Alvocidib maleate tablets and a method for preparing the same

Abstract

The application discloses maleic acid avelumab tablets and a preparation method thereof, the maleic acid avelumab tablets comprising the following components by weight percentage: 12-15% of maleic acid avelumab, 30-45% of modified beta-cyclodextrin, 3-4% of a disintegrating agent, 0.5-1% of a glidant, 0.5-2% of a lubricant, and the rest of a filler. The application also provides a preparation method thereof. The application controls the particle size of raw materials and carries out inclusion on drugs, increases the specific surface area of the drugs, makes the drugs quickly dissolve in a dissolution medium, improves the dissolution rate and dissolution amount of the drugs, and is beneficial to the absorption of the drugs in the body, the improvement of the bioavailability of the drugs and the enhancement of the therapeutic effect of the drugs.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to alevolixat maleate tablet and a preparation method thereof. BACKGROUND

[0002] Alevolixat maleate tablet is a drug developed by AkaRx Inc. for use in adult patients with chronic liver disease-related thrombocytopenia undergoing elective diagnostic procedures or surgery. Alevolixat maleate is a small molecule thrombopoietin receptor agonist that can stimulate the proliferation of bone marrow progenitor cells and megakaryocyte differentiation by simulating the biological effects of thrombopoietin, increase platelet production and increase platelet count. Alevolixat maleate belongs to BCS IV drugs, which is a low-soluble crystal drug with low solubility. It is almost insoluble in aqueous solution with pH value in the range of 1-10. More specifically, it has extremely low solubility in water, hydrochloric acid solution and pH 1.0-11.0 buffer system, and the saturated solubility in 0.1 mol / L hydrochloric acid and pH 7.0 medium is also less than 1 μg / mL. In the human body, how to improve the effective dissolution efficiency of the drug in the absorption site becomes the key to break through the bottleneck of its bioavailability. Secondly, as a polymorphic drug, alevolixat maleate is extremely sensitive to environmental humidity and is prone to crystal transformation. This crystal transformation can significantly reduce the solubility of the drug, resulting in a decrease in the dissolution of the preparation and causing stability problems. Therefore, solving the dissolution problem of the drug and ensuring the stability of the preparation are two major technical difficulties that need to be overcome in the development process of alevolixat maleate.

[0003] CN117582412A relates to the technical field of medicine, and discloses alevolixat maleate tablet prepared by mixing and crushing alevolixat maleate, flow aid and solubilizer to form a main material. The main material 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 of 2-2.5 μm, and D10≥0.5 μm. The tablet is prepared by a one-step granulation process, effectively solving the problems of low drug solubility and poor stability.

[0004] CN114652725A belongs to the field of pharmaceutical preparations, and discloses alevolixat maleate cyclodextrin inclusion complex composed of alevolixat maleate, cyclodextrin or its derivative, and high molecular additive copovidone. The inclusion complex, with its unique ingredient combination, not only significantly improves the solubility of the drug, but also has the advantages of low cyclodextrin usage and high inclusion efficiency, effectively improving the bioavailability of the drug. At the same time, its manufacturing process is simple and low in cost, the product has good stability, and the drug preparation is less affected by the inclusion material and environmental humidity.

[0005] The particle size distribution of a drug substance is an important aspect of drug development, as the particle size distribution of a drug substance can affect the dissolution properties of a formulation and can affect the bioavailability and efficacy of a pharmaceutical composition. Furthermore, the particle size distribution of a drug substance can affect the flow properties of the drug substance and the manufacturing process of a pharmaceutical composition. By precisely controlling the particle size of a drug substance, the dissolution, bioavailability and stability of the drug substance can be significantly improved, which is beneficial to improve the therapeutic effect of the drug.

[0006] However, it is difficult to comprehensively solve the problems of dissolution, bioavailability and stability by only controlling the particle size of aviptadil maleate. Aviptadil maleate belongs to a low-solubility and low-permeability drug, and it may not be able to break through the "solubility bottleneck" by only increasing the specific surface area. Micron-sized particles are prone to aggregation due to high surface energy, resulting in a decrease in the actual effective specific surface area and a decrease in dissolution efficiency. If no dispersant or solubilizer is used, the effect may be affected. Therefore, it is necessary to further optimize the solubilization technology to achieve more ideal solubilization and stability. SUMMARY

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

[0008] As a low-solubility crystalline drug, aviptadil maleate not only has small solubility, but also is 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 of the preparation and causing stability problems. As a cyclic oligosaccharide, β-cyclodextrin has a hydrophobic cavity and a hydrophilic surface, and can well include the drug, thereby improving the solubility, stability and bioavailability of the drug. However, the strong hydrogen bond network between natural β-cyclodextrin molecules results in a tight crystal structure, hindering the penetration of water molecules, resulting in low water solubility, which needs to be optimized by chemical modification.

[0009] Therefore, the present application provides a modified cyclodextrin, which is modified by amino acids and aminothiourea. The β-cyclodextrin is activated by p-toluenesulfonyl chloride, and then reacts with amino acids. The modification breaks the intramolecular hydrogen bonds of β-cyclodextrin. The hydroxyl or amino groups in the amino acid can form hydrogen bonds with water. Further, under acidic conditions, aminothiourea reacts with the hydroxyl groups on the cyclodextrin. The high-activity hydroxyl group generates an intermediate which is hydrolyzed to generate a thiol-modified cyclodextrin. The introduction of thiol groups can improve the transmembrane transport efficiency by promoting permeability, thereby improving the bioavailability of aviptadil maleate. The modified cyclodextrin has introduced hydrophilic groups, broken part of the hydrogen bonds, and increased hydrophilicity, thereby improving the solubility. Aviptadil maleate is included in the cavity of the cyclodextrin, which not only improves the solubility, but also avoids the crystal transformation of aviptadil maleate, thereby improving the stability of the preparation.

[0010] In order to achieve the above object, the application provides a maleic acid alvocidib tablet, which comprises the following components in percentage by weight: 12-15% of maleic acid alvocidib, 30-45% of modified beta-cyclodextrin, 3-4% of disintegrant, 0.5-1% of glidant, 0.5-2% of lubricant, and the rest of filler.

[0011] The preparation method of the modified beta-cyclodextrin is as follows: substitution of beta-cyclodextrin with p-toluenesulfonyl chloride, then introduction of active groups on the beta-cyclodextrin molecules through nucleophilic substitution, microwave-assisted aminothiourea for chemical modification, and finally obtaining the modified beta-cyclodextrin with functional structure.

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

[0013] X1, beta-cyclodextrin and p-toluenesulfonyl chloride are added to sodium hydroxide aqueous solution, stirred at 0-5 DEG C for 4-6 h, the pH is adjusted after filtration, and the filter cake is recrystallized and dried, then the product is added to triethylamine aqueous solution with amino acid, stirred at 80-90 DEG C under inert atmosphere for 16-20 h, and centrifuged, then the filtrate is purified and dried for the next step;

[0014] X2, the product of the previous step is added to acetic acid aqueous solution with aminothiourea, microwave reacted at 200 W and 80-90 DEG C for 40-80 min, then hydrolyzed by adding sodium hydroxide aqueous solution, the pH is adjusted to neutral at room temperature, and the modified beta-cyclodextrin is obtained after washing, filtration and dialysis.

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

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

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

[0018] Further, the mass ratio of the product of the previous step, aminothiourea, acetic acid aqueous solution and sodium hydroxide aqueous solution is 1:0.5-1.5:8-12:4-8.

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

[0020] Further, the disintegrant is selected from one or more of crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose and sodium carboxymethyl starch.

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

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

[0023] Preferably, the method for preparing the modified β-cyclodextrin comprises the following steps:

[0024] X1, β-cyclodextrin and p-toluenesulfonyl chloride are added to 1 mol / L aqueous sodium hydroxide solution, the mass ratio of β-cyclodextrin, p-toluenesulfonyl chloride and aqueous sodium hydroxide solution is 1:0.1-0.2:5-10, stirring at 0-5°C for 4-6h, adjusting the pH to 6-7 after filtration, and then filtering, drying the product after recrystallization, and adding the dried product and amino acid to 40wt% aqueous triethylamine solution, the mass ratio of the dried product, amino acid and aqueous triethylamine solution is 1:0.2-0.4:5-10, stirring at 80-90°C under inert atmosphere for 16-20h, and then centrifuging, purifying and drying the filtrate for the next step;

[0025] X2, the product of the previous step and thiosemicarbazide are added to 1wt% aqueous acetic acid solution, microwave reaction at 200W and 80-90°C for 40-80min, then hydrolysis by adding 1mol / L aqueous sodium hydroxide solution, the mass ratio of the product of the previous step, thiosemicarbazide, aqueous acetic acid solution and aqueous sodium hydroxide solution is 1:0.5-1.5:8-12:4-8, adjusting the pH to neutral at room temperature, and then washing, filtering and dialyzing to obtain the modified β-cyclodextrin.

[0026] A preparation method of alvocidib maleate tablets, the specific steps comprising:

[0027] S1, taking alvocidib maleate crude product, using airflow crushing at 150-250m / s for 25-40min or ball milling for 50-70min to make the particle size distribution of the raw material as follows: D90 particle size range of 10-30μm, D50 particle size range of 5-15μm, and D10 particle size range of 1-5μm;

[0028] S2, adding the particle size controlled alvocidib maleate raw material to 9 times the mass of 90wt% aqueous ethanol solution, and then to an equal mass of 20-30wt% modified β-cyclodextrin aqueous solution, stirring for 30-40h, centrifuging, and freeze-drying the supernatant, and then mixing with the prescription amount of filler, disintegrant and glidant for 5-20min to make the materials fully mixed and uniform;

[0029] S3, the mixed material is dispersed by a crushing and granulating machine, wherein a screen mesh of 0.8-1.2 mm is selected, and the speed is 300-500 rpm; the dispersed material is mixed with a prescription amount of lubricant for 5-10 min;

[0030] S4, the mixed material is granulated by a dry granulation method to form dry granules, the oil pressure of a compression roller is 20-60 bar, the gap between the compression rollers is 1.5-3.0 mm, the granules are further granulated at a speed of 80-120 rpm, the dry granules are further crushed and granulated, a screen mesh of 0.8-1.2 mm is selected, and the speed is 500-1000 rpm, a prescription amount of lubricant, a prescription amount of disintegrant and a prescription amount of filler are added to the granulated granules, and the mixture is mixed for 10-30 min; the mixed material is compressed into tablets by a rotary tablet press, and the average hardness of the tablets is 2-6 KG, so that the maleic acid alvocidib tablets are prepared.

[0031] The present application has the following beneficial effects:

[0032] The present application precisely controls the particle size of the raw material and performs inclusion on the drug, so that the specific surface area of the drug is increased, the drug can be quickly dissolved in a dissolution medium, the dissolution rate and dissolution amount of the drug are improved, the drug absorption in the body is facilitated, the bioavailability of the drug is improved, and the therapeutic effect of the drug is enhanced. DETAILED DESCRIPTION

[0033] Example 1

[0034] A preparation method of maleic acid alvocidib tablets, and the specific steps include the following:

[0035] S1, crude maleic acid alvocidib is taken, and air flow crushing is performed for 30 min at 200 m / s, so that the particle size distribution of the raw material is D90 particle size range of 20 μm, D50 particle size range of 10 μm, and D10 particle size range of 3 μm;

[0036] S2, the maleic acid alvocidib raw material with controlled particle size 14.75 parts is added to 9 times of mass of a 90 wt% ethanol aqueous solution, and then added to 147.5 parts of a 25 wt% modified cyclodextrin aqueous solution (modified β-cyclodextrin 36.875 parts), and after stirring for 35 h, centrifugal separation is performed, the supernatant is freeze-dried, and then mixed with 39.625 parts of lactose, 1.75 parts of crosslinked polyvidone and 0.75 parts of colloidal silicon dioxide for 5 min, so that the material is fully mixed and uniform;

[0037] S3, the mixed material is dispersed by a crushing and granulating machine, wherein a screen mesh of 0.8 mm is selected, and the speed is 300 rpm; the dispersed material is mixed with 0.5 parts of magnesium stearate for 5 min;

[0038] S4, the mixed material is granulated by dry granulation, the roller oil pressure is 40 bar, the roller gap is 2.0 mm, and then the granulation is performed at a speed of 100 rpm, the dry granules are further crushed and granulated, the screen is selected to be 0.8 mm, and the speed is 500 rpm, 0.5 parts of magnesium stearate, 1.75 parts of crosslinked povidone, and 3.5 parts of microcrystalline cellulose are added to the granules, and the mixture is mixed for 10 min, the total mixed material is pressed by a rotary tablet press, the average hardness is 4.0 KG, and tablets each containing 20 mg of alvocidib maleate are prepared.

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

[0040] X1, β-cyclodextrin and p-toluenesulfonyl chloride are added to 1 mol / L sodium hydroxide aqueous solution, the mass ratio of β-cyclodextrin, p-toluenesulfonyl chloride and sodium hydroxide aqueous solution is 1:0.12:8, stirring at 0℃ for 5h, adjusting pH to 7 after filtration, standing and filtering, the filter cake is recrystallized and dried, and then the product is added to 40wt% triethylamine aqueous solution, the mass ratio of the dried product, threonine and triethylamine aqueous solution is 1:0.3:8, stirring at 85℃ under nitrogen atmosphere for 18h, and then centrifugal separation, the filtrate is purified and dried for the next step;

[0041] X2, the product of the previous step and aminothiourea are added to 1wt% acetic acid aqueous solution, microwave reaction is performed at 200W and 85℃ for 60min, then 1mol / L sodium hydroxide aqueous solution is added for hydrolysis, the mass ratio of the product of the previous step, aminothiourea, acetic acid aqueous solution and sodium hydroxide aqueous solution is 1:1.1:10:6, the pH is adjusted to neutral at room temperature, and then washing, filtering and dialysis are performed to obtain the modified β-cyclodextrin.

[0042] Example 2

[0043] The same as example 1, the difference is that threonine is replaced by lysine.

[0044] Example 3

[0045] The same as example 1, the difference is that threonine is replaced by arginine.

[0046] Comparative example 1

[0047] The conventional crushing method is adopted, and the particle size of alvocidib maleate raw material is not accurately controlled, so that the particle size D90 of the raw material is 50μm, the particle size D50 is 30μm, and the particle size D10 is 10μm.

[0048] According to the same prescription and process as example 1, the mixing, dispersion, mixing, dry granulation, total mixing and tabletting are performed to prepare tablets each containing 20mg of alvocidib maleate.

[0049] Comparative Example 2

[0050] The raw material particle size D90 is 8 μm, D50 is 3 μm, and D10 is 0.5 μm, which are obtained by using a conventional crushing method without precisely controlling the particle size of the crude aprocitumide maleate.

[0051] According to the same prescription and process as in Example 1: mixing, dispersion, mixing, dry granulation, total mixing and tabletting are performed to prepare tablets each containing 20 mg of aprocitumide maleate.

[0052] Comparative Example 3

[0053] A preparation method of aprocitumide maleate tablets, the specific steps comprising, in mass parts:

[0054] S1, taking crude aprocitumide maleate, using 200 m / s airflow crushing for 30 min, so that the raw material particle size distribution is D90 particle size range of 20 μm, D50 particle size range of 10 μm, and D10 particle size range of 3 μm;

[0055] S2, mixing 14.75 parts of the aprocitumide maleate raw material with 75.5 parts of lactose, 1.75 parts of cross-linked povidone and 0.75 parts of colloidal silicon dioxide for 5 min, so that the materials are fully mixed and uniform;

[0056] S3, dispersing the mixed materials with a crushing and granulating machine, wherein the screen mesh is selected to be 0.8 mm, and the speed is 300 rpm, mixing the dispersed materials with 0.5 parts of magnesium stearate for 5 min;

[0057] S4, granulating the mixed materials into dry granules by dry granulation, the roller oil pressure is 40 bar, the roller gap is 2.0 mm, and the granulating speed is 100 rpm, the dry granules are further crushed and granulated, the screen mesh is selected to be 0.8 mm, and the speed is 500 rpm, 0.5 parts of magnesium stearate, 1.75 parts of cross-linked povidone and 3.5 parts of microcrystalline cellulose are added to the granules, and mixed for 10 min, the total mixed materials are tabletted by a rotary tablet press, the average hardness is 4.0 KG, and tablets each containing 20 mg of aprocitumide maleate are prepared.

[0058] Comparative Example 4

[0059] A preparation method of aprocitumide maleate tablets, the specific steps comprising, in mass parts:

[0060] S1, taking crude aprocitumide maleate, using 200 m / s airflow crushing for 30 min, so that the raw material particle size distribution is D90 particle size range of 20 μm, D50 particle size range of 10 μm, and D10 particle size range of 3 μm;

[0061] S2, 14.75 parts of the particle size controlled avacopan maleate raw material is added to 9 times the mass of 90wt% ethanol aqueous solution, and then added to 147.5 parts of 25wt% β-cyclodextrin aqueous solution (36.875 parts of β-cyclodextrin), and after stirring for 35h, centrifugal separation is performed, and the supernatant is freeze-dried and mixed with 39.625 parts of lactose, 1.75 parts of crosslinked polyvidone and 0.75 parts of colloidal silicon dioxide for 5min to fully mix the materials;

[0062] S3, the mixed materials are dispersed by a crushing and granulating machine, wherein a 0.8mm screen is selected and the speed is 300rpm, the dispersed materials are mixed with 0.5 parts of magnesium stearate for 5min;

[0063] S4, the mixed materials are granulated by a dry granulation method to form dry granules, the roller oil pressure is 40bar, the roller gap is 2.0mm, and the granulation speed is 100rpm, the dry granules are further crushed and granulated, a 0.8mm screen is selected and the speed is 500rpm, 0.5 parts of magnesium stearate, 1.75 parts of crosslinked polyvidone and 3.5 parts of microcrystalline cellulose are added to the granules, and mixed for 10min, and the mixed materials are compressed by a rotary tablet machine to form tablets, the average hardness is 4.0KG, and each tablet contains 20mg of avacopan maleate.

[0064] Test Example 1

[0065] According to the dissolution and release determination method (Chinese Pharmacopoeia 2020 edition four general rules 0931 second method), 900mL of 0.25% cetyltrimethylammonium bromide-sodium phosphate buffer solution [take anhydrous sodium phosphate dibasic 49.7g or sodium phosphate dibasic dodecahydrate 125.37g, add water 6500mL to dissolve, adjust the pH value to 6.8 with phosphoric acid, add cetyltrimethylammonium bromide solution (take cetyltrimethylammonium bromide 17.5g, add new boiling degassed water 500mL, ultrasonic to dissolve), mix well] is used as the dissolution medium, the rotation speed is 50 revolutions per minute, and the operation is carried out according to the method, and the samples are taken at 5, 10, 25, 30, 45 and 60min respectively, the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2020 edition four general rules 0401) is used to measure the absorbance at 337nm, the dissolution amount of each tablet is calculated, the dissolution rate is determined, and the specific values are shown in Table 1.

[0066] Table 1

[0067]

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

[0069] Compared with Comparative Example 3, the modified β-cyclodextrin is used to include aviptadil maleate in Examples 1-3. The modified β-cyclodextrin has a hydrophilic group introduced, which destroys part of the hydrogen bond, increases the hydrophilicity, and improves the solubility, resulting in a significant increase in the dissolution of the included aviptadil maleate. In Comparative Example 4, the β-cyclodextrin is not modified. The strong hydrogen bond network between the unmodified β-cyclodextrin molecules results in a tight crystal structure, hindering the penetration of water molecules, resulting in low water solubility. Therefore, the solubility after inclusion is not significantly improved. Compared with Examples 1-2, the dissolution of Example 3 is higher. This may be because arginine has a guanidino group in the side chain compared with threonine and lysine, which is positively charged at physiological pH and can form a strong ionic bond with the maleic acid group of aviptadil maleate, significantly enhancing the inclusion stability and hydrophilicity, and thus the solubility is improved more significantly.

[0070] Test Example 2

[0071] The tablets prepared in the examples and comparative examples were tested for disintegration time. According to the disintegration time test method in the 2020 edition of the Chinese Pharmacopoeia, 6 tablets were taken and placed in the disintegration basket of a disintegration tester (37°C constant temperature water bath). 900 mL of water was added as the medium, the lifting frequency was set to 30 times / min, and the amplitude was 55 mm. The instrument was started and the time was counted. The ordinary tablets should be completely disintegrated within 15 minutes, and there should be no hard core residue and all pass through the 2.0 mm sieve.

[0072] Table 2

[0073]

[0074] As can be seen from Table 2, the disintegration time of the examples is shorter than that of the comparative examples, which indicates that it is difficult to comprehensively solve the dissolution and release problems by only controlling the particle size of aviptadil maleate. Aviptadil maleate belongs to a drug with low solubility and low permeability. Increasing the specific surface area may not be able to break through the "solubility bottleneck". Micron-sized particles are prone to aggregation due to high surface energy, resulting in a decrease in actual effective specific surface area and a decrease in dissolution and disintegration efficiency. The examples improve the solubility by inclusion, and the drug molecule dispersion degree is improved after inclusion, the release speed is accelerated, thereby shortening the dissolution time of the drug after disintegration, and indirectly promoting disintegration. The modified β-cyclodextrin can enhance the water absorption of the tablets, accelerate the penetration of water and disintegration. Compared with Examples 1-2, the disintegration of Example 3 is faster. This may be because arginine has a guanidino group in the side chain compared with threonine and lysine, which is positively charged at physiological pH and can form a strong ionic bond with the maleic acid group of aviptadil maleate, resulting in improved solubility and indirectly leading to faster disintegration.

[0075] Test Example 3

[0076] The tablets prepared in the examples and the control example were placed under the conditions of 40°C and 75% relative humidity for 6 months, and the content of the main component and impurities were periodically detected.

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

[0078]

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

[0080] The specific results are as follows:

[0081] Table 3

[0082]

[0083] As can be seen from Table 3, the stability of the alvocidib maleate tablets in the examples is better, because the alvocidib maleate is included in the cavity of the cyclodextrin, which not only improves the solubility, but also avoids the crystal transformation of the alvocidib maleate, thereby improving the stability of the preparation. In Example 3, the arginine side chain also has a guanidino group, which is positively charged at physiological pH, and can form a strong ionic bond with the maleic acid group of alvocidib maleate, thereby significantly enhancing the inclusion stability. Through the complementation of the strong positive charge and the acidic group of the drug, the binding energy is the highest, not only the solubility is significantly improved, but also the stability is the best.

[0084] Test Example 4

[0085] In this study, a single-center, randomized, open, double-period, double-cross design was used to conduct the in vivo bioavailability experiment. The test preparation was alvocidib maleate tablets prepared by the method of Example 3, and the reference preparation was a commercially available alvocidib maleate tablet (trade name: Avicidib, with a license held by AkaRx Inc.). The specific experimental scheme is as follows:

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

[0087] Dosing regimen: The subjects in the fasting / postprandial test group were randomly divided into two sequences, and the test preparation and the reference preparation were orally taken in two periods, and the cleaning period between the two periods was 10 days.

[0088] Dosing dose: The dosing dose of the test preparation / reference preparation was 1 tablet (20 mg).

[0089] Dosing method: In the fasting dosing test, the subjects were fasted for at least 10 hours without water, and then orally took the test preparation or the reference preparation once, which was taken with about 240 mL of warm water. In the postprandial dosing test, the subjects were fasted for at least 10 hours without water, and then ate a high-fat meal, and then orally took the test preparation or the reference preparation once at 30 minutes after starting the meal, which was taken with about 240 mL of warm water.

[0090] Biological sample collection: Plasma was used as the matrix for biological sample determination, and the upper limb venous blood of the subjects was collected at 0 h before dosing and at 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 dosing, and centrifuged at 4℃ and 2600g for 10 min, and all the plasma samples were transferred and temporarily stored in a refrigerator at-20℃ or below within 2 h after blood collection, and all the plasma samples were transferred and stored in a refrigerator at-60℃ or below within 24 h after blood collection.

[0091] Biological detection: The concentration of avacincaptagene in the plasma of the healthy subjects after oral administration of the test preparation and the reference preparation was determined by LC-MS / MS method.

[0092] Bioavailability evaluation: The AUC0-t was used as the bioavailability evaluation parameter by using WinNonlin 8.0 version, and the results were as follows:

[0093] Table 4

[0094]

[0095] The experimental results show that the bioavailability of the test preparation in the fasting and postprandial groups is higher than that of the reference preparation, which indicates that the particle size of the maleic acid avacincaptagene raw material is accurately controlled, and the maleic acid avacincaptagene is coated by modified β-cyclodextrin. Since the modification destroys the intramolecular hydrogen bond of β-cyclodextrin, the hydroxyl group or amino group in the amino acid can form a hydrogen bond with water, and the introduction of the thiol group can promote the permeability and improve the transmembrane transport efficiency, so not only the solubility and stability of the maleic acid avacincaptagene are improved, but also the bioavailability is improved.

[0096] The preferred embodiments of the application have been described above in detail. It should be understood that modifications and variations to the preferred embodiments could be made by those skilled in the art in light of the teachings above. It is therefore contemplated that the application can encompass other variations and modifications that fall within the scope of the claims.

Claims

1. An avatrombopag maleate tablet, characterized in that, It includes the following components by 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; avatrombopag maleate is encapsulated within the cavity of the cyclodextrin; The method for preparing the modified β-cyclodextrin includes 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 pH, let stand, filter again, recrystallize and dry the filter cake, add the product and amino acids to an aqueous triethylamine solution, stir at 80-90°C for 16-20 hours under an inert atmosphere, centrifuge, purify and dry the filtrate for the next step; X2. The product from the previous step and aminothiourea are added to an aqueous acetic acid solution and reacted in a microwave at 200W and 80~90℃ for 40~80 min. Then, an aqueous sodium hydroxide solution is added for hydrolysis. The pH is adjusted to neutral at room temperature. After washing, filtration, and dialysis, modified β-cyclodextrin is obtained. The mass ratio of β-cyclodextrin to p-toluenesulfonyl chloride and aqueous sodium hydroxide solution is 1:0.1~0.2:5~10. The mass ratio of the dried product to the amino acid and triethylamine aqueous solution is 1:0.2~0.4:5~10; The amino acid is one of lysine, arginine, or threonine. The mass ratio of the product from the previous step to aminothiourea, aqueous acetic acid solution, and aqueous sodium hydroxide solution is 1:0.5~1.5:8~12:4~8.

2. The avatrombopag maleate tablets as described in claim 1, characterized in that, The filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, sucrose, and pregelatinized starch.

3. The avatrombopag maleate tablets as described in claim 1, characterized in that, The disintegrant is selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

4. The avatrombopag maleate tablets as described in claim 1, characterized in that, The flow aid is selected from one or two of colloidal silica and talc, and the lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, and polyethylene glycol.

5. The method for preparing avatrombopag maleate tablets according to any one of claims 1 to 4, characterized in that, The specific steps include: S1. Take crude avatrombopag maleate and pulverize it by air jet milling at 150~250m / s for 25~40min or ball milling for 50~70min to make the particle size distribution of the raw material as follows: D90 particle size range 10~30μm, D50 particle size range 5~15μm, and D10 particle size range 1~5μm. S2. Add the particle size-controlled avatrombopag maleate raw material to 9 times its mass of 90wt% ethanol aqueous solution, and then add it to an equal mass of 20~30wt% modified β-cyclodextrin aqueous solution. Stir for 30~40h and then centrifuge. After freeze-drying, mix the supernatant with filler, disintegrant and glidin for 5~20min to ensure that the material is fully mixed and uniform. S3. Disperse the mixture using a pulverizer and granulator. Use a 0.8-1.2mm screen and a speed of 300-500rpm. Mix the dispersed material with the lubricant for 5-10 minutes. S4. The uniformly mixed material is granulated into dry granules using a dry granulation method. The hydraulic pressure of the pressure roller is 20~60 bar, and the gap between the pressure rollers is 1.5~3.0 mm. Then, the granules are shaped at a speed of 80~120 rpm. The resulting dry granules are further crushed and shaped using a 0.8~1.2 mm sieve at a speed of 500~1000 rpm. Lubricant, disintegrant, and filler are added to the shaped granules and mixed for 10~30 minutes. The mixed material is then compressed into tablets using a rotary tablet press. The average hardness of the compressed tablets is 2~6 kg, producing avatrombopag maleate tablets.

Images