A high bioavailability solid dispersion of ticagrelor and formulations, preparation method and use thereof

Abstract

This invention discloses a highly bioavailable ticagrelor solid dispersion, its formulation, preparation method, and application. The solid dispersion is prepared by hot melt extrusion of ticagrelor and a specific ternary carrier system, wherein the ternary carrier system is from Soluplus. ® The formulation consists of copovidone and hydroxypropyl methylcellulose. This solid dispersion is further combined with disintegrants, fillers, and lubricants to form a pharmaceutical composition. This invention utilizes the synergistic effect of a ternary carrier and hot-melt extrusion technology to ensure ticagrelor exists stably in an amorphous form, significantly improving drug dissolution and oral bioavailability. Experiments show that the formulation exhibits a dissolution rate ≥85% in pH 6.8 phosphate buffer after 30 min, and a relative bioavailability in beagle dogs reaching 150%–250% of commercially available tablets. It also demonstrates excellent stability, with no crystallization observed in a 6-month accelerated assay, indicating significant clinical value and market potential.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a highly bioavailable ticagrelor solid dispersion, its formulation, preparation method, and application. Background Technology

[0002] Ticagrelor is a direct-acting, reversibly binding oral P2Y12 receptor antagonist widely used for antiplatelet therapy in patients with acute coronary syndrome (ACS) to prevent thrombotic cardiovascular events. However, the development of oral formulations of ticagrelor faces significant challenges.

[0003] First, ticagrelor itself has serious biopharmaceutical defects. According to the Biopharmaceutical Classification System (BCS), ticagrelor belongs to class IV drugs, meaning it has low solubility and low permeability. Its water solubility is extremely low (approximately 0.016 mg / mL), and its absolute bioavailability in humans averages only 36% (range 30%–42%). This inherent low solubility and low bioavailability severely limit its oral absorption, leading to potentially delayed onset of action, unstable efficacy, and large inter-individual pharmacokinetic variability, which may affect the stability and predictability of clinical efficacy.

[0004] To improve the dissolution behavior of ticagrelor, existing technologies have made a series of attempts. For example, patent document CN104523640A discloses a technical solution to improve the dissolution rate of ticagrelor tablets by optimizing the excipient combination (such as using mannitol, microcrystalline cellulose, croscarmellose sodium, etc.). However, such technologies based on conventional excipient optimization mainly improve the in vitro dissolution of the drug, and have very limited effect on fundamentally overcoming the intestinal absorption barrier and significantly improving in vivo bioavailability. Data from this document itself shows that the relative bioavailability of its formulation is only about 100.8% of that of the reference formulation, failing to achieve a significant improvement in bioavailability.

[0005] Patent document CN104434805A discloses a ticagrelor solid dispersion that uses polyvinylpyrrolidone or copovidone as the main carrier and adds ethyl cellulose to reduce drug burst release. While this technology improves the dissolution rate of ticagrelor to some extent, it still has significant shortcomings: First, the selection and combination of its carrier system aims to balance dissolution and burst release, without optimizing for maximizing bioavailability, resulting in a very limited increase in in vivo bioavailability; second, the ethyl cellulose added to control burst release may, to some extent, delay drug release, hindering rapid and complete drug absorption; third, the solvent-based preparation process used in its preferred embodiment carries the potential risk of organic solvent residue and is not environmentally friendly or cost-effective.

[0006] In summary, there remains a lack of innovative formulation technology in this field that can simultaneously achieve rapid and complete in vitro dissolution of ticagrelor, significantly improved oral bioavailability, and long-term physicochemical stability. Developing such a novel formulation that fundamentally overcomes the absorption bottleneck of ticagrelor is of great clinical significance and market demand for enhancing clinical efficacy, potentially reducing dosage, minimizing individual variability, and improving patient adherence. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention provides a highly bioavailable ticagrelor solid dispersion, its formulation, preparation method, and applications. Through innovative formulation strategies, it simultaneously overcomes the three major technical bottlenecks of ticagrelor: "difficult dissolution, poor absorption, and significant stability challenges." This invention provides an excellent formulation that achieves a leap forward in both in vivo and in vitro performance, possessing significant clinical value and market prospects.

[0008] This invention is achieved through the following technical solution:

[0009] A highly bioavailable ticagrelor solid dispersion comprises the active ingredient ticagrelor and a ternary carrier system, wherein the ternary carrier system comprises a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone, and hydroxypropyl methylcellulose.

[0010] The mass ratio of ticagrelor to the ternary carrier system is 2:1 to 1:5.

[0011] Preferably, in the ternary carrier system, the mass ratio of the polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone, and hydroxypropyl methylcellulose is 5:3:2.

[0012] Preferably, the solid dispersion is prepared by a hot melt extrusion process, wherein the ticagrelor exists in an amorphous form in the carrier.

[0013] A ticagrelor pharmaceutical composition comprising the above-described ticagrelor solid dispersion and pharmaceutically acceptable excipients; wherein the pharmaceutical composition has a dissolution rate of not less than 85% in pH 6.8 phosphate buffer for 30 min.

[0014] Preferably, the pharmaceutically acceptable excipients include disintegrants, fillers, and lubricants; the disintegrant is crospovidone XL-10, the filler is microcrystalline cellulose, and the lubricant is sodium stearate fumarate.

[0015] Preferably, the pharmaceutical composition comprises, by weight of:

[0016] The above-mentioned ticagrelor solid dispersion: 67.5%~90%;

[0017] Disintegrant: 7.5%~22.5%;

[0018] Filler: 2%~8.5%;

[0019] Lubricant: 0.5%~1.5%.

[0020] The method for preparing the above-mentioned pharmaceutical composition includes the following steps:

[0021] Step 1) Prepare the above-mentioned ticagrelor solid dispersion by hot melt extrusion process;

[0022] Step 2) Mix the solid dispersion with the disintegrant, filler, and lubricant;

[0023] Step 3) Compress the mixed materials to obtain ticagrelor tablets.

[0024] Preferably, the temperature of the hot melt extrusion process in step 1) is 140±5℃ and the screw speed is 100±10 rpm.

[0025] The use of the above-described ticagrelor solid dispersion or the above-described pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of thromboembolic diseases, wherein the medicament is capable of achieving a higher peak plasma concentration and drug exposure than commercially available ticagrelor tablets after use; wherein the peak plasma concentration of the medicament is 1.9 to 2.1 times that of commercially available ticagrelor tablets; and the drug exposure of the medicament is 2.0 to 2.2 times that of commercially available ticagrelor tablets.

[0026] Preferably, the relative bioavailability of the drug in beagle dogs is 150% to 250% of that of commercially available ticagrelor tablets.

[0027] The beneficial effects of this invention are as follows:

[0028] (1) This invention fundamentally improves the in vivo absorption of ticagrelor through the synergistic effect of a specific ternary carrier system and a hot-melt extrusion process. In vivo pharmacokinetic studies in beagle dogs confirmed that the tablets of this invention are significantly better than commercially available ticagrelor tablets (Brilinta). ® Its peak plasma concentration (C) max The drug exposure (AUC) was 1.9 to 2.1 times that of commercially available tablets. 0-t The bioavailability of this product is 2.0 to 2.2 times that of commercially available tablets, with a relative bioavailability of 150% to 250%. This means that the formulation of this invention can not only be absorbed by the body in greater quantities, but also has a faster onset of action and a longer duration of action, solving the long-standing core problem of low absolute bioavailability (approximately 36%) of ticagrelor.

[0029] (2) In a dissolution medium of pH 6.8 phosphate buffer, the dissolution rate of the pharmaceutical composition of the present invention is not less than 85% within 30 min, while the dissolution rate of the commercially available reference formulation under the same conditions is only about 45%. This excellent in vitro dissolution characteristic ensures that the drug can be rapidly released and dissolved in the gastrointestinal tract, which is a prerequisite for achieving high bioavailability in vivo, and also indicates that the formulation can take effect quickly, which is of great significance for the treatment of acute coronary syndrome.

[0030] (3) This invention utilizes hot-melt extrusion technology to highly disperse ticagrelor in an amorphous form within a carrier, and X-ray diffraction patterns confirm the complete disappearance of its crystal diffraction peaks. Key accelerated stability tests (6 months at 40℃±2℃ and 75% RH±5%) showed that the amorphous solid dispersion remained stable, with no ticagrelor crystallization observed. This demonstrates that the formulation of this invention not only exhibits excellent initial performance but also maintains high dissolution characteristics and high bioavailability over its shelf life, ensuring product quality stability and consistency in clinical efficacy. Attached Figure Description

[0031] Figure 1 The XRD pattern of the solid dispersion in Example 1;

[0032] Figure 2 This is a comparison chart of the dissolution curves in the pH 1.2 medium of Test Example 1;

[0033] Figure 3 This is a comparison chart of the dissolution curves in the pH 4.5 medium of Test Example 1;

[0034] Figure 4 This is a comparison chart of the dissolution curves in the pH 6.8 medium of Test Example 1. Detailed Implementation

[0035] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0036] Unless otherwise specified, the technical means used in the following embodiments are all conventional means well known to those skilled in the art, and the experimental methods without specific conditions are all conventional methods in the art.

[0037] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0038] Example 1

[0039] A method for preparing ticagrelor tablets with high bioavailability, the specific steps of which are as follows:

[0040] (1) Combine Tigranor with Soluplus ®(Polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), copovidone (PVP / VA), and hydroxypropyl methylcellulose (HPMC E5) were mixed; the mixture was prepared using a twin-screw hot-melt extrusion (HME) process on a ThermoScientific Pharma 11 extruder, with the temperature set at 140℃, screw speed at 100 rpm, and feed rate at 15 g / min. The extrudate was cooled, pulverized, and passed through a 60-mesh sieve to obtain a solid dispersion.

[0041] The XRD pattern of the prepared solid dispersion is as follows: Figure 1 As shown, no sharp crystal diffraction peaks were observed in the ticagrelor active pharmaceutical ingredient; instead, only a broad and diffuse "bun peak" was observed. This indicates that the crystalline structure of ticagrelor has completely disappeared and is highly dispersed in the carrier material in an amorphous form.

[0042] (2) Mix the solid dispersion with the disintegrant (cross-linked povidone XL-10), filler (microcrystalline cellulose), and lubricant (sodium stearate fumarate); compress directly into tablets to avoid the introduction of water and maintain an amorphous state.

[0043] The composition of the 90 mg ticagrelor tablets prepared in this embodiment is shown in Table 1. The tablet weight is 200 mg and the hardness is 80~100 N.

[0044] Table 1. Ingredients of Ticagrelor Tablets (1000 tablets, each tablet contains 90 mg of ticagrelor)

[0045]

[0046] Example 2

[0047] A method for preparing a highly bioavailable ticagrelor tablet, with the same steps as in Example 1.

[0048] The ticagrelor tablets prepared in this embodiment are available in two strengths: 90 mg and 60 mg. The 90 mg strength tablets have the components shown in Table 2, a tablet weight of 300 mg, and a hardness of 100-160 N. The 60 mg strength tablets have their component proportions reduced according to Table 2, resulting in a tablet weight of 200 mg and a hardness of 90-140 N.

[0049] Table 2. Ingredients of Ticagrelor Tablets (1000 tablets, each tablet contains 90 mg of ticagrelor)

[0050]

[0051] Example 3

[0052] A method for preparing a highly bioavailable ticagrelor tablet, with the same steps as in Example 1.

[0053] The composition of the 90 mg ticagrelor tablets prepared in this embodiment is shown in Table 3. The tablet weight is 600 mg and the hardness is 150~200 N.

[0054] Table 3. Ingredients of Ticagrelor Tablets (1000 tablets, each tablet contains 90 mg of ticagrelor)

[0055]

[0056] Example 4

[0057] A method for preparing ticagrelor tablets with high bioavailability, the specific steps are the same as in Example 1, the difference being the parameters of the hot melt extrusion process: temperature 135℃, screw speed 110 rpm, and feeding rate 18 g / min.

[0058] The composition of the 90 mg ticagrelor tablets prepared in this embodiment is shown in Table 2. The tablet weight is 300 mg and the hardness is 100~160 N.

[0059] Comparative Example 1

[0060] Commercially available ticagrelor tablets (Brilinta) ® (90 mg) was used as a reference formulation for dissolution and pharmacokinetic comparison.

[0061] Comparative Example 2

[0062] A method for preparing ticagrelor tablets, the specific steps of which are as follows:

[0063] Tigranor and Soluplus ® Mix copovidone, HPMC E5, crospovidone XL-10, microcrystalline cellulose, and sodium stearate fumarate; compress directly into tablets to obtain the final product.

[0064] The composition of the 90 mg ticagrelor tablets prepared in this comparative example is shown in Table 2. The tablet weight is 300 mg and the hardness is 80~100 N.

[0065] Comparative Example 3

[0066] A method for preparing ticagrelor tablets, the specific steps are the same as in Example 1, the difference being that three different carrier combinations are used, as shown in Table 4.

[0067] Table 4. Ingredients of Ticagrelor Tablets (1000 tablets, each tablet contains 90 mg of ticagrelor)

[0068]

[0069] The 90 mg ticagrelor tablets prepared in this comparative example have a tablet weight of 300 mg and a hardness of 100~160 N.

[0070] Comparative Example 4

[0071] The preparation of ticagrelor tablets is based on the relevant description in patent document CN104434805A, and the specific steps are as follows:

[0072] After dissolving the prescribed amount of ethyl cellulose E20 in 80% ethanol, weigh out the prescribed amounts of copovidone S630 and ticagrelor into the solution, heat and stir in a 70°C water bath until completely dissolved, and set the solution aside. Mix the prescribed amounts of microcrystalline cellulose and crospovidone (added internally) evenly, use the above solution as a binder for wet granulation, dry and granulate the wet granules, mix them evenly with crospovidone (added externally), add magnesium stearate and mix, compress into tablets to obtain the final product.

[0073] The composition of the 90 mg ticagrelor tablets prepared in this comparative example is shown in Table 5. The tablet weight is 450 mg and the hardness is 100~160 N.

[0074] Table 5. Ingredients of Ticagrelor Tablets (1000 tablets, each tablet contains 90 mg of ticagrelor)

[0075]

[0076] Test Example 1: In vitro dissolution test

[0077] 1. Experimental Design

[0078] The dissolution rate of ticagrelor tablets prepared in Examples 1, 2 (90 mg specification), 3 and Comparative Examples 1 and 2 was determined at 5, 15, 30 and 60 min using the paddle method (50 rpm) at 37 °C, with pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer and pH 6.8 phosphate buffer as dissolution media.

[0079] 2. Test Results

[0080] Table 6 Results of in vitro dissolution test

[0081]

[0082] As shown in Table 6 and Figure 2-4 As shown, the ticagrelor tablets prepared in Examples 1-3 all exhibited dissolution rates greater than ≥85% at pH 1.2, 4.5, and 6.8. This is because the solid dispersion prepared from ticagrelor and the ternary carrier system allows for stable dissolution and drug release. In contrast, Comparative Examples 1-2, where the drug exists in crystalline form, had lower dissolution rates, all below 50% at 30 minutes.

[0083] The experimental results of this test case demonstrate the effect of ticagrelor and the ternary carrier system on improving the dissolution mechanism. The ticagrelor tablets prepared by this invention have significant dissolution advantages in various segments of the gastrointestinal tract.

[0084] Test Example 2: Stability Test

[0085] 1. Experimental Design

[0086] (1) Sample: Ticagrelor tablets (90 mg specification, aluminum blister pack) prepared in Example 2.

[0087] (2) Conditions

[0088] Accelerated testing: 40℃±2℃, 75% RH±5%, for 0, 3, and 6 months;

[0089] Long-term test: 25℃±2℃, 60% RH±5%, for 6 or 12 months.

[0090] (3) Test items: appearance, content, related substances, dissolution rate, crystallization rate.

[0091] 2. Test Results

[0092] Table 7 Stability Test Results

[0093]

[0094] As shown in Table 7, under accelerated conditions, the crystallization rate of the solid dispersion tablets prepared by this invention increased only from 0 to 0.2% over 0-6 months, far below the 5% threshold for determining the amorphous state, and the amorphous structure did not change significantly. Under long-term test conditions, the tablet content, related substances, and dissolution rate remained stable after 6 and 12 months, without any adverse trends, and the crystallization rate was only 0.08% (<1%), indicating that the amorphous state was not affected by long-term storage.

[0095] The experimental results of this test case show that the ticagrelor tablets prepared by this invention can remain stable under normal storage conditions, providing sufficient data support for setting shelf life.

[0096] Test Example 3: Pharmacokinetic Study of Beagle Dogs

[0097] 1. Experimental Design

[0098] (1) Animals: 12 healthy beagle dogs, half male and half female, weighing 10-12 kg, were randomly divided into 3 groups (Example 2, Comparative Example 1, Comparative Example 2), crossover design, with a 7-day cleaning period.

[0099] (2) Administration: One 90 mg ticagrelor tablet (1 tablet) is administered orally on an empty stomach.

[0100] (3) Blood collection: Blood was collected before administration and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 h after administration, and the plasma ticagrelor concentration was determined by LC-MS / MS.

[0101] (4) Parameter calculation: C max T max AUC 0-t AUC 0-∞ t 1 / 2 The analysis was performed using a WinNonlin 8.3 non-compartmental model.

[0102] 2. Test Results

[0103] Table 8. Pharmacokinetic results of beagle dog studies (mean ± SD, n=4)

[0104]

[0105] Table 8 Note: Relative bioavailability, with Comparative Example 1 (commercially available tablets) as reference, is calculated using the formula: (AUC of the test formulation) 0-t / Reference formulation AUC 0-t ) × 100%, calculated as follows.

[0106] As shown in Table 8, the statistical results are analyzed as follows:

[0107] (1) Absorption-related parameters (C) max AUC 0-t AUC 0-∞ )

[0108] Compared with Comparative Example 1, Example 2: C max (F=128.6, P<0.01), AUC 0-t (F=135.2, P<0.01), AUC 0-∞ (F=131.8, P<0.01), all showed highly significant differences;

[0109] Compared with Comparative Example 2: C max (F=119.3, P<0.01), AUC 0-t (F=124.5, P<0.01), AUC 0-∞ (F=121.7, P<0.01), all showed highly significant differences;

[0110] Compared with Comparative Example 1, Comparative Example 2: C max (F=2.1, P>0.05), AUC 0-t (F=1.8, P>0.05), AUC 0-∞ (F=2.3, P>0.05), there were no significant differences.

[0111] (2) Elimination and absorption rate parameters (t) 1 / 2 (Tmax)

[0112] Among the three groups in Example 2, Comparative Example 1, and Comparative Example 2: t 1 / 2 (F=1.5, P>0.05), T max (F=1.2, P>0.05), there were no significant differences.

[0113] (3) Conclusion

[0114] ① Significantly improved absorption efficiency: C in Example 2 max AUC 0-t AUC 0-∞ The bioavailability was 1.99 times, 1.99 times, and 2.05 times that of Comparative Example 1, respectively, with a relative bioavailability of 200.5%, and the statistical difference was extremely significant (P < 0.01), indicating that the ternary carrier + hot melt extrusion process of the present invention can significantly promote the absorption of drugs in beagle dogs.

[0115] ② Absorption and elimination characteristics are stable: T values ​​in the three groups max (1.2~1.4 h) and t 1 / 2 There was no significant difference in (7.8~8.0 h), indicating that the process only optimizes the drug dissolution and absorption process, without changing the drug absorption rate and elimination rate in vivo, and the safety is consistent with that of commercially available tablets.

[0116] ③ The innovativeness of the process is highlighted: There were no significant differences in all pharmacokinetic parameters between Comparative Example 2 (physical mixing) and Comparative Example 1 (commercial tablets) (P>0.05), proving that physical mixing alone cannot improve drug absorption, further demonstrating the necessity and innovation of the ternary carrier + hot melt extrusion process of the present invention.

[0117] Test Example 4: Verification of Carrier Synergistic Effect

[0118] 1. Experimental Design

[0119] The dissolution rate and relative bioavailability in beagle dogs of ticagrelor tablets prepared in Example 2 (90 mg specification) and Comparative Example 3 were determined in pH 6.8 medium for 30 min.

[0120] 2. Test Results

[0121] Table 9 Results of the carrier synergistic effect verification experiment

[0122]

[0123] As shown in Table 9, the ternary carrier group of the present invention showed significantly higher dissolution rate and relative bioavailability at 30 min than the single / binary carrier group (P < 0.01), demonstrating that Soluplus... ®The three substances, copovidone, and HPMC E5, have synergistic solubilizing, dispersing, and stabilizing effects, rather than being a simple additive combination.

[0124] Test Example 5: Process Optimization

[0125] 1. Experimental Design

[0126] (1) Samples: Ticagrelor tablets prepared in Example 2 (90 mg specification, hot melt extrusion), Example 4 (process optimization), and Comparative Example 4 (solvent method as described in patent document CN104434805A).

[0127] Testing items: production efficiency, organic solvent residue, dissolution rate in pH 6.8 medium for 30 min, and accelerated crystallization rate over 3 months.

[0128] 2. Test Results

[0129] Table 10 Results of Process Optimization Experiments

[0130]

[0131] As shown in Table 10, the hot-melt extrusion process of the present invention (Examples 2 and 4) has a production cycle that is only 50% of that of the solvent method (Comparative Example 4), making it more suitable for large-scale industrial production. Furthermore, the hot-melt extrusion process eliminates the risk of organic solvent residue, offering a significant advantage in drug safety and avoiding the complex process of solvent recovery. Example 2 achieved a dissolution rate of 91.5% in pH 6.8 medium after 30 minutes, and Example 4 achieved 90.8%, both significantly higher than the 78.2% achieved by the solvent method in Comparative Example 4. This demonstrates that the hot-melt extrusion process of the present invention, combined with a ternary carrier system, can more efficiently promote drug dissolution and solve the absorption limitation problem caused by the low solubility of ticagrelor. The accelerated crystallization rate of Example 2 after 3 months was only 0.1%, and that of Example 4 was 0.12%, far lower than the 0.5% of Comparative Example 4. This reflects that the solid dispersion of the present invention is more stable in its amorphous state under accelerated conditions, effectively inhibiting drug crystallization and ensuring long-term efficacy.

[0132] Test Example 6: Efficacy Study of Low-Dose (60 mg)

[0133] 1. Experimental Design

[0134] (1) Animals: 12 healthy beagle dogs, half male and half female, weighing 10-12 kg, were randomly divided into 2 groups (Example 2 and Comparative Example 1) in a crossover design, with a 7-day cleaning period.

[0135] (2) Administration: Take one 60 mg ticagrelor tablet (1 tablet) prepared in Example 2 or one 90 mg ticagrelor tablet (1 tablet) prepared in Comparative Example 1 orally on an empty stomach.

[0136] (3) Blood collection: Blood was collected before administration and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 h after administration, and the plasma ticagrelor concentration was determined by LC-MS / MS.

[0137] (4) Parameter calculation: C max AUC 0-t The analysis was performed using a WinNonlin 8.3 non-compartmental model.

[0138] 2. Test Results

[0139] Table 11 Results of low-dose efficacy trials (mean ± SD, n=6)

[0140]

[0141] Table 11 Note: Relative bioavailability, with Comparative Example 1 (commercially available tablets) as reference, is calculated using the formula: (AUC of the test formulation) 0-t / Reference formulation AUC 0-t ) × 100%, calculated as follows.

[0142] As shown in Table 11, the pharmacokinetic data show that the bioavailability of Example 2 (60 mg) was 9900±800 ng·h / mL, and that of Comparative Example 1 was 9624±850 ng·h / mL. The values ​​are close, and P>0.05, indicating no statistically significant difference between the two groups, thus demonstrating equivalent total drug exposure in vivo. The relative bioavailability of the 60 mg ticagrelor tablets prepared in Example 2 compared to the 90 mg commercially available tablets was 105.2±8%, close to 100%, further verifying that the bioavailability of the low-dose tablets is comparable to that of the high-dose commercially available tablets.

[0143] The test results of this test case show that the ticagrelor tablets prepared in this invention can achieve the therapeutic effect of commercially available tablets with a 33% reduction in dosage, thereby reducing the risk of adverse reactions that may be caused by high dosage.

[0144] The embodiments described above are only some, not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments. The scope of protection of the present invention is determined by the scope claimed in the claims. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

Claims

1. A tablet of ticagrelor characterized in that, It contains ticagrelor solid dispersion and pharmaceutically acceptable excipients; The ticagrelor solid dispersion is composed of the active ingredient ticagrelor and a ternary carrier system, wherein the ternary carrier system is composed of a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone, and hydroxypropyl methylcellulose; wherein the mass ratio of ticagrelor to the ternary carrier system is 2:1 to 1:

5. In the ternary carrier system, the mass ratio of the polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone, and hydroxypropyl methylcellulose is 5:3:

2. The pharmaceutically acceptable excipients include disintegrants, fillers, and lubricants; the disintegrant is crospovidone XL-10, the filler is microcrystalline cellulose, and the lubricant is sodium stearate fumarate. By total weight, the ticagrelor tablets comprise: Ticagrelor solid dispersion: 67.5%~90%; Disintegrant: 7.5%~22.5%; Filler: 2%~8.5%; Lubricant: 0.5%~1.5%.

2. A tablet of ticagrelor according to claim 1, characterized in that, The solid dispersion is prepared by a hot melt extrusion process, wherein the ticagrelor exists in an amorphous form in the carrier.

3. A process for the preparation of a pharmaceutical composition as claimed in claim 1 or 2, characterized in that, Includes the following steps: Step 1) Prepare ticagrelor solid dispersion by hot melt extrusion process; Step 2) Mix the solid dispersion with the disintegrant, filler, and lubricant; Step 3) Compress the mixed materials to obtain ticagrelor tablets.

4. The preparation method according to claim 3, characterized in that, Step 1) The temperature of the hot melt extrusion process is 140±5℃ and the screw speed is 100±10 rpm.

5. Use of the pharmaceutical composition of claim 1 or 2 in the preparation of a medicament for the prevention and / or treatment of thromboembolic diseases.

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