CN108078942A - A kind of clopidogrel hydrogen sulfate tablet and preparation method thereof - Google Patents
A kind of clopidogrel hydrogen sulfate tablet and preparation method thereof Download PDFInfo
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
Abstract
The invention belongs to biomedicine technical fields, and in particular to a kind of clopidogrel hydrogen sulfate tablet and preparation method thereof, the tablet supplementary material are：Bisulfate clopidogrel, Macrogol 4000, rilanit special, methacrylic acid methyl acrylate copolymer, disintegrant and filler；The tablet is based on compound slow controlled release raw material, it adds in filler and disintegrant is prepared, wherein compound slow controlled release raw material is made of the material methyl acrylic methyl terpolymer of wax skeleton sheet material Macrogol 4000, rilanit special and insoluble matrix, after preparation being prepared into composite filler and disintegrant, on the basis of reaching and at the uniform velocity controlling the requirement of release, ensure 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 technology
Bisulfate clopidogrel is medicament for resisting platelet aggregation.Its mechanism of action clopidogrel by its active metabolite with
Blood platelet P2Y12 class adp receptors Irreversible binding generates inhibition on platelet aggregation, and clopidogrel is by blocking release
The platelet activation aggregation approach of ADP inductions also can inhibit the platelet aggregation of other agonist inductions beyond ADP, by France
Sanofi-Aventis drugmaker researchs and develops.Clopidogrel bisulfate tablet is in November, 1997 with trade name Plavix
(Plavix) be approved to list in the U.S., 2008 obtain the SFDA approval of imports, listing dosage form be 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 cannot meet myocardial metabolism
Needs, cause cardiac muscle drastically, temporary hypoxic-ischemic when, you can angina pectoris occurs.
One or more vessel lumen can be caused narrow for coronary atherosclerosis and myocardial blood flow deficiency, once blood supply is anxious
It reduces sharply less or interrupts, make myocardium serious and enduringly acute ischemia was up to 20~30 minutes or more, you can acute myocardial infarction AMI occurs
(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 during STEMI, coronary artery usually acute complete resistance
Plug, therefore direct row coronary intervention (PCI) or intravenous thrombolysis are needed, in early days, fully and persistently to open blood vessel, fill cardiac muscle
Divide Reperfu- sion.However, during NSTE-ACS, though coronary artery Serious Stenosis be usually present it is incomplete rich in hematoblastic thrombotic
Obstruction.
Acute coronary syndrome is ruptured with Coronary Atherosclerotic Plaque, and secondary acute thrombosis is pathology
One group of clinical syndrome on basis.Hematoblastic activation 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, more than 75% patient receives Antiplatelet therapy, chlorine in discharge in Present clinical practice
Pyrrole Gray is current most common Antiplatelet therapy drug, can effectively prevent the recurrence of ACS.
Therefore, the novel formulation using clopidogrel as active ingredient is researched and developed, there is important clinical significance.
The content of the invention
For these reasons, applicant tests by repeatedly creative, and research obtains a kind of new hydrogen sulfate chlorine pyrrole lattice
Thunder sustained-release tablet, the tablet are based on composite slow release raw material, add in filler and disintegrant is prepared, wherein compound slow
It is by the material methyl propylene of wax skeleton sheet material Macrogol 4000, rilanit special and insoluble matrix to release raw material
Acid-methyl acrylate copolymer composition after being prepared into preparation with composite filler and disintegrant, is released reaching at the uniform velocity control
On the basis of the requirement put, ensure 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：Bisulfate clopidogrel, Macrogol 4000, hydrogen
Change castor oil, methacrylic acid-acrylic acid methyl terpolymer, disintegrant 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, disintegrant 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, disintegrant 12
Parts by weight, 125 parts by weight of filler.
Wherein disintegrant is low-substituted hydroxypropyl cellulose.
Wherein filler is microcrystalline cellulose and mannitol.
Wherein filler is that the weight ratio of microcrystalline cellulose and mannitol is：7.0-7.5：1.
Wherein filler is that the weight ratio of microcrystalline cellulose and mannitol is：7.33：1.
The preparation method of the tablet is：
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 cross 100 mesh sieves；Microcrystalline cellulose,
Low-substituted hydroxypropyl cellulose, methacrylic acid-acrylic acid methyl terpolymer cross 60 mesh sieves；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 grain size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the grain size of collection is less than in the particle and grain size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and add in rilanit special, are uniformly mixed, tabletting obtains sustained-release tablet.
Specific embodiment
Technical scheme is illustrated with specific embodiment below, but protection scope of the present invention is without being limited thereto.
Content described in this specification embodiment is only enumerating to the way of realization of inventive concept, protection of the invention
Scope is not construed as being only limitted to the concrete form that embodiment is stated, 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 in above-mentioned specific embodiments and applications field, following specific embodiments is only to show
It is meaning property, guiding rather than restricted.Those of ordinary skill in the art under the enlightenment of this specification and are not taking off
In the case of the scope protected from the claims in the present invention, a variety of forms can also be made, these belong to the present invention
The row of protection.
The following experiments of the present invention are on the basis of multiple creative experiment, with the claimed technical solution of the present invention
Based on, the conclusive experiment of the research staff of summary.
Experiment 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 disintegrant
Propyl cellulose 12g, filler microcrystalline cellulose 15g and mannitol 110g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, stearyl alcohol cross 100 mesh sieves；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 grain size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the grain size of collection is less than in the particle and grain size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and add in rilanit special, 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 disintegrant
Propyl cellulose 12g, filler microcrystalline cellulose 15g and mannitol 110g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, stearyl alcohol cross 100 mesh sieves；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 grain size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the grain size of collection is less than in the particle and grain size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and add in rilanit special, 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 disintegrant
Propyl cellulose 12g, filler microcrystalline cellulose 15g and mannitol 110g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, stearyl alcohol cross 100 mesh sieves；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 grain size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the grain size of collection is less than in the particle and grain size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and add in rilanit special, 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
Result of the test：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.
Experiment 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, disintegrant low-substituted hydroxypropyl cellulose 12g, filler microcrystalline cellulose 15g and sweet dew
Alcohol 110g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 cross 100 mesh sieves；Microcrystalline cellulose,
Low-substituted hydroxypropyl cellulose, methacrylic acid-acrylic acid methyl terpolymer cross 60 mesh sieves；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 grain size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the grain size of collection is less than in the particle and grain size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and add in rilanit special, are uniformly mixed, tabletting obtains 1000, tablet.
Test 2 groups：Bisulfate clopidogrel 97.9g, Macrogol 4000 8g, rilanit special 3.3g, polyvinyl chloride
40g, disintegrant low-substituted hydroxypropyl cellulose 12g, filler microcrystalline cellulose 15g and mannitol 110g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 cross 100 mesh sieves；Microcrystalline cellulose,
Low-substituted hydroxypropyl cellulose, polyvinyl chloride cross 60 mesh sieves；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 grain size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the grain size of collection is less than in the particle and grain size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and add in rilanit special, are uniformly mixed, tabletting obtains 1000, tablet.
Test 3 groups：Bisulfate clopidogrel 97.9g, Macrogol 4000 8g, rilanit special 3.3g, ethyl cellulose
40g, disintegrant low-substituted hydroxypropyl cellulose 12g, filler microcrystalline cellulose 15g and mannitol 110g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 cross 100 mesh sieves；Microcrystalline cellulose,
Low-substituted hydroxypropyl cellulose, ethyl cellulose cross 60 mesh sieves；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 grain size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the grain size of collection is less than in the particle and grain size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and add in rilanit special, 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 experiment：
Different tests pack agent is taken, according to dissolution method (four general rules of Chinese Pharmacopoeia version in 2015,0,931 first method),
With pH2.0 hydrochloride buffers (0.2mol/L Klorvess Liquid 250ml are taken, adds 0.2mol/L hydrochloric acid solution 65.0ml, is diluted with water
To 1000ml) 1000ml is dissolution medium, rotating speed is 75 turns per minute, is operated in accordance with the law, during through 30 minutes, solution is taken to filter, and is made
For test solution；Bisulfate clopidogrel reference substance is taken, it is accurately weighed, it dissolution medium is added to dissolve and is diluted 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 are taken, are measured respectively, by external standard method with every hydrogen sulfate chlorine of calculated by peak area
The stripping quantity of pyrrole Gray (in terms of clopidogrel).
Result of the test is shown in Table 3：
The different Dissolution of Tablet inspection results (%) of table 3
Conclusion (of pressure testing)：Using the tablet of the insoluble framework material of polyvinyl chloride, there is phenomenon of burst release at 5 hours, because
This, can not be used using polyvinyl chloride as the auxiliary material of sustained-release tablet of the present invention.
Experiment 3
Influence factor is tested
It takes and 1 group and 3 groups of preparations of experiment is tested in experiment 2, carry out influence factor experiment；
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 hot 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)：By influence factor, experiments have shown that, 3 groups of preparations of experiment are miscellaneous after 10 days high temperature and high wet test
I content of matter, III content of impurity, total impurities content increase substantially, 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 disintegrant and filler on the basis of dissolution rate is ensured, meanwhile, also guarantee active ingredient 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, disintegrant low-substituted hydroxypropyl cellulose 120g, filler microcrystalline cellulose 150g and mannitol 1100g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 cross 100 mesh sieves；Microcrystalline cellulose,
Low-substituted hydroxypropyl cellulose, methacrylic acid-acrylic acid methyl terpolymer cross 60 mesh sieves；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 grain size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the grain size of collection is less than in the particle and grain size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and add in rilanit special, 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, disintegrant low-substituted hydroxypropyl cellulose 24g, filler microcrystalline cellulose 30g and mannitol 220g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 cross 100 mesh sieves；Microcrystalline cellulose,
Low-substituted hydroxypropyl cellulose, methacrylic acid-acrylic acid methyl terpolymer cross 60 mesh sieves；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 grain size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the grain size of collection is less than in the particle and grain size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and add in rilanit special, 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, disintegrant low-substituted hydroxypropyl cellulose 60g, filler microcrystalline cellulose 75g and mannitol 550g.
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 cross 100 mesh sieves；Microcrystalline cellulose,
Low-substituted hydroxypropyl cellulose, methacrylic acid-acrylic acid methyl terpolymer cross 60 mesh sieves；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 grain size by sieving
Granulation is re-started in 80 targeted fine powders, after 3 granulations, the grain size of collection is less than in the particle and grain size of -80 mesh of 20 mesh
80 targeted fine powders are uniformly mixed, and add in rilanit special, are uniformly mixed, tabletting obtains 5000, tablet.
7 supplementary material source of table
The embodiment is including but not limited to above-mentioned.
Claims (8)
1. a kind of clopidogrel hydrogen sulfate tablet, it is characterised in that the tablet supplementary material is：Bisulfate clopidogrel, polyethylene glycol
4000th, rilanit special, methacrylic acid-acrylic acid methyl terpolymer, disintegrant and filler.
2. a kind of clopidogrel hydrogen sulfate tablet according to claim 1, wherein 97.9 parts by weight of bisulfate clopidogrel,
Macrogol 4000 7.5-8.5 parts by weight, rilanit special 3-3.5 parts by weight, methacrylic acid-acrylic acid methyl terpolymer
38-42 parts by weight, disintegrant 11-13 parts by weight, filler 120-130 parts by weight.
3. 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.
4. according to a kind of clopidogrel hydrogen sulfate tablet of claim 1-3 any one of them, wherein disintegrant is low substitution hydroxyl
Propyl cellulose.
5. according to a kind of clopidogrel hydrogen sulfate tablet of claim 1-3 any one of them, wherein filler is microcrystalline cellulose
Element and mannitol.
6. according to a kind of bisulfate clopidogrel sustained-release tablet of claim 5 any one of them, wherein filler is fine for crystallite
Dimension element and the weight ratio of mannitol are：7.0-7.5：1.
7. a kind of clopidogrel hydrogen sulfate tablet of any one of them according to claim 5, wherein filler are crystallite
The weight ratio of cellulose and mannitol is：7.33：1.
8. according to a kind of clopidogrel hydrogen sulfate tablet of claim 1-7 any one of them, it is characterised in that the system of the tablet
Preparation Method is：
(1) bisulfate clopidogrel crosses 40 mesh screens；Mannitol, Macrogol 4000 cross 100 mesh sieves；Microcrystalline cellulose low takes
60 mesh sieves 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, and grain size is less than 80 by granulation 20 mesh screens of selection by screening
Targeted fine powder re-starts granulation, and after 3 granulations, the grain size of collection is less than 80 mesh in the particle and grain size of -80 mesh of 20 mesh
Fine powder be uniformly mixed, add in 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 |
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| WO2010144339A2 (en) * | 2009-06-08 | 2010-12-16 | Schering Corporation | A thrombin receptor antagonist and clopidogrel fixed dose tablet |
| CN101703513A (en) * | 2009-11-10 | 2010-05-12 | 沈阳药科大学 | Compound sustained-release preparation of aspirin and clopidogrel or pharmaceutically acceptable salt thereof |
| CN102485218A (en) * | 2010-12-03 | 2012-06-06 | 丽珠医药集团股份有限公司 | Clopidogrel hydrogen sulfate tablet and preparation method thereof |
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