CN115770229A

CN115770229A - Clopidogrel sulfate aspirin tablet and preparation method and application thereof

Info

Publication number: CN115770229A
Application number: CN202211606681.7A
Authority: CN
Inventors: 李明丽; 邢晋华; 刘洋; 邓长江; 陈悬悬; 王成梅
Original assignee: Shandong Nmk Pharmaceutical Research Institute Co ltd
Current assignee: Shandong Nmk Pharmaceutical Research Institute Co ltd
Priority date: 2022-12-13
Filing date: 2022-12-13
Publication date: 2023-03-10

Abstract

The invention provides a clopidogrel sulfate aspirin tablet, a preparation method and application thereof, and belongs to the technical field of medicines. The clopidogrel bisulfate aspirin tablet provided by the invention has the mass less than or equal to 0.35 g/tablet, solves the problem of difficulty in swallowing in clinical use by controlling the tablet weight, improves the clinical compliance, and utilizes the film coating layer, wherein the Opadry EZ coating powder can obviously improve the flowability of the tablet, greatly reduces the probability of throat or esophagus adhesion, is easier to swallow, and compared with other film coating systems, the friction force on the surface of the Opadry EZ coated tablet is obviously reduced once exposed to a humid condition, so that the better wet and slippery property is obtained, the clinical compliance is improved, the uncomfortable taste and smell are covered, the palatability of the tablet is improved, and the aesthetic feeling of the tablet is improved.

Description

Clopidogrel sulfate aspirin tablet and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, and in particular relates to a clopidogrel sulfate aspirin tablet as well as a preparation method and application thereof.

Background

The occurrence of cardiovascular and cerebrovascular diseases seriously jeopardizes life health, wherein the mortality rate of thrombotic diseases is high, the morbidity of thrombotic diseases is increased year by year, and the further expansion of the population is promoted by the increasing aging of the increasingly serious population. Myocardial infarction is the disease with the highest fatality rate, cerebral infarction is the disease with the highest disability rate, and the occurrence of clinical malignant diseases has a direct relationship with thrombosis. Therefore, with the rising incidence rate, the demand of antithrombotic drugs is increasing, and the development speed of the antithrombotic market is very fast, which has become one of the hot fields of drug development in the world.

The clopidogrel aspirin tablet is a compound preparation and is used for the conversion treatment of the combined medication of clopidogrel and aspirin under the following conditions: non-ST elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients who are stented after percutaneous coronary intervention; is suitable for thrombolytic ST-segment elevation type acute myocardial infarction patients treated by medicaments. The clopidogrel hydrogen sulfate aspirin tablet contains 75mg of clopidogrel hydrogen sulfate (calculated by clopidogrel) and 100mg of aspirin, is an original product imported from original research, has a supporting quotient of Sanofi K.K., and does not have a domestic clopidogrel hydrogen sulfate aspirin tablet product at present.

Chinese patent CN112587495A discloses a compound tablet preparation of aspirin and clopidogrel hydrogen sulfate, which is prepared into film coated tablet by tabletting aspirin enteric coated tablet and clopidogrel hydrogen sulfate granule, wherein the aspirin enteric coated tablet is composed of tablet containing medicine, enteric coated layer coating and isolating layer coating from inside to outside, the mass of the compound tablet preparation of aspirin and clopidogrel hydrogen sulfate is more than 0.5 g/tablet. Chinese patent CN109288805A discloses a compound aspirin clopidogrel bisulfate core-coated tablet, which comprises the following components from inside to outside: (i) aspirin tablet cores; (ii) an enteric coating layer; (iii) a clopidogrel bisulfate layer; and (iv) a film coating layer, wherein the mass of the compound aspirin clopidogrel hydrogen sulfate tablet is 1.3-1.6 g/tablet. The aspirin clopidogrel hydrogen sulfate compound tablet prepared by the prior art has large mass and is difficult to swallow in clinical use.

Disclosure of Invention

In view of the above, the invention aims to provide a clopidogrel sulfate aspirin tablet, and a preparation method and application thereof.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides a clopidogrel sulfate aspirin tablet which sequentially comprises an aspirin tablet core, an enteric coating layer, a first isolation coating layer, a clopidogrel sulfate upper medicine layer, a second isolation coating layer and a film coating layer from inside to outside, wherein the mass of the clopidogrel sulfate aspirin tablet is less than or equal to 0.35 g/tablet;

based on the mass percentage content of the clopidogrel hydrogen sulfate aspirin tablet of 100 percent,

the aspirin tablet comprises the following components: 25 to 50 percent of aspirin, 0.25 to 4.5 percent of microcrystalline cellulose and 0.25 to 2 percent of diluent;

the enteric coating layer comprises the following components: 2.5 to 6 percent of enteric coating powder, 0.25 to 1.2 percent of triethyl citrate and 1.25 to 4.8 percent of opacifier;

the composition of the first release coating layer comprises: 0.5 to 8 percent of high-substituted hydroxypropyl cellulose;

the clopidogrel sulfate medicine-applying layer comprises the following components: 19 to 38 percent of clopidogrel sulfate, 0.5 to 5 percent of adhesive, 0.05 to 2 percent of antioxidant, 0.02 to 1 percent of polyethylene glycol and 1 to 5 percent of disintegrating agent; the amount of clopidogrel sulfate is calculated as clopidogrel;

the composition of the second release coating layer comprises: 0.5 to 8 percent of high-substituted hydroxypropyl cellulose;

the film coating layer comprises the following components: 3 to 8 percent of Opadry EZ coating powder.

Preferably, the enteric coating powder comprises one or more of a copolymer of methacrylic acid and ethyl acrylate, a copolymer of methacrylic acid and methyl methacrylate, and a copolymer of methacrylic acid and methyl methacrylate.

Preferably, the opacifier comprises one or more of talc, calcium carbonate, calcium sulfate and iron oxide.

Preferably, the diluent comprises starch and/or lactose.

The invention also provides a preparation method of the clopidogrel sulfate aspirin tablet in the technical scheme, which comprises the following steps:

mixing the enteric coating powder, triethyl citrate, talcum powder and water to obtain an enteric coating layer component solution;

mixing clopidogrel sulfate, an adhesive, an antioxidant, polyethylene glycol, a disintegrating agent, a diluent and an alcohol solvent to obtain a medicinal solution;

mixing high-substituted hydroxypropyl cellulose and a plasticizer or high-substituted hydroxypropyl cellulose and water to obtain first isolation layer coating slurry;

mixing the high-substituted hydroxypropyl cellulose, the plasticizer, the talcum powder and the alcohol solution to obtain second isolation layer coating slurry;

mixing the Opadry EZ coating powder with water to obtain film coating layer slurry;

mixing aspirin, microcrystalline cellulose and a diluent, and tabletting to obtain an aspirin tablet;

performing enteric coating on the aspirin tablet by using the enteric coating layer component solution to obtain an aspirin enteric tablet;

coating the aspirin enteric-coated tablet by using the first isolating layer coating slurry to obtain an aspirin isolating enteric-coated tablet;

the aspirin isolation enteric-coated tablet is coated with the medicine coating solution to obtain clopidogrel hydrogen sulfate aspirin tablets;

carrying out second isolation layer coating on the clopidogrel hydrogen sulfate aspirin tablets by using the second isolation layer coating pulp, and then carrying out film layer coating by using the film coating layer coating pulp to obtain the clopidogrel hydrogen sulfate aspirin tablets;

the enteric coating, the first isolating layer coating, the medicine applying, the second isolating layer coating and the film layer coating are all carried out in a coating pan.

Preferably, the parameters of the first barrier layer coating include: the spraying speed is 60-120 g/min, the rotating speed of a coating pan is 3-8 rmin, and the material temperature is 28-35 ℃.

Preferably, the parameters of the enteric coating include: the spraying speed is 60-120 g/min, the coating pan rotating speed is 3-8 rmin, and the material temperature is 28-35 ℃.

Preferably, the technological parameters of the medicine application comprise: the spraying speed of the medicine solution is 60-260 g/min, the rotating speed of a coating pan is 3-12 r/min, and the material temperature is 25-45 ℃.

Preferably, the process parameters of the second barrier layer coating and the film layer coating include: the spraying speed is independently 60-120 g/min, the rotating speed of the coating pan is independently 3-8 r/min, and the material temperature is independently 25-50 ℃.

The invention also provides the application of the clopidogrel hydrogen sulfate aspirin tablet in the technical scheme or the clopidogrel hydrogen sulfate aspirin tablet prepared by the preparation method in the technical scheme in the preparation of drugs for treating cardiovascular and cerebrovascular diseases.

The invention provides a clopidogrel hydrogen sulfate aspirin tablet, which sequentially comprises an aspirin tablet core, an enteric coating layer, a first isolation coating layer, a clopidogrel hydrogen sulfate drug loading layer, a second isolation coating layer and a film coating layer from inside to outside, wherein the mass of the clopidogrel hydrogen sulfate aspirin tablet is less than or equal to 0.35 g/tablet; the clopidogrel sulfate aspirin tablet comprises the following components in percentage by mass of 100 percent: 25 to 40 percent of aspirin, 0.25 to 4.5 percent of microcrystalline cellulose and 0.25 to 2 percent of starch; the enteric coating layer comprises the following components: 2.5 to 6 percent of enteric coating powder, 0.25 to 1.2 percent of triethyl citrate and 1.25 to 4.8 percent of talcum powder; the composition of the first release coating layer comprises: 0.5 to 3 percent of high-substituted hydroxypropyl cellulose, 0.05 to 1.2 percent of talcum powder and 0.05 to 0.15 percent of plasticizer; the clopidogrel sulfate medicine feeding layer comprises the following components: 25 to 40 percent of clopidogrel sulfate, 0.5 to 5 percent of adhesive, 0.05 to 2 percent of antioxidant, 0.02 to 1 percent of polyethylene glycol, 1 to 5 percent of disintegrating agent and 2.5 to 5 percent of diluent; the amount of clopidogrel sulfate is calculated by clopidogrel; the composition of the second release coating layer comprises: 1 to 6 percent of high-substituted hydroxypropyl cellulose, 0.1 to 0.3 percent of plasticizer and 0.2 to 2.4 percent of talcum powder; the film coating layer comprises the following components: 3 to 8 percent of Opadry EZ coating powder.

Clopidogrel sulfate has high viscosity, and two problems need to be solved in the production of core-spun tablets in the prior art, namely, 1 st: sticking problem of clopidogrel sulfate; and 2, a step of: the problem of damage to aspirin tablets during clopidogrel sulfate compression is solved by enlarging the weight of the granules, and the clopidogrel sulfate layer is required to reach a certain thickness so as to protect the tablet core. In the invention, the tablet core damage and sticking phenomenon caused by pressing do not exist when the coating is adopted for medicine application, so the product quality can be maintained after the quality of the tablet is reduced. The clopidogrel hydrogen sulfate aspirin tablet has the mass less than or equal to 0.35 g/tablet, solves the problem of difficulty in swallowing in clinical use by controlling the tablet weight, improves the clinical compliance, and utilizes a film coating layer, wherein the Opadry EZ coating powder can obviously improve the flowability of the tablet, greatly reduces the probability of throat or esophagus adhesion and is easier to swallow.

The invention also provides a preparation method of the clopidogrel hydrogen sulfate aspirin tablet in the technical scheme, wherein the enteric coating, the first isolating layer coating, the medicine feeding, the second isolating layer coating and the film layer coating are carried out in a coating pan, and the coating pan is adopted to replace a core-spun tablet tabletting machine, so that the problems of high production cost and low efficiency are solved, and the bottleneck problem of restricting the domestic production of clopidogrel hydrogen sulfate aspirin tablets is solved; and clopidogrel sulfate only needs to be mixed and coated with the adhesive, the antioxidant, the polyethylene glycol, the diluent and the disintegrating agent, so that the hot-melt granulation process of clopidogrel is avoided, expensive auxiliary materials are avoided, the cost is reduced, the process is simple, and the production efficiency is greatly improved.

Drawings

Fig. 1 is a graph showing the results of comparison of dynamic friction of clopidogrel sulfate aspirin tablets obtained in comparative example 1, example 10 and example 11;

FIG. 2 is a clopidogrel dissolution curve of clopidogrel sulfate aspirin tablets and clopidogrel sulfate tablets obtained in example 1;

FIG. 3 is an aspirin dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 1 and an aspirin tablet;

fig. 4 is a clopidogrel dissolution curve of the clopidogrel sulfate aspirin tablet prepared in example 2 and a clopidogrel sulfate tablet;

FIG. 5 is an aspirin dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 2 and an aspirin tablet;

FIG. 6 is a clopidogrel dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 3 and a clopidogrel sulfate tablet;

fig. 7 is an aspirin dissolution curve of the clopidogrel sulfate aspirin tablet prepared in example 3 and an aspirin tablet;

fig. 8 is a clopidogrel dissolution curve of clopidogrel sulfate aspirin tablets and clopidogrel sulfate tablets obtained in example 4;

fig. 9 is an aspirin dissolution curve of the clopidogrel sulfate aspirin tablet prepared in example 4 and an aspirin tablet;

FIG. 10 is a clopidogrel dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 5 and a clopidogrel sulfate tablet;

fig. 11 is an aspirin dissolution curve of the clopidogrel sulfate aspirin tablet prepared in example 5 and an aspirin tablet;

fig. 12 is a clopidogrel dissolution curve of clopidogrel sulfate aspirin tablets and clopidogrel sulfate tablets obtained in example 6;

fig. 13 is an aspirin dissolution curve of the clopidogrel sulfate aspirin tablet prepared in example 6 and an aspirin tablet;

fig. 14 is a clopidogrel dissolution curve of clopidogrel sulfate aspirin tablets and clopidogrel sulfate tablets obtained in example 7;

fig. 15 is an aspirin dissolution curve of the clopidogrel sulfate aspirin tablet prepared in example 7 and an aspirin tablet;

FIG. 16 is a clopidogrel dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 8 and a clopidogrel sulfate tablet;

FIG. 17 is an aspirin dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 8 and an aspirin tablet;

FIG. 18 is a clopidogrel dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 9 and a clopidogrel sulfate tablet;

fig. 19 is an aspirin dissolution curve of the clopidogrel sulfate aspirin tablet prepared in example 9 and an aspirin tablet;

fig. 20 is a clopidogrel dissolution curve of clopidogrel sulfate aspirin tablets and clopidogrel sulfate tablets obtained in example 10;

fig. 21 is an aspirin dissolution curve of the clopidogrel sulfate aspirin tablet prepared in example 10 and an aspirin tablet.

Detailed Description

The invention provides a clopidogrel hydrogen sulfate aspirin tablet, which sequentially comprises an aspirin tablet core, an enteric coating layer, a first isolation coating layer, a clopidogrel hydrogen sulfate drug loading layer, a second isolation coating layer and a film coating layer from inside to outside, wherein the mass of the clopidogrel hydrogen sulfate aspirin tablet is less than or equal to 0.35 g/tablet;

based on the mass percentage content of the clopidogrel hydrogen sulfate aspirin tablet as 100 percent,

the aspirin tablet comprises the following components: 25 to 40 percent of aspirin, 0.25 to 4.5 percent of microcrystalline cellulose and 0.25 to 2 percent of starch;

the composition of the enteric coating layer comprises: 2.5 to 6 percent of enteric coating powder, 0.25 to 1.2 percent of triethyl citrate and 1.25 to 4.8 percent of talcum powder;

the composition of the first release coating layer comprises: 0.5 to 3 percent of high-substituted hydroxypropyl cellulose, 0.05 to 1.2 percent of talcum powder and 0.05 to 0.15 percent of plasticizer;

the clopidogrel sulfate medicine feeding layer comprises the following components: 25 to 40 percent of clopidogrel sulfate, 0.5 to 5 percent of adhesive, 0.05 to 2 percent of antioxidant, 0.02 to 1 percent of polyethylene glycol, 1 to 5 percent of disintegrating agent and 2.5 to 5 percent of diluent; the amount of clopidogrel sulfate is calculated by clopidogrel;

the composition of the second release coating layer comprises: 1 to 6 percent of high-substituted hydroxypropyl cellulose, 0.1 to 0.3 percent of plasticizer and 0.2 to 2.4 percent of talcum powder;

the film coating layer comprises the following components: 3-8% of Opadry EZ coating powder.

In the present invention, all the raw material components are commercially available products well known to those skilled in the art unless otherwise specified.

In the present invention, the particle diameter of the raw material component is independently preferably 5 to 30 μm.

In the invention, the mass of the clopidogrel sulfate aspirin tablet is preferably 0.24-0.35 g/tablet, more preferably 0.25-0.32 g/tablet, even more preferably 0.25-0.30 g/tablet, and most preferably 0.26-0.30 g/tablet.

The clopidogrel sulfate aspirin tablet comprises the following components in percentage by mass: 25 to 40 percent of aspirin, preferably 30 to 40 percent, and more preferably 35 to 48 percent; microcrystalline cellulose 0.25 to 4.5%, preferably 0.5 to 4%, more preferably 1 to 3%; the diluent is 0.25 to 2%, preferably 0.5 to 1.5%, more preferably 1 to 1.5%.

In the present invention, the ratio of the particle size of aspirin in the range of 20 to 60 mesh is preferably not less than 70%, more preferably not less than 80%.

In the present invention, the microcrystalline cellulose preferably comprises microcrystalline cellulose KG802 and/or microcrystalline cellulose pH102.

The clopidogrel hydrogen sulfate aspirin tablet provided by the invention comprises an enteric coating layer in percentage by mass: 2.5 to 6 percent of enteric coating powder, preferably 3 to 5.5 percent, and more preferably 3.5 to 5 percent; triethyl citrate 0.25-1.2%, preferably 0.5-1%, more preferably 0.6-0.8%; 1.25 to 4.8%, preferably 1.5 to 4.5%, more preferably 2 to 4%, and still more preferably 2.5 to 3.5% of talc.

In the present invention, the enteric coating powder is preferably eudragit enteric coating powder, more preferably includes at least one of a copolymer of methacrylic acid and ethyl acrylate, a copolymer of methacrylic acid and methyl methacrylate, and further preferably one or more of a copolymer of methacrylic acid and ethyl acrylate (mass ratio 1. In a particular embodiment of the invention, the enteric coating powder is preferably ewt chi L30D-55 or ewt chi L100.

In the present invention, the particle size of the talc is preferably 325 to 1000 mesh.

The first isolation coating layer comprises the following components in percentage by mass: 0.5-3% of high-substituted hydroxypropyl cellulose, preferably 1.0-2.0%, more preferably 1.25-1.75%, and the substitution degree of the high-substituted hydroxypropyl cellulose is preferably 53.4-77.5%.

In the present invention, the composition of the first isolation coating layer preferably further includes 0.05 to 1.2% by mass of talc, preferably 0.1 to 1.0% by mass, and more preferably 0.3 to 0.6% by mass.

In the present invention, the composition of the first isolating coating layer preferably further includes a plasticizer 0.05 to 0.15%, preferably 0.075 to 0.125%, and more preferably 0.075 to 0.1% by mass.

The clopidogrel sulfate aspirin tablet provided by the invention comprises the following components in percentage by mass: 25-40% of clopidogrel sulfate (calculated by clopidogrel), preferably 28-38% of clopidogrel sulfate, and further preferably 32-38% of clopidogrel sulfate; 0.5 to 5% of a binder, preferably 1 to 4.5%, more preferably 2 to 4%; 0.05 to 2 percent of antioxidant, preferably 0.1 to 1.8 percent, and more preferably 0.5 to 1.5 percent; 0.02 to 1 percent of polyethylene glycol, preferably 0.1 to 0.8 percent, and more preferably 0.3 to 0.5 percent; 1 to 5 percent of disintegrating agent, preferably 1.5 to 4.5 percent, and more preferably 2 to 4 percent; the diluent is 2.5 to 5%, preferably 3.0 to 4.5%, more preferably 3.0 to 4.0%.

In the present invention, the binder preferably comprises one or more of hypromellose, highly substituted hyprolose (H-HPC) and povidone.

In the present invention, the substitution degree of the highly substituted hydroxypropylcellulose is preferably 53.4% to 77.5%.

In the present invention, the antioxidant preferably includes one or more of vitamin E, sodium metabisulfite, sodium sulfite, and vitamin C.

In the present invention, the polyethylene glycol preferably includes polyethylene glycol 4000 and/or polyethylene glycol 6000.

In the invention, the disintegrating agent is preferably low-substituted hydroxypropyl cellulose (L-HPC), and the substitution degree of the low-substituted hydroxypropyl cellulose is preferably 7-16%.

In the present invention, the diluent preferably includes starch and/or lactose. When the diluent is preferably a mixture of starch and lactose, the mass ratio of starch to lactose in the mixture is not particularly limited, and any ratio of the mixture may be used.

The clopidogrel hydrogen sulfate aspirin tablet provided by the invention comprises the following components in percentage by mass: 1 to 6 percent of high-substituted hydroxypropyl cellulose (H-HPC), preferably 1 to 5 percent, and more preferably 1 to 4 percent.

In the present invention, the composition of the second isolation coating layer preferably further includes 0.1 to 0.3% by mass of a plasticizer, preferably 0.15 to 0.25% by mass, and more preferably 0.16 to 0.20% by mass.

In the present invention, the composition of the second isolation coating layer preferably further includes 0.2 to 2.4% by mass of talc, preferably 0.2 to 2.0% by mass, and more preferably 0.5 to 1.5% by mass.

The clopidogrel hydrogen sulfate aspirin tablet comprises the following film coating layers in percentage by mass: the Opadry EZ coating powder is 3-8%, preferably 3-6%, more preferably 3-5%.

The invention provides a preparation method of clopidogrel hydrogen sulfate aspirin tablets in the technical scheme, which comprises the following steps:

mixing high-substituted hydroxypropyl cellulose, a plasticizer, talcum powder and water to obtain first isolation layer coating slurry;

mixing the high-substituted hydroxypropyl cellulose, the plasticizer, the talcum powder and the alcohol solvent to obtain second isolating layer coating slurry;

The invention mixes the enteric coating powder, triethyl citrate, talcum powder and water to obtain the component solution of the enteric coating layer.

In the present invention, the mixing is preferably: dissolving the triethyl citrate into water, adding an opacifier for shearing, and adding the enteric coating powder under the stirring condition.

The dissolving, shearing and stirring conditions are not particularly limited in the present invention and may be in a manner well known to those skilled in the art.

The clopidogrel sulfate, the adhesive, the antioxidant, the polyethylene glycol, the disintegrating agent, the diluent and the alcohol solvent are mixed to obtain the medicinal solution, and the mixing mode is not particularly limited in the invention, and the mixing mode can be realized by adopting a mode which is well known to a person skilled in the art, such as shearing, and in the embodiment of the invention, the high-speed shearing at 1000 revolutions per minute is preferably carried out for 5 minutes.

The high-substituted hydroxypropyl cellulose, the plasticizer, the talcum powder and the water are mixed to obtain the first isolating layer coating slurry.

In the present invention, the enteric coating syrup preferably has a mass concentration of 15 to 25%, preferably 18 to 22%.

In the present invention, the mass concentration of the first separator slurry is preferably 2 to 8%, more preferably 3 to 7%.

The concentration of the clopidogrel sulfate medicine-applying layer is controlled to be 15-35%, preferably 20-30%, and the particle size of the clopidogrel sulfate is controlled to be 5-30 μm, preferably 10-20 μm.

The method comprises the steps of mixing high-substituted hydroxypropyl cellulose, a plasticizer, talcum powder and an alcohol solvent to obtain second isolating layer coating pulp, wherein the mass concentration of the second isolating layer coating pulp is preferably 2-8%, and is preferably 3-6%.

The invention is not particularly limited in the specific kind of the alcohol solvent, and the alcohol solvent known to those skilled in the art, such as ethanol, can be used.

The invention mixes the Opadry EZ coating powder with water to obtain the film layer coating slurry.

In the present invention, the mass concentration of the film layer coating syrup is preferably 8 to 25%, more preferably 10 to 18%.

The aspirin, the microcrystalline cellulose and the diluent are mixed and tabletted to obtain the aspirin tablet.

In the present invention, the pressure of the tablet is preferably 12 to 20KN.

In the present invention, the pellet is preferably a straight pellet using a punch of 7mm in diameter.

The aspirin enteric-coated tablet is obtained by carrying out enteric coating on the aspirin tablet by using the enteric coating layer component solution.

In the present invention, the parameters of the enteric coating preferably include: the spraying speed is 60-120 g/min, the rotating speed of a coating pan is 3-8 rmin, and the material temperature is 28-35 ℃.

In the present invention, the weight of the enteric coating is preferably increased by 12 to 20%, more preferably 14 to 18%.

In the invention, the tablet weight of the aspirin enteric-coated tablet is preferably 125-140 mg.

The aspirin enteric-coated tablet is coated by the first isolating layer coating slurry through the first isolating layer to obtain the aspirin isolating enteric-coated tablet.

In the present invention, the parameters for coating the first separation layer preferably include: the spraying speed is 60-120 g/min, the coating pan rotating speed is 3-8 rmin, and the material temperature is 28-35 ℃.

In the present invention, the weight of the first isolation layer coating is preferably increased by 2 to 4%, more preferably 2 to 3%.

The clopidogrel hydrogen sulfate aspirin tablet is prepared by using the medicine feeding solution to feed the aspirin isolated enteric-coated tablet.

In the present invention, the parameters for administration preferably include: the spraying speed is 60-260 g/min, the rotating speed of a coating pan is 3-12 r/min, and the material temperature is 25-45 ℃.

In the invention, the weight of the medicine is increased by 75-140%, and the weight is increased by 80-120%.

The clopidogrel hydrogen sulfate aspirin tablet is coated with a second isolation layer by using the second isolation layer coating slurry, and then is coated with a film layer by using the film layer coating slurry to obtain the clopidogrel hydrogen sulfate aspirin tablet.

In the present invention, the parameters of the second barrier layer coating and the film layer coating preferably include: the spraying speed is independently 60-120 g/min, the rotating speed of the coating pan is independently 3-8 r/min, and the material temperature is independently 30-50 ℃.

In the present invention, the weight of the second isolation layer coating is preferably increased by 2 to 5%, more preferably 2 to 4%.

In the present invention, the weight of the film layer coating is preferably increased by 2 to 7%, more preferably 3 to 5%.

After the coating of the film layer is finished, the invention preferably further comprises the step of packaging by adopting aluminum and plastic.

In the invention, the invention also provides the application of the clopidogrel sulfate aspirin tablet in the technical scheme or the clopidogrel sulfate aspirin tablet prepared by the preparation method in the technical scheme in the preparation of medicaments for treating cardiovascular and cerebrovascular diseases.

The invention is not particularly limited to the specific manner of use described, as such may be readily adapted by those skilled in the art.

The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It should be apparent that the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

(1) The clopidogrel sulfate aspirin tablet comprises the following components:

the aspirin tablet comprises the following components: 100mg of aspirin (the ratio of the particle size of 20-60 meshes is 80%), 5mg of starch and 10215mg of microcrystalline cellulose;

the enteric coating comprises the following components: triethyl citrate 0.4mg, talcum powder 5mg, purified water 50mg, eudragit L30D-5540mg;

the first isolating layer coating slurry comprises the following components: 3wt% of an aqueous solution of H-HPC;

the composition of the medicine solution is as follows: 4.5mg of adhesive H-HPC (the purchasing manufacturer is Shenzhen Yoypu medicine, inc.), 5mg of disintegrant L-HPC (the purchasing manufacturer is Shenzhen Yoypu medicine, inc.), 1mg of antioxidant vitamin E, 4mg of polyethylene glycol, 98.0mg of clopidogrel sulfate, 95% ethanol solution (abbreviated as 95% ethanol) in volume fraction, 25wt% of solid content and weight increment after loading;

the second isolating layer coating slurry comprises the following components: H-HPC, polyethylene glycol and 95% ethanol, the solid content is 3wt%;

coating slurry on the film layer: opadry EZ coating powder (model number is Opadry EZ color, and purchasing manufacturer is Shanghai Kalekang coating technology Co., ltd.) and purified water, and the solid content is 20wt%.

(2) The preparation method of the clopidogrel sulfate aspirin tablet comprises the following steps:

(2.1) uniformly mixing aspirin, starch and microcrystalline cellulose, directly tabletting by using a punch with the diameter of 7mm, and pressing under the pressure of 12kN to obtain the aspirin tablet.

(2.2) enteric coating: dissolving triethyl citrate in purified water, adding pulvis Talci, high-shearing at 1000r/min for 5min, adding Eudragit L30D-55 under slowly stirring (200 r/min), and mixing to obtain enteric coating solution; coating the aspirin tablets by using the enteric-coated coating solution at a coating speed of 60g/min, a rotating speed of the coating pan of 3r/min and a material temperature of 28 ℃ by using a coating pan to obtain the aspirin enteric-coated tablets (the tablet weight is 141 mg/tablet, and the weight is increased by 14.9 percent relative to the aspirin tablets).

(2.3) coating of the first separation layer: spraying at a speed of 60g/min, rotating at a speed of 3 revolutions per minute in a coating pan, heating the material at 28 ℃, and coating (the tablet weight is 145.2mg, and the weight is increased by 2.97%);

(2.4) medicine application: dissolving the agents H-HPC, L-HPC, vitamin E and polyethylene glycol in 95% ethanol, adding micronized clopidogrel sulfate (particle size is 5-30 μm), and high-shearing at the speed of 1000r/min for 5min to obtain a medicine solution; and coating the aspirin enteric-coated tablet by using the medicinal solution at the spraying speed of 60g/min, the rotating speed of a coating pot of 3r/min and the material temperature of 25 ℃ to obtain the clopidogrel hydrogen sulfate aspirin tablets (the weight of the tablets is 257.7mg, and the weight is increased by 77.5 percent relative to the aspirin enteric-coated tablet).

(2.5) coating of the second separation layer: coating the clopidogrel aspirin sulfate tablet by using the isolating layer coating slurry at the spraying speed of 120g/min, the rotating speed of a coating pan of 3r/min and the material temperature of 25 ℃ to obtain the clopidogrel aspirin sulfate tablet containing an isolating layer (the weight is increased by 3 percent relative to the clopidogrel aspirin sulfate tablet).

(2.6) film coating: coating the clopidogrel aspirin tablet containing the isolation coating layer by using the film layer coating slurry at a spraying speed of 60g/min, a coating pot rotating speed of 3r/min and a material temperature of 25 ℃, and carrying out aluminum-plastic packaging on the obtained clopidogrel aspirin tablet (the tablet weight is 0.278 g/tablet, and the weight is increased by 4.7 percent relative to the clopidogrel aspirin tablet containing the isolation coating layer).

Example 2

Clopidogrel sulfate aspirin tablets were prepared according to the method of example 1, differing from example 1 only in that:

the aspirin tablet comprises the following components: 100mg of aspirin (the ratio of the particle size of 20-60 meshes is 80%), 6mg of starch and 1029mg of microcrystalline cellulose;

the enteric coating comprises the following components: 0.4mg of triethyl citrate, 7mg of talcum powder, 50mg of purified water and 30D-5540mg of Equidz L, wherein the weight is increased by 16%;

the first isolating layer coating slurry comprises the following components: 5% by weight of an aqueous H-HPC solution, increased by 3%;

the composition of the medicine solution is as follows: 5mg of H-HPC, 5mg of L-HPC, 2mg of vitamin E, 5.8mg of polyethylene glycol, 98.0mg of micronized clopidogrel sulfate (particle size is 5-30 mu m), and absolute ethyl alcohol with the solid content of 28wt%;

the second isolating layer coating slurry comprises the following components: H-HPC and 95% ethanol, the solid content is 3wt%, and the weight is increased by 3%;

coating slurry on the film layer: opadry EZ coating powder and purified water, wherein the solid content is 18wt%;

obtaining clopidogrel sulfate aspirin tablets (the weight of the tablet is 0.273 g/tablet, and the weight of the tablet is increased by 5 percent compared with that of the clopidogrel sulfate aspirin tablet containing a second isolation coating layer)

Example 3

the aspirin tablet comprises the following components: 100mg of aspirin (80% of particle size of 20-60 meshes), 8mg of starch and 102-10 mg of microcrystalline cellulose;

the enteric-coated layer coating liquid comprises: 0.8mg of triethyl citrate, 9mg of talcum powder, 50mg of purified water, 100 40mg of Ewing L, 20 percent of solid content and 16 percent of weight gain;

the first isolating layer coating slurry comprises the following components: 4mg of H-HPC and 40001mg of polyethylene glycol are prepared into 5wt% aqueous solution, and the weight is increased by 3.4%;

the composition of the medicine solution is as follows: 6mg of H-HPC, 7.5mg of L-HPC, 0.25mg of vitamin E, 8mg of polyethylene glycol, 98.0mg of micronized clopidogrel sulfate (particle size is 5-30 mu m), 95% volume fraction ethanol solution (abbreviated as 95% ethanol), and 26wt% solid content;

the second isolating layer coating slurry comprises the following components: H-HPC2.7mg, talcum powder 2.7mg and absolute ethyl alcohol, the solid content is 3wt%;

coating slurry on the film layer: opadry EZ coating powder (the model is Opadry EZ color, and the purchasing manufacturer is Shanghai Kalekang coating technology limited) and purified water, wherein the solid content is 18wt%;

the clopidogrel hydrogen sulfate aspirin tablet containing the second isolation coating layer is increased by 3 percent relative to the clopidogrel hydrogen sulfate aspirin tablet;

the tablet weight of the clopidogrel sulfate aspirin tablet is 0.276 g/tablet, and is 3 percent of the weight of the clopidogrel sulfate aspirin tablet containing the second isolation coating layer.

Example 4

the aspirin tablet comprises the following components: 100mg of aspirin (the ratio of the particle size of 20-60 meshes is 80%), 7mg of starch and 8028mg of microcrystalline cellulose KG;

the enteric coating comprises the following components: triethyl citrate 0.6mg, talcum powder 8mg, purified water 50mg, eudragit L100 40mg, weight gain 16%;

the first isolating layer coating slurry comprises the following components: 4mg of H-HPC and 40001mg of polyethylene glycol are prepared into 5wt% aqueous solution, and the weight is increased by 2.4%;

the composition of the medicine solution is as follows: 5.5mg of H-HPC, 6mg of L-HPC, 0.2mg of vitamin E, 5.8mg of polyethylene glycol, 98.0mg of micronized clopidogrel sulfate (particle size is 5-30 mu m), and anhydrous ethanol with the solid content of 26wt%;

the second isolating layer coating slurry comprises the following components: 3mg of H-HPC, 2.5mg of talcum powder and absolute ethyl alcohol, wherein the solid content is 5wt%;

coating slurry on the film layer: opadry EZ coating powder (opadry EZ color, shanghai Kalerkang coating technology Co., ltd.) and purified water, the solid content is 18wt%;

the clopidogrel hydrogen sulfate aspirin tablet containing the second isolation coating layer is increased by 2.6 percent relative to the clopidogrel hydrogen sulfate aspirin tablet; the weight of the film coating is increased by 3 percent relative to the clopidogrel sulfate aspirin tablet containing the second isolation coating layer.

The tablet weight of the clopidogrel sulfate aspirin tablet is 0.27 g/tablet.

Example 5

the aspirin tablet comprises the following components: 100mg of aspirin (the ratio of the particle size of 20-60 meshes is 80%), 7mg of starch and 802 mg of microcrystalline cellulose KG;

the enteric-coated layer coating liquid comprises: 0.8mg of triethyl citrate, 8mg of talcum powder, 50mg of purified water and 30D-5540mg of Equidz L, wherein the weight is increased by 14%;

the first isolating layer coating slurry comprises the following components: 5wt% of H-HPC aqueous solution, weight gain 3.2%;

the composition of the medicine solution is as follows: 5.0mg of H-HPC, 6mg of L-HPC, 0.18mg of vitamin E, 6000.0 mg of polyethylene glycol, 98.0mg of micronized clopidogrel sulfate, absolute ethyl alcohol and 25wt% of solid content; micronization treatment of clopidogrel sulfate is obtained by micronization treatment of clopidogrel sulfate, and the particle size is 5-30 mu m;

the second isolating layer coating slurry comprises the following components: H-HPC3.5mg, talcum powder 2mg and absolute ethyl alcohol, wherein the solid content is 4wt%;

coating slurry on the film layer: opadry EZ coating powder (type opadry EZ color, purchased from shanghai kalekang coating technology limited) and purified water, with a solid content of 20wt%.

The clopidogrel hydrogen sulfate aspirin tablet containing the second isolation coating layer is increased by 3.6 percent relative to the clopidogrel hydrogen sulfate aspirin tablet, and the film coating is increased by 5 percent relative to the clopidogrel hydrogen sulfate aspirin tablet containing the second isolation coating layer.

The tablet weight of the clopidogrel sulfate aspirin tablet is 0.272 g/tablet.

Example 6

the aspirin tablet comprises the following components: 100mg of aspirin (the ratio of the particle size of 20-60 meshes is 80%), 7mg of starch and 1028mg of microcrystalline cellulose pH;

the enteric-coated layer coating liquid comprises: triethyl citrate 0.4mg, talcum powder 8mg, purified water 50mg, ewing L30D-5540mg, enteric layer weight gain 18%;

the composition of the medicine solution is as follows: 5.5mg of H-HPC, 5mg of starch, 6mg of L-HPC, 1.6mg of vitamin E, 6000.0 mg of polyethylene glycol and 98.0mg of micronized clopidogrel sulfate, and the solid content of absolute ethyl alcohol is 24wt%; micronization treatment of clopidogrel sulfate is obtained by micronization treatment of clopidogrel sulfate, and the particle size is 5-30 mu m;

the second isolating layer coating slurry comprises the following components: 3mg of H-HPC, 3mg of polyethylene glycol and absolute ethyl alcohol, wherein the solid content is 6wt%;

coating slurry on the film layer: opadry EZ coating powder (the model is Opadry EZ color, and the purchasing manufacturer is Shanghai Kalekang coating technology limited) and purified water, wherein the solid content is 20wt%;

the clopidogrel bisulfate aspirin tablet containing the second isolation coating layer is increased by 4 percent relative to the clopidogrel bisulfate aspirin tablet, and the film coating is increased by 5 percent relative to the clopidogrel bisulfate aspirin tablet containing the second isolation coating layer;

the tablet weight of the clopidogrel sulfate aspirin tablet is 0.285 g/tablet.

Example 7

the aspirin tablet comprises the following components: 100mg of aspirin (the ratio of the particle size of 20-60 meshes is 80%), 7mg of starch and 102 mg of microcrystalline cellulose;

the enteric coating comprises the following components: triethyl citrate 1.2mg, talcum powder 8mg, purified water 50mg, ewing L30D-5540mg, weight gain 15%;

the first isolating layer coating slurry comprises the following components: H-HPC3wt% aqueous solution, 3.5% weight gain;

the composition of the medicine solution is as follows: 6.5mg of H-HPC, 6mg of starch, 0.18mg of vitamin E, 6000.0 mg of polyethylene glycol, 5.0mg of L-HPC, 98.0mg of micronized clopidogrel sulfate and absolute ethyl alcohol, wherein the solid content is 26wt%; micronization treatment of clopidogrel sulfate is obtained by micronization treatment of clopidogrel sulfate, and the particle size is 5-30 mu m;

the second isolating layer coating slurry comprises the following components: H-HPC2.7mg, polyethylene glycol 60002.7mg and absolute ethanol, the solid content is 5wt%;

coating slurry on the film layer: opadry EZ coating powder (model number is Opadry EZ color, and purchasing manufacturer is Shanghai Kalekang coating technology Co., ltd.) and purified water, and the solid content is 18wt%.

The clopidogrel hydrogen sulfate aspirin tablet containing the second isolation coating layer is increased by 3 percent relative to the clopidogrel hydrogen sulfate aspirin tablet, and the film coating is increased by 5 percent relative to the clopidogrel hydrogen sulfate aspirin tablet containing the second isolation coating layer;

the tablet weight of the clopidogrel sulfate aspirin tablet is 0.279g per tablet.

Example 8

the aspirin tablet comprises the following components: 100mg of aspirin (the proportion of the particle size of 20-60 meshes is 80%), 7mg of starch and 102 mg of microcrystalline cellulose pH;

the enteric coating comprises the following components: triethyl citrate 1.4mg, talcum powder 8mg, purified water 50mg, ewing L30D-5540mg, weight gain 16.2%;

the first isolating layer coating slurry comprises the following components: 3wt% of an aqueous solution of H-HPC, increased by 2.2%;

the composition of the medicine solution is as follows: 5.5mg of H-HPC, 5mg of lactose, 6mg of L-HPC, 0.2mg of vitamin E, 6000.8mg of polyethylene glycol, 98.0mg of clopidogrel sulfate subjected to micronization treatment, absolute ethyl alcohol and the solid content of 26wt%; micronization treatment of clopidogrel sulfate is obtained by micronization treatment of clopidogrel sulfate, and the particle size is 5-30 mu m;

the second isolating layer coating slurry comprises the following components: 3mg of H-HPC, 2.4mg of polyethylene glycol and absolute ethyl alcohol, wherein the solid content is 5wt%;

the clopidogrel bisulfate aspirin tablet containing the second isolation coating layer is increased by 2.6 percent relative to the clopidogrel bisulfate aspirin tablet, and the film coating is increased by 5.4 percent relative to the clopidogrel bisulfate aspirin tablet containing the second isolation coating layer

The tablet weight of the clopidogrel sulfate aspirin tablet is 0.266 g/tablet.

Example 9

the aspirin tablet comprises the following components: 100mg of aspirin (the ratio of the particle size of 20-60 meshes is 80%), 7mg of starch and 802 mg of microcrystalline cellulose;

the enteric coating comprises the following components: triethyl citrate 1.4mg, talcum powder 8.2mg, pure water 50mg, equid L30D-5540mg, weight gain 15%;

the first isolating layer coating slurry comprises the following components: H-HPC3.4mg, polyethylene 4000.6mg, and 4wt% of water solution, the weight is increased by 2%;

the composition of the medicine solution is as follows: 4.5mg of H-HPC, 6.7mg of L-HPC, 0.12mg of vitamin E and 6000.0 mg of polyethylene glycol are dissolved in absolute ethanol solution, 98.0mg of micronized clopidogrel sulfate is added, and the solid content is 24wt%; micronization treatment of clopidogrel sulfate is obtained by micronization treatment of clopidogrel sulfate, and the particle size is 5-30 mu m;

the second isolating layer coating slurry comprises the following components: H-HPC2.7mg, talcum powder 2.7mg, absolute ethyl alcohol, solid content is 5wt%;

the clopidogrel bisulfate aspirin tablet containing the second isolation coating layer is increased by 3.6 percent relative to the clopidogrel bisulfate aspirin tablet, and the film coating is increased by 3.4 percent relative to the clopidogrel bisulfate aspirin tablet containing the second isolation coating layer

The tablet weight of the clopidogrel sulfate aspirin tablet is 0.266 g/tablet.

Example 10

the enteric coating comprises the following components: triethyl citrate 1.0mg, talcum powder 8.2mg, pure water 50mg, equid L30D-5540mg, coating weight gain 18%;

the first isolating layer coating slurry comprises the following components: 3.5 of H-HPC and 1mg of polyethylene glycol to prepare a 3wt% aqueous solution, and the coating weight is increased by 2.8%;

the composition of the medicine solution is as follows: 8mg of H-HPC, 13mg of L-HPC, 20mg of starch, 10mg of lactose, 0.12mg of vitamin E and 6000 12mg of polyethylene glycol are dissolved in an absolute ethanol solution, 98.0mg of micronized clopidogrel sulfate is added, and the solid content is 25wt%; micronization treatment of clopidogrel sulfate is obtained by micronization treatment of clopidogrel sulfate, and the particle size is 5-30 mu m;

the second isolating layer coating slurry comprises the following components: 3mg of H-HPC, 2.4mg of talcum powder and absolute ethyl alcohol, wherein the solid content is 3wt%;

coating slurry on the film layer: opadry EZ coating powder (the model is Opadry EZ color, and the purchasing manufacturer is Shanghai Kalekang coating technology Co., ltd)) and purified water, wherein the solid content is 18wt%;

the clopidogrel hydrogen sulfate aspirin tablet containing the second isolating coat layer is increased by 3.6 percent relative to the clopidogrel hydrogen sulfate aspirin tablet, and the film coat is increased by 3.4 percent relative to the clopidogrel hydrogen sulfate aspirin tablet containing the second isolating coat layer

The tablet weight of the clopidogrel sulfate aspirin tablet is 0.322 g/tablet.

Example 11:

clopidogrel sulfate aspirin tablets were prepared according to the method of example 10, differing from example 10 only in that:

replacing the colored Opadry EZ coating powder with Opadry EZ transparent coating powder, and purchasing Kalopanan coating technology Co., ltd.) and purified water, wherein the solid content is 8wt%; the weight gain of the film coating is 3.4%.

The tablet weight of the clopidogrel sulfate aspirin tablet is 0.322 g/tablet.

Comparative example 1

Clopidogrel sulfate aspirin tablets were prepared according to the method of example 10, differing from example 10 only in that: comparative example 1 was prepared by replacing the colored opadry EZ coating powder with HPMC coating solution with 15% solids.

Test experiments:

(1) Ease of swallowing test: the ease of swallowing of the clopidogrel sulfate aspirin tablets prepared in comparative example 1, example 10, and example 11 was compared by dynamic friction, and the test results are shown in fig. 1, from which it can be seen that the friction force was significantly reduced in the sample coated with the opadry EZ series product shown in fig. 1.

(2) Test of dissolution performance of clopidogrel and aspirin in clopidogrel sulfate aspirin tablets

Dissolution curve: the clopidogrel aspirin tablets (self-made) and clopidogrel aspirin sulfate tablets (reference, pionfine (china) investment limited) prepared in examples 1 to 8 were subjected to dissolution measurement by a method specified in the imported registration standard JX 20200034.

The dissolution rate is determined by a dissolution rate and release rate determination method (first method of 0931 in the four-part general rules of the 2020 edition of Chinese pharmacopoeia).

Dissolution conditions (1): 1000mL of an acid solution (2.0 g of sodium chloride, 7.0mL of hydrochloric acid and water were added to dissolve the sodium chloride, water was added to dilute the solution to 1000mL, and the pH of the solution was 1.2) was used as a dissolution medium, the rotation speed was 75 rpm, the operation was performed according to the method, and samples were taken at 30 and 120 minutes.

Dissolution conditions (2): 1000mL of phosphate buffer (pH6.8) (anhydrous potassium dihydrogen phosphate 3.401 disodium hydrogen phosphate 3.55g, dissolved and diluted with water to 1000 mL) at a rotation speed of 100 rpm for 90 minutes;

the dissolution test was carried out, and the dissolution results are shown in FIGS. 2 to 17. FIG. 2 is a clopidogrel dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 1 and a clopidogrel sulfate tablet, FIG. 3 is an aspirin dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 1 and an aspirin tablet, FIG. 4 is a clopidogrel dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 2 and a clopidogrel sulfate tablet, FIG. 5 is an aspirin dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 2 and an aspirin tablet, FIG. 6 is a clopidogrel dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 3 and a clopidogrel sulfate tablet, FIG. 7 is an aspirin dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 3 and an aspirin tablet, FIG. 8 is a clopidogrel sulfate aspirin tablet prepared in example 4 and a clopidogrel sulfate tablet, FIG. 9 is an aspirin dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 4 with an aspirin tablet, FIG. 10 is a clopidogrel dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 5 with a clopidogrel sulfate tablet, FIG. 11 is an aspirin dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 5 with an aspirin tablet, FIG. 12 is a clopidogrel dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 6 with a clopidogrel sulfate tablet, FIG. 13 is an aspirin dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 6 with an aspirin tablet, FIG. 14 is a clopidogrel sulfate aspirin tablet prepared in example 7 with a clopidogrel sulfate tablet, FIG. 15 is an aspirin dissolution curve of a clopidogrel sulfate aspirin tablet prepared in example 7 with an aspirin tablet, fig. 16 is a clopidogrel dissolution curve of a clopidogrel sulfate aspirin sheet prepared in example 8 and a clopidogrel sulfate sheet, fig. 17 is an aspirin dissolution curve of a clopidogrel sulfate aspirin sheet prepared in example 8 and an aspirin sheet, fig. 18 is a clopidogrel dissolution curve of a clopidogrel sulfate aspirin sheet prepared in example 9 and a clopidogrel sulfate sheet, fig. 19 is an aspirin dissolution curve of a clopidogrel sulfate aspirin sheet prepared in example 9 and an aspirin sheet, fig. 20 is a clopidogrel dissolution curve of a clopidogrel sulfate aspirin sheet prepared in example 10 and a clopidogrel sulfate sheet, and fig. 21 is an aspirin dissolution curve of a clopidogrel sulfate aspirin sheet prepared in example 10 and an aspirin sheet, and it can be seen from fig. 2 to 21 that clopidogrel sulfate reference sheets in the clopidogrel sulfate aspirin sheet prepared in the invention substantially coincide, and aspirin dissolution curves of the clopidogrel sulfate aspirin sheets and the aspirin sheets are similar, and the in-vitro dissolution of a self-made product is consistent with a reference preparation.

(3) The results of stability test of clopidogrel sulfate aspirin tablets prepared in examples 1 to 8 are shown in tables 1 to 8. The stability test method comprises the following steps: the relevant substance detection method specified in the imported registration standard JX20200034 is used for detection.

Table 1 stability test results of clopidogrel-related substances in clopidogrel sulfate aspirin tablets obtained in examples 1 to 8

Table 2 results of stability test of aspirin-related substances in clopidogrel sulfate aspirin tablets obtained in examples 1 to 8

As can be seen from tables 1-2, the quality of the self-preparation was comparable to that of the reference preparation.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and amendments can be made without departing from the principle of the present invention, and these modifications and amendments should also be considered as the protection scope of the present invention.

Claims

1. The clopidogrel sulfate aspirin tablet is characterized by sequentially comprising an aspirin tablet core, an enteric coating layer, a first isolation coating layer, a clopidogrel sulfate upper medicine layer, a second isolation coating layer and a film coating layer from inside to outside, wherein the mass of the clopidogrel sulfate aspirin tablet is less than or equal to 0.35 g/tablet;

the composition of the enteric coating layer comprises: 2.5 to 6 percent of enteric coating powder, 0.25 to 1.2 percent of triethyl citrate and 1.25 to 4.8 percent of opacifier;

the clopidogrel sulfate medicine-applying layer comprises the following components: 19 to 38 percent of clopidogrel sulfate, 0.5 to 5 percent of adhesive, 0.05 to 2 percent of antioxidant, 0.02 to 1 percent of polyethylene glycol and 1 to 5 percent of disintegrant; the amount of clopidogrel sulfate is calculated by clopidogrel;

2. The clopidogrel sulfate aspirin tablet of claim 1, wherein the enteric coating powder comprises one or more of a copolymer of methacrylic acid and ethyl acrylate, a copolymer of methacrylic acid and methyl methacrylate, and a copolymer of methacrylic acid and methyl methacrylate.

3. The clopidogrel sulfate aspirin tablet of claim 1, wherein the opacifier comprises one or more of talc, calcium carbonate, calcium sulfate, and iron oxide.

4. The clopidogrel sulfate aspirin tablet of claim 1, wherein the diluent comprises starch and/or lactose.

5. The process for preparing clopidogrel sulfate aspirin tablet according to any one of claims 1 to 4, characterized by comprising the steps of:

mixing the enteric coating powder, triethyl citrate, an opacifier and water to obtain an enteric coating layer component solution;

mixing clopidogrel sulfate, an adhesive, an antioxidant, polyethylene glycol, a disintegrating agent and an alcohol solvent to obtain a medicinal solution;

mixing high-substituted hydroxypropyl cellulose and water to obtain first isolation layer coating pulp;

mixing the high-substituted hydroxypropyl cellulose and an alcohol solvent to obtain second isolation layer coating slurry;

6. The method of claim 5, wherein the parameters of the first barrier layer coating include: the spraying speed is 60-120 g/min, the rotating speed of a coating pan is 3-8 r/min, and the material temperature is 28-35 ℃.

7. The method of claim 5, wherein the parameters of the enteric coating include: the spraying speed is 60-120 g/min, the rotating speed of a coating pan is 3-8 r/min, and the material temperature is 28-35 ℃.

8. The preparation method according to claim 5, wherein the process parameters of the drug delivery comprise: the spraying speed of the medicine solution is 60-260 g/min, the rotating speed of a coating pot is 3-12 r/min, and the material temperature is 25-45 ℃.

9. The method of claim 5, wherein the process parameters of the second barrier layer coating and the film layer coating comprise: the spraying speed is independently 60-120 g/min, the rotating speed of the coating pan is independently 3-8 r/min, and the material temperature is independently 25-50 ℃.

10. Use of the clopidogrel aspirin tablet of any one of claims 1 to 4 or the clopidogrel aspirin tablet prepared by the preparation method of any one of claims 5 to 9 in the preparation of a medicament for treating cardiovascular and cerebrovascular diseases.