Avantrombopag maleate tablet and preparation method thereof

Abstract

The invention discloses an atavalopag maleate tablet and a preparation method thereof. The atavalopag maleate tablet is prepared from the following components in percentage by weight: 12 to 15 percent of atavalopag maleate, 30 to 45 percent of modified beta-cyclodextrin, 3 to 4 percent of disintegrating agent, 0.5 to 1 percent of flow aid, 0.5 to 2 percent of lubricating agent and the balance of filling agent. The invention also provides a preparation method of the composition. According to the invention, the specific surface area of the medicine is increased by accurately controlling the particle size of the raw materials and clathrating the medicine, so that the medicine can be quickly dissolved in a dissolution medium, and the dissolution rate and the dissolution amount of the medicine are improved, thereby being beneficial to the absorption of the medicine in vivo, being beneficial to improving the bioavailability of the medicine and enhancing the treatment effect of the medicine.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an avatrombopag maleate tablet and a preparation method thereof. Background Art

[0002] Avatrombopag maleate tablets are developed by AkaRx Inc. for the treatment of adult patients with chronic liver disease-related thrombocytopenia who are undergoing elective diagnostic or surgical procedures. Avatrombopag maleate is a small molecule thrombopoietin receptor agonist that stimulates the proliferation of bone marrow progenitor cells and megakaryocyte differentiation by mimicking the biological effects of thrombopoietin, thereby increasing platelet production and platelet count. Avatrombopag maleate is a BCS class IV drug and a poorly soluble crystalline drug with low solubility. It is virtually insoluble in aqueous solutions within the pH range of 1-10. Specifically, it exhibits extremely low solubility in water, hydrochloric acid solutions, and buffer systems with a pH of 1.0 to 11.0. Its saturated solubility in 0.1 mol / L hydrochloric acid and pH 7.0 is less than 1 μg / mL. Enhancing the drug's effective dissolution efficiency at the absorption site under physiological pH conditions is crucial for overcoming its bioavailability bottleneck. Secondly, as a polymorphic drug, avatrombopag maleate is extremely sensitive to ambient humidity and is prone to crystal transformation. This crystal transformation can significantly reduce the drug's solubility, leading to a decrease in the dissolution rate of the formulation and posing stability risks. Therefore, addressing drug dissolution issues and ensuring formulation stability are two major technical challenges that must be overcome in the development of avatrombopag maleate formulations.

[0003] CN117582412A relates to the field of pharmaceutical technology. It discloses avatrombopag maleate tablets, which are made by mixing and grinding avatrombopag maleate with a glidant and a solubilizer. This main ingredient has specific morphology and particle size parameters, with an average aspect ratio of (1-1.5):1, a particle size distribution of D90 ≤ 4.5 μm, D50 2-2.5 μm, and D10 ≥ 0.5 μm. The tablets are prepared through a one-step granulation process, effectively addressing the issues of low drug solubility and poor stability.

[0004] CN114652725A belongs to the field of pharmaceutical preparations. The invention discloses an inclusion complex of avatrombopag maleate with cyclodextrin, composed of avatrombopag maleate, cyclodextrin or its derivatives, and the polymer additive copovidone. This inclusion complex, with its unique combination of ingredients, not only significantly enhances drug solubility but also offers the advantages of low cyclodextrin usage and high inclusion efficiency, effectively improving drug bioavailability. Furthermore, its manufacturing process is simple, cost-effective, and product stability is excellent, with the pharmaceutical preparation being less affected by packaging materials and environmental humidity.

[0005] The particle size distribution of APIs in pharmaceutical formulations is a crucial aspect of drug development, as it can influence the dissolution properties of the formulation and potentially impact the bioavailability and efficacy of the pharmaceutical composition. Furthermore, the particle size distribution of the API can affect the flowability of the API and the manufacturing process of the pharmaceutical composition. Precise control of the API particle size can significantly improve the drug's dissolution rate, bioavailability, and stability, ultimately enhancing the therapeutic efficacy of the drug.

[0006] However, controlling the particle size of avatrombopag maleate alone will not fully address dissolution, bioavailability, and stability issues. Avatrombopag maleate is a low-solubility, low-permeability drug, and simply increasing the specific surface area may not be enough to overcome the solubility bottleneck. Micron-sized particles tend to aggregate due to their high surface energy, resulting in a decrease in the actual effective specific surface area and, in turn, a reduction in dissolution efficiency. Failure to incorporate a dispersant or solubilizer may compromise efficacy. Therefore, further optimization of solubilization technology is necessary to achieve more ideal solubilization and stabilization results. Summary of the Invention

[0007] In view of the above-mentioned defects in the prior art, the technical problem to be solved by the present invention is to provide an avatrombopag maleate tablet and a preparation method thereof.

[0008] As a low-soluble crystalline drug, avatrombopag maleate not only has low solubility, but is also extremely sensitive to environmental humidity and is prone to crystal transformation. This crystal transformation phenomenon can significantly reduce the solubility of the drug, resulting in a decrease in the dissolution rate of the preparation and posing a potential stability risk. β-cyclodextrin, as a cyclic oligosaccharide, has a hydrophobic cavity and a hydrophilic surface, which can well encapsulate the drug, thereby improving the solubility, stability and bioavailability of the drug. However, the strong hydrogen bond network between natural β-cyclodextrin molecules leads to a compact crystal structure, which hinders the penetration of water molecules and results in low water solubility, requiring chemical modification to optimize performance.

[0009] Therefore, the present invention provides a modified cyclodextrin, which is modified using amino acids and thiosemicarbazide. β-cyclodextrin is activated by p-toluenesulfonyl chloride and then reacted with amino acids. This modification destroys the intramolecular hydrogen bonds of β-cyclodextrin, while the hydroxyl or amino groups in the amino acids can form hydrogen bonds with water. Furthermore, under acidic conditions, thiosemicarbazide reacts with the hydroxyl groups on the cyclodextrin, and the highly active hydroxyl groups form an intermediate that is hydrolyzed to form a thiol-modified cyclodextrin. The introduction of thiol groups can improve transmembrane transport efficiency by promoting permeability, thereby improving the bioavailability of avatrombopag maleate. The modified cyclodextrin introduces hydrophilic groups, which destroy some hydrogen bonds, increase hydrophilicity, and thus improve solubility. Avatrombopag maleate is encapsulated in the cavity of the cyclodextrin, which not only improves solubility but also prevents avatrombopag maleate from undergoing crystal transformation, thereby improving formulation stability.

[0010] To achieve the above objectives, the present invention provides an avatrombopag maleate tablet, comprising the following components in weight percentage: 12-15% avatrombopag maleate, 30-45% modified β-cyclodextrin, 3-4% disintegrant, 0.5-1% glidant, 0.5-2% lubricant, and the balance being filler.

[0011] The preparation method of the modified β-cyclodextrin comprises the following steps: β-cyclodextrin is substituted with p-toluenesulfonyl chloride, active groups are introduced into the β-cyclodextrin molecule through nucleophilic substitution, chemical modification is achieved through microwave-assisted thiosemicarbazide, and finally a modified β-cyclodextrin with a functionalized structure is obtained.

[0012] Further preferably, the preparation method of the modified β-cyclodextrin comprises the following steps:

[0013] X1. Add β-cyclodextrin and p-toluenesulfonyl chloride to an aqueous sodium hydroxide solution, stir at 0-5°C for 4-6 hours, filter, adjust the pH, let stand, and filter. Recrystallize and dry the filter cake, then add the product and amino acid to an aqueous triethylamine solution. Stir under an inert atmosphere at 80-90°C for 16-20 hours, then centrifuge. Purify and dry the filtrate before use in the next step.

[0014] X2. Add the product from the previous step and thiosemicarbazide to an aqueous acetic acid solution, carry out microwave reaction at 200W and 80-90℃ for 40-80min, then add an aqueous sodium hydroxide solution for hydrolysis, adjust the pH to neutral at room temperature, and obtain modified β-cyclodextrin after washing, filtering and dialyzing.

[0015] Furthermore, the mass ratio of the β-cyclodextrin, p-toluenesulfonyl chloride, and sodium hydroxide aqueous solution is 1:0.1-0.2:5-10.

[0016] Furthermore, the mass ratio of the dried product to the amino acid and triethylamine aqueous solution is 1:0.2~0.4:5~10.

[0017] Furthermore, the amino acid is one of lysine, arginine or threonine.

[0018] Furthermore, the mass ratio of the product of the previous step to thiosemicarbazide, acetic acid aqueous solution, and sodium hydroxide aqueous solution is 1:0.5~1.5:8~12:4~8.

[0019] Furthermore, the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, sucrose, and pregelatinized starch.

[0020] Furthermore, the disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

[0021] Furthermore, the glidant is selected from one or both of colloidal silicon dioxide and talc.

[0022] Furthermore, the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, and polyethylene glycol.

[0023] Preferably, the preparation method of the modified β-cyclodextrin comprises the following steps:

[0024] X1. Add β-cyclodextrin and p-toluenesulfonyl chloride to a 1 mol / L sodium hydroxide aqueous solution in a mass ratio of β-cyclodextrin to p-toluenesulfonyl chloride to the sodium hydroxide aqueous solution of 1:0.1-0.2:5-10, stir at 0-5°C for 4-6 hours, filter, adjust the pH to 6-7, let stand, and filter. Recrystallize and dry the filter cake, and add the resulting product and amino acid to a 40 wt% triethylamine aqueous solution in a mass ratio of the dried product to the amino acid to the triethylamine aqueous solution of 1:0.2-0.4:5-10. Stir under an inert atmosphere at 80-90°C for 16-20 hours, then centrifuge. Purify and dry the filtrate for the next step.

[0025] X2. Add the product of the previous step and thiosemicarbazide to 1 wt% acetic acid aqueous solution, react at 200 W, 80-90 ° C. for 40-80 min, and then add 1 mol / L sodium hydroxide aqueous solution for hydrolysis. The mass ratio of the product of the previous step to thiosemicarbazide, acetic acid aqueous solution, and sodium hydroxide aqueous solution is 1:0.5-1.5:8-12:4-8. Adjust the pH to neutral at room temperature, and obtain modified β-cyclodextrin after washing, filtration, and dialysis.

[0026] A method for preparing avatrombopag maleate tablets, comprising the following steps:

[0027] S1. Take crude avatrombopag maleate and grind it by air flow milling at 150-250 m / s for 25-40 min or by ball milling for 50-70 min to obtain a particle size distribution of 10-30 μm for D90, 5-15 μm for D50, and 1-5 μm for D10.

[0028] S2. Add the particle size-controlled avatrombopag maleate raw material to 9 times the mass of 90 wt% ethanol aqueous solution, and then add it to an equal mass of 20-30 wt% modified β-cyclodextrin aqueous solution, stir for 30-40 hours, and then centrifuge. After freeze-drying, mix the supernatant with the prescribed amount of filler, disintegrant, and glidant for 5-20 minutes to ensure that the materials are fully mixed;

[0029] S3. The mixed material is dispersed by a crushing and granulating machine, wherein the screen is selected to be 0.8-1.2 mm and the speed is 300-500 rpm. The dispersed material and the prescribed amount of lubricant are mixed for 5-10 minutes;

[0030] S4. The uniformly mixed material is dry-granulated into dry granules, with the roller oil pressure of 20-60 bar and the roller gap of 1.5-3.0 mm. The granules are then sized at a speed of 80-120 rpm. The prepared dry granules are further crushed and sized, with a screen size of 0.8-1.2 mm and a speed of 500-1000 rpm. The prescribed amount of lubricant, the prescribed amount of disintegrant, and the prescribed amount of filler are added to the granules after granulation, and the mixture is mixed for 10-30 minutes. The mixed material is then compressed into tablets using a rotary tablet press, and the average hardness of the compressed tablets is 2-6 kg to prepare avatrombopag maleate tablets.

[0031] Beneficial effects of the present invention:

[0032] The present invention increases the specific surface area of ​​the drug by precisely controlling the particle size of the raw materials and encapsulating the drug, so that the drug can be quickly dissolved in the dissolution medium, and the dissolution rate and dissolution amount of the drug are improved, thereby facilitating the absorption of the drug in the body, improving the bioavailability of the drug, and enhancing the therapeutic effect of the drug. DETAILED DESCRIPTION

[0033] Example 1

[0034] A method for preparing avatrombopag maleate tablets, comprising the following steps, in parts by mass:

[0035] S1. Crude avatrombopag maleate was ground using a 200 m / s airflow for 30 min to obtain a particle size distribution of 20 μm for D90, 10 μm for D50, and 3 μm for D10.

[0036] S2. Add 14.75 parts of the particle size-controlled avatrombopag maleate raw material to 9 times the mass of a 90 wt% ethanol aqueous solution, then add the mixture to 147.5 parts of a 25 wt% modified cyclodextrin aqueous solution (36.875 parts of modified β-cyclodextrin), stir for 35 hours, and then centrifuge. After freeze-drying, the supernatant is mixed with 39.625 parts of lactose, 1.75 parts of cross-linked polyvinylpyrrolidone, and 0.75 parts of colloidal silicon dioxide for 5 minutes to fully mix the materials.

[0037] S3, the mixed material was dispersed by a pulverizer, wherein the screen was 0.8 mm, the speed was 300 rpm, and the dispersed material was mixed with 0.5 parts of magnesium stearate for 5 minutes;

[0038] S4. The uniformly mixed material is dry granulated into dry granules, with a roller oil pressure of 40 bar and a roller gap of 2.0 mm. The granules are then sized at a speed of 100 rpm. The prepared dry granules are further crushed and sized, with a 0.8 mm screen and a speed of 500 rpm. 0.5 parts of magnesium stearate, 1.75 parts of cross-linked polyvinylpyrrolidone, and 3.5 parts of microcrystalline cellulose are added to the granules after granulation, and the mixture is mixed for 10 minutes. The mixed material is compressed into tablets using a rotary tablet press with an average hardness of 4.0 kg to produce tablets containing 20 mg of avatrombopag maleate per tablet.

[0039] The preparation method of the modified β-cyclodextrin comprises the following steps:

[0040] X1. Add β-cyclodextrin and p-toluenesulfonyl chloride to a 1 mol / L sodium hydroxide aqueous solution in a mass ratio of β-cyclodextrin, p-toluenesulfonyl chloride, and sodium hydroxide aqueous solution of 1:0.12:8, stir at 0°C for 5 h, filter, adjust the pH to 7, let stand, and filter. Recrystallize and dry the filter cake, and add threonine to a 40 wt% triethylamine aqueous solution in a mass ratio of the dried product to threonine and triethylamine aqueous solution of 1:0.3:8. Stir under a nitrogen atmosphere at 85°C for 18 h, then centrifuge. Purify and dry the filtrate and use it in the next step.

[0041] X2. Add the product of the previous step and thiosemicarbazide to 1 wt% acetic acid aqueous solution, react at 200 W, 85 ° C. for 60 min, and then add 1 mol / L sodium hydroxide aqueous solution for hydrolysis. The mass ratio of the product of the previous step to thiosemicarbazide, acetic acid aqueous solution, and sodium hydroxide aqueous solution is 1:1.1:10:6. Adjust the pH to neutral at room temperature, and obtain modified β-cyclodextrin after washing, filtration, and dialysis.

[0042] Example 2

[0043] The process is basically the same as Example 1, except that threonine is replaced by lysine.

[0044] Example 3

[0045] The process is basically the same as Example 1, except that threonine is replaced by arginine.

[0046] Comparative Example 1

[0047] A conventional pulverization method was used without precise control of the particle size of the avatrombopag maleate raw material, and the obtained raw material particle sizes D90, D50, and D10 were 50 μm, 30 μm, and 10 μm.

[0048] Mixing, dispersing, mixing, dry granulation, total blending and tableting were performed according to the same prescription and process as in Example 1 to prepare tablets containing 20 mg of avatrombopag maleate per tablet.

[0049] Comparative Example 2

[0050] A conventional pulverization method was used without precise control of the particle size of the avatrombopag maleate raw material, and the obtained raw material particle sizes D90, D50, and D10 were 8 μm, 3 μm, and 0.5 μm.

[0051] The same formulation and process as in Example 1 were followed: mixing, dispersing, blending, dry granulation, total mixing and tableting to prepare tablets containing 20 mg of avatrombopag maleate per tablet.

[0052] Comparative Example 3

[0053] A method for preparing avatrombopag maleate tablets, comprising the following steps, in parts by mass:

[0054] S1. Crude avatrombopag maleate was ground using a 200 m / s airflow for 30 min to obtain a particle size distribution of 20 μm for D90, 10 μm for D50, and 3 μm for D10.

[0055] S2. Mix 14.75 parts of the particle size-controlled avatrombopag maleate raw material with 75.5 parts of lactose, 1.75 parts of cross-linked polyvinylpyrrolidone, and 0.75 parts of colloidal silicon dioxide for 5 minutes to ensure that the materials are fully mixed;

[0056] S3, the mixed material was dispersed by a pulverizer, wherein the screen was 0.8 mm, the speed was 300 rpm, and the dispersed material was mixed with 0.5 parts of magnesium stearate for 5 minutes;

[0057] S4. The uniformly mixed material is dry granulated into dry granules, with a roller oil pressure of 40 bar and a roller gap of 2.0 mm. The granules are then sized at a speed of 100 rpm. The prepared dry granules are further crushed and sized, with a 0.8 mm screen and a speed of 500 rpm. 0.5 parts of magnesium stearate, 1.75 parts of cross-linked polyvinylpyrrolidone, and 3.5 parts of microcrystalline cellulose are added to the granules after granulation, and the mixture is mixed for 10 minutes. The mixed material is compressed into tablets using a rotary tablet press with an average hardness of 4.0 kg to produce tablets containing 20 mg of avatrombopag maleate per tablet.

[0058] Comparative Example 4

[0059] A method for preparing avatrombopag maleate tablets, comprising the following steps, in parts by mass:

[0060] S1. Crude avatrombopag maleate was ground using a 200 m / s airflow for 30 min to obtain a particle size distribution of 20 μm for D90, 10 μm for D50, and 3 μm for D10.

[0061] S2. Add 14.75 parts of the particle size-controlled avatrombopag maleate raw material to 9 times the mass of a 90 wt% ethanol aqueous solution, then add the solution to 147.5 parts of a 25 wt% β-cyclodextrin aqueous solution (36.875 parts of β-cyclodextrin), stir for 35 hours, and then centrifuge. After freeze-drying, the supernatant is mixed with 39.625 parts of lactose, 1.75 parts of cross-linked polyvinylpyrrolidone, and 0.75 parts of colloidal silicon dioxide for 5 minutes to fully mix the materials.

[0062] S3, the mixed material was dispersed by a pulverizer, wherein the screen was 0.8 mm, the speed was 300 rpm, and the dispersed material was mixed with 0.5 parts of magnesium stearate for 5 minutes;

[0063] S4. The uniformly mixed material is dry granulated into dry granules, with a roller oil pressure of 40 bar and a roller gap of 2.0 mm. The granules are then sized at a speed of 100 rpm. The prepared dry granules are further crushed and sized, with a 0.8 mm screen and a speed of 500 rpm. 0.5 parts of magnesium stearate, 1.75 parts of cross-linked polyvinylpyrrolidone, and 3.5 parts of microcrystalline cellulose are added to the granules after granulation, and the mixture is mixed for 10 minutes. The mixed material is compressed into tablets using a rotary tablet press with an average hardness of 4.0 kg to produce tablets containing 20 mg of avatrombopag maleate per tablet.

[0064] Test Example 1

[0065] Determined according to the dissolution and release test method (Method 2, Part IV General Chapter 0931, Chinese Pharmacopoeia 2020 Edition). 900 mL of 0.25% hexadecyltrimethylammonium bromide-disodium hydrogen phosphate buffer [take 49.7 g of anhydrous disodium hydrogen phosphate or 125.37 g of disodium hydrogen phosphate dodecahydrate, add 6500 mL of water to dissolve, adjust the pH to 6.8 with phosphoric acid, add hexadecyltrimethylammonium bromide solution (take 17.5 g of hexadecyltrimethylammonium bromide, add 500 mL of freshly boiled degassed water and ultrasonically dissolve it), and mix well] was used as the dissolution medium. The speed was 50 rpm. The operation was carried out according to the method. Samples were taken after 5, 10, 25, 30, 45, and 60 minutes, respectively. The absorbance was measured at a wavelength of 337 nm using UV-visible spectrophotometry (General Rules 0401 of Part IV of the Chinese Pharmacopoeia 2020 Edition). The dissolution amount of each tablet was calculated and the dissolution rate was determined. The details are shown in Table 1.

[0066] Table 1

[0067]

[0068] As can be seen from Table 1, compared with Control Examples 1 and 2, the specific raw material particle size in Example and Control Example 3 can increase the dissolution rate and dissolution rate of the raw material drug, which is beneficial to the absorption of the preparation in the body and is beneficial to improving the bioavailability of the drug.

[0069] Compared with Control Example 3, Examples 1 to 3 use modified β-cyclodextrin to include avatrombopag maleate. The modified cyclodextrin introduces hydrophilic groups, destroys some hydrogen bonds, increases hydrophilicity, and improves solubility, resulting in a significant increase in the dissolution of the included avatrombopag maleate. In Control Example 4, β-cyclodextrin was not modified. The strong hydrogen bond network between the unmodified β-cyclodextrin molecules resulted in a compact crystal structure, which hindered the penetration of water molecules and resulted in low water solubility. Therefore, the solubility improvement after inclusion was not obvious. Compared with Examples 1 to 2, Example 3 has a higher solubility. This may be because arginine, compared to threonine and lysine, has a guanidine group in its side chain. It is positively charged at physiological pH and can form a strong ionic bond with the maleic acid group of avatrombopag maleate, significantly enhancing the inclusion stability and hydrophilicity. Therefore, the solubility improvement is more significant.

[0070] Test Example 2

[0071] The tablets prepared in the Examples and Control Examples were tested for disintegration time using the disintegration time test method described in the 2020 Appendix of the Chinese Pharmacopoeia. Six tablets were placed in the disintegration baskets of a disintegrator (37°C constant temperature water bath). 900 mL of water was added to each basket as the medium. The instrument was set to a lifting frequency of 30 cycles / minute and an amplitude of 55 mm. The instrument was started and the timer was set. Tablets should completely disintegrate within 15 minutes. Tablets that showed no hard core residue and all passed through a 2.0 mm sieve were considered acceptable.

[0072] Table 2

[0073]

[0074] As can be seen in Table 2, the disintegration time of the Examples is shorter than that of the Controls, demonstrating that controlling the particle size of avatrombopag maleate alone is insufficient to fully address dissolution and release issues. Avatrombopag maleate is a low-solubility, low-permeability drug, and simply increasing the specific surface area may not overcome the solubility bottleneck. Micron-sized particles are prone to aggregation due to their high surface energy, resulting in a decrease in the effective specific surface area and, in turn, reduced dissolution and disintegration efficiency. The Examples, however, improve solubility through inclusion. This increases the dispersion of drug molecules and accelerates release, thereby shortening the dissolution time after disintegration and indirectly promoting disintegration. Modified β-cyclodextrin enhances tablet water absorption, accelerating water penetration and disintegration. Example 3 disintegrates faster than Examples 1-2. This may be because arginine, compared to threonine and lysine, has a guanidine group in its side chain. This positively charged guanidine group at physiological pH forms a strong ionic bond with the maleic acid group of avatrombopag maleate, enhancing solubility and indirectly leading to faster disintegration.

[0075] Test Example 3

[0076] The tablets prepared in the examples and comparative examples were placed at 40° C. and 75% relative humidity for 6 months, and the content of the main component and impurities were regularly tested.

[0077] Chromatographic conditions for relevant substances: octadecylsilane bonded silica gel as filler (Welch Ultimate Polar-RP, 4.6 mm × 250 mm, 3 μm or chromatographic column with equivalent performance); water-methanol-trifluoroacetic acid (950:50:1) as mobile phase A, acetonitrile-methanol-trifluoroacetic acid (950:50:1) as mobile phase B, and linear gradient elution according to the table below; column temperature, 35°C; flow rate, 1.0 mL per minute; detection wavelength, 254 nm; injection volume, 10 μL; injector temperature, 4°C.

[0078]

[0079] Chromatographic conditions for content determination: octadecylsilane bonded silica gel as the filler (Welch Ultimate PolarRP, 4.6 mm × 250 mm, 3 μm or a chromatographic column of equivalent performance); trifluoroacetic acid-water-acetonitrile (0.3:40:60) as the mobile phase; detection wavelength at 332 nm; flow rate at 1.0 mL / min; column temperature at 30°C; injection volume at 10 μL.

[0080] The specific results are as follows:

[0081] Table 3

[0082]

[0083] As can be seen from Table 3, the avatrombopag maleate tablets in the Examples exhibited improved stability. This is because avatrombopag maleate is encapsulated within the cyclodextrin cavity, which not only enhances solubility but also prevents avatrombopag maleate from undergoing crystal transformation, thereby improving formulation stability. Furthermore, the arginine side chain in Example 3 also contains a guanidine group, which is positively charged at physiological pH and can form a strong ionic bond with the maleic acid group of avatrombopag maleate, significantly enhancing inclusion stability. The strong positive charge complements the acidic group of the drug, resulting in the highest binding energy, significantly improving solubility and achieving optimal stability.

[0084] Test Example 4

[0085] This study employed a single-center, randomized, open-label, two-period, double-crossover design for in vivo bioavailability studies in humans. The test formulation was avatrombopag maleate tablets prepared using the method of Example 3, and the reference formulation was commercially available avatrombopag maleate tablets (trade name: Sukoxin), licensed by AkaRx Inc. The specific experimental protocol is as follows:

[0086] Subjects: 32 healthy male or female subjects aged 18 years and above were selected, including 16 subjects in the fasting test group and 16 subjects in the postprandial test group.

[0087] Dosage regimen: The subjects in the fasting / postprandial test group were randomly divided into two sequences, and the test preparation and the reference preparation were taken crosswise in two cycles, with a washout period of 10 days between the two weeks.

[0088] Dosage: The dosage of the test preparation / reference preparation is 1 tablet (20 mg).

[0089] Dosing Method: For fasting dosing trials, subjects fasted for at least 10 hours, but not withholding water, and then took a single oral dose of the test or reference formulation with approximately 240 mL of warm water. For postprandial dosing trials, subjects fasted for at least 10 hours, but not withholding water, and then took a single oral dose of the test or reference formulation with approximately 240 mL of warm water 30 minutes after the start of the meal, after having consumed a high-fat meal.

[0090] Biological sample collection: Plasma was used as the matrix for biological sample determination. Upper limb venous blood was collected from subjects at 0 h before administration and 2 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h, 7.5 h, 8 h, 8.5 h, 9 h, 10 h, 11 h, 12 h, 14 h, 16 h, 24 h, and 48 h after administration. The blood was centrifuged at 2600 g for 10 min at 4 ° C. All plasma samples were transferred to a refrigerator at -20 ° C or below for temporary storage within 2 h of blood collection. All plasma samples were transferred to a refrigerator at -60 ° C or below for storage within 24 h after blood collection.

[0091] Biological testing: The concentration of avatrombopag in the plasma of healthy subjects after oral administration of the test formulation and the reference formulation was determined by LC-MS / MS.

[0092] Bioavailability evaluation: WinNonlin version 8.0 was used, with AUC0-t as the bioavailability evaluation parameter. The results are as follows:

[0093] Table 4

[0094]

[0095] The experimental results showed that the bioavailability of the test preparation group in both the fasting and postprandial states was higher than that of the reference preparation group, indicating that the present invention precisely controls the particle size of the avatrombopag maleate raw material and coats the avatrombopag maleate with modified β-cyclodextrin. Since the modification destroys the intramolecular hydrogen bonds of β-cyclodextrin, and the hydroxyl or amino groups in the amino acids can form hydrogen bonds with water, the introduction of thiol groups can improve the transmembrane transport efficiency by promoting permeability. Therefore, not only the solubility and stability of avatrombopag maleate are improved, but also its bioavailability is improved.

[0096] The above describes in detail the preferred embodiments of the present invention. It should be understood that those skilled in the art can make numerous modifications and variations based on the concepts of the present invention without inventive effort. Therefore, any technical solutions that can be derived by those skilled in the art through logical analysis, reasoning, or limited experimentation based on the concepts of the present invention and the prior art should be within the scope of protection defined by the claims.

Claims

1. An avatrombopag maleate tablet, characterized in that: The invention comprises the following components in weight percentage: 12-15% avatrombopag maleate, 30-45% modified β-cyclodextrin, 3-4% disintegrant, 0.5-1% glidant, 0.5-2% lubricant, and the balance being filler; The preparation method of the modified β-cyclodextrin comprises the following steps: β-cyclodextrin is substituted with p-toluenesulfonyl chloride, active groups are introduced into the β-cyclodextrin molecule through nucleophilic substitution, chemical modification is achieved through microwave-assisted thiosemicarbazide, and finally a modified β-cyclodextrin with a functionalized structure is obtained.

2. The avatrombopag maleate tablets according to claim 1, wherein The preparation method of the modified β-cyclodextrin comprises the following steps: X1. Add β-cyclodextrin and p-toluenesulfonyl chloride to an aqueous sodium hydroxide solution, stir at 0-5°C for 4-6 hours, filter, adjust the pH, let stand, and filter. Recrystallize and dry the filter cake, then add the product and amino acid to an aqueous triethylamine solution. Stir under an inert atmosphere at 80-90°C for 16-20 hours, then centrifuge. Purify and dry the filtrate before use in the next step. X2. Add the product from the previous step and thiosemicarbazide to an aqueous acetic acid solution, carry out microwave reaction at 200W and 80-90℃ for 40-80min, then add an aqueous sodium hydroxide solution for hydrolysis, adjust the pH to neutral at room temperature, and obtain modified β-cyclodextrin after washing, filtering and dialyzing.

3. The avatrombopag maleate tablets according to claim 2, characterized in that: The mass ratio of the beta-cyclodextrin, p-toluenesulfonyl chloride, and sodium hydroxide aqueous solution is 1:0.1-0.2:5-10.

4. The avatrombopag maleate tablets according to claim 2, wherein: The mass ratio of the dried product to the amino acid and triethylamine aqueous solution is 1:0.2-0.4:5-10.

5. The avatrombopag maleate tablets according to claim 2, wherein: The amino acid is one of lysine, arginine or threonine.

6. The avatrombopag maleate tablets according to claim 2, characterized in that: The mass ratio of the product of the previous step to thiosemicarbazide, acetic acid aqueous solution, and sodium hydroxide aqueous solution is 1:0.5~1.5:8~12:4~8.

7. The avatrombopag maleate tablets according to claim 1, wherein: The filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, sucrose, and pregelatinized starch.

8. The avatrombopag maleate tablets according to claim 1, wherein: The disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

9. The avatrombopag maleate tablets according to claim 1, wherein: The glidant is selected from one or both of colloidal silicon dioxide and talc, and the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, and polyethylene glycol.

10. The method for preparing avatrombopag maleate tablets according to any one of claims 1 to 9, wherein: The specific steps include: S1. Take crude avatrombopag maleate and grind it by air flow milling at 150-250 m / s for 25-40 min or by ball milling for 50-70 min to obtain a particle size distribution of 10-30 μm for D90, 5-15 μm for D50, and 1-5 μm for D10. S2. Add the particle size-controlled avatrombopag maleate raw material to 9 times the mass of 90 wt% ethanol aqueous solution, and then add it to an equal mass of 20-30 wt% modified cyclodextrin aqueous solution, stir for 30-40 hours, and then centrifuge. After freeze-drying, mix the supernatant with the prescribed amount of filler, disintegrant, and glidant for 5-20 minutes to ensure that the materials are fully mixed; S3. The mixed material is dispersed by a crushing and granulating machine, wherein the screen is selected to be 0.8-1.2 mm and the speed is 300-500 rpm. The dispersed material and the prescribed amount of lubricant are mixed for 5-10 minutes; S4. The uniformly mixed material is dry-granulated into dry granules, with the roller oil pressure of 20-60 bar and the roller gap of 1.5-3.0 mm. The granules are then sized at a speed of 80-120 rpm. The prepared dry granules are further crushed and sized, with a screen size of 0.8-1.2 mm and a speed of 500-1000 rpm. The prescribed amount of lubricant, the prescribed amount of disintegrant, and the prescribed amount of filler are added to the granules after granulation, and the mixture is mixed for 10-30 minutes. The mixed material is then compressed into tablets using a rotary tablet press, and the average hardness of the compressed tablets is 2-6 kg to prepare avatrombopag maleate tablets.

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