Ticagrelor and aspirin compound preparation and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a ticagrelor and aspirin compound preparation and a preparation method thereof. The first purpose of the invention is to provide a ticagrelor and aspirin compound preparation. The ticagrelor and aspirin compound preparation comprises a ticagrelor shell layer and an aspirin tablet core wrapped in the ticagrelor shell layer, the ticagrelor shell layer comprises a ticagrelor quick release layer and a ticagrelor slow release layer; the aspirin tablet core comprises aspirin API and a tablet core layer auxiliary material, and the particle size D90 of the aspirin API is 50-250 [mu] m. The second purpose of the invention is to provide a method for preparing the compound preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and more specifically, to a ticagrelor-aspirin composite preparation and a preparation method thereof. Background Art

[0002] The combination of ticagrelor and aspirin is a common medication strategy for patients with acute coronary syndrome (ACS). There are a variety of combination preparations of ticagrelor and aspirin for this medication strategy.

[0003] Chinese patent document CN114533744A provides a ticagrelor-aspirin compound pellet preparation and a preparation method thereof, wherein the preparation is prepared by filling aspirin enteric-coated pellets, ticagrelor immediate-release pellets and ticagrelor sustained-release pellets into a capsule shell using a capsule filling machine. However, the pellet process is relatively complicated and the production cost is high, which is not conducive to the popularity of the product.

[0004] Chinese patent document CN106619549B provides a compound preparation of ticagrelor and aspirin, which is a double-layer tablet, wherein ticagrelor is arranged in the first layer, and aspirin is arranged in the second layer, wherein ticagrelor and aspirin are arranged in the first layer and the second layer respectively, and since ticagrelor and aspirin are arranged separately and not in direct contact, the stability of ticagrelor and aspirin is ensured, and their mutual influence is prevented, and the storage time is extended. It is only an ordinary compound preparation, and the ticagrelor drug layer and the aspirin drug layer are not treated as quick-release or sustained-release preparations, which leads to the problem of interference between the active ingredients during the dissolution process.

[0005] Chinese patent document CN111991399A provides a method for preparing a novel compound preparation of ticagrelor and aspirin, specifically a compound preparation of aspirin enteric-coated tablets and ticagrelor sustained-release tablets, wherein the ticagrelor sustained-release tablets contain a sustained-release component and a rapid-release component. The patented preparation method results in the phenomenon that the active ingredients are easily adhered to the tablet pressing device during the tablet pressing process, resulting in the problem of unqualified product quality.

[0006] It can be seen that there are still many deficiencies in the prior art of ticagrelor aspirin compound preparation. Summary of the invention

[0007] The present invention aims to overcome at least one defect of the above-mentioned prior art and provide a ticagrelor-aspirin composite preparation and a preparation method thereof.

[0008] The first aspect of the present invention is to provide a ticagrelor-aspirin composite preparation, comprising a ticagrelor outer shell layer and an aspirin core wrapped inside the ticagrelor outer shell layer;

[0009] The outer shell layer of ticagrelor includes a ticagrelor immediate-release layer and a ticagrelor sustained-release layer;

[0010] The aspirin tablet core comprises an aspirin API and a tablet core layer auxiliary material, wherein the particle size D90 of the aspirin API is 50-250 μm.

[0011] Preferably, the particle size D90 of aspirin API is 100-200 μm.

[0012] The ticagrelor aspirin composite preparation of the present invention is organically coordinated with the ticagrelor immediate-release layer, the ticagrelor sustained-release layer, and the aspirin tablet core. After taking, the ticagrelor immediate-release component is first dissolved, which can quickly inhibit platelet activation and aggregation. The ticagrelor immediate-release part is completely released and then the aspirin tablet core is exposed, which effectively delays the release time of the aspirin tablet core, facilitates the control of aspirin not being released in the stomach, and reduces adverse reactions. In addition, the ticagrelor sustained-release layer is used to extend the onset time of ticagrelor to enhance the therapeutic effect on patients taking it. The present invention's research shows that the selection of aspirin API with a particle size D90 of 50-250 μm can significantly reduce the sticking phenomenon of the aspirin tablet core in the tableting process, avoid the sticking of the ticagrelor aspirin composite preparation during the tableting process, and ensure that the dissolution performance of aspirin within 2-12 hours meets the treatment requirements.

[0013] In some embodiments, the core layer excipients include a first disintegrant, a first filler, a first glidant and a first lubricant. In terms of weight, the aspirin core tablet includes: 70-90 parts of aspirin API, 2-8 parts of the first disintegrant, 5-25 parts of the first filler, 0.5-3 parts of the first glidant, and 1-5 parts of the first lubricant.

[0014] Preferably, the aspirin tablet core comprises the following components in parts by weight: 75-85 parts of aspirin API, 2-5 parts of a first disintegrant, 10-20 parts of a first filler, 1-2 parts of a first glidant, and 2-4 parts of a first lubricant.

[0015] Tests show that when this formula is used in aspirin tablet cores, the sticking phenomenon in the tableting process can be further reduced, thereby improving product stability.

[0016] Tests have shown that aspirin within this particle size range can reduce sticking during the tableting process.

[0017] In some embodiments, the first lubricant is sodium stearyl fumarate or talc.

[0018] In some embodiments, the first glidant is colloidal silicon dioxide or talc.

[0019] In some embodiments, the immediate-release layer of ticagrelor includes a first ticagrelor API and a sustained-release excipient, and the sustained-release layer of ticagrelor includes a second ticagrelor API and an immediate-release excipient, wherein the weight of the first ticagrelor API is equivalent to 15-35% of the total weight of the immediate-release layer of ticagrelor, the weight of the second ticagrelor API is equivalent to 15-35% of the total weight of the sustained-release layer of ticagrelor, and the weight ratio of the first ticagrelor API to the second ticagrelor API is 1:1-1:3.

[0020] The research and tests of the present invention show that when the first ticlomir API and the second ticlomir API both adopt the above-mentioned setting method, it can ensure that ticlomir can have both the effects of rapid onset and long-term maintenance of efficacy, thereby cooperating with the aspirin tablet core layer to improve the therapeutic effect on patients. In addition, the above-mentioned ticlomir API setting method can prevent the composite preparation from sticking during the tableting process.

[0021] In some embodiments, the rapid-release excipients include a gastric mucosal protective agent, a second disintegrant, a second filler, a first binder, and a second lubricant. In terms of weight parts, the rapid-release layer of ticagrelor includes: 15-35 parts of the first ticagrelor API, 15-40 parts of the gastric mucosal protective agent, 2-10 parts of the second disintegrant, 35-55 parts of the second filler, 2-8 parts of the first binder, and 0.5-3 parts of the second lubricant.

[0022] The ticagrelor rapid-release layer of the present invention can ensure that the ticagrelor in the rapid-release portion can quickly inhibit platelet activation and aggregation, thereby achieving the purpose of rapid onset of effect. In addition, the gastric mucosal protective agent further reduces the damage to the gastrointestinal tract caused by aspirin in the tablet core, thereby reducing the probability of occurrence of diseases such as gastritis, gastric bleeding, and gastric perforation.

[0023] In some embodiments, the gastric mucosal protective agent is selected from any one or more of hydrotalcite, sucralfate, and bismuth potassium citrate.

[0024] In some embodiments, the sustained-release excipients include sustained-release materials, a third filler, a second adhesive, a second glidant, and a third lubricant. In terms of weight, the ticagrelor sustained-release layer includes: 15-35 parts of the second ticagrelor, 30-50 parts of sustained-release materials, 25-45 parts of the third filler, 2-8 parts of the second adhesive, 0.5-3 parts of the second glidant, and 0.5-3 parts of the third lubricant.

[0025] The ticagrelor sustained-release layer of the present invention can ensure that the ticagrelor in the sustained-release portion can achieve the purpose of long-term effectiveness.

[0026] In some embodiments, the first filler, the second filler, or the third filler is selected from any one or more of lactose, microcrystalline cellulose, mannitol, starch, or pregelatinized starch, preferably a combination of microcrystalline cellulose and lactose.

[0027] In some embodiments, the disintegrant is selected from any one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone and partially pregelatinized starch, preferably cross-linked polyvinylpyrrolidone.

[0028] In some embodiments, the first binder or the second binder is selected from any one or more of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, hydroxypropyl methylcellulose or hydroxypropyl cellulose, preferably hydroxypropyl cellulose.

[0029] In some embodiments, the second glidant is selected from colloidal silicon dioxide or talc, preferably colloidal silicon dioxide.

[0030] In some embodiments, the second lubricant or the third lubricant is selected from any one of talc, hydrogenated vegetable oil, sodium stearyl fumarate or magnesium stearate, preferably magnesium stearate and sodium stearyl fumarate.

[0031] In some embodiments, the sustained-release material is selected from any one or more of hydroxypropylmethylcellulose, sodium carboxymethylcellulose, xanthan gum, sodium alginate, carbomer or polyethylene oxide.

[0032] In some embodiments, it further comprises an isolation coating layer and an enteric coating layer disposed between the ticagrelor drug-containing outer layer and the aspirin tablet core, wherein the isolation coating layer and the enteric coating layer sequentially coat the aspirin tablet core from the inside to the outside;

[0033] It also includes a film coating layer coated on the drug-containing outer layer of ticagrelor.

[0034] In some embodiments, the coating material used in the isolation coating layer is Opadry II (OPADRY II).

[0035] In some embodiments, the coating material used in the enteric coating layer is Eudragit (L30D55).

[0036] In some embodiments, the film coating layer is coated with Opadry II (OPADRY II).

[0037] The present invention protects the aspirin tablet core through the isolation coating layer and the enteric coating layer, avoids the risk of aspirin dissolving in the stomach, and further reduces the probability of gastritis, gastric bleeding, gastric perforation and other diseases after taking the medicine. In addition, the film coating layer can protect the ticagrelor aspirin compound preparation, and cooperates with the isolation coating layer and the enteric coating layer to effectively control the release time of aspirin.

[0038] The second aspect of the present invention is to provide a method for preparing the ticagrelor aspirin composite preparation, comprising the following steps: taking the components of the ticagrelor immediate-release layer and subjecting them to wet granulation, followed by drying and mixing, to obtain ticagrelor immediate-release total mixed particles; taking the components of the ticagrelor sustained-release layer and subjecting them to wet granulation, followed by drying and mixing, to obtain ticagrelor sustained-release total mixed particles; mixing and tableting the components of the aspirin tablet core by direct powder compression, and subjecting them to a coating process, to obtain an aspirin coated tablet core;

[0039] The Ticagrelor immediate-release mixed granules, the Ticagrelor sustained-release mixed granules and the aspirin coated tablet cores are tableted and then coated to prepare the Ticagrelor aspirin composite preparation.

[0040] In some embodiments, during the wet granulation process of the immediate-release layer of ticagrelor, the second lubricant is added externally after granulation; during the wet granulation process of the sustained-release layer of ticagrelor, the second glidant and the third lubricant are added externally after granulation.

[0041] Compared with the prior art, the beneficial effects of the present invention are as follows: through the organic combination of the ticagrelor immediate-release layer, the ticagrelor sustained-release layer, and the aspirin tablet core, the ticagrelor immediate-release component is first dissolved after taking, which can quickly inhibit platelet activation and aggregation. After the immediate-release part of ticagrelor is completely released, the enteric-coated aspirin tablet core is exposed. Due to the early release of the gastric mucosal protective agent in the immediate-release part, the damage to the gastrointestinal tract caused by aspirin in the tablet core can be further reduced, and the probability of gastritis, gastric bleeding, gastric perforation and other diseases can be reduced. At the same time, because the enteric coating isolates the contact between aspirin and ticagrelor, even if the two components are pressed into tablets together, it does not affect the stability of the tablet, and swallowing a single tablet greatly improves the patient's compliance;

[0042] In addition, the present invention can solve the sticking problem of powder direct compression by using aspirin with a fixed particle size range in combination with a lubricant and a glidant in a specific ratio, thereby simplifying the process and reducing production costs. DETAILED DESCRIPTION

[0043] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0044] The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, methods and instruments used are conventional materials, reagents, methods and instruments in the art unless otherwise specified, and can be obtained through commercial channels by those skilled in the art.

[0045] Example 1

[0046] This embodiment provides a ticagrelor-aspirin combination preparation, the formula of which is shown in Table 1.

[0047] Table 1 Example 1 Prescription Table

[0048]

[0049]

[0050] Among them, the particle size D90 of aspirin is 150 μm.

[0051] The preparation method of Example 1 is as follows: S1. The raw materials and auxiliary materials other than the lubricant in the ticagrelor immediate-release layer are wet-granulated, and the lubricant is added after granulation for lubrication, followed by drying and mixing to obtain ticagrelor immediate-release total mixed granules;

[0052] The other raw materials and auxiliary materials except the glidant and lubricant in the ticagrelor sustained-release layer are subjected to wet granulation, and the glidant and lubricant are added and mixed after granulation, and then dried and mixed to obtain the ticagrelor sustained-release total mixed granules;

[0053] The raw and auxiliary materials of the aspirin tablet core are mixed and tableted by a powder direct compression method, and then subjected to a coating process to obtain an aspirin coated tablet core;

[0054] S2. Compress the Ticagrelor immediate-release mixed granules, Ticagrelor sustained-release mixed granules and aspirin coated tablet cores prepared in step S1, and then coat them to prepare a Ticagrelor aspirin composite preparation.

[0055] Example 2

[0056] This embodiment provides a ticagrelor-aspirin combination preparation, the formula of which is shown in Table 2.

[0057] Table 2. Prescription table of Example 2

[0058]

[0059]

[0060] Among them, the particle size D90 of aspirin is 150 μm.

[0061] Example 2 Preparation method: Same as Example 1.

[0062] Example 3

[0063] This embodiment provides a ticagrelor-aspirin combination preparation, the formula of which is shown in Table 3.

[0064] Table 3 Example 3 Prescription Table

[0065]

[0066]

[0067] Among them, the particle size D90 of aspirin is 110 μm.

[0068] Example 3 Preparation method: Same as Example 1.

[0069] Example 4

[0070] This embodiment provides a ticagrelor-aspirin combination preparation, the formula of which is shown in Table 4.

[0071] Table 4 Example 4 Prescription Table

[0072]

[0073]

[0074] Among them, the particle size D90 of aspirin is 150 μm.

[0075] Example 4 Preparation method: Same as Example 1.

[0076] Example 5

[0077] This embodiment provides a ticagrelor-aspirin combination preparation, the formula of which is shown in Table 5.

[0078] Table 5 Example 5 Prescription Table

[0079]

[0080]

[0081] Among them, the particle size D90 of aspirin is 150 μm.

[0082] Example 5 Preparation method: Same as Example 1.

[0083] Example 6

[0084] This embodiment provides a ticagrelor-aspirin combination preparation, the formula of which is shown in Table 6.

[0085] Table 6. Prescription table of Example 6

[0086]

[0087] Among them, the particle size D90 of aspirin is 150 μm.

[0088] Example 6 Preparation method: Same as Example 1.

[0089] Example 7

[0090] This embodiment provides a ticagrelor-aspirin combination preparation, the formula of which is shown in Table 7.

[0091] Table 7. Prescription table of Example 7

[0092]

[0093] Among them, the particle size D90 of aspirin is 150 μm.

[0094] Example 7 Preparation method: Same as Example 1.

[0095] Example 8

[0096] This embodiment provides a ticagrelor-aspirin combination preparation, the formula of which is shown in Table 8.

[0097] Table 8. Prescription table of Example 8

[0098]

[0099] Among them, the particle size D90 of aspirin is 150 μm.

[0100] Preparation method of Example 8: Same as that of Example 1.

[0101] Comparative Example 1

[0102] This comparative example provides a ticagrelor-aspirin composite preparation, the prescription and preparation method are exactly the same as those in Example 3, the only difference being that the particle size D90 of aspirin is 280 μm.

[0103] Comparative Example 2

[0104] This comparative example provides a ticagrelor-aspirin composite preparation, the prescription and preparation method are exactly the same as those in Example 3, the only difference being that the particle size D90 of aspirin is 30 μm.

[0105] Comparative Example 3

[0106] This comparative example provides a ticagrelor aspirin combination preparation. Compared with Example 1, the prescription of this comparative example is only to replace the lubricant of the tablet core layer from sodium stearyl fumarate to polyethylene glycol, and the other raw materials and amounts are exactly the same as those in Example 1.

[0107] Among them, the particle size D90 of aspirin is 110 μm.

[0108] Comparative Example 3 Preparation method: same as Example 1.

[0109] Comparative Example 4

[0110] This comparative example provides a ticagrelor aspirin combination preparation, the prescription of which is shown in Table 9. Compared with Example 5, only the lubricant ratio in the tablet core layer is reduced.

[0111] Table 9. Prescription table of comparative example 4

[0112]

[0113]

[0114] Among them, the particle size D90 of aspirin is 150 μm.

[0115] Comparative Example 4 Preparation method: same as Example 5.

[0116] Comparative Example 5

[0117] This comparative example provides a ticagrelor aspirin composite preparation, the prescription of which is shown in Table 10. Compared with Example 5, only the proportion of the lubricant in the tablet core layer is increased.

[0118] Table 10. Comparative Example 5 Prescription Table

[0119]

[0120]

[0121] Among them, the particle size D90 of aspirin is 150 μm.

[0122] Comparative Example 5 Preparation method: same as Example 5.

[0123] Comparative Example 6

[0124] This comparative example provides a ticagrelor aspirin combination preparation. Compared with Example 6, the prescription of this comparative example only replaces the glidant in the tablet core layer from colloidal silicon dioxide to sodium dodecyl sulfate, and other raw materials and auxiliary materials and their amounts remain unchanged.

[0125] Among them, the particle size D90 of aspirin is 150 μm.

[0126] Comparative Example 6 Preparation method: same as Example 1.

[0127] Comparative Example 7

[0128] This comparative example provides a ticagrelor aspirin combination preparation, the prescription of which is shown in Table 11. Compared with Example 8, only the proportion of the glidant in the tablet core layer is reduced.

[0129] Table 11. Prescription table of comparative example 7

[0130]

[0131]

[0132] Among them, the particle size D90 of aspirin is 150 μm.

[0133] Comparative Example 7 Preparation method: same as Example 1.

[0134] Comparative Example 8

[0135] This comparative example provides a ticagrelor aspirin combination preparation, the prescription of which is shown in Table 12. Compared with Example 8, only the proportion of the glidant in the tablet core layer is increased.

[0136] Table 12. Prescription table of comparative example 8

[0137]

[0138]

[0139] Among them, the particle size D90 of aspirin is 150 μm.

[0140] Comparative Example 8 Preparation method: same as Example 8.

[0141] Test Case

[0142] 1. Dissolution test

[0143] 1.1 Test Method

[0144] Dissolution method: basket method;

[0145] Dissolution volume: 1000ml;

[0146] Dissolution medium: 0h~2h, pH 4.5+0.5% Tween 80; 2h~24h, pH 6.8+0.5% Tween 80;

[0147] Temperature: 37°C;

[0148] Speed: 100rpm;

[0149] Sampling volume: 5ml;

[0150] Whether to replenish fluid: Yes;

[0151] After sampling at different time points, the content is tested using high performance liquid chromatography and the dissolution rate is calculated.

[0152] 1.2 Eligibility criteria

[0153]

[0154] 1.3 Aspirin Dissolution Summary Table

[0155] Table 13. Summary of aspirin dissolution in Example 3 and Comparative Example 1

[0156]

[0157] Table 14. Summary of aspirin dissolution in Examples 1, 2 and Comparative Example 3

[0158]

[0159] Table 15. Summary of aspirin dissolution in Examples 4, 5 and Comparative Examples 4, 5

[0160]

[0161] Table 16. Summary of aspirin dissolution in Example 6 and Comparative Example 6

[0162]

[0163]

[0164] Table 17. Summary of aspirin dissolution in Examples 7, 8 and Comparative Examples 7, 8

[0165]

[0166] 1.4 Summary of Ticagrelor Dissolution

[0167] Table 18. Summary of dissolution of ticagrelor in Examples 1-4

[0168]

[0169] Table 19. Summary of dissolution of ticagrelor in Examples 5-8

[0170]

[0171] 2. Summary of sticking and punching

[0172] 2.1 Judgment method

[0173] The adhesion between the preparation and the tablet press during the tableting process of each embodiment and comparative example was observed with naked eyes and summarized in the following table.

[0174] Table 20. Summary of sticking and punching conditions of Examples 1-8 and Comparative Examples 1-8

[0175] Example No. Sticking situation Comparative Example No. Sticking situation Example 1 Non-stick punch Comparative Example 2 Sticky Example 2 Non-stick punch Comparative Example 3 Sticky Example 3 Non-stick punch Comparative Example 4 Sticky Example 4 Non-stick punch Comparative Example 5 Non-stick punch, but low hardness Example 5 Non-stick punch Comparative Example 6 Sticky Example 6 Non-stick punch Comparative Example 7 Sticky Example 7 Non-stick punch Comparative Example 8 Sticky Example 8 Non-stick punch

[0176] 3. Test Summary

[0177] It can be seen from the reference table that compared with Example 3, Comparative Example 1 only increases the particle size of the drug particles in the aspirin tablet core layer to above 250 μm, which results in a lower dissolution rate of aspirin within 12 hours, affecting the bioavailability of the preparation, while Comparative Example 2 reduces the particle size of the drug particles in the aspirin tablet core layer to less than 50 μm, which results in sticking during the tableting process of Comparative Example 2, which indicates that setting the particle size of the drug particles in the aspirin tablet core layer to 50-250 μm in the present invention can avoid the sticking phenomenon.

[0178] Referring to the table, compared with Example 1, Comparative Example 3 only uses polyethylene glycol as the lubricant in the core layer of the aspirin tablet, which results in sticking phenomenon in the tableting process of Comparative Example 3, which indicates that the sodium stearyl fumarate and talcum powder selected by the present invention as the lubricant for the core layer of the aspirin tablet can avoid the sticking phenomenon.

[0179] Referring to the table, compared with Example 5, in Comparative Example 4, only the amount of lubricant in the core layer of the aspirin tablet is reduced to less than 1%, resulting in sticking during the tableting process, while in Comparative Example 5, only the amount of lubricant in the core layer of the aspirin tablet is increased to more than 5%, resulting in low hardness of the prepared tablets, which does not meet the factory requirements. This shows that setting the lubricant amount ratio in the core layer of the aspirin tablet to 1-5% in the present invention can avoid sticking.

[0180] Referring to the table, compared with Example 6, Comparative Example 6 only uses sodium lauryl sulfate as the glidant in the core layer of the aspirin tablet, which results in sticking during the tableting process. This shows that the present invention uses talcum powder and colloidal silicon dioxide as the glidant in the core layer of the aspirin tablet to avoid the sticking phenomenon.

[0181] Referring to the table, compared with Example 8, in Comparative Example 7, only the amount of the glidant in the core layer of the aspirin tablet is reduced to less than 0.5%, resulting in sticking during the tableting process, while in Comparative Example 8, only the amount of the glidant in the core layer of the aspirin tablet is increased to more than 3%, resulting in sticking during the tableting process. This shows that setting the amount of the glidant in the core layer of the aspirin tablet to 0.5-3% in the present invention can avoid the sticking phenomenon.

[0182] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the technical solution of the present invention, and are not intended to limit the specific implementation methods of the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the claims of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

1. A ticagrelor-aspirin composite preparation, characterized in that: It includes a ticagrelor shell layer and an aspirin core tablet wrapped inside the ticagrelor shell layer; The outer shell layer of ticagrelor includes a ticagrelor immediate-release layer and a ticagrelor sustained-release layer; The aspirin tablet core comprises an aspirin API and a tablet core layer auxiliary material, wherein the particle size D90 of the aspirin API is 50-250 μm.

2. The ticagrelor-aspirin combination preparation according to claim 1, characterized in that The particle size D90 of aspirin API is 100-200 μm.

3. The ticagrelor-aspirin combination preparation according to claim 1, characterized in that: The tablet core layer excipients include a first disintegrant, a first filler, a first glidant and a first lubricant. Calculated by weight, the aspirin tablet core includes: 70-90 parts of aspirin API, 2-8 parts of the first disintegrant, 5-25 parts of the first filler, 0.5-3 parts of the first glidant, and 1-5 parts of the first lubricant.

4. The ticagrelor-aspirin combination preparation according to claim 3, characterized in that: In terms of weight, the aspirin tablet core includes: 75-85 parts of aspirin API, 2-5 parts of a first disintegrant, 10-20 parts of a first filler, 1-2 parts of a first glidant, and 2-4 parts of a first lubricant.

5. The ticagrelor-aspirin combination preparation according to claim 1, characterized in that: The first lubricant is sodium stearyl fumarate or talc; and / or, The first glidant is colloidal silicon dioxide or talc.

6. The ticagrelor-aspirin combination preparation according to claim 1, characterized in that: The immediate-release layer of ticagrelor includes a first ticagrelor API and immediate-release excipients, and the sustained-release layer of ticagrelor includes a second ticagrelor API and sustained-release excipients, wherein the weight of the first ticagrelor API is equivalent to 15-35% of the total weight of the immediate-release layer of ticagrelor, the weight of the second ticagrelor API is equivalent to 15-35% of the total weight of the sustained-release layer of ticagrelor, and the weight ratio of the first ticagrelor API to the second ticagrelor API is 1:1-1:

3.

7. The ticagrelor-aspirin combination preparation according to claim 6, characterized in that: The rapid-release excipients include a gastric mucosal protective agent, a second disintegrant, a second filler, a first binder, and a second lubricant. In terms of weight, the ticagrelor rapid-release layer includes: 15-35 parts of the first ticagrelor API, 15-40 parts of the gastric mucosal protective agent, 2-10 parts of the second disintegrant, 35-55 parts of the second filler, 2-8 parts of the first binder, and 0.5-3 parts of the second lubricant; and / or, The sustained-release excipients include sustained-release materials, a third filler, a second adhesive, a second glidant, and a third lubricant. Calculated by weight, the ticagrelor sustained-release layer includes: 15-35 parts of the second ticagrelor, 30-50 parts of sustained-release materials, 25-45 parts of the third filler, 2-8 parts of the second adhesive, 0.5-3 parts of the second glidant, and 0.5-3 parts of the third lubricant.

8. The ticagrelor-aspirin combination preparation according to claim 7, characterized in that: The sustained-release material is selected from any one or more of hydroxypropylmethylcellulose, sodium carboxymethylcellulose, xanthan gum, sodium alginate, carbomer or polyethylene oxide.

9. The ticagrelor-aspirin combination preparation according to any one of claims 1 to 8, characterized in that: It also includes an isolation coating layer and an enteric coating layer disposed between the ticagrelor drug-containing outer layer and the aspirin tablet core, wherein the isolation coating layer and the enteric coating layer sequentially coat the aspirin tablet core from the inside to the outside; and / or, It also includes a film coating layer coated on the drug-containing outer layer of ticagrelor.

10. A method for preparing the ticagrelor-aspirin combination preparation according to any one of claims 1 to 9, characterized in that: The following steps are involved: The components of the ticagrelor immediate-release layer are subjected to wet granulation, and then dried and mixed to obtain ticagrelor immediate-release total mixed granules; the components of the ticagrelor sustained-release layer are subjected to wet granulation, and then dried and mixed to obtain ticagrelor sustained-release total mixed granules; the components of the aspirin tablet core are mixed and tableted by a powder direct compression method, and subjected to a coating process to obtain an aspirin coated tablet core; The Ticagrelor immediate-release mixed granules, the Ticagrelor sustained-release mixed granules and the aspirin coated tablet cores are tableted and then coated to prepare the Ticagrelor aspirin composite preparation.

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