sulfate tablet more easily is converted into clopidogrel acid, and the clopidogrel dextroisomer more easily is converted into laevoisomer.Existing report shows that the laevoisomer of clopidogrel does not almost have the effect of anti-platelet aggregation, and the toxicity of the laevoisomer of animal test results demonstration clopidogrel is apparently higher than the dextroisomer of clopidogrel.
Summary of the invention
Technical problem to be solved by this invention provides a kind of clopidogrel hydrogen sulfate tablet of new prescription, it is converted into clopidogrel acid in order to the clopidogrel in effective inhibition clopidogrel hydrogen sulfate tablet and the clopidogrel dextroisomer is converted into laevoisomer, thereby improves bisulfate clopidogrel sheet clinical application safety and effectiveness.
For achieving the above object, the present invention is by the following technical solutions: clopidogrel hydrogen sulfate tablet, with the bisulfate clopidogrel is principal agent, be equipped with filler, disintegrating agent, fluidizer and lubricant, it is characterized in that it has added one or both mixture in vitamin C, the BHA, its percentage by weight is 0.05～5%, is preferably 0.1～3%.The present invention adds vitamin C or/and behind the BHA, the clopidogrel hydrogen sulfate tablet that makes shows that in stability study the content of clopidogrel acid in the product and clopidogrel laevoisomer does not almost significantly increase, obviously improve the stability of clopidogrel hydrogen sulfate tablet, improved clinical application safety and effectiveness.And do not add vitamin C or/and the prepared clopidogrel hydrogen sulfate tablet of BHA shows that in stability study the clopidogrel acid in the product and the content of clopidogrel laevoisomer have tangible increase.
In the above-mentioned clopidogrel hydrogen sulfate tablet, principal agent is a bisulfate clopidogrel, and its percentage by weight is 10～50%, is preferably 12～40%; Filler is selected one or more the mixture in lactose, mannitol, microcrystalline Cellulose, the pregelatinized Starch for use, and its percentage by weight is 20～80%, is preferably 30～70%; Disintegrating agent is selected one or more the mixture in carboxymethylstach sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, the low-substituted hydroxypropyl cellulose for use, and its percentage by weight is 2～20%, is preferably 5～15%; Fluidizer is selected micropowder silica gel for use, and its percentage by weight is 0.5～5%, is preferably 1.0～4%; Lubricant is selected one or more the mixture in Macrogol 4000, polyethylene glycol 6000, Pulvis Talci, hydrogenated vegetable oil, the castor oil hydrogenated for use, and its percentage by weight is 0.5～15%, is preferably 1.0～10%.
The present invention also provides a kind of preparation method of above-mentioned clopidogrel hydrogen sulfate tablet, and its preparation method is:
1) with vitamin C or/and BHA with after filler mixes, mixes the back dry granulation with principal agent and other adjuvants; Or with vitamin C or/and after BHA is dissolved in certain density alcoholic solution or water,, mix the back dry granulation again with principal agent and other adjuvants with adjuvant mixture complete wetting after drying; Or with vitamin C or/and BHA with after adjuvant and principal agent mix, is that wetting agent is granulated drying with certain density alcoholic solution or water; Or with vitamin C or/and BHA be dissolved in certain density alcoholic solution or the water, with the mixture wet granulation of principal agent and adjuvant, drying, granule; 2) will operate 1) granule of gained with add the adjuvant mix homogeneously after, tabletting; 3) bag film-coat; 4) packing.
Vitamin C of the present invention is or/and BHA energy good restraining clopidogrel is converted into clopidogrel acid and the clopidogrel dextroisomer is converted into laevoisomer, improve the stability of clopidogrel hydrogen sulfate tablet, improved clinical application safety and effectiveness.
The present invention is further illustrated below in conjunction with the specific embodiment.
The specific embodiment
Embodiment 1 prescription: (making 1000)
| Principal agent | 32.6g |
| Mannitol | 45g |
| Microcrystalline Cellulose | 50g |
| Macrogol 4000 | 10g |
| Cross-linking sodium carboxymethyl cellulose | 15g |
| Vitamin C | 0.2g |
| Micropowder silica gel | 6g |
| Pulvis Talci | 6g |
| The stomach dissolution type coating powder | 5.0g |
Method for making: with vitamin C by equivalent progressively increase method with mix the back after microcrystalline Cellulose mixes again with principal agent, mannitol, Macrogol 4000, partial cross-linked sodium carboxymethyl cellulose, part micropowder silica gel, part Pulvis Talci with dry granulation legal system granule, the gained granule again with cross-linking sodium carboxymethyl cellulose, micropowder silica gel, the Pulvis Talci mix homogeneously of remainder, tabletting, the bag film-coat, packing.
Embodiment 2 prescriptions: (making 1000)
| Principal agent | 32.6g |
| Lactose | 80g |
| Microcrystalline Cellulose | 60g |
| Pregelatinized Starch | 30 |
| Polyethylene glycol 6000 | 10 |
| Carboxymethylstach sodium | 20g |
| Vitamin C | 10g |
| Micropowder silica gel | 6g |
| Castor oil hydrogenated | 4g |
| The stomach dissolution type coating powder | 7.6g |
Method for making: with vitamin C by equivalent progressively increase method be that wetting agent is granulated with water with principal agent, lactose, pregelatinized Starch, polyethylene glycol 6000, part carboxymethylstach sodium again after microcrystalline Cellulose mixes, dry, granulate, add remaining carboxymethylstach sodium, micropowder silica gel, Pulvis Talci mix homogeneously, tabletting, the bag film-coat, packing.
Embodiment 3
Prescription: (making 1000)
| Principal agent | 97.9g |
| Mannitol | 85g |
| Microcrystalline Cellulose | 75g |
| Pregelatinized Starch | 55g |
| Polyethylene glycol 6000 | 20g |
| Polyvinylpolypyrrolidone | 20g |
| Vitamin C | 8g |
| Micropowder silica gel | 8g |
| Pulvis Talci | 4g |
| The stomach dissolution type coating powder | 11.2g |
Method for making: vitamin C is dissolved in the quantitative water, adds 95% alcoholic solution and be made into the alcoholic solution that contains alcohol amount 50%, get wetting agent.With mannitol with after microcrystalline Cellulose mixes, with the wetting agent complete wetting, drying, material 1.Get principal agent, material 1, pregelatinized Starch, polyethylene glycol 6000, partial cross-linked polyvidone, part micropowder silica gel, part Pulvis Talci mixing back with dry granulation legal system granule, the gained granule again with polyvinylpolypyrrolidone, micropowder silica gel, the Pulvis Talci mix homogeneously of remainder, tabletting, the bag film-coat.
Embodiment 4
Prescription: (making 1000)
| Principal agent | 97.9g |
| Lactose | 35g |
| Microcrystalline Cellulose | 50g |
| Pregelatinized Starch | 25g |
| Polyethylene glycol 6000 | 10g |
| Carboxymethylstach sodium | 15g |
| Vitamin C | 2g |
| Micropowder silica gel | 8g |
| Pulvis Talci | 8g |
| The stomach dissolution type coating powder | 7.5g |
Method for making: with vitamin C by equivalent progressively increase method with mix with principal agent, lactose, part partially pregelatinized starch, polyethylene glycol 6000, carboxymethylstach sodium, part micropowder silica gel, part Pulvis Talci again after microcrystalline Cellulose mixes the back with, dry granulation, the gained granule again with pregelatinized Starch, carboxymethylstach sodium, micropowder silica gel, the Pulvis Talci mix homogeneously of remainder, tabletting, the bag film-coat, packing.
Embodiment 5
Prescription: (making 1000)
| Principal agent | 97.9g |
| Mannitol | 150g |
| Microcrystalline Cellulose | 100g |
| Pregelatinized Starch | 60g |
| Macrogol 4000 | 15g |
| Carboxymethylstach sodium | 40g |
| BHA | 15g |
| Micropowder silica gel | 15g |
| Pulvis Talci | 10g |
| The stomach dissolution type coating powder | 15.0g |
Method for making: BHA is dissolved in quantitative 95% alcoholic solution, adds gauge water and be made into the alcoholic solution that contains alcohol amount 50%, get wetting agent.After principal agent, mannitol, microcrystalline Cellulose, pregelatinized Starch, Macrogol 4000, the mixing of part carboxymethylstach sodium, to granulate with above-mentioned wetting agent, drying gets granule.The gained granule again with carboxymethylstach sodium, micropowder silica gel, the Pulvis Talci mix homogeneously of remainder, tabletting, bag film-coat, packing.
Below by detecting the beneficial effect that the present invention has is described.
One, detects index and method
1. be filler (Ultron ES-OVM) with ovomucoid bonding spherical silica gel; The detection wavelength is 220nm; With acetonitrile-0.01mol/L potassium dihydrogen phosphate (25: 75) is mobile phase; Quicken to investigate with long-term stable experiment, the content of clopidogrel acid and clopidogrel laevoisomer in the detection bisulfate clopidogrel sheet, with kind USP30 regulation, the content of clopidogrel acid and clopidogrel laevoisomer is respectively 0.2% and 1.0%.
Two, embodiment sample detection result
(1) clopidogrel acid and clopidogrel isomer testing result
(2)
1, accelerated test (40 ± 2 ℃, Rh75 ± 5%)
2, long-time stability are investigated (25 ± 2 ℃, Rh60 ± 5%)
From on can draw, clopidogrel is converted into clopidogrel acid to vitamin C of the present invention and the clopidogrel dextroisomer is converted into laevoisomer or/and BHA can well suppress.
The above only is preferred embodiment of the present invention.Every foundation technical spirit of the present invention all falls within the scope of protection of the present invention any simple modification, equivalent variations and modification that above embodiment did.
Claims (7)
1, clopidogrel hydrogen sulfate tablet, with the bisulfate clopidogrel is principal agent, be equipped with filler, disintegrating agent, fluidizer and lubricant, it is characterized in that it has added one or both mixture in vitamin C, the BHA, its percentage by weight is 0.05～5%.
2, clopidogrel hydrogen sulfate tablet according to claim 1 is characterized in that being vitamin C or/and the percentage by weight of BHA is 0.1～3%.
3, clopidogrel hydrogen sulfate tablet according to claim 1 is characterized in that being that filler selects one or more the mixture in lactose, mannitol, microcrystalline Cellulose, the pregelatinized Starch for use, and its percentage by weight is 20～80%.
4, clopidogrel hydrogen sulfate tablet according to claim 1, it is characterized in that being that disintegrating agent selects one or more the mixture in carboxymethylstach sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, the low-substituted hydroxypropyl cellulose for use, its percentage by weight is 2～20%.
5, clopidogrel hydrogen sulfate tablet according to claim 1 is characterized in that being that fluidizer selects micropowder silica gel for use, and its percentage by weight is 0.5～5%.
6, clopidogrel hydrogen sulfate tablet according to claim 1, it is characterized in that being that lubricant selects one or more the mixture in Macrogol 4000, polyethylene glycol 6000, Pulvis Talci, hydrogenated vegetable oil, the castor oil hydrogenated for use, its percentage by weight is 0.5～15%.
7, according to the preparation method of each described clopidogrel hydrogen sulfate tablet of claim 1-6, its step is as follows:
1) with vitamin C or/and BHA with after filler mixes, mixes the back dry granulation with principal agent and other adjuvants; Or with vitamin C or/and after BHA is dissolved in alcoholic solution or water,, mix the back dry granulation again with principal agent and other adjuvants with adjuvant mixture complete wetting after drying; Or with vitamin C or/and BHA with after adjuvant and principal agent mix, is that wetting agent is granulated drying with alcoholic solution or water; Or with vitamin C or/and BHA be dissolved in alcoholic solution or the water, with the mixture wet granulation of principal agent and adjuvant, drying, granule; 2) with 1) granule of gained with add the adjuvant mix homogeneously after, tabletting; 3) bag film-coat; 4) packing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200810061954 CN101590023B (en) | 2008-05-30 | 2008-05-30 | Clopidogrel hydrogen sulfate tablet and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200810061954 CN101590023B (en) | 2008-05-30 | 2008-05-30 | Clopidogrel hydrogen sulfate tablet and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
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| CN101590023A true CN101590023A (en) | 2009-12-02 |
| CN101590023B CN101590023B (en) | 2012-12-26 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 200810061954 Expired - Fee Related CN101590023B (en) | 2008-05-30 | 2008-05-30 | Clopidogrel hydrogen sulfate tablet and preparation method thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101791309A (en) * | 2010-03-31 | 2010-08-04 | 中国药科大学 | Oral solid preparation containing clopidogrel hydrogen sulfate |
| CN102058550A (en) * | 2010-12-30 | 2011-05-18 | 江苏亚邦强生药业有限公司 | Clopidogrel bisulfate tablet and preparation method thereof |
| CN102247333A (en) * | 2010-05-18 | 2011-11-23 | 山东方明药业股份有限公司 | Clopidogrel hydrogen sulfate tablet and preparation method thereof |
| CN101766573B (en) * | 2010-02-05 | 2013-02-13 | 上海安必生制药技术有限公司 | Preparation process of clopidogrel bisulfate solid preparation |
| CN103284972A (en) * | 2013-06-28 | 2013-09-11 | 门毅 | Prescription of clopidogrel bisulfate tablet and preparation process thereof |
| CN104688694A (en) * | 2013-12-04 | 2015-06-10 | 长春海悦药业有限公司 | Pharmaceutical composition containing clopidogrel hydrogen sulfate |
| CN106137994A (en) * | 2016-08-18 | 2016-11-23 | 成都新柯力化工科技有限公司 | A kind of stable tablet of clopidogrel and preparation method thereof |
| CN108420798A (en) * | 2017-02-15 | 2018-08-21 | 江苏威凯尔医药科技有限公司 | A kind of immediate release drug formulations of anti-coagulants and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101212954A (en) * | 2005-05-10 | 2008-07-02 | 伊兰制药国际有限公司 | Nanoparticulate clopidogrel formulations |
| CN101690719A (en) * | 2007-07-01 | 2010-04-07 | 深圳信立泰药业股份有限公司 | Bisulfate clopidogrel solid preparation, particles and preparation method thereof |
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2008
- 2008-05-30 CN CN 200810061954 patent/CN101590023B/en not_active Expired - Fee Related
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766573B (en) * | 2010-02-05 | 2013-02-13 | 上海安必生制药技术有限公司 | Preparation process of clopidogrel bisulfate solid preparation |
| US9144550B2 (en) | 2010-02-05 | 2015-09-29 | Shanghai Anbison Laboratory Co., Ltd. | Preparation method of the solid formulation of Clopidogrel bisulfate |
| CN101791309B (en) * | 2010-03-31 | 2013-01-23 | 中国药科大学 | Oral solid preparation containing clopidogrel hydrogen sulfate |
| CN101791309A (en) * | 2010-03-31 | 2010-08-04 | 中国药科大学 | Oral solid preparation containing clopidogrel hydrogen sulfate |
| CN102247333A (en) * | 2010-05-18 | 2011-11-23 | 山东方明药业股份有限公司 | Clopidogrel hydrogen sulfate tablet and preparation method thereof |
| CN102058550B (en) * | 2010-12-30 | 2016-04-27 | 江苏亚邦强生药业有限公司 | Clopidogrel bisulfate tablet and preparation method thereof |
| CN102058550A (en) * | 2010-12-30 | 2011-05-18 | 江苏亚邦强生药业有限公司 | Clopidogrel bisulfate tablet and preparation method thereof |
| CN103284972A (en) * | 2013-06-28 | 2013-09-11 | 门毅 | Prescription of clopidogrel bisulfate tablet and preparation process thereof |
| CN104688694A (en) * | 2013-12-04 | 2015-06-10 | 长春海悦药业有限公司 | Pharmaceutical composition containing clopidogrel hydrogen sulfate |
| CN104688694B (en) * | 2013-12-04 | 2018-09-11 | 长春海悦药业股份有限公司 | A kind of pharmaceutical composition containing bisulfate clopidogrel |
| CN106137994A (en) * | 2016-08-18 | 2016-11-23 | 成都新柯力化工科技有限公司 | A kind of stable tablet of clopidogrel and preparation method thereof |
| CN106137994B (en) * | 2016-08-18 | 2018-11-09 | 成都新柯力化工科技有限公司 | A kind of stable tablet of clopidogrel and preparation method thereof |
| CN108420798A (en) * | 2017-02-15 | 2018-08-21 | 江苏威凯尔医药科技有限公司 | A kind of immediate release drug formulations of anti-coagulants and preparation method thereof |
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| CN101590023B (en) | 2012-12-26 |
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