Preparation method of clopidogrel and aspirin coated chip compound preparation

Abstract

The invention discloses a clopidogrel and aspirin coated tablet compound preparation, which is a tablet prepared from an inner layer aspirin enteric-coated tablet core and outer layer clopidogrel hydrogen sulfate particles through core-spun pressing, and a coated tablet prepared by coating the tablet with two layers of films, and particularly discloses a preparation method of the clopidogrel and aspirin coated tablet compound preparation. According to the compound preparation prepared by the invention, the stickiness of the medicine is reduced, the fluency of the tabletting process is improved, the problems of precipitation, gun blockage and the like in the coating process are solved by adopting a specific coating material for coating, and meanwhile, the pressure resistance of tablets is improved; and the problems of poor flowability, non-uniform particles and low yield of medicine particles are solved, so that the stability of the compound preparation is improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceuticals and relates to a compound preparation of clopidogrel aspirin coated chip and a preparation method thereof. Background Art

[0002] Clopidogrel bisulfate is a platelet aggregation inhibitor jointly developed and promoted by Sanofi Pharmaceuticals Inc and Bristol-Myers Squibb Company. It was first approved for marketing in the United States on November 17, 1997. The marketed dosage form is tablets with a specification of 75 mg. The approved indications are for reducing atherosclerotic events (myocardial infarction, stroke, and vascular death) in the following patients: patients with recent stroke, patients with recent myocardial infarction, or patients with diagnosed peripheral arterial disease. Subsequently, new specifications (25 mg, 300 mg) and new indications (for acute coronary syndrome) of this product have been approved for marketing in many countries and regions.

[0003] Aspirin irreversibly inhibits platelet aggregation by inhibiting platelet cyclooxygenase and can effectively prevent the formation of thrombus. Aspirin can cause damage to the digestive tract mucosa, and long-term use may cause gastric and duodenal mucosal ulcers and bleeding in patients. Enteric-coated aspirin tablets can reduce the direct irritation of aspirin to the gastric mucosa. There is a P2Y12 receptor for adenosine diphosphate (ADP) on the high-density granules of platelet cells, which will accelerate the platelet aggregation process, while clopidogrel is a blocker of the P2Y12 receptor and can irreversibly inhibit platelet aggregation. The mechanisms of action of aspirin and clopidogrel are different, and they play an antiplatelet role from two different pathways. When used in combination, they can produce a synergistic effect of additive action, which is called "dual antiplatelet therapy". For extremely high-risk populations of ischemic cardiovascular and cerebrovascular diseases and patients after stent implantation, platelets in the body are in a hypercoagulable state, so it is necessary to use the "dual antiplatelet therapy" method to inhibit platelet activity, and the combination of aspirin and clopidogrel can be used.

[0004] The combination tablet of clopidogrel bisulfate and aspirin of Sanofi was approved in Singapore in August 2008 under the trade name CoPlavix, and then approved in Europe in November 2015 under the trade name DuoPlavin, and has now been approved in more than 70 countries / regions. In order to reduce the gastrointestinal irritation of aspirin, Sanofi Japan developed a new combination tablet, that is, enteric-coated aspirin as the inner core and clopidogrel bisulfate as the outer layer, combined into a coated chip, and was launched in Japan in September 2013 under the trade name ComPlavix, with the specification of 75 mg of clopidogrel / 100 mg of aspirin. The prescription process of this new combination tablet was introduced in the original patent CN105407877. The inner core and the outer layer are separated by a three-layer coating composed of an acid-resistant layer inserted between two isolation layers. The acid-resistant layer contains at least one acid-resistant polymer and talc powder at least 40% by weight relative to the acid-resistant polymer.

[0005] It is described in patent CN105407877 that the amount of talc powder should be more than 40% by weight relative to the acid-resistant polymer to obtain a complete acid-resistant tablet. 25% of talc powder cannot withstand the secondary pressing process of the coated chip, resulting in an acid-sensitive aspirin inner core. According to the enteric coating prescription in Example 1 of the original patent CN105407877, the talc powder is easy to settle, and there is a little flocculation phenomenon in the coating solution at room temperature, which is easy to block the gun, and the coating process is not smooth enough.

[0006] The coating solution formula used for the isolation layer 1 is triethyl citrate, talc powder, and hydroxypropyl methylcellulose. It was found during the research process that this formula can more effectively slow down the generation of salicylic acid and increase the stability of the aspirin tablet core.

[0007] In the original patent CN105407877 and the Lepu patent CN112587495, the hot melt granulation of the clopidogrel layer is achieved by a fluidized bed. And the fluidized bed granulation in the Lepu patent CN112587495 also requires opening the bin and turning the materials halfway for secondary granulation. After investigation, using a wet granulator with a water bath sandwich or electric heating can effectively improve the particle yield, reduce the granulation time, lower the fine powder rate, make the granulation uniform, and improve the particle fluidity.

[0008] To solve the above problems, in this application, aspirin starchified granules are prepared by dry granulation. Through the wrapping of corn starch, the stickiness of aspirin is reduced, and the smoothness of the tableting process is improved. Triethyl citrate is used as a plasticizer and talc powder as an anti-adhesive agent for the isolation layer 1, which delays the generation of salicylic acid and increases the stability of the aspirin tablet core. When performing enteric coating, by using enteric coating materials MAE30DP, Eudragit L30D-55, etc., and reduce the dosage of talc powder. Add glyceryl monostearate and diglyceryl monostearate as anti-adhesives to the formulation to improve the stability of the enteric coating solution, making the coating process easier to control. At the same time, when compression molding with the core of clopidogrel bisulfate granules, it has better pressure resistance. The hot melt granulation of clopidogrel uses a hot melt wet granulator with a water bath sandwich layer for hot melt granulation, which improves the problems of poor particle fluidity, uneven particles, and low yield in fluidized bed hot melt granulation. The production process of the prepared clopidogrel bisulfate and aspirin compound tablets is smooth, and the enteric-coated aspirin tablets prepared with this formulation have better stability compared with the original research formulation of Sanofi. Currently, the compound tablets of aspirin and clopidogrel bisulfate on the market have problems such as easy sedimentation of the coating formulation, difficult control of the coating process, and high growth of the hydrolysis product salicylic acid of aspirin. And the existing technology uses fluidized bed hot melt granulated particles with poor fluidity. These problems lead to low product stability and unsmooth coating. Therefore, there is an urgent need in the art for a new preparation method of clopidogrel aspirin coated tablets to overcome the defects of the existing technology. Summary of the Invention

[0009] To achieve the above objectives, the main technical solutions adopted in the present invention are as follows: Optimize the prescription and process of the isolation layer 1 and enteric coating to delay the growth of salicylic acid, the hydrolysis product of aspirin, improve the stability of its samples, solve the problems of talc precipitation and gun jamming during the enteric coating process of aspirin, and improve the process fluency. At the same time, a preparation method of a compound tablet of aspirin and clopidogrel bisulfate is also provided. The enteric coating process of this method is smooth, the enteric-coated aspirin tablets have good pressure resistance, the process is relatively simple, the compound preparation has good stability, and it is suitable for mass production, storage, and transportation.

[0010] The solid content in this application all refers to the mass fraction.

[0011] The present invention adopts the following technical solutions:

[0012] A compound preparation of clopidogrel aspirin coated tablets, which is a tablet formed by core compression molding of an inner enteric-coated aspirin tablet core and an outer layer of clopidogrel bisulfate granules, and then made into a coated tablet through two-layer film coating;

[0013] In the present invention, the inner enteric-coated aspirin tablet core is composed of a drug-containing tablet, isolation layer 1 coating, enteric layer coating, and isolation layer 2 coating from the inside to the outside, and the ratio of the drug-containing tablet, isolation layer 1 coating, enteric layer coating, and isolation layer 2 coating is 124:2.48 - 6.20:25.30 - 33.85:3.04 - 7.81;

[0014] Further, the medicated core tablets in the enteric-coated aspirin tablets are prepared from a filler, a binder, a glidant, and a lubricant. Based on the mass of aspirin, the proportions of the excipients are as follows: filler 5-15%, more preferably 7-11%; binder 7-15%, more preferably 9-12%; glidant 0.1-0.6%, more preferably 0.2-0.4%; lubricant 0.2-0.8%, more preferably 0.3-0.7%;

[0015] The binder in the medicated core tablets is selected from any one or more of corn starch, polyvinylpyrrolidone, copolyvinylpyrrolidone (i.e., PVP / VA), hydroxypropyl methylcellulose (i.e., HPMC), and ethylcellulose (i.e., EC);

[0016] The filler in the medicated core tablets is selected from any one or more of pregelatinized starch, dextrin, microcrystalline cellulose, lactose, mannitol, and sorbitol;

[0017] The glidant in the medicated core tablets is selected from any one or more of colloidal silica, talc, sodium stearyl fumarate, and sucrose fatty acid ester;

[0018] The lubricant in the medicated core tablets is selected from any one or more of stearic acid, magnesium stearate, sodium lauryl sulfate, and glyceryl behenate;

[0019] Furthermore, the coating of the first isolation layer in the enteric-coated aspirin tablets is prepared from a film coating premix, preferably an Opadry gastro-resistant film coating premix.

[0020] The weight gain of the coating of the first isolation layer is 1-8%, more preferably 2%-5%;

[0021] Furthermore, the enteric coating of the enteric-coated aspirin tablets is composed of a coating material and a gastric tolerance polymer composition. The mass ratio of each component is as follows: gastric tolerance polymer: talc: triethyl citrate: glyceryl monostearate and distearate: polysorbate 80 is 10: 2.5-3.9: 1.8-2.2: 0.45-0.55: 0.18-0.22; Further, in the enteric coating, the gastric tolerance polymer coating material is a BASF enteric coating material MAE30DP or Evonik Eudragit L30D-55;

[0022] The weight gain of the enteric coating is 18%-30%, more preferably 20%-26%;

[0023] Furthermore, the coating of the second isolation layer in the enteric-coated aspirin tablets is composed of HPMC and polyethylene glycol, and the mass ratio of the two is (8-10): 1; More preferably, the mass ratio of the two is 9: 1;

[0024] Among them, the weight gain of the coating of the isolation layer 2 is 1-8%, more preferably 2%-5%;

[0025] Specifically, the weight of the enteric-coated aspirin tablet core is 154 mg to 172 mg, preferably 158 mg to 168 mg.

[0026] In the present invention, the outer layer of clopidogrel bisulfate particles is composed of clopidogrel bisulfate, anhydrous lactose, polyethylene glycol 6000, pregelatinized starch, tocopherol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, hydrogenated castor oil, and sucrose stearate;

[0027] Specifically, the parts of each component in the outer layer of clopidogrel bisulfate particles are as follows: 95-105 parts of clopidogrel bisulfate, 87-93 parts of anhydrous lactose, 21-25 parts of polyethylene glycol 6000, 96-100 parts of microcrystalline cellulose, 23-26 parts of low-substituted hydroxypropyl cellulose, 13-16 parts of pregelatinized starch, 0.1-0.3 parts of tocopherol, 3-4 parts of hydrogenated castor oil, and 2.0-2.5 parts of sucrose stearate;

[0028] In the present invention, the enteric-coated aspirin tablet core and the clopidogrel bisulfate particles are pressed using an approximately 11 mm round punch. In the prepared compound preparation of clopidogrel aspirin coated tablets, the specifications of aspirin and clopidogrel bisulfate are 100 mg: 70-80 mg (calculated as clopidogrel). And it is a film-coated tablet, and the film coating consists of two layers, the bottom layer is the isolation layer coating, and the outer layer is the film coating.

[0029] Furthermore, the two-layer film coating includes: the first film coating layer, which is composed of hydroxypropyl methylcellulose (i.e., HPMC) and talcum powder, and the second film coating layer material is Opadry gastro-resistant film coating premix;

[0030] Specifically, the mass ratio of HPMC to talcum powder in the first film coating layer is 5.8-7.0:1, and a coating solution with a solid content of 5%-8% is prepared, and the coating weight gain is 1.5%-2.5%. The second film coating layer material is Opadry gastro-resistant film coating premix, and a coating solution with a solid content of 6%-10% is prepared, and the coating weight gain is 2.5%-3.5%;

[0031] The second aspect of the present invention provides a preparation method for any of the above compound preparations of clopidogrel aspirin coated tablets, including the following steps:

[0032] Prepare clopidogrel bisulfate particles and enteric-coated aspirin tablets separately, then mix and press them according to the above ratio, and then perform two-layer coating to obtain;

[0033] Further, the preparation method of the clopidogrel bisulfate granules comprises the following steps: taking 10% - 20% by mass of pregelatinized starch and tocopherol according to the above ratio, granulating and mixing them in a wet granulator to obtain mixture 1; mixing mixture 1 with 10% - 20% by mass of pregelatinized starch using a mixing hopper to obtain mixture 2, then mixing mixture 2 using a twin-screw extruder, and screening and dispersing it through a 0.8 - 1.0 mm sieve to obtain a mixture with uniform tocopherol; adding clopidogrel bisulfate, anhydrous lactose, polyethylene glycol 6000, 40% - 60% low-substituted hydroxypropyl cellulose, mixture 2, and the remaining 60% - 80% by mass of pregelatinized starch according to the above ratio into a hot-melt wet granulator for mixing, with a mixing time of 5 - 15 minutes, setting the water bath temperature at 75 - 90 °C, preferably 85 °C, waiting for the material temperature to rise to 65 - 75 °C, and then performing granulation operation, where the stirring speed is 80 - 120 rpm, the chopping speed is 500 - 1200 rpm, and the granulation time is 15 - 25 minutes. Then, the prepared granules are sized through a 0.8 - 1.2 mm sieve, and 232 - 236 parts of the sized granules, 95 - 100 parts of microcrystalline cellulose, 10 - 15 parts of low-substituted hydroxypropyl cellulose, 2 - 5 parts of hydrogenated castor oil, and 1.5 - 4 parts of sucrose stearate are added to a lifting mixer and mixed evenly to obtain the clopidogrel bisulfate granules;

[0034] Further, the preparation of the enteric-coated aspirin tablets comprises the following steps:

[0035] S21 The preparation of the aspirin medicated core tablets comprises the following steps: After aspirin is crushed and sized, it is mixed evenly with a filler, the mixed material is granulated in a dry granulator, the obtained granules are screened using a vibrating sieve, the granules that fail to pass through the sieve are processed by a crushing and sizing machine, the sieve aperture is 0.8 mm - 1.2 mm, and the sized granules are combined with the granules that have passed through the sieve to obtain aspirin granules. The prepared aspirin granules, filler, glidant, and lubricant are mixed evenly in a lifting mixer, and then compressed into tablets, controlling the hardness at 2 - 5 kg;

[0036] S22 Preparation of the coating of the first isolating layer: Weigh HPMC, talc powder, and triethyl citrate according to the above ratio, add them to 9 - 11 times the weight of purified water under stirring conditions, and continue to stir slowly until completely dissolved to prepare a coating solution with a solid content of 8 - 10% by mass percentage, and perform coating, with the weight gain of the first isolating layer coating being 1 - 7%.

[0037] S32 Enteric coating:

[0038] S321: Add polysorbate 80 and glyceryl mono- and distearate according to the above ratio to hot water at a temperature above 80 °C to prepare a solution with a solid content of 5 - 8%, stir and dissolve it, and then cool it to below 10 - 30 °C to obtain solution 1;

[0039] S322: Homogenize and disperse triethyl citrate and purified water evenly to form a homogeneous solution. Add talc powder to the above homogeneous solution, continue to homogenize and disperse to form a solution with a solid content of 15 - 25% by mass percentage, and cool it to below 10 - 30 °C to obtain Solution 2.

[0040] S333: Pass the aqueous dispersion of the coating material through a sieve of ≥80 mesh, discard the insoluble matter on the sieve. After weighing the filtrate according to the prescription amount, add it to a dry and clean slurry preparation tank and continuously stir to obtain Solution 3.

[0041] S334: Mix the prepared Solution 1 and Solution 2, add them to Solution 3 under stirring conditions to obtain a suspension. Under stirring conditions, mix the suspension and the coating material according to a mass ratio of 1:1.4 - 1.5, continue to stir for 1 - 3 h, coat, and dry. The weight gain of the enteric coating layer is 20 - 26%.

[0042] S33 Preparation of the second isolation layer coating:

[0043] Weigh HPMC and talc powder according to the above ratio, mix them, and add purified water with a mass 9 - 11 times that of the mixture under stirring conditions. Continue to stir slowly until it is completely dissolved to form a coating solution with a solid content of 5 - 12% by mass percentage. Coat, and the weight gain of the second isolation layer coating is 1 - 8%.

[0044] Further, mixing the two according to the above ratio and tableting includes the following steps:

[0045] Mix the prepared enteric-coated aspirin tablets and clopidogrel bisulfate granules according to a ratio of 1:2.1 - 2.2, use a round punch with a diameter of 10 - 12 mm, and tablet under a pressure of 15 KN - 25 KN. Control the tablet weight variation within ±5% to obtain tablets with a hardness of 3 - 10 kg.

[0046] Further, the two-layer coating includes the following steps:

[0047] S41 Preparation of the coating solution 1 for the first film coating layer: Prepare a coating solution with a solid content of 5 - 8% by mass percentage from HPMC and talc powder according to the above ratio, and coat to make the weight gain of the first film coating layer 2 - 4%.

[0048] S42 Preparation of the coating solution 2 for the second film coating layer: Prepare a coating solution with a solid content of 7 - 11% by mass percentage from the film coating premix, and coat to make the weight gain of the second film coating layer 3 - 5%.

[0049] The third aspect of the present invention provides the use of any of the above clopidogrel aspirin coated tablet compound preparations in the preparation of drugs for inhibiting platelet aggregation, reducing myocardial infarction in patients with atherosclerosis, treating transient cerebral ischemia or stroke.

[0050] Beneficial effects

[0051] The technical solution of the present invention has the following beneficial effects:

[0052] 1. The enteric-coated aspirin tablets are prepared by dry granulation: In this application, the enteric-coated aspirin granules are prepared by dry granulation. Through the wrapping of corn starch, the stickiness of aspirin is reduced, and the smoothness of the tabletting process is improved.

[0053] 2. The coating of the enteric-coated aspirin tablets is optimized: First, triethyl citrate is used as a plasticizer and talc powder is used as an anti-sticking agent in the isolating layer 1, which delays the generation of salicylic acid and increases the stability of the aspirin tablet core; Second, by using enteric coating materials MAE30DP, EudragitL30D-55, etc. to prepare the enteric coating, while reducing the dosage of the anti-sticking agent talc powder and increasing the dosage of the anti-sticking agent glyceryl monostearate and glyceryl distearate, improving the stability of the enteric coating solution, solving the problems of talc powder precipitation and gun jamming during the coating process, making the coating process easier to control, and having better pressure resistance when core-tabletting with clopidogrel bisulfate granules;

[0054] 3. The hot-melt granulation of clopidogrel is carried out by using a hot-melt wet granulator with a water bath sandwich layer, which improves the problems of poor particle fluidity, uneven particles and low yield in the hot-melt granulation using a fluidized bed;

[0055] In summary, the compound preparation prepared by the present invention has better stability compared with the prior art. Specific embodiments

[0056] In order to better explain the present invention for easy understanding, the present invention will be described in detail below through specific embodiments.

[0057] In a specific embodiment, the specification of the compound preparation contains 75 mg of clopidogrel and 100 mg of aspirin;

[0058] In a specific embodiment, the specification of the compound preparation is that the drug content per tablet is 500 mg to 600 mg, preferably 510 mg to 570 mg, more preferably 530 mg to 555 mg;

[0059] Preparation of aspirin plain tablets in Examples 1-3 and Comparative Example 1

[0060] Table 1 Preparation prescription of aspirin plain tablets

[0061]

[0062] Preparation process:

[0063] 1. Aspirin is passed through a 1.2 mm sieve using a pulverizing and sizing machine and then added to the mixing hopper together with corn starch. The mixing speed is 10 rpm and the mixing time is 20 min.

[0064] 2. The mixed material is added to a dry granulator. The feeding speed is 11 - 15 rpm, the roller speed is 10 - 14 rpm, the crushing knife speed is 100 rpm, the first-stage sizing sieve is 10 * 10 mm and the speed is 100 rpm, the second-stage sizing sieve is 16 mesh and the speed is 300 rpm, the pressure of the pressing wheel is about 19 - 21 KN, and the cooling water temperature of the pressing wheel is 15 - 20 °C.

[0065] 3. Microcrystalline cellulose, colloidal silicon dioxide, and stearic acid are passed through a 0.8 - 1.0 mm sieve for sizing and then added to the prepared dry granules of aspirin in the mixing hopper. The mixing speed is 10 rpm and the mixing time is 20 min.

[0066] 4. Tableting is carried out using a shallow concave round punch with a diameter of about 7.1 mm, and the hardness is controlled at 2 - 4 kg.

[0067] 5. The comparative example is obtained by removing the outer clopidogrel layer of the original research (2K005B) clopidogrel aspirin tablets of Sanofi and simultaneously removing the aspirin coating.

[0068] Examples 5 - 8, Comparative Example 9: Preparation of enteric-coated aspirin tablet cores

[0069] Table 2 Formulation for the preparation of enteric-coated aspirin tablet cores

[0070]

[0071] Preparation process:

[0072] Coating of the first isolation layer:

[0073] Preparation of the coating solution:

[0074] Weigh the prescribed amount of film coating premix (gastric-soluble type) and add an appropriate amount of purified water to prepare a 9 wt% coating solution.

[0075] Coating parameters:

[0076] Put the tablet cores into a coating machine, set the inlet air speed at 1200 rpm, the heating temperature at 40 - 60 °C, preheat the enteric-coated aspirin tablet cores, control the material temperature at 40 - 45 °C, turn on the spray gun pressure at 0.2 - 0.5 mpa, the atomization pressure at 0.2 - 0.5 mpa, the flattening pressure at 0.2 - 0.5 mpa, turn on the peristaltic pump for spraying liquid, control the speed at 10 - 30 rpm, pay attention to monitoring the material temperature and fluidization state during the coating process, and adjust the parameters according to the actual situation to prevent the tablet cores from sticking.

[0077] Coating of the enteric layer:

[0078] Examples 4, 6, and 7

[0079] Preparation of the coating solution:

[0080] Add the prescribed amount of polysorbate 80 and glyceryl mono- and distearate to hot water at a temperature above 80°C to prepare a solution with a solids content of 5 - 8 wt%. After stirring and dissolving, cool it to below 10 - 30°C. Homogeneously disperse triethyl citrate and purified water, add talc powder to the homogeneous solution of triethyl citrate and purified water, and continue to homogeneously disperse to prepare a solution with a solids content of 15 - 25 wt%. Cool it to below 10 - 30°C. For the coating material Pass the aqueous dispersion of MAE30DP or Eudragit L30D-55 through an 80-mesh stainless steel sieve, discard the insoluble matter on the sieve. After weighing the filtrate according to the prescription amount, add it to a dry and clean slurry preparation tank and continuously stir for 1 h. The solids content of the coating solution is 20%.

[0081] Coating parameters:

[0082] Put the tablet cores into a coating machine, set the inlet air rotation speed at 1200 rpm, the heating temperature at 40 - 60°C, preheat the aspirin tablet cores, control the material temperature at 40 - 45°C, turn on the spray gun pressure at 0.2 - 0.5 mpa, the atomization pressure at 0.2 - 0.5 mpa, and the flattening pressure at 0.2 - 0.5 mpa. Turn on the peristaltic pump to spray the liquid, control the rotation speed at 10 - 30 rpm, pay attention to monitoring the material temperature and fluidization state during the coating process, and adjust the parameters according to the actual situation to prevent the tablet cores from sticking. After the coating is completed, control the material temperature at 40°C - 50°C and dry for 30 min.

[0083] Examples 5, Comparative Example 8

[0084] Preparation of the coating solution:

[0085] Homogeneously disperse triethyl citrate and purified water, add the prescribed amount of talc powder to the homogeneous solution of triethyl citrate and purified water, and continue to homogeneously disperse to prepare a solution with a solids content of 15 - 25%. Cool it to below 10 - 30°C. For the coating material Pass the aqueous dispersion of MAE30DP or Eudragit L30D-55 through an 80-mesh stainless steel sieve, discard the insoluble matter on the sieve. After weighing the filtrate according to the prescription amount, add it to a dry and clean slurry preparation tank and continuously stir for 1 h. The solids content of the coating solution is 20%.

[0086] Coating parameters:

[0087] Put the tablet cores into a coating machine. Set the inlet air rotation speed at 1200 rpm and the heating temperature at 40 - 60 °C to preheat the aspirin tablet cores, and control the material temperature at 40 - 45 °C. Turn on the spray gun pressure at 0.2 - 0.5 mpa, the atomization pressure at 0.2 - 0.5 mpa, and the flattening pressure at 0.2 - 0.5 mpa. Turn on the peristaltic pump to spray liquid, and control the rotation speed at 10 - 30 rpm. Pay attention to monitoring the material temperature and fluidization state during the coating process, and adjust the parameters according to the actual situation to prevent the tablet cores from sticking. After the coating is completed, control the material temperature at 40 °C - 50 °C and dry for 30 minutes.

[0088] Example 9, Preparation of Clopidogrel Bisulfate Granules in Comparative Example 10

[0089] Table 3 Prescription for the Preparation of Clopidogrel Bisulfate Granules

[0090] Raw and auxiliary materials Single-dose amount (mg) Clopidogrel bisulfate 97.88 Anhydrous lactose 87.44 Polyethylene glycol 6000 22.3 Low-substituted hydroxypropyl cellulose 12.15 Tocopherol 0.18 Pregelatinized starch 14.5

[0091] Preparation process:

[0092] 1. Pretreatment

[0093] Weigh 10% - 50% of the pregelatinized starch dosage in the prescription and add it to a wet granulator; turn on the wet granulator, and slowly add tocopherol under stirring to obtain mixture 1; mix mixture 1 and the same amount of pregelatinized starch using a mixing hopper to obtain mixture 2. Then mix mixture 2 using a twin-screw extruder, and finally pass it through a 0.8 mm sieve for screening and dispersion;

[0094] 2. Mixing

[0095] Add the weighed clopidogrel bisulfate, anhydrous lactose, polyethylene glycol 6000, low-substituted hydroxypropyl cellulose, the remaining pregelatinized starch, and the pregelatinized starch mixed powder of vitamin E to the wet granulator and mix evenly;

[0096] 3. Granulation

[0097] Use a G6 hot-melt wet granulator with a water bath sandwich to perform hot-melt granulation on the material. Set the water bath temperature at 75 - 90 °C, preferably 85 °C. Wait for the material temperature to rise to 65 - 75 °C and then perform granulation operations, with a stirring speed of 80 - 120 rpm, a chopping speed of 1000 - 1200 rpm, a granulation time of 15 - 25 minutes, and continue stirring during cooling until the temperature reaches 30 - 40 °C. Screen the material through a 0.8 - 1.2 mm sieve for sizing and discharge. Add the obtained granules, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, hydrogenated castor oil, and sucrose stearate to a lifting mixer and mix evenly to obtain clopidogrel bisulfate granules.

[0098] Comparative Example 10

[0099] 1. Pretreatment

[0100] Weigh 10%-50% of the amount of pregelatinized starch in the prescription and add it to the wet granulator; turn on the wet granulator and slowly add tocopherol under stirring to obtain mixture 1; mix mixture 1 and the same amount of pregelatinized starch using a mixing hopper to obtain mixture 2. Then mix mixture 2 using a twin-screw extruder and finally pass it through a 0.8 mm sieve for sieving and dispersion.

[0101] 2. Mixing

[0102] Add the weighed clopidogrel bisulfate, anhydrous lactose, polyethylene glycol 6000, low-substituted hydroxypropyl cellulose, the remaining pregelatinized starch, and the pregelatinized starch mixed powder of vitamin E to the wet granulator and mix evenly;

[0103] 3. Granulation

[0104] Use an XYT fluidized bed granulator for hot melt granulation. Set the inlet air temperature at 70-90°C, the fan speed at 1000 rpm, the air volume frequency at 58 Hz. Keep the material at a temperature above 70°C for a granulation time of 30-45 min until there is no obvious fine powder; cool down and continue stirring until the temperature is below 40°C, then discharge. Screen the granules using a 0.8 mm sieve. Add the obtained granules, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, hydrogenated castor oil, and sucrose stearate to a lifting mixer and mix evenly to obtain clopidogrel bisulfate granules.

[0105] Example 11, Comparative Example 12

[0106] Table 4 Preparation Prescription of Clopidogrel Bisulfate Aspirin Tablets

[0107]

[0108] Example 11

[0109] 1. Tabletting

[0110] Use a SYNTHESIS500TTH core-coated tabletting machine, use a round punch with a diameter of 11 mm. Add the enteric-coated aspirin tablet cores of Examples 4-8 to be tableted (add them separately) to the hopper, turn on the oscillator. After normal operation, add the clopidogrel bisulfate granules of Example 11, adjust the filling depth of the first layer and the second layer, and jog the turntable speed for tabletting debugging. The output is 10*1000 tablets / hour, the feeding boot speed is 40 l / min, ensure that the tablet core is in the center position, set the main pressure of the tabletting machine at 16 KN - 22 KN, control the tablet weight difference within ±5%, and the tablet hardness at 3-10 kg.

[0111] 2. Coating

[0112] Coating solution preparation:

[0113] Bottom coating solution: Weigh medicinal ethanol and purified water according to the prescription amount and add them to the stirring tank to prepare 75% ethanol. Turn on the pneumatic stirrer, slowly add hypromellose, and stir for 30 - 60 min after adding to make it fully dispersed. Let it stand for 12 - 24 hours, then add talc powder and continue stirring for 1 h.

[0114] Outer coating solution: Weigh medicinal ethanol and purified water according to the prescription amount and add them to the stirring tank to prepare 75% ethanol. Turn on the pneumatic stirrer, slowly add the film coating premix (gastric soluble type), and continue stirring for 60 min, then pass through an 80 - mesh sieve.

[0115] Coating: Use a BGB - 150 high - efficiency coating machine, set the heating temperature at 50 °C, adjust the rotation speed of the coating pan at 18 - 30 rpm according to the actual situation, and adjust the rotation speed of the peristaltic pump to achieve the best coating effect. Bottom coating: Control the material temperature at 35 - 40 °C. When the weight gain of the bottom coating reaches 1.5 - 3.5%, stop spraying the liquid and carry out drying for 30 - 45 min.

[0116] Outer coating: Control the material temperature at 35 - 40 °C. When the weight gain of the outer coating reaches 2.5 - 4.0%, stop coating and carry out drying for 30 - 45 min. After drying, cool down and take out the tablets.

[0117] Comparative Example 12

[0118] 1. Tabletting

[0119] Use a SYNTHESIS 500TTH core - tablet press, use a round punch with a diameter of 11 mm for tabletting. Add the enteric - coated aspirin tablet cores of Examples 4 - 8 to be tableted (add them separately) into the hopper, turn on the oscillator. After normal operation, add the clopidogrel bisulfate granules of Comparative Example 10, adjust the filling depth of the first layer and the filling depth of the second layer, and jog the turntable speed for tabletting debugging. The output is 10 * 1000 tablets / hour, the feeding boot speed is 40 l / min, ensure that the tablet core is in the center position, set the main pressure of the tablet press at 16 KN - 22 KN, control the tablet weight difference within ±5%, and the tablet hardness at 3 - 10 kg.

[0120] 2. Coating

[0121] Coating solution preparation:

[0122] Bottom coating solution: Weigh medicinal ethanol and purified water according to the prescription amount and add them to the stirring tank to prepare 75% ethanol. Turn on the pneumatic stirrer, slowly add hypromellose, and stir for 30 - 60 min after adding to make it fully dispersed. Let it stand for 12 - 24 hours, then add talc powder and continue stirring for 1 h.

[0123] Outer coating solution: Weigh medicinal ethanol and purified water according to the prescription amount and add them to the stirring tank to prepare 75% ethanol. Turn on the pneumatic stirring, slowly add the film coating premix (gastric soluble type), continue stirring for 60 minutes, and then pass through an 80-mesh sieve.

[0124] Coating: Use a BGB-150 high-efficiency coating machine, set the heating temperature to 50 °C, adjust the rotation speed of the coating pan to 18 - 30 rpm according to the actual situation, and adjust the rotation speed of the peristaltic pump to achieve the best coating effect. Bottom coating: Control the material temperature at 35 - 40 °C. When the bottom coating weight gain reaches 1.5 - 3.5%, stop spraying the liquid and carry out drying for 30 - 45 minutes.

[0125] Outer coating: Control the material temperature at 35 - 40 °C. When the outer coating weight gain reaches 2.5 - 4.0%, stop coating and carry out drying for 30 - 45 minutes. After drying, cool down and take out the tablets.

[0126] Table 5 Preparation combination of clopidogrel bisulfate and aspirin tablets

[0127]

[0128] (II) Experimental examples

[0129] 1. Experiment on the dissolution and stability of clopidogrel bisulfate and aspirin compound preparation

[0130] (1) Dissolution detection method

[0131] The dissolution is determined by high performance liquid chromatography (General Principles 0512, Volume IV of the Chinese Pharmacopoeia 2020 Edition).

[0132] Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (recommended chromatographic column: Waters Xterra Shield RP8 4.6 mm × 5 cm, 3.5 μm or a chromatographic column with equivalent performance). Use a solution of potassium dihydrogen phosphate at 1.36 g / L (adjust the pH to 2.5 ± 0.05 with phosphoric acid) - acetonitrile = 4:1 as the mobile phase; the flow rate is 2.0 ml per minute; the column temperature is 25 °C; the running time is 6 minutes; the detection wavelength is 215 nm, and the injection volume is 5 μl.

[0133] System suitability requirements: Inject the reference solution continuously for 5 needles, and the RSD of the peak areas of each component should not be greater than 2.0%.

[0134] Determination method: Calculate the contents of aspirin and corrected salicylic acid by the external standard method based on the peak areas. After multiplying the salicylic acid content by 1.304, add it to the aspirin content to obtain the total amount of aspirin dissolved in each tablet buffer solution; use the chromatographic peak of clopidogrel as the reference substance, calculate the dissolution amount of clopidogrel bisulfate in each tablet respectively, and multiply the result by 0.766 to obtain the dissolution amount of clopidogrel in each tablet.

[0135] (2) Dissolution curve determination method

[0136] The dissolution and release determination method (the first method in General Chapter 0931, Volume IV of Chinese Pharmacopoeia 2020 Edition) was used for determination.

[0137] Dissolution amount in acid: The dissolution conditions were as follows: 1000 ml of 0.1 mol / L hydrochloric acid solution (9 ml of hydrochloric acid was taken and diluted to 1000 ml with water) was used as the dissolution medium, the rotation speed was 75 revolutions per minute. The operation was carried out according to the law, and samples were taken at 30 minutes and 120 minutes.

[0138] Dissolution amount in phosphate buffer solution (pH 6.8): After sampling at 120 minutes under the dissolution conditions of the dissolution amount in acid, the acid solution in each dissolution cup was discarded. Immediately, the rotating basket was added to 1000 ml of pH 6.8 phosphate solution (0.1 mol / L hydrochloric acid solution and 0.2 mol / L sodium phosphate solution = 3:1, mixed evenly, and the pH value of the solution was adjusted to 6.8 ± 0.05 with 2 mol / L hydrochloric acid solution or 2 mol / L sodium hydroxide solution) preheated to 37°C ± 0.5°C. The dissolution continued, the rotation speed was 100 revolutions per minute, the operation was carried out according to the law, and samples were taken at 90 minutes. An appropriate amount of the solution was taken and filtered through a 0.45 μm polyethersulfone (PES) filter membrane.

[0139] 2. Related substances determination method

[0140] 2.1 Related substances 1: Determined by high performance liquid chromatography (General Chapter 0512 of Chinese Pharmacopoeia 2020 Edition).

[0141] Twenty tablets of this product were taken and ground finely. Approximately 725 mg of the powder (equivalent to about 130 mg of clopidogrel bisulfate and aspirin) was accurately weighed and placed in a 20 ml volumetric flask. 10 ml of methanol was added, and it was ultrasonically treated in an ice-water bath for 15 minutes. After the solution was cooled to room temperature, it was diluted to the mark with the diluent and shaken well. It was filtered through a 0.45 μm polyvinylidene fluoride filter membrane (PVDF) or a hydrophobic polytetrafluoroethylene filter membrane (PTFE). The first 2 ml of the initial filtrate was discarded, and the subsequent filtrate was taken as the test solution.

[0142] Chromatographic conditions: Octadecylsilane chemically bonded silica gel was used as the filler (recommended chromatographic column: Agilent Zorbax XDB C18 4.6 mm * 25 cm, 5 μm or a chromatographic column with equivalent efficiency); methanol - sodium pentanesulfonate solution (0.96 g / L, adjusted to pH 2.5 ± 0.05 with phosphoric acid) (5:95) was used as mobile phase A; methanol - acetonitrile (5:95) was used as mobile phase B; the flow rate was 1.0 ml per minute; the column temperature was 30°C; the detection wavelength was 220 nm; gradient elution was carried out according to the following table; the injection volume was 10 μl. An accurately measured amount of the test solution was injected into the liquid chromatograph, the chromatogram was recorded, and the contents of each impurity were calculated by the external standard method based on the peak areas respectively.

[0143]

[0144]

[0145] 2.2 Related Substances 2 Enantiomers and Salicylic Acid are determined by high performance liquid chromatography (General Rule 0512).

[0146] Take 1 tablet of this product, grind it finely, and transfer all of it to a 200 ml volumetric flask. Add 160 ml of anhydrous ethanol and ultrasonicate in an ice bath for at least 45 minutes (during ultrasonication, manually shake the volumetric flask for 1 minute every 15 minutes). After the solution has cooled to room temperature, dilute it to the mark with anhydrous ethanol and mix well. Filter through a 0.45 μm polyvinylidene fluoride membrane (PVDF) or a hydrophobic polytetrafluoroethylene membrane (PTFE), discard the first 2 ml of the initial filtrate, and take the subsequent filtrate as the test solution.

[0147] Chromatographic conditions: Use cellulose tris(4-methylbenzoate) silica gel as the filler (it is recommended to use Chiralcel OJ, 250 mm * 4.6 mm, 10 μm chromatographic column); use a mixture of anhydrous ethanol solution of 0.05% trifluoroacetic acid - n-heptane (45:55) as the mobile phase; the flow rate is 0.6 ml per minute; the detection wavelengths are 235 nm (for determining the content of clopidogrel; related substance 2: clopidogrel impurity III and salicylic acid) and 250 nm (for determining the content of aspirin); the injection volume is 10 μl; the column temperature is 25 °C; the temperature of the autosampler is 4 °C; the running time is 25 minutes.

[0148] Take 10 μl of the test solution and inject it into the liquid chromatograph respectively. Calculate the contents of clopidogrel impurity III and salicylic acid by the external standard method based on the peak areas.

[0149] 3. Assay

[0150] It is carried out by high performance liquid chromatography (General Rule 0512 in Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0151] Take 5 tablets of this product, grind them finely, and transfer all of them to a 250 ml volumetric flask. Add 200 ml of anhydrous ethanol and ultrasonicate in an ice bath for at least 45 minutes (during ultrasonication, manually shake the volumetric flask for 1 minute every 15 minutes). After the solution has cooled to room temperature, dilute it to the mark with anhydrous ethanol and mix well. Filter this solution through a 0.45 μm polyvinylidene fluoride membrane (PVDF) or a hydrophobic polytetrafluoroethylene membrane (PTFE), discard the first 2 ml of the initial filtrate, and take the subsequent filtrate. Accurately measure 5.0 ml of the subsequent filtrate, place it in a 20 ml volumetric flask, dilute it to the mark with anhydrous ethanol, and mix well to obtain the solution.

[0152] Chromatographic conditions: The filler is cellulose tris(4-methylbenzoate) silica gel (Chiralcel OJ, 250 mm * 4.6 mm, 10 μm chromatographic column is recommended); the mobile phase is an anhydrous ethanol solution of 0.05% trifluoroacetic acid - n-heptane (45:55); the flow rate is 0.6 ml per minute; the detection wavelengths are 235 nm (for determining the content of clopidogrel; related substances 2: clopidogrel impurity III and salicylic acid) and 250 nm (for determining the content of aspirin); the injection volume is 10 μl; the column temperature is 25 °C; the temperature of the autoinjector is 4 °C; the running time is 25 minutes.

[0153] Precisely measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively. Record the chromatogram and calculate according to the external standard method with the peak area.

[0154] 4. Determination results

[0155] 4.1 Investigation on the preparation parameters of aspirin tablets with different prescriptions

[0156]

[0157] The experimental results prove that the dry-processed aspirin plates prepared from the prescriptions of Examples 1 - 3 are continuous, with moderate texture and comparable plate thickness. At the same time, compared with Comparative Example 4, there is no consistency in the hardness, disintegration time of the pressed tablets, and the dissolution rate in pH 6.8 medium for 30 min.

[0158] 4.2 Preparation of clopidogrel bisulfate granules

[0159] Inspection items Example 9 Comparative Example 10 Yield / % 99.3 96.5 Granulation time / m 25 60-75 Angle of repose / ° 38.9 40.7 Fine powder condition Moderate amount of fine powder Large amount of fine powder

[0160] The experimental results prove that the clopidogrel bisulfate granules prepared by the hot-melt wet granulation method have a higher yield, shorter granulation time, and better fluidity than the clopidogrel bisulfate granules prepared by the fluidized bed, and are suitable for industrial production.

[0161] 4.3 Comparison of the dissolution curves of aspirin in pH 1.0 + pH 6.8 media in the clopidogrel bisulfate - aspirin compound preparation and the Sanofi preparation (2K005B)

[0162]

[0163] 4.4 Comparison of the dissolution curves of clopidogrel in pH 1.0 medium in the clopidogrel bisulfate - aspirin compound preparation and the Sanofi preparation (2K005B)

[0164]

[0165]

[0166] The experimental results prove that the amount of talcum powder (30%, 50%) has little overall effect on the dissolution of enteric-coated aspirin core tablets. The amount of glyceryl monostearate and glyceryl distearate significantly affects the film-breaking time of enteric-coated tablets, and then affects the dissolution. Moreover, the pressure during the tableting of the coated chip also has a great influence on the dissolution of clopidogrel in pH 1.0 medium. Low pressure will accelerate the release of clopidogrel, while high pressure will reduce the dissolution rate of clopidogrel. And, from different preparation methods of clopidogrel, the dissolution of tablets pressed from clopidogrel prepared by fluidized bed granulation is significantly faster than that of tablets prepared by hot melt wet granulation. Therefore, hot melt wet granulation is preferred to prepare clopidogrel granules.

[0167] 5. Results of stability experiment

[0168] Results of related substances in accelerated stability

[0169]

[0170] The enteric-coated aspirin tablets of the present invention are composed of three layers of coating, namely, drug-containing core tablets, isolation coating 1, enteric coating, and isolation coating 2. The production process is simple. The product quality is stable and the impurities are controllable. It can achieve the characteristics of rapid release of clopidogrel in the stomach and release of enteric-coated aspirin tablets in the intestine. The compound preparation can reduce the medication frequency of patients and improve the compliance of patients. The present invention also has the advantages of significantly improving production efficiency, increasing the material yield, etc., and has advantages such as smooth production process and good process stability.

Claims

1. A clopidogrel-aspirin chip-packaged composite preparation, characterized in that: The tablets are formed by core-coating an inner layer of enteric-coated aspirin tablets and an outer layer of clopidogrel hydrogen sulfate granules, and then coated with two layers of film to form a core.

2. The clopidogrel-aspirin chip-packaged composite preparation according to claim 1, characterized in that: The inner layer enteric-coated aspirin tablet core is composed of a drug-containing tablet, an isolation layer 1 coating, an enteric layer coating and an isolation layer 2 coating from the inside to the outside, and the ratio of the drug-containing tablet, the isolation layer 1 coating, the enteric layer coating and the isolation layer 2 coating is 124:2.48-6.20:25.30-33.85:3.04-7.

81.

3. The clopidogrel-aspirin chip-packaged composite preparation according to claim 2, characterized in that: In the enteric-coated aspirin tablet core, the drug-containing tablet is made of filler, binder, glidant and lubricant. Based on the mass of aspirin, the proportions of auxiliary materials are as follows: filler 5-15%, more preferably 7-11%; binder 7-15%, more preferably 9-12%; glidant 0.1-0.6%, more preferably 0.2-0.4%; lubricant 0.2-0.8%, more preferably 0.3-0.7%.

4. The clopidogrel-aspirin chip-packaged composite preparation according to claim 3, characterized in that: In the drug-containing tablet, the adhesive is selected from any one or more of corn starch, povidone, copovidone (ie PVP / VA), hydroxypropyl methylcellulose (ie HPMC), and ethyl cellulose (ie EC).

5. The clopidogrel-aspirin chip-packaged composite preparation according to claim 3, characterized in that: In the drug-containing tablet, the filler is selected from any one or more of pregelatinized starch, dextrin, microcrystalline cellulose, lactose, mannitol and sorbitol.

6. The clopidogrel-aspirin chip-packaged composite preparation according to claim 3, characterized in that: In the drug-containing tablet, the glidant is selected from any one or more of colloidal silicon dioxide, talcum powder, sodium stearyl fumarate, and sucrose fatty acid ester.

7. The clopidogrel-aspirin chip-packaged composite preparation according to claim 3, characterized in that: In the drug-containing tablet, the lubricant is selected from any one or more of stearic acid, magnesium stearate, sodium lauryl sulfate, and glyceryl behenate.

8. The clopidogrel-aspirin chip-packaged composite preparation according to claim 3, characterized in that: In the enteric-coated aspirin tablet core, the isolation layer 1 coating is prepared from a film coating premix, preferably an Opadry gastric-soluble film coating premix; further, the isolation layer 1 coating has a weight gain of 1% to 8%, more preferably 2% to 5%.

9. The clopidogrel-aspirin chip-packaged composite preparation according to claim 3, characterized in that: In the enteric-coated aspirin tablet core, the enteric layer coating is composed of a coating material and a gastric-resistant polymer composition, and the mass ratio of each component is 10: 2.5-3.9: 1.8-2.2: 0.45-0.55: 0.18-0.22 for gastric-resistant polymer: talc: triethyl citrate: mono- and distearic glycerol: polysorbate 80; further, in the enteric layer coating, the gastric-resistant polymer coating material is BASF enteric coating material MAE 30DP or Evonik Eudragit L30D-55; further, the enteric layer coating weight gain is 18% to 30%, more preferably 20% to 26%.

10. The clopidogrel-aspirin chip-packaged composite preparation according to claim 3, characterized in that: In the enteric-coated aspirin tablet core, the isolation layer 2 coating is composed of HPMC and polyethylene glycol, and the mass ratio of the two is (8-10):1; more preferably, the mass ratio of the two is 9:1; further, the isolation layer 2 coating has a weight gain of 1-8%, more preferably 2%-5%.

11. The clopidogrel-aspirin chip-packaged composite preparation according to claim 3, characterized in that: The weight of the enteric-coated aspirin tablet core is 154 mg to 172 mg, preferably 158 mg to 168 mg.

12. The clopidogrel-aspirin chip-packaged composite preparation according to claim 1, characterized in that: The outer layer of clopidogrel hydrogen sulfate particles consists of clopidogrel hydrogen sulfate, anhydrous lactose, polyethylene glycol 6000, pregelatinized starch, tocopherol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, hydrogenated castor oil, and sucrose stearate.

13. The clopidogrel-aspirin chip-packaged composite preparation according to claim 2, characterized in that: The proportions of the components in the outer layer of clopidogrel hydrogen sulfate particles are as follows: 95-105 parts of clopidogrel hydrogen sulfate, 87-93 parts of anhydrous lactose, 21-25 parts of polyethylene glycol 6000, 96-100 parts of microcrystalline cellulose, 23-26 parts of low-substituted hydroxypropyl cellulose, 13-16 parts of pregelatinized starch, 0.1-0.3 parts of tocopherol, 3-4 parts of hydrogenated castor oil, and 2.0-2.5 parts of sucrose stearate.

14. The clopidogrel-aspirin chip-packaged composite preparation according to claim 13, characterized in that: The enteric-coated aspirin tablet core and clopidogrel bisulfate granules are pressed using a round punch of about 11 mm. The specifications of aspirin and clopidogrel bisulfate in the prepared clopidogrel-aspirin chip composite preparation are 100 mg: 70-80 mg, calculated on the basis of clopidogrel.

15. The clopidogrel-aspirin chip-packaged composite preparation according to claim 3, characterized in that: The compound preparation is a film-coated tablet, and the film coating consists of two layers, the bottom layer is an isolation layer coating, and the outer layer is a film coating; Further, the two-layer film coating comprises: a first film coating layer, which is composed of hydroxypropyl methylcellulose (i.e., HPMC) and talcum powder, and a second film coating layer, whose material is Opadry gastric soluble film coating premix; Furthermore, the mass ratio of HPMC to talc in the first film coating layer is 5.8-7.0:1, and the coating solution is prepared with a solid content of 5%-8%, and the coating weight gain is 1.5%-2.5%; Furthermore, the second film coating layer material is Opadry gastric soluble film coating premix, which is prepared into a coating solution with a solid content of 6% to 10%, and a coating weight gain of 2.5% to 3.5%.

16. A method for preparing the clopidogrel-aspirin chip composite preparation according to any one of claims 1 to 15, characterized in that it comprises the following steps: The clopidogrel bisulfate granules and aspirin enteric-coated tablets are prepared separately, and then mixed and pressed into tablets according to the above ratio, and then double-coated to obtain the tablets.

17. The method for preparing the clopidogrel-aspirin chip-packaged composite preparation according to claim 16, wherein the method for preparing the clopidogrel hydrogen sulfate granules comprises the following steps: According to the above ratio, 10% to 20% of the mass of pregelatinized starch and tocopherol are taken in a wet granulator for granulation and mixing to make mixture 1; the mixture 1 is mixed with 10% to 20% of the mass of pregelatinized starch in a mixing hopper to make mixture 2; the mixture 2 is mixed in a twin-screw extruder, and then sieved and dispersed through a 0.8 to 1.0 mm sieve to obtain a uniform mixture of tocopherol; according to the above ratio, clopidogrel hydrogen sulfate, anhydrous lactose, polyethylene glycol 6000, 40% to 60% of low-substituted hydroxypropyl cellulose, mixture 2, and the remaining mass of 60% to 80% of pregelatinized starch are added to a hot melt wet granulator for granulation. The mixing step is as follows: mixing for 5 to 15 minutes, setting the water bath temperature to 75-90° C., preferably 85° C., and when the material temperature rises to 65 to 75° C., granulation is performed, wherein the stirring speed is 80 to 120 rpm, the chopping speed is 500 to 1200 rpm, and the granulation time is 15 to 25 minutes. The obtained granules are then sieved through a 0.8 to 1.2 mm mesh, and 232 to 236 parts of the granules after granulation are added to a lifting mixer and mixed evenly with 95 to 100 parts of microcrystalline cellulose, 10 to 15 parts of low-substituted hydroxypropyl cellulose, 2 to 5 parts of hydrogenated castor oil, and 1.5 to 4 parts of sucrose stearate to obtain clopidogrel hydrogen sulfate granules.

18. The method for preparing the clopidogrel aspirin chip-coated composite preparation according to claim 16, wherein the preparation of the enteric-coated aspirin tablets comprises the following steps: S1 The preparation of aspirin-containing tablets includes the following steps: grinding and granulating aspirin and mixing it with a filler, adding the mixed materials to a dry granulator for granulation, sieving the obtained granules with an oscillating screen, treating the granules that cannot pass through the sieve with a grinding and granulating machine, the sieve mesh size is 0.8mm-1.2mm, combining the granules after granulation with the sieved granules to obtain aspirin granules, mixing the prepared aspirin granules, filler, glidant and lubricant in a lifting mixer, and pressing the mixed materials into tablets to control the hardness to 2-5kg; Preparation of S2 isolation layer 1 coating: HPMC, talcum powder and triethyl glycerol are weighed according to the above ratio, added into 9 to 11 times the weight of purified water under stirring, and continued to slowly stir to completely dissolve them to form a coating solution with a solid content of 8 to 10% by weight, and then the coating is carried out. The isolation layer coating increases in weight by 1 to 7%. S3 enteric coating: S31: adding polysorbate 80 and glyceryl mono- and distearate according to the above ratio into hot water at a temperature greater than 80° C. to prepare a solution having a solid content of 5 to 8%, stirring and dissolving, and then cooling to below 10 to 30° C. to obtain solution 1; S32: Triethyl citrate and purified water are homogenized and dispersed uniformly to prepare a homogenous liquid, talcum powder is added to the homogenous liquid, and the homogenization and dispersion are continued to prepare a solution with a solid content of 15 to 25% by mass, and the temperature is reduced to below 10 to 30° C. to obtain Solution 2; S33: Pass the aqueous dispersion of the coating material through a sieve of ≥80 mesh, discard the insoluble matter on the sieve, weigh the filtrate according to the prescription amount, add it into a dry and clean slurry mixing barrel and continue stirring to obtain solution 3; S34: after mixing the prepared solution 1 and solution 2, add the mixture to the solution 3 under stirring, stir to obtain a suspension, mix the suspension and the coating material in a mass ratio of 1:1.4-1.5 under stirring, continue stirring for 1-3 hours, coat, dry, and increase the weight of the enteric layer coating by 20-26%; The preparation of S4 isolation layer 2 coating includes: Weigh HPMC and talcum powder according to the above ratio, mix, add 9 to 11 times the mass of the mixture into purified water under stirring, continue to slowly stir to completely dissolve it to prepare a coating solution with a solid content of 5 to 12%, and coat the isolation layer 2 with a coating weight increase of 1 to 8%.

19. The method for preparing the clopidogrel-aspirin chip-coated composite preparation according to claim 16, wherein the step of mixing the two in the above-mentioned ratio and tableting them comprises the following steps: The prepared enteric-coated aspirin tablets and clopidogrel bisulfate granules are mixed in a ratio of 1:2.1-2.2, and are pressed into tablets using a round punch with a diameter of 10-12 mm and a pressure of 15 KN-25 KN, with the tablet weight difference controlled at ±5%, to obtain tablets with a hardness of 3-10 kg.

20. The method for preparing the clopidogrel-aspirin chip-coated composite preparation according to claim 16, wherein the second layer coating comprises the following steps: S41: preparing a coating solution 1 for the first film coating layer: mixing HPMC and talcum powder according to the above ratio to prepare a coating solution with a solid content of 5 to 8% by mass, and coating the solution so that the weight of the first film coating layer increases by 2 to 4%; S42: preparing the coating solution 2 for the second film coating layer: preparing the film coating premix into a coating solution with a solid content of 7-11% by weight, and coating the film so that the coating weight of the second film coating layer increases by 3-5%.

21. Use of the clopidogrel-aspirin chip composite preparation according to any one of claims 1 to 15 in the preparation of drugs for inhibiting platelet aggregation, reducing myocardial infarction in patients with atherosclerosis, and treating transient cerebral ischemia or stroke.

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