CN101690719A - Bisulfate clopidogrel solid preparation, particles and preparation method thereof - Google Patents
Bisulfate clopidogrel solid preparation, particles and preparation method thereof Download PDFInfo
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- CN101690719A CN101690719A CN200710129305A CN200710129305A CN101690719A CN 101690719 A CN101690719 A CN 101690719A CN 200710129305 A CN200710129305 A CN 200710129305A CN 200710129305 A CN200710129305 A CN 200710129305A CN 101690719 A CN101690719 A CN 101690719A
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Abstract
The invention relates to a bisulfate clopidogrel solid preparation, particles and a preparation method thereof. Particles contained by the solid preparation are solid mixture formed from bisulfate clopidogrel, cellulose excipients and molten adhesive with the melting point between 50 and 86 DEG, and an additionally added excipient of the particles contains weak alkaline lubricants and crosslinked polyvinylpyrrolidone. The solid preparation and the particles thereof are prepared by a melting-granulating method. The solid preparation has the advantages of solving sticking-picking problems existing in the preparation process, effectively reducing the degradation of clopidogrel during storage, reducing the incidence of transforming clopidogrel dextroisomer into clopidogrel levisomer and increasing the stability and security of the solid preparation.
Description
Technical field
The present invention relates to solid preparation, its granule of a kind of medicine and preparation method thereof, especially clopidogrel bisulfate solid preparation, its granule and prepare this solid preparation and particulate method thereof by melt granulation.
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 acid usually with its sulphate form administration.Its structure is as follows:
The bisulfate clopidogrel oral tablet is degraded to clopidogrel acid: WO2005048992 easily and points out the clopidogrel wet degraded of chance easily in depositing process; Point out among the WO2005070464 that bisulfate clopidogrel and magnesium stearate, polyvinylpyrrolidone or colloid coexistence are easy to degrade.Therefore, in order to improve its stability and to improve bioavailability, for many years, research worker is devoted to the transformation to clopidogrel bisulfate solid preparation.In the clopidogrel hydrogen sulfate tablet, the dextroisomer of clopidogrel can be converted into clopidogrel laevoisomer---the SR25989 of more amount.Point out among the patent US4847265 that SR25989 does not have anti-platelet activity, and toleration in vivo is poor; People such as Reist point out that in zoopery, the SR25989 of higher dosage can cause animal convulsions (Drug Metabolism and Disposition (2000), 28 (12): 1405-1410).All the time do not solve the optimal content of levorotatory in the tablet for a long time.
Among the CN0318076 (WO9729753) the resinousness material is mixed with clopidogrel, formation has the polymer resin preparation of blood coagulation resisting function, thereby solves its not moisture resistance defective, but the cost height of resin material can cause the increase of medicine cost.
The preparation that clopidogrel and wax material and aluminium silicate are mixed and made into is disclosed among the WO2002024167.WO2005048992 passes through to adopt hydrophobic auxiliary (as: hydrogenated vegetable oil), and obtains granule coating with the polymeric coatings material in conjunction with dry granulation, obtains the damp stable formulation of a kind of chance.
EP1310245 is open to be that lubricant solves the unstability that magnesium stearate produces with zinc stearate place of magnesium stearate magnesium, points out also in this patent that microcrystalline Cellulose is that filler can cause that the dissolution of bisulfate clopidogrel descends, and is not suitable for selecting for use; Then adopt stearic acid to substitute magnesium stearate among the US5520928; WO0001364 uses Polyethylene Glycol (PEG) place of magnesium stearate magnesium; Add benzoic acid, tartaric acid or fumaric acid and antioxidant and magnesium stearate among the US4591592 and use simultaneously, effectively improve stability of formulation, wherein the consumption of magnesium stearate is 0.008 times of active component.WO2005070464 discloses with castor oil hydrogenated and sodium carboxymethyl cellulose and has share the unstability that solves preparation.But find in the practice when replacing magnesium stearate, sticking takes place in the preparation process easily, influence the quality of solid preparation with other lubricants.
Improve the disintegration time of clopidogrel among the JP3397385 by the adding sucrose fatty acid ester.Then disclose sucrose fatty acid ester among the JP7089875 and had the effect that improves solid preparation prolongation disintegration, and pointed out that sucrose fatty acid ester can be applied to prepare the preparation of clopidogrel, also can be applied to melt granulation.In the embodiment 5 of this patent, operating weight is polyethylene glycol 6000 and crystalline cellulose adsorption activity medicine under molten condition of 0.23 times of active medicine, and granulate back and sucrose fatty acid ester and weight are that the fixed oil (can substitute with magnesium stearate) of 0.04 times of active medicine is mixed with tablet.Use lactose and pregelatinized Starch as filler in the prescription.But saccharide or starch based adjuvant are unstable under strong acidic condition, thereby make acidic drug that the medicine color change take place in depositing process, cause content to descend.
Summary of the invention
The purpose of this invention is to provide a kind of bisulfate clopidogrel solid preparation, solved clopidogrel bisulfate solid preparation and deposited unstability in the process, improved safety and effectiveness that medicine uses; Also solve the sticking problem in the clopidogrel tablet formulation process simultaneously, improved the quality of medicine.
The granule of bisulfate clopidogrel solid preparation of the present invention is the solid mixture that the binding agent of bisulfate clopidogrel and cellulose family adjuvant and fused fusing point 50-86 ℃ forms; Add adjuvant and contain alkalescence lubricant and crospolyvinylpyrrolidone; Described solid preparation comprises tablet, capsule or granule.
Solid mixture of the present invention is even or uneven, and the mixture under the cooling molten condition obtains solid mixture.
Cellulose family adjuvant of the present invention mainly plays filler in solid preparation, preferably but added cellulose family adjuvant, filler or the disintegrating agent of disintegrating agent effect unessential the time.The cellulose family adjuvant is common pharmaceutic adjuvant, for example: methylcellulose, ethyl cellulose, micropowder cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, microcrystalline Cellulose or low-substituted hydroxypropyl cellulose etc.More preferably microcrystalline Cellulose and low-substituted hydroxypropyl cellulose; Wherein, microcrystalline Cellulose is a filler, and low-substituted hydroxypropyl cellulose is a disintegrating agent.
The preferable amount of cellulose family adjuvant of the present invention is 0.79-3.43 a times of bisulfate clopidogrel quality.More preferably consumption is: as the consumption of the cellulose excipient of filler be the bisulfate clopidogrel quality 0.48-1.98 doubly, as the consumption of the cellulose excipient of other effects be the bisulfate clopidogrel quality 0.31-1.59 doubly.
The cellulose family adjuvant that the present invention uses has good stability to acidic drug, and especially microcrystalline Cellulose and low-substituted hydroxypropyl cellulose can prevent the bisulfate clopidogrel degraded of becoming sour.
Fusing point 50-86 of the present invention ℃ binding agent is to be solid state when lower temperature (below 45 ℃), at higher temperature (50 ℃ to 95 ℃ time) is the adjuvant of liquid condition, comprise Polyethylene Glycol, Brazil wax, castor oil hydrogenated, castor wax, hydrogenated soya phosphatide, spermaceti, Lac sodium alginate or agar, preferred Polyethylene Glycol.Consumption is 0.42-1.73 a times of bisulfate clopidogrel quality.
Alkalescence lubricant of the present invention is the higher fatty acid salt of alkali metal or alkaline-earth metal, and the higher fatty acid salt of alkali metal or alkaline-earth metal helps the tablet molding as lubricant.Preferred magnesium stearate.The consumption of alkalescence lubricant is 0.08-0.34 a times of bisulfate clopidogrel quality.
The preferable amount of crospolyvinylpyrrolidone of the present invention is 0.14-0.59 a times of bisulfate clopidogrel quality.
Clopidogrel bisulfate solid of the present invention is particulate to add granule and can also contain polyol surfactant and make tablet, and the surfactant of described polyalcohols comprises: solid type surfactants such as sorbitol ester, sucrose fatty acid ester or glyceryl alcohol derivant.The preferably sucrose fatty acid ester.The preferable amount of the surfactant of polyalcohols of the present invention is 0.02-0.08 a times of bisulfate clopidogrel.
In experimentation, find, when with the higher fatty acid salt series lubricant agent of other non-alkali metal or alkaline-earth metal, or when the consumption of magnesium stearate low excessively, when being less than 0.08 times of bisulfate clopidogrel quality, sticking takes place in the preparation process easily, and rate is low in flakes, increases production cost; When the magnesium stearate consumption is excessive, cause sliver easily, influence the quality of the pharmaceutical preparations equally.When the consumption of magnesium stearate is 0.08-0.34 times of bisulfate clopidogrel quality, can solve the sticking problem in the preparation process effectively, but, under this consumption, magnesium stearate easily and bisulfate clopidogrel react and cause degrading in the tablet storing process.
Therefore, another object of the present invention provides a kind of preparation method of clopidogrel bisulfate solid preparation, this method has not only effectively solved the clopidogrel degraded that the use because of magnesium stearate and polyvidone causes, also reduce the incidence rate that clopidogrel is converted into its levorotatory, effectively controlled the content of levorotatory.
The particulate preparation method of clopidogrel bisulfate solid of the present invention may further comprise the steps:
1) be that 50-86 ℃ binding agent mixes with bisulfate clopidogrel and cellulose family adjuvant and fusing point;
2) mixture heated of step 1) gained to 50-90 ℃ to there not being powder, cooling is granulated;
3) with step 2) granule of gained and alkalescence lubricant and crospolyvinylpyrrolidone mixed granule.
The cellulose family adjuvant mainly plays filler in the said method, preferably but added the cellulose family adjuvant of disintegrating agent effect unessential the time.The cellulose family adjuvant is common pharmaceutic adjuvant, for example: methylcellulose, ethyl cellulose, micropowder cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, microcrystalline Cellulose or low-substituted hydroxypropyl cellulose etc.Preferably microcrystalline cellulose and low-substituted hydroxypropyl cellulose.Wherein, microcrystalline Cellulose is a filler, and low-substituted hydroxypropyl cellulose is a disintegrating agent.Described fusing point 50-86 ℃ binding agent can be Polyethylene Glycol, Brazil wax, castor oil hydrogenated, castor wax, hydrogenated soya phosphatide, spermaceti, Lac sodium alginate or agar; Preferred Polyethylene Glycol.Described alkalescence lubricant is the higher fatty acid salt of alkali metal or alkaline-earth metal; Preferred magnesium stearate.
Bisulfate clopidogrel, cellulose family adjuvant and fusing point are that 50-86 ℃ binding agent can be positioned in V-Mixer or the ball-type pulverizer and mixed 30 minutes in the said method step 1), can mix with principal agent and other adjuvant material at normal temperatures, mix with principal agent and other adjuvants again after also can being heated to fusion.
What said method step 2) adopt is melt granulation process, utilizes binding agent to be solid state when lower temperature (below 45 ℃), is the character of liquid condition at higher temperature (50 ℃ to 95 ℃ time), puts coldly by heating, and material is made granule.Its method be mixture heated that step 1) is obtained to 50-90 ℃, make binding agent become molten condition, in jacketed pan or fluid bed or pulverizer, be heated to material and be to place after moist softening shape does not have powder and be cooled to below 45 ℃.Through the granulation of sieving of 24 mesh sieves, obtain granule by the binding agent parcel.
In the said method step 3) with 2) granule through the binding agent parcel that obtains mixes with alkalescence lubricant and crospolyvinylpyrrolidone, avoid contacting of crospolyvinylpyrrolidone and bisulfate clopidogrel effectively, improved the stability of solid preparation; When selecting magnesium stearate for use, even increase the consumption of magnesium stearate, the degraded that also can not produce clopidogrel.
The solid particle that said method makes can be made corresponding solid preparation through method commonly used, as tablet, capsule or granule.
The present invention also further provides a kind of preparation method of tablet of bisulfate clopidogrel, and this method is a tabletting behind the solid particle that will make through the particulate preparation method of above-mentioned clopidogrel bisulfate solid and the polyol surfactant mix homogeneously.The surfactant of described polyalcohols comprises: sorbitol ester, sucrose fatty acid ester and glyceryl alcohol derivant etc.The preferably sucrose fatty acid ester.
The preparation method that is clopidogrel hydrogen sulfate tablet of the present invention can be:
1) bisulfate clopidogrel and microcrystalline Cellulose, low-substituted hydroxypropyl cellulose and Polyethylene Glycol is mixed;
2) mixture heated of step 1) gained to 50-90 ℃ to there not being powder, cooling is granulated;
3) with step 2) granule of gained and magnesium stearate, crospolyvinylpyrrolidone and sucrose fatty acid ester mixed solid particle, tabletting.
It is unexpected that the clopidogrel hydrogen sulfate tablet of finding that prescription of the present invention adopts melt granulation to make show that in stability test the content of clopidogrel laevoisomer does not wherein almost obviously increase, further improve the stability of clopidogrel hydrogen sulfate tablet, improved clinical safety.And when adopting melt granulation,, can not cause that also the dissolution of clopidogrel hydrogen sulfate tablet descends even use a large amount of microcrystalline Cellulose as filler, guaranteed that clopidogrel has good bioavailability when using.
The clopidogrel hydrogen sulfate tablet that prescription of the present invention adopts melt granulation to make shows that in stability test free acid content does not wherein obviously increase.
The present invention has not only effectively solved clopidogrel and has deposited becoming sour and unstability that the existence of magnesium stearate causes in the process, better controlled the content of levorotatory; Improved the sticking problem in the tablet formulation process; And the melt granulation The Application of Technology has also been avoided the decline of the tablet dissolution that the filler microcrystalline Cellulose causes; Almost do not have the saccharide adjuvant in the preparation, be suitable for diabetics and take.
Specific embodiment
1, the unit sheet heavily is 0.08g, the tablet of clopidogrel content 25mg/ sheet
● prescription
| Form | Content (g) |
| Bisulfate clopidogrel | ??32.6 |
| Microcrystalline Cellulose | ??15.8 |
| Low-substituted hydroxypropyl cellulose | ??10.0 |
| Polyethylene glycol 6000 | ??13.7 |
| Crospolyvinylpyrrolidone | ??4.7 |
| Magnesium stearate | ??2.66 |
| Sucrose fatty acid ester | ??0.67 |
● preparation technology
1) 13.7g polyethylene glycol 6000 and 32.6g bisulfate clopidogrel, 15.8g microcrystalline Cellulose, 10.0g low-substituted hydroxypropyl cellulose being placed the ball-type pulverizer be heated to 50 degree mixed 30 minutes between 90 degree;
2) keep the crusher cavity temperature, making mixed material be moist softening shape does not have till the Powdered existence, and soft ring material is taken out, put cold, with 24 mesh sieves sieve granule
3) granule of gained and 4.7g crospolyvinylpyrrolidone, 2.66g magnesium stearate, 0.67g sucrose fatty acid ester mix homogeneously tabletting.
2, the heavy 0.23g of unit sheet, the tablet of clopidogrel content 25mg/ sheet
● prescription
| Form | Content (g) |
| Bisulfate clopidogrel | ??32.6 |
| Microcrystalline Cellulose | ??60.0 |
| Low-substituted hydroxypropyl cellulose | ??51.95 |
| Polyethylene glycol 6000 | ??50.0 |
| Crospolyvinylpyrrolidone | ??19.27 |
| Magnesium stearate | ??8.91 |
| Sucrose fatty acid ester | ??2.75 |
● preparation technology
1) the 50.0g polyethylene glycol 6000 was mixed in V-Mixer 30 minutes with 32.6g principal agent, 60.0g microcrystalline Cellulose, 51.95g low-substituted hydroxypropyl cellulose;
2) mixture is joined in the jacketed pan,, temperature of charge is controlled in 50 degree to 95 degree, material is not when moist softening shape has powder takes out by feeding hot water or oil or other heated liquid, put cold, with the 24 mesh sieves gained granule that sieves;
3) gained granule and 19.27g crospolyvinylpyrrolidone, 8.91g magnesium stearate, 2.75g sucrose fatty acid ester mix homogeneously tabletting.
3, the heavy 0.23g of unit sheet, the tablet of clopidogrel content 25mg/ sheet
● prescription
| Form | Content (g) |
| Bisulfate clopidogrel | ??32.6 |
| Microcrystalline Cellulose | ??64.78 |
| Form | Content (g) |
| Low-substituted hydroxypropyl cellulose | ??41.0 |
| Polyethylene glycol 6000 | ??56.17 |
| Crospolyvinylpyrrolidone | ??19.27 |
| Magnesium stearate | ??10.91 |
| Sucrose fatty acid ester | ??2.75 |
● preparation technology 1
1) place V-Mixer to mix 30 minutes 56.17g polyethylene glycol 6000 and 32.6g bisulfate clopidogrel, 64.78g microcrystalline Cellulose, 41.0g low-substituted hydroxypropyl cellulose;
2) mixture joins in the fluidized bed pelletizer, and temperature of charge control 50 degree to 95 degree, are not when moist softening shape has powder material and take out, and puts coldly, sieves with 24 mesh sieves;
3) gained granule and 19.27g crospolyvinylpyrrolidone, 10.91g magnesium stearate, mix homogeneously tablettings such as 2.75g sucrose fatty acid ester.
● preparation technology 2
1) 32.6g bisulfate clopidogrel, 64.78g microcrystalline Cellulose, 41.0g low-substituted hydroxypropyl cellulose are placed V-Mixer mixed 30 minutes;
2) said mixture is joined in the fluidized bed pelletizer, temperature control 50 degree make material be fluidized state to 95 degree;
3) 56.17g polyethylene glycol 6000 heat fused is become liquid after, spray in the fluid bed, be fully mixed to no powder with mixture, feed the cold wind cooling, take out, sieve with 24 mesh sieves;
4) gained granule and 19.27g crospolyvinylpyrrolidone, 10.91g magnesium stearate, mix homogeneously tablettings such as 2.75g sucrose fatty acid ester.
4, stability test data
Prior art described in the table refers to according to the disclosed Plavix of EP1310245 description
TMThe tablet made of prescription.
1) long-term stable experiment
The tablet of prescription of the present invention and prepared is remarkable to the levorotatory effect of control tablet, and levorotatory increased hardly in storage period (in two years), between 0.22%-0.45%; Reference substance then increases obviously in storage period (in two years), between 0.29%-1.3%.
It is better that the tablet of prescription of the present invention and prepared gets effect to the free acid content of controlling clopidogrel hydrogen sulfate tablet, and free acid increases slower in storage period (in two years), between 0.02%-0.20%; Reference substance then obviously increases in storage period (in two years), between 0.04%-1.2%.
2) accelerated stability test
In the time of 6 months, levorotatory reaches 2.5% to reference substance at 40 ℃ ± 2 ℃ relative humidity 75% ± 5% accelerated stability tests, and the tablet of formulation and technology of the present invention preparation deposits that levorotatory then only reaches 0.63% in the process.
The other products of contrast is at 60 ℃ ± 2 ℃ relative humidity 75% ± 5% accelerated stability tests in the time of 6 months, and free acid reaches 2.1%, and the individual slices mottle phenomenon that has been corroded; The tablet of formulation and technology of the present invention preparation deposits that free acid then only reaches 0.43% in the process, and does not have the mottle phenomenon.
Claims (10)
1. bisulfate clopidogrel solid preparation, the granule that it is characterized in that described solid preparation are bisulfate clopidogrel and cellulose family adjuvant with fused fusing point is that 50-86 ℃ binding agent mixes the solid mixture that forms; The particulate adjuvant that adds contains alkalescence lubricant and crospolyvinylpyrrolidone; Described solid preparation comprises tablet, capsule or granule.
2. bisulfate clopidogrel solid preparation as claimed in claim 1 is characterized in that described binding agent is: Polyethylene Glycol Brazil wax, castor oil hydrogenated, castor wax, hydrogenated soya phosphatide, spermaceti, Lac sodium alginate or agar; Described alkalescence lubricant is the higher fatty acid salt of alkali metal or alkaline-earth metal.
3. bisulfate clopidogrel solid preparation as claimed in claim 1 or 2, the consumption that it is characterized in that described alkalescence lubricant are 0.08-0.34 times of bisulfate clopidogrel quality.
4. bisulfate clopidogrel solid preparation as claimed in claim 1 is characterized in that described cellulose family adjuvant is microcrystalline Cellulose and low-substituted hydroxypropyl cellulose.
5. bisulfate clopidogrel solid preparation as claimed in claim 1 or 2 is characterized in that described binding agent is a Polyethylene Glycol; Described alkalescence lubricant is a magnesium stearate.
6. bisulfate clopidogrel solid preparation as claimed in claim 1 is characterized in that described particulate adding also contain polyol surfactant in the adjuvant.
7. as claim 1 or 2 or 4 or 6 described bisulfate clopidogrel solid preparation, it is characterized in that adopting the ad hoc approach preparation, described ad hoc approach comprises following steps:
1) be that 50-86 ℃ binding agent mixes with bisulfate clopidogrel and cellulose family adjuvant and fusing point;
2) mixture heated of step 1) gained to 50-90 ℃ to there not being powder, cooling is granulated;
3) with step 2) granule of gained and alkalescence lubricant and crospolyvinylpyrrolidone mixed granule;
4) make solid preparation.
8. particulate preparation method of clopidogrel bisulfate solid is characterized in that may further comprise the steps:
1) be that 50-86 ℃ binding agent mixes with bisulfate clopidogrel and cellulose family adjuvant and fusing point;
2) mixture heated of step 1) gained to 50-90 ℃ to there not being powder, cooling is granulated;
3) with step 2) granule of gained and alkalescence lubricant and crospolyvinylpyrrolidone mixed granule.
9. the preparation method of a clopidogrel hydrogen sulfate tablet, it is characterized in that: the granule that will make by the method for claim 8 mixes with solid polyalcohol class surfactant, and tabletting makes tablet.
10. the preparation method of clopidogrel hydrogen sulfate tablet as claimed in claim 9 is characterized in that may further comprise the steps:
1) bisulfate clopidogrel is mixed with microcrystalline Cellulose, low-substituted hydroxypropyl cellulose and Polyethylene Glycol;
2) mixture heated of step 1) gained to 50-90 ℃ to there not being powder, cooling is granulated;
3) with step 2) granule of gained and magnesium stearate, crospolyvinylpyrrolidone and sucrose fatty acid ester mixed solid particle, tabletting.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN200710129305A CN101690719A (en) | 2007-07-01 | 2007-07-01 | Bisulfate clopidogrel solid preparation, particles and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710129305A CN101690719A (en) | 2007-07-01 | 2007-07-01 | Bisulfate clopidogrel solid preparation, particles and preparation method thereof |
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|---|---|
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| CN200710129305A Pending CN101690719A (en) | 2007-07-01 | 2007-07-01 | Bisulfate clopidogrel solid preparation, particles and preparation method thereof |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101590023B (en) * | 2008-05-30 | 2012-12-26 | 浙江京新药业股份有限公司 | Clopidogrel hydrogen sulfate tablet and preparation method thereof |
| CN103181885A (en) * | 2011-12-30 | 2013-07-03 | 北京韩美药品有限公司 | Clopidogrel solid preparation and preparation method thereof |
| CN104586803A (en) * | 2015-02-12 | 2015-05-06 | 浙江华海药业股份有限公司 | Preparation method of empagliflozin microcrystalline cellulose composition |
| CN104688694A (en) * | 2013-12-04 | 2015-06-10 | 长春海悦药业有限公司 | Pharmaceutical composition containing clopidogrel hydrogen sulfate |
| CN105380916A (en) * | 2015-12-18 | 2016-03-09 | 北京华禧联合科技发展有限公司 | Tablets containing clopidogrel hydrogen sulfate and preparation method thereof |
| CN105616407A (en) * | 2015-12-04 | 2016-06-01 | 深圳信立泰药业股份有限公司 | Clopidogrel hydrogen sulfate solid preparation and preparation method thereof |
| CN107213131A (en) * | 2015-09-08 | 2017-09-29 | 深圳信立泰药业股份有限公司 | Packaging technique for treating angiocardiopathy solid pharmaceutical preparation |
| CN108186604A (en) * | 2018-03-28 | 2018-06-22 | 北京睿悦生物医药科技有限公司 | A kind of bisulfate clopidogrel particle and preparation method thereof |
| CN113057944A (en) * | 2019-12-13 | 2021-07-02 | 海南华益泰康药业有限公司 | Preparation method of tablets with improved performance |
| CN114732788A (en) * | 2022-04-14 | 2022-07-12 | 浙江高跖医药科技股份有限公司 | Clopidogrel hydrogen sulfate solid preparation and preparation process thereof |
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2007
- 2007-07-01 CN CN200710129305A patent/CN101690719A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101590023B (en) * | 2008-05-30 | 2012-12-26 | 浙江京新药业股份有限公司 | Clopidogrel hydrogen sulfate tablet and preparation method thereof |
| CN103181885A (en) * | 2011-12-30 | 2013-07-03 | 北京韩美药品有限公司 | Clopidogrel solid preparation and preparation method 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 |
| CN104586803A (en) * | 2015-02-12 | 2015-05-06 | 浙江华海药业股份有限公司 | Preparation method of empagliflozin microcrystalline cellulose composition |
| CN107213131A (en) * | 2015-09-08 | 2017-09-29 | 深圳信立泰药业股份有限公司 | Packaging technique for treating angiocardiopathy solid pharmaceutical preparation |
| WO2016161991A3 (en) * | 2015-12-04 | 2016-12-01 | 深圳信立泰药业股份有限公司 | Clopidogrel bisulphate solid preparation and preparation method therefor |
| CN105616407B (en) * | 2015-12-04 | 2016-12-28 | 深圳信立泰药业股份有限公司 | A kind of clopidogrel bisulfate solid preparation and preparation method thereof |
| CN105616407A (en) * | 2015-12-04 | 2016-06-01 | 深圳信立泰药业股份有限公司 | Clopidogrel hydrogen sulfate solid preparation and preparation method thereof |
| CN105380916A (en) * | 2015-12-18 | 2016-03-09 | 北京华禧联合科技发展有限公司 | Tablets containing clopidogrel hydrogen sulfate and preparation method thereof |
| CN108186604A (en) * | 2018-03-28 | 2018-06-22 | 北京睿悦生物医药科技有限公司 | A kind of bisulfate clopidogrel particle and preparation method thereof |
| CN113057944A (en) * | 2019-12-13 | 2021-07-02 | 海南华益泰康药业有限公司 | Preparation method of tablets with improved performance |
| CN113057944B (en) * | 2019-12-13 | 2022-09-16 | 华益泰康药业股份有限公司 | Preparation method of tablets with improved performance |
| CN114732788A (en) * | 2022-04-14 | 2022-07-12 | 浙江高跖医药科技股份有限公司 | Clopidogrel hydrogen sulfate solid preparation and preparation process thereof |
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