CN100400035C - Clopidogrel sulfate solid preparation, and its preparing method - Google Patents
Clopidogrel sulfate solid preparation, and its preparing method Download PDFInfo
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- CN100400035C CN100400035C CNB2006100631517A CN200610063151A CN100400035C CN 100400035 C CN100400035 C CN 100400035C CN B2006100631517 A CNB2006100631517 A CN B2006100631517A CN 200610063151 A CN200610063151 A CN 200610063151A CN 100400035 C CN100400035 C CN 100400035C
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Abstract
The present invention relates to a solid preparation of clopidogrel hydrochloride and its preparation method. It is characterized by that in said sold preparation the palmitoleostearin and micropowder silica gel are added, and its preparation method adopts a grinding equivalent progressively-increasing method so as to raise the stability and safety of said solid preparation.
Description
[technical field]
The present invention relates to solid preparation of a kind of medicine and preparation method thereof, especially the solid preparation of clopidogrel sulfate and prepare the method for this solid preparation by grinding the equivalent incremental method.
[background technology]
Clopidogrel is a kind of epigamic anticoagulant, combines with its receptor by the inhibition adenosine phosphate and works.Clopidogrel is a kind of prodrug of non-activity, becomes active metabolite performance drug effect through liver cell pigment P450 metabolic conversion.Patent FR2215948 and FR2530247 disclose clopidogrel and have had significant antiplatelet aggregation and antithrombotic effect.Clopidogrel reaches the curative effect of prevention of stroke and heart attack, and can treat with prevention of arterial atherosis effectively by suppressing the chance that platelet aggregation has reduced obstruction of artery.
Clopidogrel is usually with its sulphate form administration.Its structure is as follows:
There are a lot of defectives in the tablet of existing commercially available clopidogrel sulfate, and for a long time, research mainly concentrates on and solves the problem that clopidogrel is degraded to clopidogrel acid to the clopidogrel sulfate solid preparation, improves its stability.
Reported among the patent EP1310245 that the interaction between clopidogrel and the conventional lubricants magnesium stearate can cause clopidogrel to be degraded to clopidogrel acid.Disclose in this patent and used zinc stearate, stearic acid or sodium stearyl fumarate place of magnesium stearate magnesium to solve the problem that clopidogrel is degraded to clopidogrel acid as lubricant.Dry method or wet granule compression tablet are adopted in the preparation of its tablet.
Patent US5520928 (1996-05-28) discloses with the prescription of stearic acid place of magnesium stearate magnesium as lubricant, and compressing dry granulation is adopted in the preparation of its tablet, solves the problem that clopidogrel is degraded to clopidogrel acid; Patent WO0001364 discloses with the prescription of Polyethylene Glycol place of magnesium stearate magnesium as lubricant, and wet granulation is adopted in the preparation of its tablet, solves the problem that clopidogrel is degraded to clopidogrel acid; US4591592 (1986-05-27) has announced that stearic acid, benzoic acid, tartaric acid or fumaric acid are made antioxidant and magnesium stearate together uses the problem that clopidogrel is degraded to clopidogrel acid that solves, and wet granulation is adopted in the preparation of its tablet.
WO2005/070464 discloses by using hydrogenated vegetable oil and carboxymethyl starch sodium to share as lubricant and has overcome the problem that clopidogrel in the tablet is degraded to clopidogrel acid.Direct pressed powder is adopted in the preparation of disclosed tablet in this patent.
But, find that in practice in the clopidogrel sulfate tablet, the dextroisomer of clopidogrel can be converted into the clopidogrel laevoisomer of more amount.The laevoisomer of prior art report clopidogrel does not almost have the effect of anti-platelet aggregation, and the zoopery result shows that the toxicity of the laevoisomer of clopidogrel is significantly higher than the dextroisomer of clopidogrel.Clopidogrel is mainly used in heart and the intravascular stent operation clinically, this operation risk height, even the content of clopidogrel levorotatory has increase slightly, success rate for operation also has a significant impact, the dextroisomer of clopidogrel very easily is converted into the clopidogrel laevoisomer in the existing tablet, increases toxicity and operation risk.Therefore the prescription to this medicine is very high clinically, and the content of clopidogrel levorotatory has become an important parameter of quality of production control.And the optimal content of clopidogrel levorotatory is not resolved always.
[summary of the invention]
The solid preparation that the purpose of this invention is to provide a kind of clopidogrel sulfate, solved the problem that clopidogrel dextroisomer in the clopidogrel sulfate solid preparation is converted into the clopidogrel laevoisomer, improve the safety and the stability of clopidogrel solid preparation, make its more effective performance therapeutical effect.
Adopt following technical scheme among the present invention: with clopidogrel sulfate as principal agent, with Lactis Anhydrous, pregelatinized Starch, polyglycereol stearate, carboxymethyl starch sodium, micropowder silica gel, glyceryl palmitostearate etc. as adjuvant, compressing dry granulation.
Among the present invention, find to use glyceryl palmitostearate and micropowder silica gel can well suppress that the clopidogrel dextroisomer is converted into the clopidogrel laevoisomer in the clopidogrel solid preparation.
Its content of above-mentioned clopidogrel sulfate is 14.3～40.0% of solid preparation weight.
Above-mentioned glyceryl palmitostearate is a lubricant, and its content is 0.8～1.2% of solid preparation weight, and the content of micropowder silica gel is 3.3～4.8% of solid preparation weight.
In the above-mentioned adjuvant, the content of Lactis Anhydrous is 19.7～28.5% of solid preparation weight; The content of pregelatinized Starch is 12.5～18.0% of solid preparation weight; The content of polyglycereol stearate is 17.1～24.7% of solid preparation weight; Carboxymethyl starch sodium is as disintegrating agent, and its content is 5.9～8.5% of solid preparation weight.
Above-mentioned solid preparation comprises: tablet, capsule, granule etc.
The invention provides a kind of preparation method of clopidogrel sulfate solid preparation, this method is by grinding the preparation of equivalent incremental method.
Said method is:
1) the polyglycereol stearate is mixed evenly tabletting of back with clopidogrel sulfate, gained tablet grinding and sieving is granulated.
2) will operate 1) tabletting again behind gained granule and Lactis Anhydrous, pregelatinized Starch, the micropowder silica gel mix homogeneously, gained tablet grinding and sieving is granulated.
3) will operate 2) gained granule and carboxymethyl starch sodium and glyceryl palmitostearate mix homogeneously be after proper method is made corresponding solid preparation.
Aforesaid operations 1) in, in order can fully to mix, with above-mentioned material in the ball-type pulverizer, mix pulverize 30 minutes after, will pulverize cavity and interior material thereof again and be warming up to 45 degree Celsius and spend to 55 and ground again 30 minutes.Described suppress tablet, hardness is 2.0kg/cm
2To 2.8kg/cm
2The granule of described pulverizing is to pulverize by Fast granulate machine 1.0mm screen cloth granulate, and sieve is got the above fine grained of 60 orders.
Aforesaid operations 2) suppress to such an extent that tablet hardness is 2.0kg/cm in
2To 2.8kg/cm
2The granule of described pulverizing is to pulverize by Fast granulate machine 1.0mm screen cloth granulate, and sieve is got 40 order to 60 purpose granules.
Aforesaid operations 3) method suitable in is made solid preparation, comprises that direct compacting obtains tablet, mix homogeneously dress glue capsule etc.
The unexpected discovery, the clopidogrel sulfate tablet that grinding equivalent incremental method of the present invention makes shows that in stability test the content of clopidogrel laevoisomer does not wherein almost obviously increase, further improve the stability of clopidogrel hydrogen sulfate salt tablets agent, improved clinical safety simultaneously.
Below through detecting explanation beneficial effect of the present invention.
One, detects index and method
With ULTRONES-OVM is filler, and 25 ℃ of column temperatures, detecting wavelength is under the 220nm condition, is mobile phase with the potassium dihydrogen phosphate (25: 75) of acetonitrile-0.01mol/L, quickens to detect with long-term stable experiment the content of left-handed clopidogrel.National Specification, the content of clopidogrel levorotatory must not surpass 1%.
Two, the testing result of left-handed clopidogrel in embodiment sample and the prior art reference substance
1, long-term stable experiment
2, accelerated stability test
[specific embodiment]
1, the unit sheet heavily is 0.175g, the tablet formulation of clopidogrel content 25mg/ sheet and grinding equivalent incremental method preparation technology
| Form | Content (g) |
| Clopidogrel hydrogenesulphate | 32.6 |
| Lactis Anhydrous | 64.78 |
| Pregelatinized Starch | 41.0 |
| The polyglycereol stearate | 56.17 |
| Carboxymethyl starch sodium | 19.27 |
| Micropowder silica gel | 10.91 |
| Glyceryl palmitostearate | 2.75 |
1), with clopidogrel hydrogenesulphate 32.6g and polyglycereol stearate 56.17g mix homogeneously, tabletting is pulverized the back with the gained tablet and is crossed 60 mesh sieves.
2) will operate 1) granule and Lactis Anhydrous 64.78g, pregelatinized Starch 41.0g and the abundant mixed pressuring plate of micropowder silica gel 10.91g that obtain, the gained tablet is pulverized the back cross the 40-60 mesh sieve.
3), will operate 2) tabletting behind gained material and carboxymethyl starch sodium 19.27g and the glyceryl palmitostearate 2.75g mix homogeneously.
2, the unit sheet heavily is 0.150g, the tablet formulation of clopidogrel content 25 mg/ sheets and grinding equivalent incremental method preparation technology
| Form | Content (g) |
| Clopidogrel hydrogenesulphate | 32.6 |
| Lactis Anhydrous | 55.2 |
| Pregelatinized Starch | 34.9 |
| The polyglycereol stearate | 47.8 |
| Carboxymethyl starch sodium | 13.9 |
| Micropowder silica gel | 8.3 |
| Glyceryl palmitostearate | 2.24 |
1), with clopidogrel hydrogenesulphate 32.6g and polyglycereol stearate 47.8g mix homogeneously, tabletting is pulverized the back with the gained tablet and is crossed 60 mesh sieves.
2) will operate 1) granule and Lactis Anhydrous 55.2g, pregelatinized Starch 34.9g and the abundant mixed pressuring plate of micropowder silica gel 8.3g that obtain, the gained tablet is pulverized the back cross the 40-60 mesh sieve.
3), will operate 2) tabletting behind gained material and carboxymethyl starch sodium 13.9g and the glyceryl palmitostearate 2.24g mix homogeneously.
3, the unit sheet heavily is 0.063g, the tablet formulation of clopidogrel content 25mg/ sheet and grinding equivalent incremental method preparation technology
| Form | Content (g) |
| Clopidogrel hydrogenesulphate | 32.6 |
| Lactis Anhydrous | 15.8 |
| Pregelatinized Starch | 10.0 |
| The polyglycereol stearate | 13.7 |
| Carboxymethyl starch sodium | 4.7 |
| Micropowder silica gel | 2.66 |
| Glyceryl palmitostearate | 0.67 |
1), with clopidogrel hydrogenesulphate 32.6g and polyglycereol stearate 56.17g mix homogeneously, tabletting is pulverized the back with the gained tablet and is crossed 60 mesh sieves.
2) will operate 1) granule and Lactis Anhydrous 64.78g, pregelatinized Starch 41.0g and the abundant mixed pressuring plate of micropowder silica gel 10.91g that obtain, the gained tablet is pulverized the back cross the 40-60 mesh sieve.
3), will operate 2) tabletting behind gained material and carboxymethyl starch sodium 19.27g and the glyceryl palmitostearate 2.75g mix homogeneously.
Claims (2)
1. the solid preparation of a clopidogrel sulfate, it is characterized in that with content being that the clopidogrel sulfate of 14.3-40.0% of solid preparation weight is as principal agent, allocate content into and be 19.7～28.5% Lactis Anhydrous of solid preparation weight, content is 12.5～18.0% pregelatinized Starch of solid preparation weight, content is 17.1～24.7% polyglycereol stearate of solid preparation weight, content is 5.9～8.5% carboxymethyl starch sodium of solid preparation weight, content is that 0.8～1.2% glyceryl palmitostearate of 3.3～4.8% micropowder silica gel of solid preparation weight and solid preparation weight is an adjuvant, adopts and grinds the preparation of equivalent incremental method; Described solid preparation is a tablet, and described grinding equivalent incremental method comprises the steps:
1) the polyglycereol stearate is mixed evenly tabletting of back with clopidogrel sulfate, gained tablet grinding and sieving is granulated;
2) will operate 1) tabletting again behind gained granule and Lactis Anhydrous, pregelatinized Starch, the micropowder silica gel mix homogeneously, gained tablet grinding and sieving is granulated;
3) will operate 2) behind gained granule and carboxymethyl starch sodium and the glyceryl palmitostearate mix homogeneously directly compacting obtain tablet.
2. the preparation technology of clopidogrel sulfate solid preparation as claimed in claim 1 is characterized by:
1) the polyglycereol stearate is mixed evenly tabletting of back with clopidogrel sulfate, gained tablet grinding and sieving is granulated;
2) will operate 1) tabletting again behind gained granule and Lactis Anhydrous, pregelatinized Starch, the micropowder silica gel mix homogeneously, gained tablet grinding and sieving is granulated;
3) will operate 2) behind gained granule and carboxymethyl starch sodium and the glyceryl palmitostearate mix homogeneously directly compacting obtain tablet.
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| CNB2006100631517A CN100400035C (en) | 2006-10-18 | 2006-10-18 | Clopidogrel sulfate solid preparation, and its preparing method |
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| CNB2006100631517A CN100400035C (en) | 2006-10-18 | 2006-10-18 | Clopidogrel sulfate solid preparation, and its preparing method |
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| CN100400035C true CN100400035C (en) | 2008-07-09 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9144550B2 (en) | 2010-02-05 | 2015-09-29 | Shanghai Anbison Laboratory Co., Ltd. | Preparation method of the solid formulation of Clopidogrel bisulfate |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101926756B (en) * | 2010-08-12 | 2012-01-18 | 北京赛科药业有限责任公司 | Solid preparation of clopidogrel or pharmaceutically acceptable salt thereof |
| CN102199161B (en) * | 2011-03-30 | 2013-07-03 | 天津红日药业股份有限公司 | Benzene sulfonic acid clopidogrel with crystal form I, preparation method thereof and application thereof |
| CN102285996A (en) * | 2011-03-30 | 2011-12-21 | 天津红日药业股份有限公司 | Benzenesulfonic acid clopidogrel crystal form II, preparation method and application thereof |
| 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 |
| CN106265564B (en) * | 2016-08-18 | 2019-05-10 | 深圳汉草药研纳米生物科技有限公司 | A kind of clopidogrel tablet and preparation method thereof that phase transition is stable |
| CN106265563B (en) * | 2016-08-18 | 2019-04-09 | 上海耀大生物科技有限公司 | A kind of clopidogrel tablet and preparation method thereof with targeted delivery function |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1310245A1 (en) * | 2001-11-09 | 2003-05-14 | SHERMAN, Bernard Charles | Clopidogrel bisulfate tablet formulation |
| WO2004072084A1 (en) * | 2003-02-13 | 2004-08-26 | Helm Ag | Salt of benzosulfonic acid containing clopidogrel and use thereof for the production of pharmaceutical formulations |
| WO2005070464A2 (en) * | 2004-01-21 | 2005-08-04 | Biofarma Ilac Sanayi Ve Ticaret A.S. | A tablet formulation of clopidogrel bisulphate |
| DE202005013839U1 (en) * | 2005-09-01 | 2005-10-27 | Helm Ag | Tablet containing monobasic acid salt of clopidogrel, useful for preventing thromboembolic events, e.g. stroke or myocardial infarction, contains no ionic or basic auxiliaries or polyethylene glycol |
-
2006
- 2006-10-18 CN CNB2006100631517A patent/CN100400035C/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1310245A1 (en) * | 2001-11-09 | 2003-05-14 | SHERMAN, Bernard Charles | Clopidogrel bisulfate tablet formulation |
| WO2004072084A1 (en) * | 2003-02-13 | 2004-08-26 | Helm Ag | Salt of benzosulfonic acid containing clopidogrel and use thereof for the production of pharmaceutical formulations |
| WO2005070464A2 (en) * | 2004-01-21 | 2005-08-04 | Biofarma Ilac Sanayi Ve Ticaret A.S. | A tablet formulation of clopidogrel bisulphate |
| DE202005013839U1 (en) * | 2005-09-01 | 2005-10-27 | Helm Ag | Tablet containing monobasic acid salt of clopidogrel, useful for preventing thromboembolic events, e.g. stroke or myocardial infarction, contains no ionic or basic auxiliaries or polyethylene glycol |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9144550B2 (en) | 2010-02-05 | 2015-09-29 | Shanghai Anbison Laboratory Co., Ltd. | Preparation method of the solid formulation of Clopidogrel bisulfate |
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| CN1935119A (en) | 2007-03-28 |
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Address after: Area A, 4th Floor, Digital Peninsula, No. 2, Hongliu Road, Fubao Community, Fubao Street, Futian District, Shenzhen, Guangdong, 518017 Patentee after: SHENZHEN SALUBRIS PHARMACEUTICALS Co.,Ltd. Address before: 518040 37 / F, main building, chegongmiao Lvjing Plaza, 6009 Shennan Avenue, Shenzhen, Guangdong Patentee before: SHENZHEN SALUBRIS PHARMACEUTICALS Co.,Ltd. |