CN108186604A - A kind of bisulfate clopidogrel particle and preparation method thereof - Google Patents
A kind of bisulfate clopidogrel particle and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5063—Compounds of unknown constitution, e.g. material from plants or animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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Abstract
The present invention relates to a kind of bisulfate clopidogrel particle, the bisulfate clopidogrel particle is prepared using fusion method with the method that coating method is combined, and is coated bisulfate clopidogrel with coating material and is obtained.Obtained particle is used to be mixed with other auxiliary materials and carries out tabletting, disclosure satisfy that the requirement of preferable tabletting：The tableting processes are stablized, not sticking, and the tablet quality of acquisition is high, are convenient for amplification production.The invention further relates to the preparation methods of the bisulfate clopidogrel particle.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of bisulfate clopidogrel particle and preparation method thereof.
Background technology
Cardiovascular and cerebrovascular thrombotic diseases are the lethal Important cause of disease of common disease and China in China.China's myocardial infarction
And the average attack rate of cerebral thrombus is more than the people of 50 people/100,000, and at present with people's living habit and the variation of diet, morbidity
Rate is in growth trend year by year.
Bisulfate clopidogrel (Clopidogrel hydrogen sulfate) be it is a kind of have can not retroactive inhibition blood it is small
Plate aggregation Thienopyridines, the mechanism of action be by the way that adenosine diphosphate (ADP) is prevented to be combined with platelet receptor, from
And reduce the hematoblastic quantity of aggegation.Therefore, bisulfate clopidogrel inhibits platelet aggregation clinically for antithrombotic,
Suitable for having the apoplexy broken out in the recent period, myocardial infarction and the patient for making a definite diagnosis peripheral arterial disease, it is athero- which can reduce artery
The incidence of hardening event (such as myocardial infarction, apoplexy and vascular death) is a kind of of great value drug of clinic.At present,
What is clinically used both at home and abroad is typically clopidogrel hydrogen sulfate tablet.
Bisulfate clopidogrel can generate great stickiness, and may send out due to the characteristic of itself during preparation
The transformation of raw crystal form, therefore bibliography and related patents is avoid the problem, it is proposed that different method for preparing tablet thereof, including powder
Last pressed disc method, fusion method granulating tabletting process etc.；In addition because main ingredient, which meets water, becomes glutinous, wet granule compression tablet method is directly eliminated.
Notification number is that the Chinese patent document of CN101766573B discloses a kind of clopidogrel hydrogen sulfate tablet, it contains
Following compositions：Bisulfate clopidogrel as active component, as antiplastering aid/coverture superfine silica gel powder and be selected from down
The carrier of group：Diluent, adhesive, glidant, disintegrant and/or lubricant.This document additionally provides the hydrogen sulfate chlorine
The preparation method of pyrrole Gray's tablet including bisulfate clopidogrel powder and superfine silica gel powder are mixed, forms premixing particle；With
Diluent is mixed, and the alcoholic solution for adding adhesive carries out wet granulation, obtains wet granular；It is dried and whole grain, obtains
Obtain dry particl；It is mixed with glidant, disintegrant and lubricant, then carries out tabletting, obtain clopidogrel hydrogen sulfate tablet；
Optionally it is coated.The method can effectively reduce the bonding situation in punching course, improve final product quality.
Notification number is that the Chinese patent document of CN101791309B discloses a kind of the oral solid of containing clopidogrel hydrogen sulfate
Body preparation, the solid composite of the preparation containing clopidogrel hydrogen sulfate, it include 100 parts by weight bisulfate clopidogrel and
The atoleine of 5-100 parts by weight and the mixture of talcum powder.The composition can realize the industry of clopidogrel bisulfate tablet
Metaplasia is produced.
For powder pressing method, test and find through the present inventor, either using in partial supplementary material plus or auxiliary material it is additional
Or all mixing carries out tabletting, sticking problem can all occur, tabletting cannot be completed well.
For fusion method granulating tabletting process, either using in partial supplementary material plus or auxiliary material it is additional or be all mixed into
Still there is sticking situation in row tabletting, discovery, it is impossible to solve the problems, such as existing sticking, while the product aberration obtained is apparent, tabletting
It is unstable.
Invention content
There is a need in the art for the preparation methods to clopidogrel hydrogen sulfate tablet to make improvements, and is pressed in the prior art with overcoming
The problem of piece sticking so that bisulfate clopidogrel tabletting is stablized, and can obtain the product of high-quality.
Through the present inventor the study found that bisulfate clopidogrel is first made using fusion method with the method that coating method is combined
Into particle, then mixed again with other auxiliary materials and carry out tabletting, disclosure satisfy that the requirement of preferable tabletting：The tableting processes are stablized, no
Sticking, the tablet quality of acquisition is high, is convenient for amplification production.
One aspect of the present invention is related to a kind of bisulfate clopidogrel particle, the bisulfate clopidogrel as a result,
Grain is prepared using fusion method with the method that coating method is combined, and is coated bisulfate clopidogrel with coating material and is obtained.
Further, the coating material is adhesive or lubricant, can be polyethylene glycol, hydrogenation castor specifically
One or more mixtures in sesame oil, glycerin monostearate and Brazil wax.Mentioned component due to its physicochemical property with
And especially with the compatibility of bisulfate clopidogrel and medicine-releasing performance, particularly suitable as sulfuric acid in technical scheme
The coating material of clopidogrel hydrogen particle.
Further, in the bisulfate clopidogrel particle, bisulfate clopidogrel and coating material as main ingredient
Mass ratio be 1：0.10~0.40.The thickness of the mass ratio of coating material and bisulfate clopidogrel needs consideration coating,
The integrality and reliability of coatings, and between anti-sticking punching performance and medicine-releasing performance of the requirement in tablet compression processes
Obtain balance.Preferably, the mass ratio of bisulfate clopidogrel and coating material is 1：0.17~0.38.
Further, the grain size of the bisulfate clopidogrel is less than or equal to 40 mesh.Hydrogen sulfate chlorine pyrrole as main ingredient
The grain size of Gray has larger impact for the stability of tablet press, anti-sticking punching performance and medicine-releasing performance, and needs to consider
With the suitability of selected auxiliary material.Preferably, the grain size of the bisulfate clopidogrel is less than or equal to 60 mesh, for example, 60-
400 mesh；More preferably less than or equal to 80 mesh, for example, 80-320 mesh.
In the technical solution of the present invention, for the crystal form of bisulfate clopidogrel, there is no limit the hydrogen sulfate chlorine pyrrole lattice
Thunder can be I types crystal or II type crystal.
Another aspect of the present invention is related to a kind of preparation method of bisulfate clopidogrel particle, the preparation method packet
Include following steps：
(1) 40 mesh sieve is crossed using as the bisulfate clopidogrel of main ingredient, coating material is crossed into 80 mesh sieve, mixing for standby use；Its
The mass ratio of middle bisulfate clopidogrel and coating material as main ingredient is 1：0.10~0.40；
(2) temperature is increased so that coating material melting, makes the coating material of melting be evenly coated at hydrogen sulfate chlorine pyrrole lattice
Thunder surface；
(3) by the dry materials of acquisition, separation and cure, obtain bisulfate clopidogrel particle.
The step of coating material cladding, dry, separation and curing, can be for example, by shot-blasting machine, air blower, stream
Change the pharmaceutical fields commonly used equipments such as bed to carry out, and required technology is ripe for those skilled in the art such as fluidized drying
Know.
In one embodiment, 60 mesh sieve, further preferred 80 mesh of mistake are crossed using as the bisulfate clopidogrel of main ingredient
Sieve.
Further, the coating material is adhesive or lubricant, can be polyethylene glycol, rilanit special, single hard
One or more mixtures in glycerol and Brazil wax.
On the basis of above-mentioned main ingredient and coating material quality proportioning, in order to ensure the integrality of coatings, uniformity
And reliability, it needs to define the grain size of coating material, so that the grain size of coating material and the grain size of main ingredient match.
Therefore, coating material is preferably sieved with 100 mesh sieve in step (1), more preferable 120 mesh of mistake sieve.
In addition, in above-mentioned coating material into processing temperature when on the basis of component selections, needing further to consider coatings
Degree so that reduce the influence for main ingredient to the greatest extent, and coating material is controlled rapidly and uniformly to wrap up and is attached in granules of main drug.
Therefore, temperature is controlled at 55 DEG C~92 DEG C, preferably 60 DEG C~90 DEG C, more preferably 70 DEG C~88 DEG C in step (2).
For the crystal form of bisulfate clopidogrel, there is no limit the bisulfate clopidogrel can be I types in this method
Crystal or II type crystal.
Another aspect of the invention is related to above-mentioned bisulfate clopidogrel particle and is preparing clopidogrel hydrogen sulfate tablet
In application.The bisulfate clopidogrel particle uses in clopidogrel hydrogen sulfate tablet is prepared, and obtained sulfuric acid
Clopidogrel hydrogen tablet is used for the generation of prevention of arterial atherosis thrombosis event
The application is included tabletting after the bisulfate clopidogrel particle of above-mentioned acquisition and auxiliary materials and mixing.The accessory package
It includes but is not limited to mannitol, microcrystalline cellulose, hydroxypropylcellulose, Lactis Anhydrous, starch, silica, titanium dioxide, talcum
Powder, magnesium stearate etc..
Technical solution of the present invention has the following advantages that：
1st, the present invention just makes main ingredient auxiliary with other by heating coating material, and be coated on the outer surface of granules of main drug
Material isolation is come, and avoid main ingredient is influenced by other ingredients；Main ingredient is made not contact plunger die for tabletting press again simultaneously, avoided again in this way
Glutinous punching.
2nd, technical solution of the present invention operability is strong, and process is reliable and stable, is produced convenient for amplification.
3rd, the accessibility of clinical application can be solved, avoids a large amount of imports of this kind of drug, the economy for mitigating domestic patient is born
Load.
Description of the drawings
Fig. 1 is to be ground using the tablet of the bisulfate clopidogrel particle preparation obtained in embodiment 1 and embodiment 2 with former
Dissolution curve.
Specific embodiment
Following embodiment is used to illustrate technical solution of the present invention, but be not limited to the scope of the present invention.
Embodiment 1
Bisulfate clopidogrel granular recipe：
Bisulfate clopidogrel 97.875mg (75mg, in terms of clopidogrel)
Macrogol 6000 20mg
Preparation method：
1) main ingredient bisulfate clopidogrel is crossed into 80 mesh sieve, Macrogol 6000 is crossed 120 mesh sieve, is uniformly mixed spare；
2) said mixture temperature is risen to 75 DEG C, melt coating material and is evenly coated at bisulfate clopidogrel table
Face；
3) by the dry materials of acquisition, separation and cure, obtain bisulfate clopidogrel particle.
Embodiment 2
Bisulfate clopidogrel granular recipe：
Bisulfate clopidogrel 97.875mg (75mg, in terms of clopidogrel)
Macrogol 6000 30mg
Rilanit special 4mg
Preparation method：
1) main ingredient bisulfate clopidogrel is crossed into 40 mesh sieve, Macrogol 6000 and rilanit special cross 80 mesh sieve, mixing
It is uniformly spare；
2) said mixture temperature is risen to 92 DEG C, melt coating material and is evenly coated at bisulfate clopidogrel table
Face；
3) by the dry materials of acquisition, separation and cure, obtain bisulfate clopidogrel particle.
Embodiment 3
Bisulfate clopidogrel granular recipe：
Bisulfate clopidogrel 97.875mg (75mg, in terms of clopidogrel)
Glycerin monostearate 25mg
Preparation method：
1) main ingredient bisulfate clopidogrel is crossed into 60 mesh sieve, glycerin monostearate sieves with 100 mesh sieve, and is uniformly mixed spare；
2) said mixture temperature is risen to 90 DEG C, melt coating material and is evenly coated at bisulfate clopidogrel table
Face；
3) by the dry materials of acquisition, separation and cure, obtain bisulfate clopidogrel particle.
Embodiment 4
Bisulfate clopidogrel granular recipe：
Bisulfate clopidogrel 97.875mg (75mg, in terms of clopidogrel)
Glycerin monostearate 17mg
Rilanit special 3.3mg
Preparation method：
1) main ingredient bisulfate clopidogrel being sieved with 100 mesh sieve, glycerin monostearate and rilanit special cross 150 mesh sieve,
It is uniformly mixed spare；
2) said mixture temperature is risen to 90 DEG C, melt coating material and is evenly coated at bisulfate clopidogrel table
Face；
3) by the dry materials of acquisition, separation and cure, obtain bisulfate clopidogrel particle.
Embodiment 5
Bisulfate clopidogrel granular recipe：
Bisulfate clopidogrel 97.875mg (75mg, in terms of clopidogrel)
Macrogol 6000 16mg
Rilanit special 4mg
Preparation method：
1) main ingredient bisulfate clopidogrel is crossed into 80 mesh sieve, Macrogol 6000 and rilanit special cross 140 mesh sieve, mixing
It is uniformly spare；
2) said mixture temperature is risen to 68 DEG C, melt coating material and is evenly coated at bisulfate clopidogrel table
Face；
3) by the dry materials of acquisition, separation and cure, obtain bisulfate clopidogrel particle.
Embodiment 6
Bisulfate clopidogrel granular recipe：
Bisulfate clopidogrel 97.875mg (75mg, in terms of clopidogrel)
Macrogol 6000 17mg
Brazil wax 3mg
Preparation method：
1) main ingredient bisulfate clopidogrel is crossed into 40 mesh sieve, Macrogol 6000 and Brazil wax cross 120 mesh sieve, mixing
It is uniformly spare；
2) said mixture temperature is risen to 90 DEG C, melt coating material and is evenly coated at bisulfate clopidogrel table
Face；
3) by the dry materials of acquisition, separation and cure, obtain bisulfate clopidogrel particle.
Embodiment 7
Bisulfate clopidogrel granular recipe：
Bisulfate clopidogrel 97.875mg (75mg, in terms of clopidogrel)
Macrogol 6000 20mg
Brazil wax 3mg
Preparation method：
1) main ingredient bisulfate clopidogrel is crossed into 60 mesh sieve, Macrogol 6000 and Brazil wax cross 120 mesh sieve, mixing
It is uniformly spare；
2) said mixture temperature is risen to 90 DEG C, melt coating material and is evenly coated at bisulfate clopidogrel table
Face；
3) by the dry materials of acquisition, separation and cure, obtain bisulfate clopidogrel particle.
Embodiment 8
Bisulfate clopidogrel granular recipe：
Bisulfate clopidogrel 97.875mg (75mg, in terms of clopidogrel)
Macrogol 6000 20mg
Preparation method：
1) main ingredient bisulfate clopidogrel is crossed into 60 mesh sieve, Macrogol 6000 is crossed 120 mesh sieve, is uniformly mixed spare；
2) said mixture temperature is risen to 68 DEG C, melt coating material and is evenly coated at bisulfate clopidogrel table
Face；
3) by the dry materials of acquisition, separation and cure, obtain bisulfate clopidogrel particle.
Embodiment 9
The bisulfate clopidogrel particle that will be obtained in embodiment 1-8, respectively with pressing existing method and work after auxiliary materials and mixing
Skill tabletting.Through continuously suppressing 3 hours, it is showed no sticking situation.It can be seen that Yi Shang bisulfate clopidogrel granular recipe and system
The method of granulating that Preparation Method, i.e. fusion method and coating method are combined efficiently solves clopidogrel hydrogen sulfate tablet production
Sticking problem in the process, and can steady production.
10 Dissolution Rate Testing of embodiment
Condition：PH3.0, solvent 1000ml, rotating speed：50 revs/min, temperature：37±0.5℃.It is surveyed with reference to Chinese Pharmacopoeia dissolution
Fixed second method：Slurry processes.
Use the hydrogen sulfate chlorine pyrrole that embodiment 1 (170421-1) and embodiment 2 (170421-2) is used to prepare in embodiment 9
The tablet of Gray's particle preparation grinds (import drugs registration certificate number with original：H20140436, import drugs packing authentication code：State
The quasi- word J20130083 of medicine dispenses enterprise：Sai Nuofei (Hangzhou) pharmaceutical Co. Ltd, trade name：Plavix (PLAVIX), sample
Lot number：6A546, specification：75mg, valid until：2019.04) dissolution Experimental comparison has been carried out, it is similar that dissolution is as a result ground to original.
As a result it see the table below the dissolution curve in 1 and Fig. 1.
Table 1
| Time：Minute | 5 | 10 | 15 | 20 | 30 | 45 | 60 |
| 6A546 | 22.16% | 43.27% | 59.72% | 72.55% | 87.76% | 92.46% | 93.78% |
| 170421-1 | 20.74% | 46.58% | 63.51% | 75.66% | 89.44% | 94.59% | 94.62% |
| 170421-2 | 19.71% | 38.98% | 55.61% | 68.77% | 86.64% | 92.42% | 93.98% |
By the dissolution curve in table 1 and Fig. 1 it is found that bisulfate clopidogrel is used fusion method by technical scheme
Particle is first made with the method that coating method is combined, is then mixed again with other auxiliary materials and carries out tabletting, disclosure satisfy that preferable tabletting
Requirement：The tableting processes are stablized, not sticking, and stripping curve and the original of the tablet of acquisition are ground similar, and height thereby is achieved
The product of quality is convenient for amplification production.
Although above having used general explanation and specific embodiment, the present invention is described in detail, at this
On the basis of invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Therefore,
These modifications or improvements without departing from theon the basis of the spirit of the present invention belong to the scope of protection of present invention.
Claims (8)
1. a kind of bisulfate clopidogrel particle, which is characterized in that the bisulfate clopidogrel particle is using fusion method and packet
Prepared by the method that clothing method is combined, coat bisulfate clopidogrel with coating material and obtain.
2. bisulfate clopidogrel particle according to claim 1, which is characterized in that the coating material is poly- second two
One or more mixtures in alcohol, rilanit special, glycerin monostearate and Brazil wax.
3. bisulfate clopidogrel particle according to claim 2, which is characterized in that the bisulfate clopidogrel particle
In, it is 1 as the bisulfate clopidogrel of main ingredient and the mass ratio of coating material：0.10~0.40.
4. bisulfate clopidogrel particle according to claim 3, which is characterized in that the grain of the bisulfate clopidogrel
Diameter is less than or equal to 40 mesh.
5. a kind of preparation method of bisulfate clopidogrel particle, which is characterized in that the preparation method includes the following steps：
(1) 40 mesh sieve is crossed using as the bisulfate clopidogrel of main ingredient, coating material is crossed into 80 mesh sieve, mixing for standby use；Wherein make
It is 1 for the bisulfate clopidogrel of main ingredient and the mass ratio of coating material：0.10~0.40；
(2) temperature is increased so that coating material melting, makes the coating material of melting be evenly coated at bisulfate clopidogrel table
Face；
(3) by the dry materials of acquisition, separation and cure, obtain bisulfate clopidogrel particle.
6. preparation method according to claim 5, which is characterized in that the coating material is polyethylene glycol, hydrogenated castor
One or more mixtures in oil, glycerin monostearate and Brazil wax.
7. preparation method according to claim 5, which is characterized in that control temperature at 55 DEG C~92 DEG C in step (2).
8. the bisulfate clopidogrel particle according to any one of claim 1-4 is preparing clopidogrel hydrogen sulfate tablet
Middle use, and obtained clopidogrel hydrogen sulfate tablet is used for the generation of prevention of arterial atherosis thrombosis event.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114831950A (en) * | 2022-04-29 | 2022-08-02 | 广州新济药业科技有限公司 | Nitroglycerin coating, nitroglycerin sublingual tablet and preparation method thereof |
| CN115737578A (en) * | 2022-11-23 | 2023-03-07 | 石家庄四药有限公司 | Clopidogrel hydrogen sulfate and aspirin compound tablet and preparation method thereof |
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| 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 |
| 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 |
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| WO2008001201A2 (en) * | 2006-06-28 | 2008-01-03 | Wockhardt Ltd | Pharmaceutical compositions of clopidogrel |
| 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 |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114831950A (en) * | 2022-04-29 | 2022-08-02 | 广州新济药业科技有限公司 | Nitroglycerin coating, nitroglycerin sublingual tablet and preparation method thereof |
| CN114831950B (en) * | 2022-04-29 | 2023-05-05 | 广州新济药业科技有限公司 | Nitroglycerin coating, nitroglycerin sublingual tablet and preparation method thereof |
| CN115737578A (en) * | 2022-11-23 | 2023-03-07 | 石家庄四药有限公司 | Clopidogrel hydrogen sulfate and aspirin compound tablet and preparation method thereof |
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Application publication date: 20180622 |