CN108078942B - A kind of clopidogrel hydrogen sulfate tablet and preparation method thereof - Google Patents
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Abstract
The invention belongs to biomedicine technical fields, more particularly to a kind of clopidogrel hydrogen sulfate tablet and preparation method thereof, the tablet supplementary material are as follows: bisulfate clopidogrel, Macrogol 4000, rilanit special, methacrylic acid-acrylic acid methyl terpolymer, disintegrating agent and filler；The tablet is based on compound slow controlled release raw material, filler is added and disintegrating agent is prepared, wherein compound slow controlled release raw material is made of the material methyl copolymer of acrylic acid and methyl acrylate of wax skeleton sheet material Macrogol 4000, rilanit special and insoluble matrix, after being prepared into preparation with composite filler and disintegrating agent, on the basis of reaching the requirement at the uniform velocity controlling release, guarantee that the tablet impurity content is stablized.
Description
Technical field
The invention belongs to biomedicine technical fields, and in particular to a kind of clopidogrel hydrogen sulfate tablet and its preparation side
Method.
Background technique
Bisulfate clopidogrel is medicament for resisting platelet aggregation.Its mechanism of action clopidogrel by its active metabolite with
Blood platelet P2Y12 class adp receptor Irreversible binding generates inhibition on platelet aggregation, and clopidogrel is by blocking release
The platelet activation aggregation approach of ADP induction also can inhibit the platelet aggregation of other agonist inductions other than ADP, by France
The research and development of Sanofi-Aventis drugmaker.Clopidogrel bisulfate tablet is in November, 1997 with trade name Plavix
(Plavix) it is approved to list in the U.S., the acquisition SFDA approval of import in 2008, listing dosage form is conventional tablet, external listing specification
For 75mg, 300mg, import China specification is 75mg.
Update shows that there is nearly million novo acutes coronary syndrome (ACS) patient in China every year, every year because ACS is dead
The number died is 700,000, and morbidity and mortality are also constantly rising, domestic situation very severe.ACS is relatively tight in coronary heart disease
One kind of weight, with the characteristics of the constriction ache in prothorax of paroxysmal, because its morbidity is anxious, state of an illness weight, often lead to patient because
Acute myocardial ischemia and it is dead, 1/2 cardiovascular death is attributed to ACS.
Most ACS are the unstable results of Coronary Atherosclerotic Plaque.Only a few ACS is by non-Atherosclerosis
(such as arteritis, wound, interlayer, thromboembolism, congenital anomaly, abuse cocaine or heart intervention treating are simultaneously caused by the property changed disease
Send out disease).When blood supply coronarius and cardiac muscle need conflict between blood, coronary blood flow is not able to satisfy myocardial metabolism
Needs, cause cardiac muscle sharply, temporary hypoxic-ischemic when, angina pectoris can occur.
Coronary atherosclerosis can cause one or more vessel lumen narrow and myocardial blood flow is insufficient, once blood supply is anxious
It reduces sharply less or interrupts, make myocardium serious and enduringly up to 20~30 minutes or more acute myocardial infarction AMI can occur for acute ischemia
(AMI)。
Atherosclerotic plaque it is unstable be ACS morbidity Common Mechanism.Although the pathology of STEMI and NSTE-ACS
Mechanism includes Coronary Atherosclerotic Plaque rupture, thrombosis, but when STEMI, coronary artery usually acute complete resistance
Plug, therefore direct row coronary intervention (PCI) or intravenous thrombolysis are needed, in early days, sufficiently and persistently to open blood vessel, fill cardiac muscle
Divide Reperfu- sion.However, when NSTE-ACS, though to be usually present the thrombotic rich in blood platelet incomplete for coronary artery Serious Stenosis
Obstruction.
Acute coronary syndrome is ruptured with Coronary Atherosclerotic Plaque, and secondary acute thrombosis is pathology
One group of clinical syndrome on basis.The activation of blood platelet plays a crucial role in the Development process of ACS, through drug
Or also play the part of important role in the recurrence of PTCA or and STENTS ischemic event.
Antiplatelet therapy is the foundation stone of ACS patient's treatment.In past 20 years, Antiplatelet therapy has become ACS
The conventional means of secondary prevention afterwards, Present clinical practice in 75% or more patient discharge when receive Antiplatelet therapy, chlorine
Pyrrole Gray is most common Antiplatelet therapy drug, can effectively prevent the recurrence of ACS.
Therefore, research and development have important clinical significance using clopidogrel as the novel formulation of active constituent.
Summary of the invention
For these reasons, applicant obtains a kind of novel hydrogen sulfate chlorine pyrrole lattice by repeatedly creative test, research
Thunder sustained-release tablet, which is that filler is added and disintegrating agent is prepared based on composite slow release raw material, wherein compound slow
Releasing raw material is by the material methyl propylene of wax skeleton sheet material Macrogol 4000, rilanit special and insoluble matrix
Acid-methyl acrylate copolymer composition after being prepared into preparation with composite filler and disintegrating agent, is released reaching at the uniform velocity control
On the basis of the requirement put, guarantee that the tablet impurity content is stablized.
The present invention is as follows by technical solution.
A kind of clopidogrel hydrogen sulfate tablet, the tablet supplementary material are as follows: bisulfate clopidogrel, Macrogol 4000, hydrogen
Change castor oil, methacrylic acid-acrylic acid methyl terpolymer, disintegrating agent and filler.
A kind of preferred clopidogrel hydrogen sulfate tablet, wherein 97.9 parts by weight of bisulfate clopidogrel, polyethylene glycol
4000 7.5-8.5 parts by weight, rilanit special 3-3.5 parts by weight, methacrylic acid-acrylic acid methyl terpolymer 38-42 weight
Part, disintegrating agent 11-13 parts by weight, filler 120-130 parts by weight.
A kind of preferred clopidogrel hydrogen sulfate tablet, wherein 97.9 parts by weight of bisulfate clopidogrel, polyethylene glycol
4000 8 parts by weight, 3.3 parts by weight of rilanit special, 40 parts by weight of methacrylic acid-acrylic acid methyl terpolymer, disintegrating agent 12
Parts by weight, 125 parts by weight of filler.
Wherein disintegrating agent is low-substituted hydroxypropyl cellulose.
Wherein filler is microcrystalline cellulose and mannitol.
Wherein filler is the weight ratio of microcrystalline cellulose and mannitol are as follows: 7.0-7.5:1.
Wherein filler is the weight ratio of microcrystalline cellulose and mannitol are as follows: 7.33:1.
The tablet the preparation method comprises the following steps:
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 sieve with 100 mesh sieve；Microcrystalline cellulose,
Low-substituted hydroxypropyl cellulose, methacrylic acid-acrylic acid methyl terpolymer cross 60 meshes；Above-mentioned supplementary material is uniformly mixed, and is obtained
To spare supplementary material；
(2) spare supplementary material addition dry granulating machine to be pelletized, grain made parameter feeding speed selects 12-13 revs/min,
Squeeze pressure selects 14-18kg, and extrusion speed selects 10-11 revs/min, and granulation 20 mesh screens of selection are small by partial size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the partial size of collection is less than in the particle and partial size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and rilanit special is added, and are uniformly mixed, tabletting obtains sustained-release tablet.
Specific embodiment
Below the technical scheme of the invention is illustrated by a specific example, but the scope of the present invention is not limited thereto.
Content described in this specification embodiment is only enumerating to the way of realization of inventive concept, protection of the invention
Range should not be construed as being limited to the specific forms stated in the embodiments, and protection scope of the present invention is also and in art technology
Personnel conceive according to the present invention it is conceivable that equivalent technologies mean.Although embodiment of the invention below is retouched
It states, but the invention is not limited to above-mentioned specific embodiments and applications field, following specific embodiments is only to show
It is meaning property, guiding, rather than it is restrictive.Those skilled in the art under the enlightenment of this specification and are not taking off
In the case where the range protected from the claims in the present invention, a variety of forms can also be made, these belong to the present invention
The column of protection.
The following tests of the present invention are on the basis of multiple creative test, with the claimed technical solution of the present invention
Based on, the conclusive test of the research staff of summary.
Test 1
Disintegration time limited, friability test
Test 1 group: bisulfate clopidogrel 97.9g, stearyl alcohol 28g, rilanit special 23.3g, the low substitution hydroxyl of disintegrating agent
Propyl cellulose 12g, filler microcrystalline cellulose 15g and mannitol 110g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, stearyl alcohol sieve with 100 mesh sieve；Microcrystalline cellulose, low substitution
Hydroxypropyl cellulose；Above-mentioned supplementary material is uniformly mixed, and obtains spare supplementary material；
(2) spare supplementary material addition dry granulating machine to be pelletized, grain made parameter feeding speed selects 12-13 revs/min,
Squeeze pressure selects 14-18kg, and extrusion speed selects 10-11 revs/min, and granulation 20 mesh screens of selection are small by partial size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the partial size of collection is less than in the particle and partial size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and rilanit special is added, and are uniformly mixed, tabletting obtains 1000, tablet.
Test 2 groups: bisulfate clopidogrel 97.9g, stearyl alcohol 20g, rilanit special 31.3g, the low substitution hydroxyl of disintegrating agent
Propyl cellulose 12g, filler microcrystalline cellulose 15g and mannitol 110g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, stearyl alcohol sieve with 100 mesh sieve；Microcrystalline cellulose, low substitution
Hydroxypropyl cellulose；Above-mentioned supplementary material is uniformly mixed, and obtains spare supplementary material；
(2) spare supplementary material addition dry granulating machine to be pelletized, grain made parameter feeding speed selects 12-13 revs/min,
Squeeze pressure selects 14-18kg, and extrusion speed selects 10-11 revs/min, and granulation 20 mesh screens of selection are small by partial size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the partial size of collection is less than in the particle and partial size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and rilanit special is added, and are uniformly mixed, tabletting obtains 1000, tablet.
Test 3 groups: bisulfate clopidogrel 97.9g, stearyl alcohol 36g, rilanit special 15.3g, the low substitution hydroxyl of disintegrating agent
Propyl cellulose 12g, filler microcrystalline cellulose 15g and mannitol 110g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, stearyl alcohol sieve with 100 mesh sieve；Microcrystalline cellulose, low substitution
Hydroxypropyl cellulose；Above-mentioned supplementary material is uniformly mixed, and obtains spare supplementary material；
(2) spare supplementary material addition dry granulating machine to be pelletized, grain made parameter feeding speed selects 12-13 revs/min,
Squeeze pressure selects 14-18kg, and extrusion speed selects 10-11 revs/min, and granulation 20 mesh screens of selection are small by partial size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the partial size of collection is less than in the particle and partial size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and rilanit special is added, and are uniformly mixed, tabletting obtains tablet.
Friability, disintegration time limited detection (according to Chinese Pharmacopoeia 2015 editions) are carried out to above-mentioned tablet, testing result is shown in Table 1:
The different tablet testing results of table 1
Test result: it is above-mentioned experiments have shown that, adjust the proportionate relationship of wax material in tablet, the friability of the tablet and collapse
The solution time limit does not meet States Pharmacopoeia specifications, and applicant continues to test.
Test 2
Dissolution Rate Testing
Test 1 group: bisulfate clopidogrel 97.9g, Macrogol 4000 8g, rilanit special 3.3g, metering system
Acid-methyl acrylate copolymer 40g, disintegrating agent low-substituted hydroxypropyl cellulose 12g, filler microcrystalline cellulose 15g and sweet dew
Alcohol 110g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 sieve with 100 mesh sieve；Microcrystalline cellulose,
Low-substituted hydroxypropyl cellulose, methacrylic acid-acrylic acid methyl terpolymer cross 60 meshes；Above-mentioned supplementary material is uniformly mixed, and is obtained
To spare supplementary material；
(2) spare supplementary material addition dry granulating machine to be pelletized, grain made parameter feeding speed selects 12-13 revs/min,
Squeeze pressure selects 14-18kg, and extrusion speed selects 10-11 revs/min, and granulation 20 mesh screens of selection are small by partial size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the partial size of collection is less than in the particle and partial size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and rilanit special is added, and are uniformly mixed, tabletting obtains 1000, tablet.
Test 2 groups: bisulfate clopidogrel 97.9g, Macrogol 4000 8g, rilanit special 3.3g, polyvinyl chloride
40g, disintegrating agent low-substituted hydroxypropyl cellulose 12g, filler microcrystalline cellulose 15g and mannitol 110g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 sieve with 100 mesh sieve；Microcrystalline cellulose,
Low-substituted hydroxypropyl cellulose, polyvinyl chloride cross 60 meshes；Above-mentioned supplementary material is uniformly mixed, and obtains spare supplementary material；
(2) spare supplementary material addition dry granulating machine to be pelletized, grain made parameter feeding speed selects 12-13 revs/min,
Squeeze pressure selects 14-18kg, and extrusion speed selects 10-11 revs/min, and granulation 20 mesh screens of selection are small by partial size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the partial size of collection is less than in the particle and partial size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and rilanit special is added, and are uniformly mixed, tabletting obtains 1000, tablet.
Test 3 groups: bisulfate clopidogrel 97.9g, Macrogol 4000 8g, rilanit special 3.3g, ethyl cellulose
40g, disintegrating agent low-substituted hydroxypropyl cellulose 12g, filler microcrystalline cellulose 15g and mannitol 110g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 sieve with 100 mesh sieve；Microcrystalline cellulose,
Low-substituted hydroxypropyl cellulose, ethyl cellulose cross 60 meshes；Above-mentioned supplementary material is uniformly mixed, and obtains spare supplementary material；
(2) spare supplementary material addition dry granulating machine to be pelletized, grain made parameter feeding speed selects 12-13 revs/min,
Squeeze pressure selects 14-18kg, and extrusion speed selects 10-11 revs/min, and granulation 20 mesh screens of selection are small by partial size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the partial size of collection is less than in the particle and partial size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and rilanit special is added, and are uniformly mixed, tabletting obtains 1000, tablet.
Friability, disintegration time limited detection (according to Chinese Pharmacopoeia 2015 editions) are carried out to above-mentioned tablet, testing result is shown in Table 2:
The different tablet testing results of table 2
Conclusion (of pressure testing): it is above-mentioned experiments have shown that, after insoluble framework material is added in preparation prescription, friability and disintegration
Time limit meets the requirements.
Above-mentioned tablet is subjected to dissolution rate detection test:
Different tests group tablet is taken, according to dissolution method (four general rules of Chinese Pharmacopoeia version in 2015,0,931 first method),
With pH2.0 hydrochloride buffer (0.2mol/L Klorvess Liquid 250ml is taken, adds 0.2mol/L hydrochloric acid solution 65.0ml, is diluted with water
It is dissolution medium to 1000ml) 1000ml, revolving speed is 75 turns per minute, operates according to methods, when through 30 minutes, solution is taken to filter, makees
For test solution；Bisulfate clopidogrel reference substance is taken, it is accurately weighed, add dissolution medium to dissolve and dilute and is made in every 1ml
Solution containing 0.1mg is as bisulfate clopidogrel reference substance solution.
20 μ l of contrast solution and test solution is taken, is measured respectively, by external standard method with every hydrogen sulfate chlorine of calculated by peak area
The amount of dissolution of pyrrole Gray (in terms of clopidogrel).
Test result is shown in Table 3:
The different Dissolution of Tablet inspection results (%) of table 3
: using the tablet of the insoluble framework material of polyvinyl chloride, there is phenomenon of burst release at 5 hours in conclusion (of pressure testing), because
This, can not be used using polyvinyl chloride as the auxiliary material of sustained-release tablet of the present invention.
Test 3
Influence factor test
It takes and tests 1 group and 3 groups of preparations of test in test 2, carry out influence factor test；
Detection method of content and impurity content detection method are according to 2015 editions two 1354-1355 pages of methods of Chinese Pharmacopoeia
It is detected, the results are shown in Table 4, table 5, table 6.
The different preparation high temperature test results (60 DEG C) of table 4
The different preparation highlight test results of table 5
The different preparation highlight test results of table 6
Conclusion (of pressure testing): experiments have shown that, testing 3 groups of preparations after 10 days high temperature and high humidity test by influence factor, miscellaneous
I content of matter, III content of impurity, total impurities content increase obviously, and do not meet standards of pharmacopoeia requirement, and Tablets
Impurity content variable quantity very little absolutely proves sustained-release tablet excellent in stability of the present invention.
By above-mentioned experiments have shown that, Macrogol 4000, rilanit special, methacrylic acid-in sustained-release tablet of the present invention
Methyl acrylate copolymer and disintegrating agent and filler on the basis of guaranteeing dissolution rate, meanwhile, also guarantee active constituent is steady
Qualitative etc., therefore, the composition of invention formulation auxiliary material has important scientific meaning.
Prepare embodiment
Embodiment 1
Bisulfate clopidogrel 979g, Macrogol 4000 80g, rilanit special 33g, methacrylic acid-acrylic acid first
Ester copolymer 400g, disintegrating agent low-substituted hydroxypropyl cellulose 120g, filler microcrystalline cellulose 150g and mannitol 1100g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 sieve with 100 mesh sieve；Microcrystalline cellulose,
Low-substituted hydroxypropyl cellulose, methacrylic acid-acrylic acid methyl terpolymer cross 60 meshes；Above-mentioned supplementary material is uniformly mixed, and is obtained
To spare supplementary material；
(2) spare supplementary material addition dry granulating machine to be pelletized, grain made parameter feeding speed selects 12-13 revs/min,
Squeeze pressure selects 14-18kg, and extrusion speed selects 10-11 revs/min, and granulation 20 mesh screens of selection are small by partial size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the partial size of collection is less than in the particle and partial size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and rilanit special is added, and are uniformly mixed, tabletting obtains 10000, tablet.
Embodiment 2
Bisulfate clopidogrel 195.8g, Macrogol 4000 16g, rilanit special 6.6g, methacrylic acid-acrylic
Sour methyl terpolymer 80g, disintegrating agent low-substituted hydroxypropyl cellulose 24g, filler microcrystalline cellulose 30g and mannitol 220g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 sieve with 100 mesh sieve；Microcrystalline cellulose,
Low-substituted hydroxypropyl cellulose, methacrylic acid-acrylic acid methyl terpolymer cross 60 meshes；Above-mentioned supplementary material is uniformly mixed, and is obtained
To spare supplementary material；
(2) spare supplementary material addition dry granulating machine to be pelletized, grain made parameter feeding speed selects 12-13 revs/min,
Squeeze pressure selects 14-18kg, and extrusion speed selects 10-11 revs/min, and granulation 20 mesh screens of selection are small by partial size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the partial size of collection is less than in the particle and partial size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and rilanit special is added, and are uniformly mixed, tabletting obtains 2000, tablet.
Embodiment 3
Bisulfate clopidogrel 489.5g, Macrogol 4000 40g, rilanit special 16.5g, methacrylic acid-acrylic
Sour methyl terpolymer 200g, disintegrating agent low-substituted hydroxypropyl cellulose 60g, filler microcrystalline cellulose 75g and mannitol 550g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 sieve with 100 mesh sieve；Microcrystalline cellulose,
Low-substituted hydroxypropyl cellulose, methacrylic acid-acrylic acid methyl terpolymer cross 60 meshes；Above-mentioned supplementary material is uniformly mixed, and is obtained
To spare supplementary material；
(2) spare supplementary material addition dry granulating machine to be pelletized, grain made parameter feeding speed selects 12-13 revs/min,
Squeeze pressure selects 14-18kg, and extrusion speed selects 10-11 revs/min, and granulation 20 mesh screens of selection are small by partial size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the partial size of collection is less than in the particle and partial size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and rilanit special is added, and are uniformly mixed, tabletting obtains 5000, tablet.
7 supplementary material source of table
The embodiment is including but not limited to above-mentioned.
Claims (4)
1. a kind of clopidogrel hydrogen sulfate tablet, it is characterised in that the tablet supplementary material are as follows: bisulfate clopidogrel, polyethylene glycol
4000, rilanit special, methacrylic acid-acrylic acid methyl terpolymer, disintegrating agent and filler；
Wherein 97.9 parts by weight of bisulfate clopidogrel, Macrogol 4000 7.5-8.5 parts by weight, rilanit special 3-3.5 weight
Measure part, methacrylic acid-acrylic acid methyl terpolymer 38-42 parts by weight, disintegrating agent 11-13 parts by weight, filler 120-130 weight
Measure part；Wherein disintegrating agent is low-substituted hydroxypropyl cellulose；Wherein filler is the weight ratio of microcrystalline cellulose and mannitol are as follows:
7.0-7.5:1.
2. a kind of clopidogrel hydrogen sulfate tablet according to claim 1, wherein 97.9 parts by weight of bisulfate clopidogrel, gather
4,000 8 parts by weight of ethylene glycol, 3.3 parts by weight of rilanit special, 40 parts by weight of methacrylic acid-acrylic acid methyl terpolymer collapse
Solve 12 parts by weight of agent, 125 parts by weight of filler.
3. a kind of clopidogrel hydrogen sulfate tablet according to claim 1, wherein filler is microcrystalline cellulose and sweet dew
The weight ratio of alcohol are as follows: 7.33:1.
4. a kind of clopidogrel hydrogen sulfate tablet according to claim 1-3, it is characterised in that the system of the tablet
Preparation Method are as follows:
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 sieve with 100 mesh sieve；Microcrystalline cellulose low takes
60 meshes are crossed for hydroxypropyl cellulose, methacrylic acid-acrylic acid methyl terpolymer；Above-mentioned supplementary material is uniformly mixed, and is obtained standby
Use supplementary material；
(2) spare supplementary material addition dry granulating machine is pelletized, grain made parameter feeding speed selects 12-13 revs/min, squeezes
Pressure selects 14-18kg, and extrusion speed selects 10-11 revs/min, granulation 20 mesh screens of selection, by sieving partial size less than 80
Targeted fine powder re-starts granulation, after 3 granulations, the partial size of collection -80 mesh of 20 mesh particle and partial size less than 80 mesh
Fine powder be uniformly mixed, be added rilanit special, be uniformly mixed, tabletting obtains sustained-release tablet.
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| CN1927167A (en) * | 2006-09-29 | 2007-03-14 | 何岩 | Clopidogrel slow, controlled release formulation |
| CN101606918A (en) * | 2008-06-18 | 2009-12-23 | 慈博生物医药技术（上海）有限公司 | Clopidogrel hydrogensulfate enteric-coated sustained-release tablet and preparation thereof |
| AU2010259003A1 (en) * | 2009-06-08 | 2011-11-10 | Merck Sharp & Dohme Corp. | A thrombin receptor antagonist and clopidogrel fixed dose tablet |
| CN101703513B (en) * | 2009-11-10 | 2014-04-23 | 沈阳药科大学 | Compound sustained-release preparation of aspirin and clopidogrel or pharmaceutically acceptable salt thereof |
| CN102485218B (en) * | 2010-12-03 | 2013-05-29 | 丽珠医药集团股份有限公司 | Clopidogrel hydrogen sulfate tablet and preparation method thereof |
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