CN109662948B - Platelet aggregation inhibitor and preparation method thereof - Google Patents
Platelet aggregation inhibitor and preparation method thereof Download PDFInfo
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- CN109662948B CN109662948B CN201710954723.9A CN201710954723A CN109662948B CN 109662948 B CN109662948 B CN 109662948B CN 201710954723 A CN201710954723 A CN 201710954723A CN 109662948 B CN109662948 B CN 109662948B
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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
- A61K9/2095—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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- 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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
The invention discloses a platelet aggregation inhibitor and a preparation method thereof. The method comprises the following steps: (1) mixing crystal I clopidogrel hydrogen sulfate with a disintegrating agent, then adding a bonding agent for granulation, and drying and then finishing granules to obtain dry granules; (2) mixing the dry particles obtained in the step (1) with an anti-sticking agent to obtain mixed particles; (3) and (3) mixing the mixed granules obtained in the step (2) with a filler, then mixing with a glidant and a lubricant, tabletting and coating. The preparation method solves the sticking problem in the production process, simultaneously overcomes the stability problems of the degradation of active ingredients and the configuration transformation of products, and all the equipment used by the preparation method is common equipment in the pharmaceutical industry, is suitable for mass production, and has low production cost and high efficiency.
Description
Technical Field
The invention relates to a platelet aggregation inhibitor and a preparation method thereof.
Background
Clopidogrel is an induced inhibitor of platelet aggregation and acts by inhibiting the binding of adenosine phosphate to the receptor. Clopidogrel is an inactive prodrug, which is metabolized and converted into active metabolites by hepatocyte pigment P450 to exert drug effect. It reduces the chance of arterial occlusion by inhibiting platelet aggregation, achieves the effect of preventing stroke and heart attack, and is effective in treating and preventing atherosclerosis.
Clopidogrel hydrogen sulfate, also known as clopidogrel hydrogen sulfate, is chemically named as S (+) -2- (2-chlorophenyl) -2- (4,5,6, 7-tetrahydrothiophene) [3,2-c]Bipyridine-5) methyl acetate hydrogensulfate of formula C16H16ClNO2S·H2SO4Molecular weight 419.90, having the following chemical formula:
clopidogrel bisulfate is easily dissolved in acidic water and methanol and dissolved in ethanol. Two major problems mainly exist in the development and production of the variety: (1) the phenomena of unsmooth, deficiency and shrapnel on the surface of the tablet caused by easy sticking and punching in the process are avoided; (2) the stability problem is that: the clopidogrel hydrogen sulfate has carboxylic ester bonds in the structure, and is easy to be broken under the influence of pH, temperature, moisture and the like to form impurities A; is easy to be converted from dextroisomer into levoisomer without platelet aggregation, and the toxicity of the levoisomer is obviously higher than that of dextroisomer.
Polymorphic phenomena of clopidogrel hydrogen sulfate exist (U.S. patent No. US6767913, European patent No. EP20020805215 and the like), and the characteristics of each crystal form are factors which must be considered in the process of preparation development.
European patent EP20020805215 discloses various crystalline forms of clopidogrel hydrogen sulfate. Generally, the more thermodynamically stable the crystal form, the less soluble it is. Among the commonly used amorphous clopidogrel bisulfate, I type and II type clopidogrel bisulfate, the clopidogrel bisulfate of II type has the best thermodynamic stability and the lowest solubility; amorphous clopidogrel bisulfate has the best solubility and the worst thermodynamic stability, and is easy to be converted into I type and II type which have more stable thermodynamics; the stability and the solubility of the I-type clopidogrel bisulfate are between those of the clopidogrel bisulfate and the clopidogrel bisulfate, so that the clopidogrel bisulfate is an ideal medicine crystal form. However, the clopidogrel hydrogen sulfate I crystal form is easy to generate serious sticking phenomenon in the preparation process and has a stability problem, so researchers continuously try to solve the problem in recent years.
Chinese patent CN101590023B discloses a clopidogrel hydrogen sulfate tablet and a preparation method thereof. The clopidogrel hydrochloride preparation is characterized in that one or two of vitamin C and butylated hydroxyanisole are added to inhibit the clopidogrel from being converted into clopidogrel acid and inhibit the dextroisomer from being converted into the levoisomer. However, vitamin C and butylated hydroxyanisole are easily oxidized and degraded, so that certain damage is caused to human bodies.
Chinese patent CN103417502B discloses a clopidogrel hydrogen sulfate tablet and a preparation process thereof. The clopidogrel bisulfate and the hydroxypropyl cellulose are prepared into microcapsules by a liquid-in-liquid drying method, and then the microcapsules are mixed with auxiliary materials commonly used in pharmaceutics and tabletted to obtain the clopidogrel bisulfate tablet. The method has good stability, can completely avoid the sticking problem in the process, but has limited batch and is not beneficial to large-scale production.
Chinese patent CN104083333A discloses a clopidogrel hydrogen sulfate tablet and a preparation method thereof, and particularly relates to clopidogrel hydrogen sulfate tablets which are prepared by mixing clopidogrel hydrogen sulfate with internal auxiliary materials (starch, mannitol, microcrystalline cellulose, hydroxypropyl cellulose and sodium carboxymethylcellulose), granulating, adding the external auxiliary materials, tabletting and coating. The product prepared in the patent solves the sticking problem in the process, but the microcrystalline cellulose in the internal auxiliary material is difficult to separate from the alcohol in the adhesive, so that the drying time is too long, and the stability of the product is easy to reduce.
Chinese patent CN1935119A discloses a clopidogrel hydrogen sulfate solid preparation prepared by a dry granulation process. Due to the sticking characteristic of the clopidogrel hydrogen sulfate I, when the process of the patent is reproduced, the phenomenon of extremely serious roller sticking occurs, and the process cannot be carried out.
The three-phase granulation method is also reported to be adopted for granulation, and because the liquid drop of the three-phase granulation method is larger, and clopidogrel hydrogen sulfate is dissolved in ethanol, the uneven hardness of the granules is easy to cause. If the auxiliary materials are added for granulation, the microcrystalline cellulose in the filler can firmly bind the ethanol, the drying time of the granules is long, and the stability of the clopidogrel hydrogen sulfate is not good. If water is used as the binder, water is also detrimental to its stability.
The method disclosed by the above fails to provide a method for industrially producing clopidogrel hydrogen sulfate tablets which can better solve the problems of sticking and poor stability.
Disclosure of Invention
The invention aims to solve the technical problems that in the prior art, the I crystal form clopidogrel bisulfate tablet in a platelet aggregation inhibitor has serious sticking phenomenon in the industrialization process, is not beneficial to mass production, and finally has poor product stability due to degradation of active ingredients and configuration transformation of the product, and provides the platelet aggregation inhibitor and the preparation method thereof. The product prepared by the preparation method has good stability, the equipment used by the preparation method is common equipment for tablet dosage forms, special equipment is not needed, the sticking phenomenon does not occur in the preparation process, and the preparation method is suitable for mass production, low in production cost and high in efficiency.
The invention provides a preparation method of a platelet aggregation inhibitor, which comprises the following steps:
(1) mixing crystal I clopidogrel hydrogen sulfate with a disintegrating agent, then adding a bonding agent for granulation, and drying and then finishing granules to obtain dry granules;
(2) mixing the dry particles obtained in the step (1) with an anti-sticking agent to obtain mixed particles;
(3) mixing the mixed granules obtained in the step (2) with a filler, then mixing with a glidant and a lubricant, tabletting and coating;
wherein, the clopidogrel hydrogen sulfate tablet of the crystal form I comprises the following components in percentage by weight: the clopidogrel hydrogen sulfate crystal form I comprises 20-45% of clopidogrel hydrogen sulfate crystal form I, 1-10% of disintegrating agent, 0.1-2% of anti-adhesion agent, 40-90% of filling agent, 0.5-3% of flow aid, 0.5-10% of lubricant and 3-5% of coating material for coating; and the weight ratio of the dosage of the adhesive to the sum of the dosages of the clopidogrel hydrogen sulfate crystal I and the disintegrant is (0.9-1.1): 1;
wherein the adhesive is ethanol water solution with the volume fraction of 90-99%; the anti-adhesion agent is micro silica gel powder; the glidant is micro-powder silica gel; the lubricant is one or more of stearic acid, talcum powder, PEG4000, PEG6000 and sodium lauryl sulfate; the coating material is gastric soluble opadry.
In the step (1), those skilled in the art know that the bulk drug of clopidogrel bisulfate crystal form i can be pretreated as required before use, and preferably, the clopidogrel bisulfate crystal form i is sieved by a 200-mesh sieve before use.
In step (1), the disintegrant is a disintegrant conventionally used in the art, preferably one or more of sodium carboxymethyl starch, croscarmellose sodium and crospovidone, and more preferably sodium carboxymethyl starch or croscarmellose sodium.
In the step (1), the granulation process is a conventional granulation process in the art, and the specific method of granulation is not particularly limited as long as the final granules can pass through a 40-60 mesh sieve.
In step (3), the filler is a filler conventionally used in the art, preferably one or more of microcrystalline cellulose, starch, pregelatinized starch, mannitol, lactose, and dextrin, more preferably microcrystalline cellulose and/or lactose.
In step (3), the tabletting operation and conditions are those conventional in the art.
In the step (3), the using condition of the coating material is the conventional using condition of the coating material, and the aqueous solution of the coating material is used as a coating solution for coating; the mass concentration of the coating liquid is preferably 5-20%.
In the invention, the dosage of the crystal form I clopidogrel hydrogen sulfate is preferably 31.68 percent; the dosage of the disintegrating agent is preferably 1.94-2.91%; the dosage of the anti-adhesion agent is preferably 1.5%; the amount of the filler is preferably 59.59%; the amount of the lubricant is preferably 0.97 to 1.94%; the amount of the coating material is preferably 2.91%; the weight ratio of the dosage of the adhesive to the sum of the dosages of the clopidogrel hydrogen sulfate crystal I and the disintegrant is 1: 1.
In the present invention, the binder is preferably an aqueous ethanol solution with a volume fraction of 95%.
In the present invention, the silica fume is silica fume conventionally used in the art, and is commercially available, for example, from WACKER
Silica gel micropowder of N20 Pharma.
In the present invention, the lubricant is preferably stearic acid or PEG 6000.
In the present invention, the coating material is preferably
ambⅡ。
The invention also provides a platelet aggregation inhibitor prepared by the method.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the preparation method solves the sticking problem in the production process, simultaneously overcomes the stability problems of the degradation of active ingredients and the configuration transformation of products, and all the equipment used by the preparation method is common equipment in the pharmaceutical industry, is suitable for mass production, and has low production cost and high efficiency.
Drawings
FIG. 1 is a dissolution profile of example 1, example 2 and a reference formulation of the present invention.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The following effects are shown in the mass comparison, dissolution, and the determination methods and standards of related substances and isomers in examples 2 to 4, which are described in USP 39.
The tablet pressing operation in examples 1-4 and comparative examples 1 and 2 below is a conventional operation, i.e., the material is placed in a hopper, the tablet press is inching, the hardness and tablet weight are adjusted to the required values, and then the tablet press is operated.
The croscarmellose sodium, the sodium carboxymethyl starch, the FMC, the lactose, the BASF, and the PEG6000 in the following examples 1 to 4 and comparative examples 1 and 2 were obtained from dfpharma, DFE, the microcrystalline cellulose, the DFE pharma, the BASF, and the CLARIANT, respectively.
Examples 1 to 4, comparative examples 1 and 2
The components listed in table 1 were used to prepare clopidogrel hydrogen sulfate crystalline form i tablets of examples 1-4 and comparative examples 1 and 2.
TABLE 1
Example 1
The preparation process comprises the following steps:
1. sieving crystal form I clopidogrel hydrogen sulfate with a 200-mesh sieve, mixing the crystal form I clopidogrel hydrogen sulfate with croscarmellose sodium in a fluidized bed, granulating with 95% ethanol, drying, and grading with a 40-60-mesh sieve to obtain dry granules;
2. mixing the micro silica gel powder with the prepared dry particles to form mixed particles;
3. mixing the mixed granules with lactose and microcrystalline cellulose, mixing with stearic acid and silica gel micropowder to obtain final granules, tabletting, and coating. Wherein the mass concentration of the coating liquid is 5 percent.
Example 2
The preparation process comprises the following steps:
1. sieving clopidogrel hydrogen sulfate crystal form I with a 200-mesh sieve, mixing the sieved clopidogrel hydrogen sulfate crystal form I with sodium carboxymethyl starch in a fluidized bed, granulating with 95% ethanol, drying, and granulating with a 40-60-mesh sieve to obtain dry granules;
2. mixing the micro silica gel powder with the prepared dry particles to form mixed particles;
3. mixing the mixed granules with lactose and microcrystalline cellulose, mixing with PEG6000 and silica gel micropowder to obtain final granule, tabletting, and coating. Wherein the mass concentration of the coating liquid is 20 percent.
Example 3
The preparation process of example 3 is the same as that of example 2.
Example 4
The preparation process of example 4 is the same as example 1.
Comparative example 1
The preparation process comprises the following steps:
and (3) sieving the crystal form I clopidogrel bisulfate with a 200-mesh sieve, mixing with sodium carboxymethyl starch and superfine silica powder, performing dry granulation, and grading with a 40-60-mesh sieve. Mixing the obtained granule with lactose and microcrystalline cellulose, mixing with PEG6000 and silica gel micropowder to obtain mixed granule, tabletting, and coating.
Comparative example 2
The preparation process comprises the following steps:
sieving clopidogrel hydrogen sulfate with a 200-mesh sieve, uniformly mixing with croscarmellose sodium, adding superfine silica gel powder, mixing with microcrystalline cellulose and lactose, adding superfine silica gel powder and stearic acid, mixing to obtain final granules, tabletting, and coating.
Effect example 1
Table 2 shows the appearance of the clopidogrel bisulfate crystal form I tablets of examples 1 to 4, comparative examples 1 and 2. As can be seen from Table 2, the process of the present invention solves the sticking problem during the preparation of clopidogrel hydrogen sulfate tablets.
TABLE 2
| Examples | Appearance of the product |
| Example 1 | Smooth sheet surface and no sticking and punching phenomenon |
| Example 2 | Smooth sheet surface and no sticking and punching phenomenon |
| Example 3 | Smooth sheet surface and no sticking and punching phenomenon |
| Example 4 | Smooth sheet surface and no sticking and punching phenomenon |
| Comparative example 1 | The roller sticking phenomenon is serious, and the granulation process can not be carried out |
| Comparative example 2 | The striking and sticking of the spring plate are obvious, and the tabletting can not be carried out |
Effect example 2
Table 3 gives the mass ratio of examples 1 and 2 and reference formulation PLAVIX (boraviv).
Table 3, examples 1 and 2 and reference formulation mass ratio
| Investigation item | Limit requirements | Example 1 | Example 2 | PLAVIX (Boliwei) |
| Disintegration time (min) | <15min | 11～14min | 11～14min | 12～14min |
| Content (%) | 90.0～110.0 | 100.07 | 99.61 | 99.11 |
| Dissolution (%) | 30min≥80 | 89.31 | 88.75 | 89.46 |
| Impurity A | ≤1.2 | 0.049 | 0.056 | 0.026 |
| Isomers | ≤1.5 | 0.079 | 0.081 | 0.455 |
| Total miscellaneous | ≤2.5 | 0.207 | 0.179 | 0.614 |
Effect example 3
Table 4 shows the time-dependent release of dissolution of examples 1 and 2 and of the reference preparation PLAVIX, where f2The similarity factor represents a parameter for measuring the similarity of two preparations. Fig. 1 is a dissolution profile of example 1, example 2 and the reference formulation.
Table 4, examples 1 and 2 and the reference preparation show the amount of released dissolution at different times
Effect example 4
After the samples are placed under the conditions of 40 +/-2 ℃ and 75% +/-5% relative humidity, the samples are respectively taken at months 1, 2, 3 and 6 for key item detection. The results of the accelerated tests of PLAVIX (Boraviv) for examples 1 and 2 and the reference formulation are given in tables 5 to 7, respectively.
Table 5, accelerated test results of example 1
Table 6, accelerated test results of example 2
TABLE 7 accelerated test results for reference formulation PLAVIX
Stability test effects of examples 1 and 2 the results of examples 2 and 3 show that the quality of the formulation of the present invention conforms to the USP.
The results of the 6 th month accelerated test and release profile of examples 1 and 2 and the reference formulation show that the formulations of the present invention are of consistent quality and have a lower isomer content than the reference formulation.
The various properties of the clopidogrel hydrogen sulfate crystalline form i tablets prepared in examples 3 and 4 are comparable to those of examples 1 and 2.
In conclusion, the invention not only overcomes the sticking problem in the tabletting process, but also solves the problems of active ingredient degradation and configuration transformation, and the dissolution behavior of the invention is consistent with that of a reference preparation-boli. The equipment used in the invention is common equipment for tablet dosage forms, and special equipment is not needed. Therefore, the method has the remarkable advantages of cost saving, high production efficiency, good stability and the like.
While specific embodiments of the invention have been described above, it will be appreciated by those skilled in the art that this is by way of example only, and that the scope of the invention is defined by the appended claims. Various changes and modifications to these embodiments may be made by those skilled in the art without departing from the spirit and scope of the invention, and these changes and modifications are within the scope of the invention.
Claims (10)
1. A preparation method of a clopidogrel hydrogen sulfate preparation comprises the following steps:
(1) mixing crystal I clopidogrel hydrogen sulfate with a disintegrating agent, then adding a bonding agent for granulation, and drying and then finishing granules to obtain dry granules;
(2) mixing the dry particles obtained in the step (1) with an anti-sticking agent to obtain mixed particles;
(3) mixing the mixed granules obtained in the step (2) with a filler, then mixing with a glidant and a lubricant, tabletting and coating;
wherein, the clopidogrel hydrogen sulfate tablet of the crystal form I comprises the following components in percentage by weight: the dosage of the crystal I clopidogrel hydrogen sulfate is 31.68%, the dosage of the disintegrating agent is 1.94-2.91%, the dosage of the anti-adhesion agent is 1.5%, the dosage of the filling agent is 59.59%, the dosage of the glidant is 0.5-3%, the dosage of the lubricant is 0.97-1.94%, and the dosage of the coating material for coating is 2.91%; and the weight ratio of the dosage of the adhesive to the sum of the dosages of the clopidogrel hydrogen sulfate crystal I and the disintegrant is (0.9-1.1): 1;
wherein the adhesive is ethanol water solution with volume fraction of 90-99%; the anti-adhesion agent is micro silica gel powder; the glidant is micro-powder silica gel; the lubricant is one or more of stearic acid, talcum powder, PEG4000, PEG6000 and sodium lauryl sulfate; the coating material is gastric soluble opadry.
2. The process according to claim 1, wherein in step (1), the clopidogrel hydrogen sulfate form i is sieved through a 200-mesh sieve before use;
in the step (1), the disintegrating agent is one or more of sodium carboxymethyl starch, croscarmellose sodium and crospovidone;
in the step (1), the whole grain operation is to pass through a 40-60-mesh sieve.
3. The method of claim 2, wherein the disintegrant is sodium carboxymethyl starch or croscarmellose sodium.
4. The method according to claim 1, wherein in the step (3), the filler is one or more of microcrystalline cellulose, starch, pregelatinized starch, mannitol, lactose, and dextrin;
in the step (3), the coating is carried out by taking the water solution of the coating material as a coating solution.
5. The process according to claim 4, wherein the filler is microcrystalline cellulose and/or lactose; the mass concentration of the coating liquid is 5-20%.
6. The process according to claim 1, wherein the weight ratio of the amount of the binder to the sum of the amounts of the clopidogrel hydrogen sulfate crystal form i and the disintegrant is 1: 1.
7. The method of claim 1, wherein the binder is an aqueous ethanol solution with a volume fraction of 95%.
8. The method of claim 1, wherein the lubricant is stearic acid or PEG 6000.
9. The method of claim 1, wherein the coating material is opadry
Ⅱ。
10. A clopidogrel bisulfate preparation prepared by the preparation method as set forth in any one of claims 1 to 9.
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| CN101721410B (en) * | 2008-10-30 | 2012-01-25 | 南京正大天晴制药有限公司 | Solid medicinal composition of clopidogrel hydrogen sulfate |
| US20120207825A1 (en) * | 2009-09-17 | 2012-08-16 | Sunilendu Bhushan Roy | Pharmaceutical compositions for reducing alcohol-induced dose dumping |
| CN101766573B (en) * | 2010-02-05 | 2013-02-13 | 上海安必生制药技术有限公司 | Preparation process of clopidogrel bisulfate solid preparation |
| CN102309482B (en) * | 2011-06-20 | 2013-04-10 | 海南良方医药有限公司 | Clopidogrel hydrogensulfate composition and preparation method thereof |
| CN104083333B (en) * | 2014-07-09 | 2017-02-15 | 乐普药业股份有限公司 | Clopidogrel hydrogen sulfate tablet 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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