Compositions for the treatment of hepatitis c and methods of making the same

Abstract

The present application provides a composition for treating hepatitis C and a preparation method thereof. The composition comprises a compound of formula (I) or a pharmaceutically acceptable salt or crystal form thereof as an active ingredient. The composition or tablet can effectively treat hepatitis C, and has simple preparation process, high safety, good stability and rapid dissolution.

Description

[0001] Priority information This invention claims priority and benefit to patent application No. 2025103516195, filed with the China National Intellectual Property Administration on March 24, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the pharmaceutical field, and more specifically, to compositions for treating hepatitis C and methods for preparing the same. Background Technology

[0003] Hepatitis C is a global infectious disease caused by the hepatitis C virus (HCV). It is mainly transmitted through blood, blood products, and bodily fluids. 55% to 85% of patients with acute HCV infection progress to chronic hepatitis. About 5% to 15% develop cirrhosis 20 years after infection, with an annual incidence of 3% to 4% of decompensated cirrhosis. 2% to 4% of cirrhosis patients develop liver cancer (HCC) each year. HCV poses a serious threat to the health and lives of patients. Moreover, CHC patients often have hidden symptoms, and the diagnosis and antiviral treatment rates for HCV infection are low. There are many hidden sources of infection in the population, making it a serious social and public health problem.

[0004] According to data updated by the World Health Organization (WHO) in April 2016, the global chronic HCV infection rate is approximately 1.1%, affecting about 100 million people. With increasing public health awareness and a growing understanding of hepatitis C, the detection rate of infected individuals and the proportion of those willing to receive treatment are constantly increasing. Therefore, it is anticipated that the number of people requiring treatment and the clinical demand will continue to grow.

[0005] HCV includes at least six genotypes and multiple subtypes. Datamonitor reported in 2014 that genotype 1 is the most common globally, followed by genotypes 3, 2, and 4. In China, genotypes 1b and 2a are relatively common, with genotype 1b being the most prevalent (56.8%), followed by genotypes 2 (24.1%) and 3 (9.1%). Genotypes 4 and 5 were not found, and genotype 6 was relatively rare (6.3%).

[0006] Therefore, developing more and more effective drugs for the treatment of hepatitis C as soon as possible is the unremitting goal of drug researchers.

[0007] The compound of formula (I) disclosed in Chinese patent application CN 108299532A is an innovative compound, a nucleoside inhibitor of hepatitis C virus NS5B polymerase. It competitively inhibits the natural substrate, phosphorylates into its triphosphate active form within cells, binds to the catalytic active site of NS5B polymerase, enters the nascent nucleotide chain, and causes premature termination of chain elongation, thus giving this compound pan-genotypic anti-hepatitis C virus activity. Chinese patent application CN117586329A discloses the crystal form of the compound of formula (I).

[0008] Formula (I). Summary of the Invention

[0009] Based on existing technology, the inventors of this application have developed, through experiments, a pharmaceutical formulation using the compound shown in Formula (I) or its pharmaceutically acceptable salt or crystal form as the active ingredient. The compound shown in Formula (I) or its pharmaceutically acceptable salt or crystal form has poor flowability, is prone to agglomeration, has a distinctive irritating odor, tastes bitter when taken orally directly, and is not conducive to drug absorption. The inventors unexpectedly discovered that by controlling the particle size of the compound shown in Formula (I) or its pharmaceutically acceptable salt or crystal form as the active ingredient, formulations prepared from active pharmaceutical ingredients within this particle size range can effectively improve the drug's dissolution rate, achieving a dissolution rate of over 80% within 30 minutes and high bioavailability.

[0010] Based on this, in a first aspect of the invention, a composition is provided. In some embodiments, the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt or crystal form thereof as an active ingredient. Formula (I), The particle size of the active ingredient satisfies the following conditions: D V (90) ≤ 60 μm; or D V (90) ≤ 40 μm; or D V (90) ≤ 35 μm; or D V (90) ≤ 30 μm; or D V (90) ≤ 25 μm; or D V (90) ≤ 24 μm; or D V (90) ≤ 23 μm; or D V (90) ≤ 22 μm; or D V (90) ≤ 21 μm.

[0011] In some embodiments, the particle size of the active ingredient satisfies the condition: D V (90) ≥ 5 μm.

[0012] In some embodiments, the particle size of the active ingredient in the composition satisfies the following conditions: 5 μm ≤ D V (90) ≤ 60 μm, or 5 μm ≤ D V (90) ≤ 40 μm, or 5 μm ≤ D V (90) ≤35 μm, or 5 μm ≤ D V (90) ≤ 30 μm, or 5 μm ≤ D V (90) ≤ 25 μm, or 5 μm ≤ D V (90) ≤22 μm, or 5 μm ≤ D V (90) ≤ 21 μm.

[0013] In some embodiments, the particle size of the active ingredient in the composition satisfies the following conditions: D V (50) ≤ 10 μm, or D V (50) ≤ 4 μm, or D V (50) ≤ 3.5 μm.

[0014] In some embodiments, the particle size of the active ingredient satisfies the condition: D V (50) ≥ 2 μm.

[0015] In some embodiments, the particle size of the active ingredient in the composition satisfies the following conditions: 2 μm ≤D V (50) ≤ 10 μm, or 2 μm ≤ D V (50) ≤ 4 μm, or 2 μm ≤ D V (50) ≤ 3.5μm.

[0016] In some embodiments, the particle size of the active ingredient in the composition satisfies at least one of the following conditions: 2 μm ≤ D V (50) ≤ 10 μm, 5 μm≤D V (90) ≤ 60 μm.

[0017] The inventors have discovered that compositions containing active ingredients within the particle size range described in this invention exhibit rapid dissolution. The compositions of this invention are effective in treating hepatitis C and are highly safe and have a rapid onset of action.

[0018] In some embodiments, the particle size of the active ingredient satisfies the following condition: 2 μm ≤ D V (50) ≤ 10μm, 5 μm≤D V (90) ≤ 25 μm; or 2 μm ≤ D V (50) ≤ 10 μm, 5 μm≤D V (90) ≤ 24 μm; or 2 μm ≤ D V (50) ≤ 10 μm, 5 μm≤D V (90) ≤ 23 μm; or 2 μm ≤ D V (50) ≤ 10 μm, 5 μm≤D V (90) ≤ 22 μm. This further increases the dissolution rate of the compositions of the present invention containing active ingredients within this particle size range.

[0019] In some embodiments, the particle size of the active ingredient satisfies the following condition: 2 μm ≤ D V (50) ≤ 10μm, 5 μm≤D V (90) ≤ 21 μm. Consequently, the dissolution rate of the compositions of the present invention containing active ingredients within this particle size range is further significantly improved.

[0020] In some embodiments, the composition comprises the crystal form of the compound shown in formula (I) as an active ingredient. The X-ray powder diffraction pattern of the crystal form of the compound shown in formula (I) contains diffraction peaks at the following 2θ angles: 10.35±0.2°, 10.56±0.2°, 13.39±0.2°, 15.68±0.2°, 15.82±0.2°, 20.42±0.2°, 20.84±0.2°, 21.71±0.2°.

[0021] In some embodiments, the X-ray powder diffraction pattern of the crystal form includes diffraction peaks at the following 2θ angles: 4.28±0.2°, 6.69±0.2°, 10.35±0.2°, 10.56±0.2°, 11.83±0.2°, 12.78±0.2°, 13.39±0.2°, 15.68±0.2°, 15.82±0.2°, 16.79±0.2°, 17.59 ±0.2°, 17.83±0.2°, 20.00±0.2°, 20.42±0.2°, 20.84±0.2°, 21.71±0.2°, 23.50±0.2°, 24.73±0.2°, 26.36±0.2°, 26.52±0.2°, 27.38±0.2°, 28.18±0.2°, 29.95±0.2°, 31.30±0.2°.

[0022] In some embodiments, the X-ray powder diffraction pattern of the crystal form includes diffraction peaks at the following 2θ angles: 4.28±0.2°, 5.58±0.2°, 6.69±0.2°, 8.23±0.2°, 10.35±0.2°, 10.56±0.2°, 11.83±0.2°, 12.78±0.2°, 13.39±0.2°, 15.68±0.2°, 15.8°. 2±0.2°, 16.45±0.2°, 16.79±0.2°, 17.59±0.2°, 17.83±0.2°, 18.93±0.2°, 20.00±0.2°, 20.42±0.2°, 20.84±0.2°, 21.71±0.2°, 21.99±0.2°, 23.17±0.2°, 23.50±0.2°, 23.78±0 0.2°, 24.73±0.2°, 25.71±0.2°, 26.36±0.2°, 26.52±0.2°, 27.38±0.2°, 28.18±0.2°, 29.95±0.2°, 31.30±0.2°, 33.17±0.2°, 34.80±0.2°.

[0023] In some embodiments, the X-ray powder diffraction pattern of the crystal form includes diffraction peaks at the following 2θ angles: 4.28 ± 0.2°, 5.58 ± 0.2°, 6.69 ± 0.2°, 8.23 ​​± 0.2°, 8.52 ± 0.2°, 10.35 ± 0.2°, 10.56 ± 0.2°, 11.17 ± 0.2°, 11.83 ± 0.2°, 12.78 ± 0.2°, 13.39 ± 0.2°, 15.68 ± 0.2°, 15.82 ± 0.2°, 16.45 ± 0.2°, 16.79 ± 0.2°, 17.59 ± 0.2°, 17.83 ± 0.2°, 18.93 ± 0.2°. 0.2°, 20.00 ± 0.2°, 20.42 ± 0.2°, 20.84 ±0.2°, 21.71 ± 0.2°, 21.99 ± 0.2°, 23.17 ± 0.2°, 23.50 ± 0.2°, 23.78 ±0.2°, 24.10 ± 0.2°, 24.42 ± 0.2°, 24.73 ± 0.2°, 25.71 ± 0.2°, 26.36 ±0.2°, 26.52 ± 0.2°, 26.88 ± 0.2°, 27.38 ± 0.2°, 28.18 ± 0.2°, 29.00 ±0.2°, 29.95 ± 0.2°, 31.30 ± 0.2°, 33.17 ± 0.2°, 33.95 ± 0.2°, 34.80 ± 0.2°, 36.50 ± 0.2°.

[0024] In some embodiments, the crystal form is crystal form A as described in patent application CN117586329A.

[0025] According to the embodiments of the present invention, the crystal form exhibits high stability before and after formulation production and during sample storage. The crystal form in the formulation remains unchanged, and its anti-hepatitis C virus activity does not change before and after formulation preparation.

[0026] In some embodiments, the mass fraction of the active ingredient, based on the total weight of the composition, is 25%-60%, 30%-55%, 35%-50%, 35%~45%, 36%~44%, 37%~43%, 38%~42%, 39%~42%, 40%~42%, 41%~42%, about 40%, about 41%, or about 42%. The inventors have found that the mass fraction of the active ingredient in the composition of the present invention within the above ranges can effectively ensure the stability, efficacy, and safety of the composition in treating hepatitis C.

[0027] In some embodiments, the composition further includes a pharmaceutically acceptable excipient, said excipient being at least one selected from fillers, disintegrants, flow aids, lubricants, and adhesives.

[0028] In some embodiments, the composition further includes a pharmaceutically acceptable excipient, said excipient being at least one selected from fillers, disintegrants, binders, flow aids, and lubricants.

[0029] In some embodiments, the filler includes one or more selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch, sorbitol, dicalcium phosphate, starch, sucrose, and dextrin.

[0030] In some embodiments, the filler includes one or more of lactose, microcrystalline cellulose, mannitol, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose.

[0031] In some embodiments, the filler includes lactose and one or more selected from microcrystalline cellulose, mannitol, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose.

[0032] In some embodiments, the disintegrant includes one or more of crospovidone, low-substituted hydroxypropyl cellulose, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, dry starch, corn starch, pregelatinized starch, microcrystalline cellulose, sodium alginate, calcium carboxymethyl cellulose, and magnesium aluminum silicate.

[0033] In some embodiments, the flow aid is one or a combination of colloidal silica, talc.

[0034] In some embodiments, the lubricant is one or more of sodium stearate fumarate, magnesium stearate, stearic acid, glyceryl behenate, polyethylene glycol 6000, hydrogenated castor oil, and sodium lauryl sulfate.

[0035] In some embodiments, the adhesive is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, starch paste, sodium carboxymethyl cellulose, ethyl cellulose, povidone, and gelatin.

[0036] In some embodiments, the filler includes at least one of an internal filler and an external filler.

[0037] In some embodiments, the weight ratio of the internal filler to the external filler is (5~15):1, (6~13):1, (7~12):1, (8~9):1, 11:1, 9:1, 8:1 or 7:1.

[0038] In some embodiments, the lubricant includes at least one of an external lubricant and an internal lubricant.

[0039] The inventors of this application discovered during the formulation development process that the application of the above-mentioned excipients in wet granulation can improve the in vitro dissolution rate and in vivo absorption of the active ingredient described in this invention.

[0040] In some embodiments, the mass fraction of the active ingredient is 25%-60%, 30%-55%, 35%-50%, 35%~45%, 36%~44%, 37%~43%, 38%~42%, 39%~42%, 40%~42%, or 41%~42%, based on the total weight of the composition.

[0041] In some embodiments, the filler mass fraction is 30%~65%, 35%~60%, 40%~55%, 44%~50%, or 45%~50% based on the total weight of the composition.

[0042] In some embodiments, the mass fraction of the disintegrant is 4% to 10%, 4% to 8%, or 5% to 7% based on the total weight of the composition.

[0043] In some embodiments, the mass fraction of the disintegrant is 4%, 5%, 6%, 7%, 8%, or 9% based on the total weight of the composition.

[0044] In some embodiments, the disintegrant includes at least one of an exogenous disintegrant and an endogenous disintegrant.

[0045] In some embodiments, the mass fraction of the internally added disintegrant is 2.5% to 6.0% or 2.5% to 4.0% based on the total weight of the composition.

[0046] In some embodiments, the mass fraction of the internally added disintegrant is 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, or 6.0% based on the total weight of the composition.

[0047] In some embodiments, the mass fraction of the added disintegrant is 2% to 4% based on the total weight of the composition.

[0048] In some embodiments, the mass fraction of the added disintegrant is 2%, 2.5%, 3.0%, 3.5%, or 4% based on the total weight of the composition.

[0049] In some embodiments, the mass fraction of the gliding agent is 0.5% to 3%, 0.5% to 2.5%, 0.5% to 2%, or 0.5% to 1.5% based on the total weight of the composition.

[0050] In some embodiments, the gliding agent is present in a mass fraction of 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, or 3% based on the total weight of the composition.

[0051] In some embodiments, the mass fraction of the lubricant is 0.5%~5%, 0.5%~4%, 0.5%~3%, 0.5%~2%, or 0.5%~1.5% based on the total weight of the composition.

[0052] In some embodiments, the mass fraction of the lubricant is 0.5%, 1.0%, 1.5%, 2%, 3%, 4%, or 5% based on the total weight of the composition.

[0053] In some embodiments, the adhesive has a mass fraction of 0.5% to 7%, 0.5% to 6.5%, 0.5% to 6%, 0.5% to 5.5%, 0.5% to 5%, 0.5% to 4.5%, 0.5% to 3.0%, 0.5% to 2.5%, 0.5% to 2.0%, or 0.5% to 1.5% based on the total weight of the composition.

[0054] In some embodiments, the adhesive is expressed as a mass fraction of 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5%, 5.5%, 6%, 6.5%, or 7% based on the total weight of the composition.

[0055] In some embodiments, the mass fraction of the added filler is 38% to 45%, 39% to 45%, or 40% to 45% based on the total weight of the composition.

[0056] In some embodiments, the mass fraction of the added filler is 42.33%, 43.83%, or 44.83% based on the total weight of the composition.

[0057] In some embodiments, the mass fraction of the added filler is 3% to 8% or 4% to 6% based on the total weight of the composition.

[0058] In some embodiments, the mass fraction of the added filler is 4%, 5%, or 6% based on the total weight of the composition.

[0059] In some embodiments, the mass fraction of the internally added disintegrant is 2.5% to 6.0% or 2.5% to 4.0% based on the total weight of the composition.

[0060] In some embodiments, the mass fraction of the internally added disintegrant is 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, or 6.0% based on the total weight of the composition.

[0061] In some embodiments, the mass fraction of the added disintegrant is 2% to 4% based on the total weight of the composition.

[0062] In some embodiments, the mass fraction of the added disintegrant is 2%, 2.5%, 3.0%, 3.5%, or 4% based on the total weight of the composition.

[0063] In some embodiments, the filler includes internal fillers and external fillers, wherein the internal filler is selected from at least one of microcrystalline cellulose, lactose, mannitol, and pregelatinized starch.

[0064] In some embodiments, the internal filler includes lactose and microcrystalline cellulose, lactose and pregelatinized starch, or mannitol and microcrystalline cellulose.

[0065] In some embodiments, the internal filler includes lactose and microcrystalline cellulose, wherein the weight ratio of lactose to microcrystalline cellulose is 1:1 to 8:1, 2:1 to 7:1, or 3:1 to 7:1.

[0066] In some embodiments, the internal filler comprises lactose and microcrystalline cellulose, wherein the weight ratio of lactose to microcrystalline cellulose is 3:1, 4:1, 5:1, 6:1, or 7:1.

[0067] In some embodiments, the internal filler includes mannitol and microcrystalline cellulose, wherein the weight ratio of mannitol to microcrystalline cellulose is 1:1 to 6:1, 1:1 to 5:1, 1:1 to 4:1, 1:1 to 3:1, 1:1 to 2:1 or 1:1 to 1.5:1.

[0068] In some embodiments, the internal filler includes lactose and pregelatinized starch, wherein the weight ratio of lactose to pregelatinized starch is 1:1 to 5:1 or 2:1 to 5:1.

[0069] In some implementations, the added filler includes microcrystalline cellulose.

[0070] In some embodiments, the disintegrant includes internally added disintegrants and externally added disintegrants.

[0071] In some embodiments, the internal or external disintegrant is croscarmellose sodium.

[0072] In some embodiments, the ratio of the internally added disintegrant to the externally added disintegrant is 0.7:1 to 3:1 or 0.75:1 to 2:1.

[0073] In some embodiments, the ratio of the internally added disintegrant to the externally added disintegrant is 0.75:1, 0.8:1, 1:1, 1.3:1, 1.5:1 or 2:1.

[0074] In some embodiments, the lubricant includes external lubricants and internal lubricants.

[0075] In some implementations, the lubricant is an external lubricant.

[0076] In some embodiments, the external lubricant is magnesium stearate or sodium stearate fumarate.

[0077] In some embodiments, the internal lubricant is magnesium stearate or sodium stearate fumarate.

[0078] In some implementations, the excipients within the above-mentioned quality range are used in dry granulation to effectively disperse the active pharmaceutical ingredient, improve the in vitro dissolution rate and in vivo absorption, and improve the dissolution rate of the formulation prepared by the dry granulation process.

[0079] In some preferred embodiments, the excipients within the aforementioned mass range are used in wet granulation, which can further effectively disperse the active pharmaceutical ingredient, improve the in vitro dissolution rate and in vivo absorption, and thus further improve the dissolution rate of the formulation prepared by the wet granulation process.

[0080] In some embodiments, the mass ratio of the active ingredient, the filler, the binder, the disintegrant, the flow aid, and the lubricant in the composition is (35~45):(45~50):(0.5~4.5):(4~10):(0.5~1.5):(0.5~2). This can further improve the dissolution rate of the prepared composition.

[0081] In some embodiments, the mass ratio of the active ingredient, the filler, the binder, the disintegrant, the flow aid, and the lubricant in the composition is 42:49:1:6:1:1.5 or 42:49:1:6:1:1. This can further improve the dissolution rate of the prepared composition.

[0082] In some embodiments, the composition is in the form of an oral formulation.

[0083] In some embodiments, the composition is in the form of a solid oral dosage form.

[0084] In some embodiments, the dosage form of the composition is a capsule, tablet, granule, pill, powder, or sustained-release formulation.

[0085] In some embodiments, the dosage form of the composition is a capsule, tablet, granule, or pill, which is prepared by dry granulation or wet granulation.

[0086] In some embodiments, the composition is in the form of capsules, tablets, granules, or pills, which are prepared by dry granulation. Dry granulation can effectively disperse the active pharmaceutical ingredient, improve the in vitro dissolution rate and in vivo absorption, and increase the dissolution rate of the dosage form prepared by the dry granulation process.

[0087] In some preferred embodiments, the composition is in the form of capsules, tablets, granules, or pills, which are prepared by wet granulation. Wet granulation can further effectively disperse the active pharmaceutical ingredient, improve the in vitro dissolution rate and in vivo absorption, and thus further improve the dissolution rate of the dosage form prepared by the wet granulation process.

[0088] In other embodiments, the mass ratio of the active ingredient, the filler, the binder, the disintegrant, the flow aid, and the lubricant in the composition is (35~45):(45~50):(0.5~4.5):(4~10):(0.5~1.5):(0.5~2), and the composition is in the dosage form of capsules, tablets, granules, or pills, which are prepared by dry granulation. Dry granulation can effectively disperse the active pharmaceutical ingredient, improve the in vitro dissolution rate and in vivo absorption, and improve the dissolution rate of the dosage form prepared by the dry granulation process.

[0089] In some preferred embodiments, the mass ratio of the active ingredient, the filler, the binder, the disintegrant, the flow aid, and the lubricant in the composition is (35~45):(45~50):(0.5~4.5):(4~10):(0.5~1.5):(0.5~2), and the dosage form of the composition is capsules, tablets, granules, or pills, which are prepared by wet granulation. Wet granulation can further effectively disperse the active pharmaceutical ingredient, improve the in vitro dissolution rate and in vivo absorption, and thus further improve the dissolution rate of the dosage form prepared by the wet granulation process.

[0090] In other embodiments, the mass ratio of the active ingredient, the filler, the binder, the disintegrant, the flow aid, and the lubricant in the composition is 42:49:1:6:1:1.5 or 42:49:1:6:1:1. The composition is in the dosage form of capsules, tablets, granules, or pills, prepared by dry granulation. Dry granulation effectively disperses the active pharmaceutical ingredient, improves in vitro dissolution rate and in vivo absorption, and enhances the dissolution rate of dosage forms prepared by dry granulation. In some other preferred embodiments, the mass ratio of the active ingredient, the filler, the binder, the disintegrant, the flow aid, and the lubricant in the composition is 42:49:1:6:1:1.5 or 42:49:1:6:1:1, and the dosage form of the composition is capsules, tablets, granules, or pills, which are prepared by wet granulation. Wet granulation can further effectively disperse the active pharmaceutical ingredient, improve the in vitro dissolution rate and in vivo absorption, and thus further improve the dissolution rate of the dosage form prepared by the wet granulation process.

[0091] The tablets according to embodiments of the present invention can be used to effectively treat hepatitis C, and have good stability, rapid dissolution, and high safety.

[0092] In some implementations, the tablet is a single-dose formulation or a multi-dose formulation. A single-dose formulation is one tablet administered once daily to the patient to achieve the desired therapeutic effect, while a multi-dose formulation is one tablet administered multiple times daily to the patient to achieve the desired therapeutic effect.

[0093] In some embodiments, the tablets are formulations of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg. It should be noted that, in this application, a 50 mg tablet means that the mass of the compound represented by formula (I) in the tablet is approximately 50 mg, with a fluctuation of no more than 5 mg from approximately 50 mg; a 100 mg tablet means that the mass of the compound represented by formula (I) in the tablet is approximately 100 mg, with a fluctuation of no more than 10 mg from approximately 100 mg; a 200 mg tablet means that the mass of the compound represented by formula (I) in the tablet is approximately 200 mg, with a fluctuation of no more than 20 mg from approximately 200 mg; a 300 mg tablet means that the mass of the compound represented by formula (I) in the tablet is approximately 300 mg, with a fluctuation of no more than 30 mg from approximately 300 mg; a 400 mg tablet means that the mass of the compound represented by formula (I) in the tablet is approximately 400 mg, with a fluctuation of no more than 40 mg from approximately 400 mg; and a 500 mg tablet means that the mass of the compound represented by formula (I) in the tablet is approximately 500 mg, with a fluctuation of no more than 50 mg from approximately 500 mg.

[0094] According to another specific embodiment of the present invention, the tablet is a 300 mg formulation.

[0095] In some embodiments, the tablets of the present invention include an internal filler and an external filler, wherein the internal filler includes microcrystalline cellulose and lactose, and the external filler includes microcrystalline cellulose.

[0096] In some embodiments, the mass ratio of microcrystalline cellulose to lactose in the tablets of the present invention is 1:3 to 1:7.

[0097] In some embodiments, the disintegrant in the tablets of the present invention is croscarmellose sodium.

[0098] In some embodiments, the flow aid in the tablets of the present invention is colloidal silica.

[0099] In some embodiments, the lubricant in the tablets of the present invention is sodium stearate fumarate.

[0100] In some embodiments, the binder in the tablets of the present invention is hydroxypropyl methylcellulose.

[0101] In a second aspect of the invention, a method for preparing tablets is provided. In some embodiments, the method includes: (1) sequentially granulating an active ingredient with a first internal additive and performing a first premixing treatment; (2) performing a second premixing treatment with a second internal additive; (3) performing a dry granulation treatment on the second premixed product; (4) performing a third premixing treatment with a first external additive; (5) performing a total mixing treatment with the third premixed product and the second external additive; (6) performing a tableting treatment on the total mixing product to obtain the tablet; wherein the active ingredient comprises a compound of formula (I) or a pharmaceutically acceptable salt or crystal form thereof, and the particle size of the active ingredient satisfies at least one of the following conditions: 2 μm ≤ D V (50)≤ 10 μm or 5 μm≤D V (90) ≤ 60 μm. In some embodiments, the first internal additive includes, but is not limited to, an internal filler, an internal binder, an internal disintegrant, or any combination thereof. In some embodiments, the second internal additive includes, but is not limited to, an internal lubricant. In some embodiments, the first external additive includes, but is not limited to, an external filler, an external disintegrant, a flow aid, or any combination thereof. In some embodiments, the second external additive includes, but is not limited to, an external lubricant. The filler, binder, disintegrant, filler, flow aid, and lubricant each have the definitions described in this application. Formulations prepared by dry granulation can disperse the compound of formula (I) or its pharmaceutically acceptable salt or its crystal form, improve in vitro dissolution rate, improve bioavailability and in vivo absorption, and reduce the dosage.

[0102] In some implementations, after tableting, the process further includes coating the resulting uncoated tablets. This effectively masks unpleasant odors and improves oral compliance and adherence.

[0103] In a third aspect of the invention, a method for preparing tablets is provided. In some embodiments, the method includes: (1) premixing an active ingredient with an additive; (2) wet granulating the premixed product; (3) drying the wet granulated product; (4) mixing the dried product with an additive; and (5) compressing the mixed product into tablets to obtain the tablets; wherein the active ingredient comprises a compound of formula (I) or a pharmaceutically acceptable salt or crystal form thereof, and the particle size of the active ingredient satisfies at least one of the following conditions: 2 μm ≤ D V (50)≤ 10 μm or 5 μm≤D V (90) ≤ 60 μm. In some embodiments, the added material includes, but is not limited to, added fillers, added binders, added disintegrants, added lubricants, or any combination thereof. In some embodiments, the added material includes, but is not limited to, added fillers, added disintegrants, flow aids, added lubricants, or any combination thereof. The fillers, binders, disintegrants, fillers, flow aids, and lubricants each have the definitions described in this application. During process development, the inventors unexpectedly discovered that formulations prepared by wet granulation can more effectively disperse the compound shown in formula (I) or its pharmaceutically acceptable salt or its crystal form compared to formulations prepared by dry granulation, further improving flowability, increasing in vitro dissolution rate, improving bioavailability and in vivo absorption, and effectively reducing the dosage.

[0104] In some implementations, after tableting, the process further includes coating the resulting uncoated tablets. This effectively masks unpleasant odors and improves oral compliance and adherence.

[0105] In some embodiments, the total mixing process of the dried product and the additive includes: granulating the dried product and the additive; and then performing the total mixing process on the granulated product.

[0106] In some embodiments, the process of mixing the dried product with the additives includes: granulating the dried product; mixing the granulated product with other additives besides the added lubricant; and mixing the mixed product with the added lubricant.

[0107] In a fourth aspect, the present invention provides a tablet. In some embodiments, the tablet is prepared using the method described in the second or third aspect. Thus, the tablet prepared using the method of the present invention can effectively disperse the compound of formula (I) or a pharmaceutically acceptable salt thereof or its crystal form, improve in vitro dissolution rate, improve bioavailability and in vivo absorption, thereby reducing the dosage.

[0108] In a fifth aspect, the present invention provides a tablet. In some embodiments, the tablet is prepared by a preparation method comprising the following steps: (1) premixing an active ingredient with an additive; (2) wet granulating the premixed product; (3) drying the wet granulated product; (4) mixing the dried product with an additive; and (5) compressing the mixed product to obtain the tablet; wherein the active ingredient comprises a compound of formula (I) or a pharmaceutically acceptable salt or crystal form thereof, and the particle size of the active ingredient satisfies at least one of the following conditions: 2 μm ≤ D V (50)≤ 10 μm or 5 μm≤D V (90) ≤ 60 μm. In some embodiments, the added material includes, but is not limited to, added fillers, added binders, added disintegrants, added lubricants, or any combination thereof. In some embodiments, the added material includes, but is not limited to, added fillers, added disintegrants, gliding agents, added lubricants, or any combination thereof. The fillers, binders, disintegrants, fillers, gliding agents, and lubricants each have the definitions described in this application. During process development, the inventors unexpectedly discovered that tablets prepared by wet granulation can effectively disperse the compound of formula (I) or its pharmaceutically acceptable salt or its crystal form compared to tablets prepared by dry granulation, improving in vitro dissolution rate, increasing bioavailability and in vivo absorption, and effectively reducing the dosage.

[0109] In some embodiments, after tableting, the process further includes coating the resulting uncoated tablets to obtain the tablets described in this invention. This effectively masks unpleasant odors and improves oral compliance and adherence.

[0110] In some embodiments, the total mixing process of the dried product and the additive includes: granulating the dried product and the additive; and then performing the total mixing process on the granulated product.

[0111] In some embodiments, the process of mixing the dried product with the additives includes: granulating the dried product; mixing the granulated product with other additives besides the added lubricant; and mixing the mixed product with the added lubricant. Invention Details Before describing the invention in more detail, it should be understood that the invention is not limited to the specific embodiments described herein, as such embodiments can vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications and patents referenced herein are incorporated herein by reference in their entirety.

[0112] Where numerical ranges are provided, it should be understood that, unless the context clearly indicates otherwise, interpolated values ​​between the upper and lower limits of the range, and any other stated or interpolated values ​​within the range, are covered within the present invention, up to one-tenth of the unit of the upper and lower limits. The upper and lower limits of these smaller ranges may be included independently within the smaller range and also covered within the present invention. Certain ranges are provided herein with values ​​previously referred to by the term “about.” The term “about” is used herein to provide textual support for stated numerical values. In the context in which it is provided, unstated values ​​that are close to or approximate to a specific stated value are substantially equivalent to the specific stated value. The term “about” or “approximately” refers to an acceptable error for a particular value as determined by those skilled in the art, depending in part on how the value is measured or determined. In some embodiments, the term “about” or “approximately” refers to within 1, 2, 3, or 4 standard deviations. In some implementations, the terms “about” or “approximately” refer to 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.

[0113] For reference on these and other pharmaceutically acceptable excipients or processes mentioned in this article, please refer to the extensive literature on the subject, specifically Handbook of Pharmaceutical Excipients, 3rd edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete, edited by HPFiedler, 4th edition, edited by Cantor, Aulendorf and earlier editions.

[0114] The compositions or formulations provided by this invention can be administered to a patient alone, or co-administered or combined with other active agents. The terms "co-administered" and "combined" include the simultaneous or sequential administration of two or more therapeutic agents without a specific time limit. In one embodiment, the agents are simultaneously present in cells or within an individual, or exert biological or therapeutic effects simultaneously. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in different compositions or unit dosage forms. In some implementations, the first agent is administered before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), simultaneously with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the second therapeutic agent.

[0115] "Active ingredient" or "active agent" refers to a substance intended for treatment (e.g., human treatment, veterinary treatment) (including preventative and therapeutic treatment). An active ingredient includes any substance used as a medicine to treat, prevent, delay, alleviate, or improve a disease, symptom, or disorder.

[0116] The term "pharmaceutically acceptable salt" refers to an inorganic or organic acid salt; in some embodiments, the inorganic or organic acid salt may be a monosalt or a disalt. In some embodiments, the inorganic acid salt is selected from hydrohalides, halogen-series oxy-acid salts, carbon-series oxy-acid salts, nitrogen-series oxy-acid salts, boron-series oxy-acid salts, silicon-series oxy-acid salts, phosphorus-series oxy-acid salts, or sulfur-series inorganic acid salts; the organic acid salt is selected from carboxylates, sulfonates, sulfites, or thiocarboxylates. In other embodiments, the inorganic acid salt is selected from hydrochlorides, sulfates, hydrogen sulfates, nitrates, borates, hydrobromides, hydroiodates, carbonates, bicarbonates, sulfites, perchlorates, persulfates, hemisulfates, bisulfates, phosphates, hydrogen phosphates, dihydrogen phosphates, or metaphosphates. In some embodiments, the organic acid salt is selected from formate, acetate, benzoate, malonate, succinate, methanesulfonate, ethanesulfonate, citrate, benzenesulfonate, p-toluenesulfonate, malate, tartrate, succinate, fumarate, glycolate, hydroxyethylsulfonate, maleate, lactate, lactobionate, bis(hydroxynaphthalate), salicylate, galactobionate, glucono-2-ethylhexanoate, mandelate, gluconate, 1,2-ethanedisulfonate, 2-naphthalenesulfonate, oxalate, triacetate, etc. Fluoroacetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, butyrate, camphorate, camphor sulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethylsulfonate, glyceryl phosphate, heptate, hexanoate, 2-hydroxy-ethanesulfonate, laurate, lauryl sulfate, nicotinate, oleate, palmitate, pyrate, pectate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, undecanoate, or pentanoate.

[0117] The term "oral preparation" refers to a form of drug that is administered orally and absorbed into the bloodstream through the gastrointestinal tract, including tablets, granules, capsules, oral solutions, etc.

[0118] The term "solid oral dosage form" refers to tablets, dispersible tablets, instant-dissolving tablets, fast-dissolving tablets, quick-melting tablets, orally dissolving tablets, orally dispersible tablets, lyophilized units, porous tablets, conventional tablets, coated tablets, uncoated tablets, enteric-coated tablets (gastro-resistant tablets), effervescent tablets, soluble tablets, chewable tablets, oral lyophilized products, oral sustained-release formulations, powders, oral powders, pills, granules, capsules, and / or granules. In some embodiments, a solid oral dosage form is a capsule. In some embodiments, a solid oral dosage form is a tablet.

[0119] The term "filler" refers to microcrystalline cellulose, lactose, compressible sugar, sugar, dextrose, dextrin, maltodextrin, xylitol, sorbitol, mannitol, dicalcium phosphate, sucrose, sodium chloride, calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, magnesium oxide, kaolin, powdered cellulose, pregelatinized starch, starch, barium sulfate, magnesium trisilicate, aluminum hydroxide, and combinations thereof. In some embodiments, the filler of the present invention comprises at least microcrystalline cellulose. In other embodiments, the filler of the present invention comprises lactose and one or more selected from microcrystalline cellulose, mannitol, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose. In some embodiments, the microcrystalline cellulose is microcrystalline cellulose 101. In some embodiments, the lactose is lactose Granulac 200 or lactose Flowlac 100.

[0120] The term "disintegrant" includes, but is not limited to, corn starch, calcium carboxymethyl cellulose (CMC-Ca), sodium carboxymethyl cellulose (CMC-Na), crospovidone, low-substituted hydroxypropyl cellulose, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, microcrystalline cellulose, dry starch, pregelatinized starch, sodium alginate, magnesium aluminum silicate, crospovidone polyvinylpyrrolidone (PVP), alginate, sodium alginate, and guar gum. In some embodiments, the crospovidone is crospovidone XL. In some embodiments, the sodium carboxymethyl starch is sodium carboxymethyl starch DST.

[0121] The term "flow aid" includes, but is not limited to, silica, colloidal silica, magnesium trisilicate, powdered cellulose, starch, and talc. In some embodiments of the present invention, the flow aid is colloidal silica or talc, or a combination thereof. In some embodiments of the present invention, the flow aid is colloidal silica (anhydrous) A200.

[0122] The term "lubricant" includes, but is not limited to: magnesium stearate, sodium stearate fumarate, stearic acid, glyceryl behenate, hydrogenated castor oil, sodium lauryl sulfate, aluminum stearate or calcium stearate, PEG 4000-8000, talc, sodium benzoate, glyceryl monofatty acids (e.g., having a molecular weight of 200 to 800 Daltons, such as glyceryl monostearate), and glyceryl behenate (e.g., Compritol). ® 888, ATO Gattefossé, France), glyceryl distearate (e.g., Precirol) ® ATO5 Gattefossé (France), polyethylene glycol (PEG, BASF), hydrogenated cottonseed oil (e.g., Lubritab) ® JRSPharma, Germany), hydrogenated castor oil (Kolliwax) ®(HCO). In some embodiments of the present invention, the lubricant is magnesium stearate. In some embodiments of the present invention, the lubricant is magnesium stearate MF-2-V. In some embodiments of the present invention, the lubricant is sodium stearate fumarate.

[0123] The term "dispersion unit" refers to a device used to uniformly disperse a sample into a measurement medium (such as air or liquid). Its core function is to ensure that particles remain monodisperse during measurement, preventing particle agglomeration from affecting the accuracy of particle size distribution results. Common types of dispersion units include: 1. Wet dispersion units: suitable for liquid media (such as water or organic solvents), which uniformly disperse particles through ultrasonic oscillation or mechanical stirring. 2. Dry dispersion units: suitable for powder samples, which use airflow (such as compressed air) to suspend and disperse particles. For example, the dispersion unit can be a sample inlet cell, which also serves as the optical path for particle size detection.

[0124] In this invention, the excipients can be any type of excipient commonly used in the art. For example, the lactose described in this invention can be any type commonly used in the art, including but not limited to lactose Granulac 200, lactose Flowlac 100, or a mixture thereof. Similarly, the microcrystalline cellulose described in this invention can be any type commonly used in the art, including but not limited to microcrystalline cellulose PH102 or microcrystalline cellulose PH101.

[0125] The term “Dv(50)” refers to the particle size at which the cumulative particle size distribution percentage of a sample reaches 50%, and the term “Dv(90)” refers to the particle size at which the cumulative particle size distribution percentage of a sample reaches 90%.

[0126] In this invention, the term "200 mg, 300 mg, 400 mg, or 500 mg formulation" refers to the fact that the 200 mg, 300 mg, 400 mg, or 500 mg unit formulations of this invention contain approximately 200 mg, approximately 300 mg, approximately 400 mg, or approximately 500 mg of the compound represented by formula (I), respectively. The 200 mg, 300 mg, 400 mg, or 500 mg unit formulations of this invention can be, but are not limited to, one capsule, one tablet, one packet of granules, or one packet of pills. Preferably, the 200 mg, 300 mg, or 400 mg unit formulations of this invention are tablets containing approximately 200 mg, approximately 300 mg, approximately 400 mg, or approximately 500 mg of the compound represented by formula (I), respectively.

[0127] In this invention, "dosage" refers to mass dosage, and "%" refers to mass percentage.

[0128] In this invention, "SDS" refers to sodium dodecyl sulfate.

[0129] The particle size of the active ingredient in this invention was determined using a Malvern particle size analyzer, and the specific measurement method is as follows: 1. Weigh an appropriate amount of the test sample (approximately 6 mg; for unknown samples, adjust the amount according to the sample particle size) into a 10 ml glass beaker. Add 6 ml of n-heptane solution and one drop of Span 80. Stir to dissolve the Span 80 in the n-heptane. Sonicate for 50 seconds (stir rapidly while sonicating) to obtain the treated test sample. The sonication position should be directly above one of the sound sources of the sonicator (i.e., the circular bottom of the sonicator). During sonication, the liquid level in the sonicator should be higher than the liquid level in the beaker, and the bottom of the beaker should not touch the mesh. Keep the sonication position the same for each time.

[0130] 2. Clean the dispersion unit once with isopropanol and twice with n-heptane; 3. Add approximately 100 ml of n-heptane to the dispersion unit to fill it, and slowly adjust the stirring speed to 2000 rpm; 4. Set the instrument parameters according to the table below, and click "Start" to measure the background;

[0131] 5. Add all the prepared sample to the dispersion unit, and clean the glass beaker with n-heptane. Add the cleaning solution to the dispersion unit to make the occlusion range between 10% and 20% (if the occlusion exceeds the range, change the sample amount and repeat steps 1 to 5). Slowly adjust the speed to 0 and wait 3 seconds until the gas in the dispersion system escapes. Then slowly readjust the speed to 2000 rpm and wait 30 seconds until the occlusion is relatively stable. 6. Click "Start" to test the sample, repeat three times, and take the average value.

[0132] The dissolution analysis method of this invention is as follows: (1) Dissolution medium: pH 4.5 acetate buffer solution containing 0.25% sodium dodecyl sulfate (w / v); medium volume: 900ml±9ml; dissolution method: paddle method; rotation speed: 50rpm; medium temperature: 37℃±0.5℃; sampling position: at the midpoint between the tip of the paddle and the liquid surface, and 10mm away from the wall of the dissolution cup; sampling volume: 5mL; sampling time: 5min, 10min, 15min, 20min, 30min, 45min, 60min.

[0133] (2) Dissolution medium: purified aqueous solution containing 0.5% sodium dodecyl sulfate (w / v); medium volume: 900ml±9ml; dissolution method: paddle method; rotation speed: 50rpm; medium temperature: 37℃±0.5℃; sampling position: at the midpoint between the tip of the paddle and the liquid surface, and 10mm away from the wall of the dissolution cup; sampling volume: 5mL; sampling time: 5min, 10min, 15min, 20min, 30min, 45min, 60min.

[0134] (3) Dissolution medium: pH 4.5 acetate buffer solution containing 0.5% sodium dodecyl sulfate (w / v); medium volume: 900ml±9ml; dissolution method: paddle method; rotation speed: 50rpm; medium temperature: 37℃±0.5℃; sampling position: at the midpoint between the tip of the paddle and the liquid surface, and 10mm away from the wall of the dissolution cup; sampling volume: 5mL; sampling time: 5min, 10min, 15min, 20min, 30min, 45min, 60min.

[0135] The angle of repose has been widely used in many disciplines to characterize the flow properties of solids. It is a characteristic parameter related to interparticle friction or relative motion resistance between particles. It is the maximum angle formed between a free inclined plane of powder accumulation and the horizontal plane in a static equilibrium state.

[0136] The method for determining the angle of repose in this invention: The static angle of repose is determined by a complete set of equipment consisting of a feeding funnel, an electric stirrer, a fixed diameter receiving base with an eighth-circle circumference (height adjustable), and a main support. Before testing, ensure the funnel is upright and that all components are protected from vibration. Adjust the height of the receiving base to the "0" mark on the vertical scale. The funnel must be dry, and its bottom outlet should be plugged with a movable lever. Place the weighed, uncompressed test sample into the funnel. Open the bottom opening of the funnel and allow the powder to flow out naturally due to its own fluidity (if it cannot flow out naturally, insert an electric stirrer into the funnel and start stirring to assist the powder flow). Once all the powder has flowed out of the funnel and accumulated on the receiving base, carefully adjust the height of the receiving base until the tip of the powder cone is level with the funnel opening. Avoid causing secondary flow or collapse of the cone. Read the cone height H and cone radii R1, R2, R3, R4, R5, R6, R7, and R8 on the vertical scale. The angle of repose α can be calculated by measuring the height and radius of the powder cone, taking the average of eight measurements. The calculation formula is as follows: α = arctan(cone height / chassis radius) The final angle of repose α is obtained by taking the average of three consecutive measurements.

[0137] Evaluation of powder flowability using angle of repose

[0138] (Reference: Public Notice on the Draft Standard for the Determination of Powder Flowability (Second Time), January 2024) The following examples are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention.

[0139] The active pharmaceutical ingredient (API) used in the following examples is crystal form A of the compound shown in formula (I), and the preparation method of crystal form A is referred to in patent application CN117586329A.

[0140] Example 1: Investigation of the particle size range of active ingredients The compound shown in formula (I) is a poorly soluble drug with poor powder flowability and is prone to clumping. Preparation process: Weigh the ingredients according to the formula in Table 1 and add them to the granulation pot. Set the stirring speed of the premixing impeller to 190 rpm and the cutting speed of the premixing blade to 1500 rpm. After premixing, set the stirring speed of the liquid addition / granulation impeller to 190 / 190 rpm and the cutting speed of the liquid addition / granulation blade to 2500 / 2500 rpm. Control the liquid addition time to 275±35s and the granulation time to 180s. After granulation, sieve the wet granules and put them into a fluidized bed for drying. Set the air inlet temperature to 65±15℃. Then set the granulator parameters to 1442±6 rpm. Put the dried granules and all the added excipients into the granulator for granulation. Mix them in a mixing tank at 10 rpm for 15 min. Put the total mixed granules into a tablet press and press them into uncoated tablets that meet the requirements. Finally, use a coating machine to spray coating liquid to coat the uncoated tablets with a film to obtain the finished product.

[0141] Table 1 Formulation table for particle size range investigation

[0142] Acceptable raw material particle size ranges were determined based on the similarity of dissolution results. The batches examined included batches 1-1, 1-2, 1-3, 1-4, 1-5, and 1-6, investigating the effect of different raw material particle size distributions on formulation dissolution. The results are as follows: Table 2. Angle of repose of active drugs with different particle sizes, angle of repose of total mixed particles of the prepared formulation, and dissolution data of the formulated tablets in pH 4.5 (acetate buffer solution) + 0.25% SDS medium.

[0143] The results showed that the particle size range of the active pharmaceutical ingredient was 2 μm ≤ D V (50) ≤ 10 μm, 5 μm≤D V(90) Within the ≤ 60 μm range, the formulation of the active pharmaceutical ingredient dissolves well. A dissolution rate of ≥ 80% within 30 min is considered acceptable. Based on the dissolution trends of formulations with different particle sizes, D can be inferred. v (90) When the size is greater than 60µm, the dissolution rate of the formulation will be less than 80% in 30 min.

[0144] Example 2: Preparation of tablets using wet granulation and filling processes and dry granulation and filling processes. Table 3. Formulation Information for Wet and Dry Granulation / Filling Processes

[0145] 2.1 Preparation method of tablets by wet granulation: (1) According to the prescription table in Table 3, premix the compound of formula (I) (particle size: Dv(50) (μm)=3.734, Dv(90) (μm)=14.734) with colloidal silica (added) in a PE bag. Then weigh in the other added materials except magnesium stearate and mix for 5 min. Finally, weigh the magnesium stearate (added) into the PE bag, pass it through a 40-mesh sieve, and mix for another 5 min to obtain the premixed powder. Take a sample to test the moisture content of the premix. (2) Add an appropriate amount of purified water to the premixed powder to granulate (add purified water while stirring manually) until the material is "formed into a ball when squeezed by hand and dispersed when lightly pressed". (3) Use a forced-air drying oven at 50°C to dry the moisture content until it is equal to that of the premixed material. Then, take the dried granules and pass them through a 20-mesh sieve. (4) Pass the added material through a 20-mesh sieve and mix the sieved material with the granulated granules for 5 minutes to obtain the total mixed granules. (5) Put the total mixed granules into a tablet press and press it into a tablet that meets the requirements. Finally, use a coating machine to spray coating liquid to coat the tablets with a film to obtain the finished product.

[0146] The angle of repose of the total mixed particles (°) was 36.45, indicating that the particles prepared by the wet granulation and filling process have good flowability.

[0147] 2.2 Dry granulation method for preparing tablets: (1) First, manually mix API and colloidal silica (added internally) in the same PE bag, then mix with microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose (added internally), and finally sieve with mannitol alternately. Use a 032R sieve on a granulator to sieve the granules and turn on the granulator to obtain sieved granules; (2) Transfer the sieved granules to a 6L mixing tank and premix for 20 minutes to obtain premix 1; (3) Then weigh magnesium stearate (added internally) and mix with about 3 times the amount of premix 1, pass through a 30-mesh sieve, and add to the mixing hopper and mix for 5 minutes to obtain premix 2; (3) Put premix 2 into a dry granulator, select a sinusoidal pressure roller and a blade cutting blade, set the horizontal screw speed to 15~20 rpm and the vertical screw speed to 300~350 rpm. rpm, roller speed 4~6rpm, roller pressure 30~35Bar, granulator speed 1500rpm, granulator screen 0065, roller spacing 0.5mm, granulation to obtain granules; (4) mix microcrystalline cellulose (added), cross-linked sodium carboxymethyl cellulose (added), colloidal silica (added) with 3 times the amount of granulated granules, pass through a 20 mesh screen, mix for 5min to obtain premix 3; (5) mix magnesium stearate with about 3 times the amount of premix 3, pass through a 20 mesh screen, add to the mixing hopper and mix for 5min to obtain total mixed granules; (6) put the total mixed granules product into the tablet press, press into uncoated tablets that meet the requirements, and finally use a coating machine to spray coating liquid to coat the uncoated tablets with a film to obtain the finished product.

[0148] Pharmacokinetic testing: Pharmacokinetic evaluation of tablets prepared by wet or dry granulation processes after oral administration to dogs. The formulation in Table 3 was administered orally (po) to gorilla dogs at a dose of 500 mg / dog. Blood samples (0.3 mL) were collected at time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, and 24 hours. Plasma samples were collected by centrifugation at 4000 rpm for 10 minutes and stored at -70°C. A standard curve was established based on the sample concentrations. The concentration of GS331007 in the plasma samples was determined using an AB SCIEXAPI 4000 LC-MS / MS in MRM mode. Pharmacokinetic parameters were calculated using the non-compartmental model method in WinNonLin 6.3 software based on the drug concentration-time curve. The number of animals in this experiment was N=3, and blood was collected timed with a single QD (quick-dose) administration. The results are shown in Table 4.

[0149]

[0150] Table 4. Pharmacokinetic results of tablets prepared by wet granulation and dry granulation processes for oral administration in dogs.

[0151] Table 4 shows that, after oral administration, the main active metabolite GS331007 of the wet-granulated formulation of the present invention has a C-value in beagle dogs. max and AUC last All are relatively high. Among them, the wet granulation formulation of the present invention has a higher exposure in beagle dogs, better absorption, and better pharmacokinetic properties compared with the dry granulation formulation.

[0152] Example 3: Investigation of the effect of adding fillers and disintegrants on dissolution. Prepare tablets of compound (I) according to the formulation shown below, and determine the dissolution rate.

[0153] Preparation method: (1) Add the compound of formula (I) and the added material to the wet granulation pot according to the formula ratio of the following formula 3-1 for premixing. Set the stirring speed of the premixing impeller to 200 rpm, the cutting speed of the premixing blade to 1500 rpm, and the premixing time to 300 s; (2) After the premixing is completed, perform wet granulation on the premixed product. Set the stirring speed of the liquid addition / granulation impeller to 200 / 200 rpm, the cutting speed of the liquid addition / granulation blade to 2500 / 2500 rpm, control the liquid addition time to 275±35 s, and the granulation time to 300 s. 180s; (3) After granulation, the wet granulation product is sieved and then put into a fluidized bed for drying. The air inlet temperature is set to 65±15℃; (4) The granulator parameters are set to 1442±6rpm. The dried granules and all the added excipients are put into the granulator for granulation; (5) The granulated granules are put into a mixing tank and mixed at 10rpm for 15min to obtain total mixed granules; (6) The total mixed granules are put into a tablet press and pressed into tablets that meet the requirements. Finally, the tablets are coated with coating liquid by spraying coating liquid to obtain the finished product.

[0154] Prescription 3-1: Prescription amount 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 40.69%, microcrystalline cellulose 8.14%, hydroxypropyl methylcellulose 1% and croscarmellose sodium 6%, external additives: colloidal silica 1% and sodium stearate fumarate 1.5%.

[0155] Table 5. Dissolution data of Formulation 3-1 in pH 4.5 (acetate buffer) + 0.25% SDS medium.

[0156] Note: N / A indicates that the data was not measured.

[0157] The experimental results in Table 5 show that the composition of the present invention has good dissolution when a disintegrant (such as croscarmellose sodium cellulose in this embodiment) and a filler (such as microcrystalline cellulose in this embodiment) are added.

[0158] Example 4: Investigation of the effect of simultaneous internal and external addition of fillers and disintegrants on dissolution. Prepare tablets of compound (I) according to the formulation shown below, and determine the dissolution rate.

[0159] Preparation method: Preparation process of prescription 4-1: According to the prescription in prescription 4-1, add the compound of formula (I) and the internal material into the wet granulation pot for premixing. Set the stirring speed of the premixing impeller to 200 rpm, the cutting speed of the premixing blade to 1500 rpm, and the premixing time to 600 s; (2) After the premixing is completed, perform wet granulation on the premixed product. Set the stirring speed of the liquid addition / granulation impeller to 200 / 200 rpm, the cutting speed of the liquid addition / granulation blade to 3000 / 3000 rpm, control the liquid addition time to 275±35 s, and the granulation time to 300 s; (3) After the granulation is completed, sieve the wet granulation product and put it into the fluidized bed for drying. (3) Set the air inlet temperature to 65±15℃; (4) Set the granulator parameters to 1442±6rpm and put the dried granules into the granulator for granulation; (5) Put the granulated granules and other additives except sodium stearate fumarate into the mixing tank and mix at 10rpm for 10min; (6) Take 3 times the amount of mixed granules of sodium stearate, mix them with sodium stearate fumarate, pass them through a 30-mesh sieve, and put them into the mixing tank. Mix at 10rpm for 5min to obtain total mixed granules; (7) Put the total mixed granules into the tablet press and press them into uncoated tablets that meet the requirements. Finally, use a coating machine to spray coating liquid to coat the uncoated tablets with a film to obtain the finished product.

[0160] Preparation process of prescriptions 4-2 to 4-4: According to the prescriptions in prescriptions 4-2 to 4-4, the compound of formula (I) and the added material are added to the wet granulation pot for premixing. The stirring speed of the premixing impeller is set to 190 rpm, the cutting speed of the premixing blade is set to 1500 rpm, and the premixing time is 300 s; (2) After the premixing is completed, the premixed product is wet granulated. The stirring speed of the liquid addition / granulation impeller is set to 190 / 190 rpm, the cutting speed of the liquid addition / granulation blade is set to 2500 / 2500 rpm, and the liquid addition time is controlled to be 275±35 s. Granulation time 180s; (3) After granulation, the wet granulation product is sieved and then put into a fluidized bed for drying, and the air inlet temperature is set to 65±15℃; (4) Set the granulator parameters to 1442±6rpm, and put the dried granules and all the added excipients into the granulator for granulation; (5) Put the granulated granules into a mixing tank and mix at 10rpm for 15min to obtain total mixed granules; (6) Put the total mixed granules into a tablet press and press it into a tablet that meets the requirements. Finally, use a coating machine to spray coating liquid to coat the tablets with a film to obtain the finished product.

[0161] Prescription 4-1: Prescription dosage 400 mg, total tablets 960 mg, containing 41.67% of compound (I), internal additives: lactose 35.27%, microcrystalline cellulose 7.06%, hydroxypropyl methylcellulose 3%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.0%.

[0162] Prescription 4-2: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 32.87%, microcrystalline cellulose 10.96%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0163] Prescription 4-3: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 36.44%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0164] Prescription 4-4: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 38.35%, microcrystalline cellulose 5.48%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0165] Table 6-1 Angle of repose of total mixed particles and dissolution data of tablets in purified water + 0.5% SDS medium for Formulation 4-1

[0166] Table 6-2 Angle of repose of total mixed granules and dissolution data of tablets in pH 4.5 (acetate buffer solution) + 0.25% SDS medium for formulations 4-2 to 4-4

[0167] Experimental results show that the composition of the present invention also has good dissolution when both the filler and the disintegrant are added internally and externally.

[0168] Example 5: Investigation of the effect of binder dosage on dissolution Prepare tablets of compound (I) according to the formulation shown below, and determine the dissolution rate.

[0169] Preparation method: According to the formulas 5-1 to 5-4, the compound of formula (I) and the added material are added to the wet granulation pot for premixing. The stirring speed of the premixing impeller is set to 190 rpm, the cutting speed of the premixing blade is set to 1500 rpm, and the premixing time is 300 s; (2) After the premixing is completed, the premixed product is wet granulated. The stirring speed of the liquid addition / granulation impeller is set to 190 / 190 rpm, the cutting speed of the liquid addition / granulation blade is set to 2500 / 2500 rpm, the liquid addition time is controlled to be 275±35 s, and the granulation time is controlled to be 300 s. 180s; (3) After granulation, the wet granulation product is sieved and then put into a fluidized bed for drying. The air inlet temperature is set to 65±15℃; (4) The granulator parameters are set to 1442±6rpm. The dried granules and all the added excipients are put into the granulator for granulation; (5) The granulated granules are put into a mixing tank and mixed at 10rpm for 15min to obtain total mixed granules; (6) The total mixed granules are put into a tablet press and pressed into tablets that meet the requirements. Finally, the tablets are coated with coating liquid by spraying coating liquid to obtain the finished product.

[0170] Prescription 5-1: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 36.94%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 0.50%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0171] Prescription 5-2: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 36.44%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0172] Prescription 5-3: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 35.94%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1.5% and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1% and sodium fumarate stearate 1.5%.

[0173] Prescription 5-4: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 34.44%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 3%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0174] Prescription 5-5: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 32.94%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 4.5% and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1% and sodium fumarate stearate 1.5%.

[0175] Table 7 Angle of repose of total mixed granules of formulations 5-1 to 5-5 and dissolution data of tablets in pH 4.5 (acetate buffer solution) + 0.25% SDS medium.

[0176] As shown in Table 7, the experimental results of formulations 5-1 to 5-5 indicate that when the amount of hydroxypropyl methylcellulose binder is 0.50% to 4.50%, the composition of the present invention has good flowability and good dissolution.

[0177] Example 6: Investigation of the effect of the amount of internal disintegrant on dissolution. Prepare tablets of compound (I) according to the formulation shown below, and determine the dissolution rate.

[0178] Preparation method: (1) Weigh the internal material according to the prescription 6-1 into a PE bag, mix the compound of formula (I) with the internal material for 5 minutes, pass through a 40-mesh sieve and mix for another 5 minutes to obtain a premixed powder, and take a sample to test the moisture content of the premix; (2) After the premix is ​​completed, add an appropriate amount of purified water to the premixed powder to granulate (add purified water while stirring manually) until the material is in the state of "forming a ball when squeezed by hand and dispersing when lightly pressed", and pass through a 20-mesh sieve to obtain wet granules; (3) Use a forced-air drying oven at 50°C to dry the moisture content to be equal to the moisture content of the premix, and then the drying is completed. Take the dried granules and pass through a 20-mesh sieve; (4) Pass the external material through a 20-mesh sieve, and mix the sieved material with the granulated granules for 5 minutes to obtain total mixed granules; (5) Put the total mixed granules into a tablet press and press it into a tablet that meets the requirements. Finally, use a coating machine to spray coating liquid to coat the tablets with a film to obtain the finished product.

[0179] (2) According to the formulas in formulas 6-2 to 6-4, the compound of formula (I) and the added material are added to the wet granulation pot for premixing. The stirring speed of the premixing impeller is set to 190 rpm, the cutting speed of the premixing blade is set to 1500 rpm, and the premixing time is 300 s; (2) After the premixing is completed, the premixed product is wet granulated. The stirring speed of the liquid addition / granulation impeller is set to 190 / 190 rpm, the cutting speed of the liquid addition / granulation blade is set to 2500 / 2500 rpm, the liquid addition time is controlled to be 275±35 s, and the granulation time is 1 80s; (3) After granulation, the wet granulation product is sieved and then put into a fluidized bed for drying. The air inlet temperature is set to 65±15℃; (4) The granulator parameters are set to 1442±6rpm. The dried granules and all the added excipients are put into the granulator for granulation; (5) The granulated granules are put into a mixing tank and mixed at 10rpm for 15min to obtain total mixed granules; (6) The total mixed granules are put into a tablet press and pressed into tablets that meet the requirements. Finally, the tablets are coated with coating liquid by spraying coating liquid to obtain the finished product.

[0180] Prescription 6-1: Prescription dosage 500 mg, total tablets 1200 mg, containing 41.67% of compound (I), internal additives: mannitol 23.67%, microcrystalline cellulose 18.66%, hydroxypropyl methylcellulose 3%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1%.

[0181] Prescription 6-2: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 36.94%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 2.5%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0182] Prescription 6-3: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 36.44%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0183] Prescription 6-4: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 35.44%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 4%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0184] Table 8-1 Angle of repose of total mixed granules and dissolution data of tablets in pH 4.5 (acetate buffer) + 0.5% SDS medium for Formulation 6-1

[0185] Table 8-2 Angle of repose of total mixed granules and dissolution data of tablets in pH 4.5 (acetate buffer solution) + 0.25% SDS medium for formulations 6-2~6-4

[0186] The experimental results of formulations 6-1 to 6-4 in Tables 8-1 and 8-2 show that when the amount of the internal disintegrant croscarmellose sodium is 2.5%-4.0%, the composition of the present invention has good flowability and good dissolution.

[0187] Example 7: Investigation of the effect of added disintegrant dosage on dissolution rate Prepare tablets of compound (I) according to the formulation shown below, and determine the dissolution rate.

[0188] Preparation method: According to the formulas 7-1 to 7-3, the compound of formula (I) and the added material are added to the wet granulation pot for premixing. The stirring speed of the premixing impeller is set to 190 rpm, the cutting speed of the premixing blade is set to 1500 rpm, and the premixing time is 300 s; (2) After the premixing is completed, the premixed product is wet granulated. The stirring speed of the liquid addition / granulation impeller is set to 190 / 190 rpm, the cutting speed of the liquid addition / granulation blade is set to 2500 / 2500 rpm, the liquid addition time is controlled to be 275±35 s, and the granulation time is controlled to be 300 s. 180s; (3) After granulation, the wet granulation product is sieved and then put into a fluidized bed for drying. The air inlet temperature is set to 65±15℃; (4) The granulator parameters are set to 1442±6rpm. The dried granules and all the added excipients are put into the granulator for granulation; (5) The granulated granules are put into a mixing tank and mixed at 10rpm for 15min to obtain total mixed granules; (6) The total mixed granules are put into a tablet press and pressed into tablets that meet the requirements. Finally, the tablets are coated with coating liquid by spraying coating liquid to obtain the finished product.

[0189] Prescription 7-1: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 37.44%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 2%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0190] Prescription 7-2: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 36.44%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0191] Prescription 7-3: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 35.44%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 4%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0192] Table 9 Angle of repose of total mixed granules of formulations 7-1 to 7-3 and dissolution data of tablets in pH 4.5 (acetate buffer solution) + 0.25% SDS medium.

[0193] As shown by the experimental results of prescriptions 7-1 to 7-3 in Table 9, when the proportion of the added disintegrant croscarmellose sodium is 2%-4%, the composition of the present invention has good flowability and good dissolution.

[0194] Example 8: Investigation of the effect of the amount of added filler on dissolution Prepare tablets of compound (I) according to the formulation shown below, and determine the dissolution rate.

[0195] Preparation method: According to the formulas in formulas 8-1 to 8-3, the compound of formula (I) and the added material are added to the wet granulation pot for premixing. The stirring speed of the premixing impeller is set to 190 rpm, the cutting speed of the premixing blade is set to 1500 rpm, and the premixing time is 300 s; (2) After the premixing is completed, the premixed product is wet granulated. The stirring speed of the liquid addition / granulation impeller is set to 190 / 190 rpm, the cutting speed of the liquid addition / granulation blade is set to 2500 / 2500 rpm, the liquid addition time is controlled to be 275±35 s, and the granulation time is controlled to be 300 s. 180s; (3) After granulation, the wet granulation product is sieved and then put into a fluidized bed for drying. The air inlet temperature is set to 65±15℃; (4) The granulator parameters are set to 1442±6rpm. The dried granules and all the added excipients are put into the granulator for granulation; (5) The granulated granules are put into a mixing tank and mixed at 10rpm for 15min to obtain total mixed granules; (6) The total mixed granules are put into a tablet press and pressed into tablets that meet the requirements. Finally, the tablets are coated with coating liquid by spraying coating liquid to obtain the finished product.

[0196] Prescription 8-1: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 37.44%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 4%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0197] Prescription 8-2: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 36.44%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0198] Prescription 8-3: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 35.44%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 6%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0199] Table 10 Angle of repose of total mixed granules of formulations 8-1 to 8-3 and dissolution data of tablets in pH 4.5 (acetate buffer solution) + 0.25% SDS medium.

[0200] The experimental results of prescriptions 8-1 to 8-3 in Table 10 show that when the proportion of the added filler microcrystalline cellulose is 4%-6%, the composition of the present invention has good flowability and compressibility, and good dissolution.

[0201] Example 9: Investigation of the effect of lubricant dosage on dissolution Prepare tablets of compound (I) according to the formulation shown below, and determine the dissolution rate.

[0202] Preparation method: According to the prescriptions in prescriptions 9-1 to 9-3, the compound of formula (I) and the added material were added to the wet granulation pot for premixing. The stirring speed of the premixing impeller was set to 190 rpm, the cutting speed of the premixing blade was set to 1500 rpm, and the premixing time was 300 s. (2) After the premixing was completed, the premixed product was wet granulated. The stirring speed of the liquid addition / granulation impeller was set to 190 / 190 rpm, the cutting speed of the liquid addition / granulation blade was set to 2500 / 2500 rpm, the liquid addition time was controlled to be 275±35 s, and the granulation time was 180 s. s; (3) After granulation, the wet granulation product is sieved and then put into a fluidized bed for drying. The air inlet temperature is set to 65±15℃; (4) The granulator parameters are set to 1442±6rpm. The dried granules and all the added excipients are put into the granulator for granulation; (5) The granulated granules are put into a mixing tank and mixed at 10rpm for 15min to obtain total mixed granules; (6) The total mixed granules are put into a tablet press and pressed into tablets that meet the requirements. Finally, the tablets are coated with coating liquid by spraying coating liquid to obtain the finished product.

[0203] Preparation method of prescriptions 9-4~9-6: According to the prescriptions in prescriptions 9-4~9-6, add the compound of formula (I) and the added material into the wet granulation pot for premixing. Set the stirring speed of the premixing impeller to 200 rpm, the cutting speed of the premixing blade to 1500 rpm, and the premixing time to 300 s; (2) After the premixing is completed, perform wet granulation on the premixed product. Set the stirring speed of the liquid addition / granulation impeller to 200 / 120 rpm, the cutting speed of the liquid addition / granulation blade to 3000 / 3000 rpm, control the liquid addition time to 275±35 s, and the granulation time to 180 s; (3) After the granulation is completed, put the wet granulation product into the flow trough after sieving. (3) Dry the bed and set the air inlet temperature to 65±15℃; (4) Set the granulator parameters to 1442±6rpm and put the dried granules into the granulator for granulation; (5) Put the granulated granules and other additives except sodium stearate fumarate into the mixing tank and mix at 10rpm for 10min; (6) Take 3 times the amount of mixed granules of sodium stearate, mix them with sodium stearate fumarate and pass them through a 30-mesh sieve, and put them into the mixing tank and mix at 10rpm for 5min to obtain total mixed granules; (7) Put the total mixed granules into the tablet press and press them into uncoated tablets that meet the requirements. Finally, use a coating machine to spray coating liquid to coat the uncoated tablets with a film to obtain the finished product.

[0204] Prescription 9-1: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 36.94%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.0%.

[0205] Prescription 9-2: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 36.44%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0206] Prescription 9-3: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 35.94%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 2%.

[0207] Prescription 9-4: Prescription dosage 400 mg, total tablets 960 mg, containing 41.67% of compound (I), internal additives: lactose 37.36%, microcrystalline cellulose 7.47%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 0.5%.

[0208] Prescription 9-5: Prescription dosage 400 mg, total tablets 960 mg, containing 41.67% of compound (I), internal additives: lactose 36.94%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1%.

[0209] Prescription 9-6: Prescription dosage 400 mg, total tablets 960 mg, containing 41.67% of compound (I), internal additives: lactose 36.53%, microcrystalline cellulose 7.31%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0210] Table 11-1 Angle of repose of total mixed particles and dissolution data of tablets in pH 4.5 (acetate buffer solution) + 0.25% SDS medium for formulations 9-1 to 9-3

[0211] Table 11-2 Angle of repose of total mixed particles of formulations 9-4 to 9-6 and dissolution data of tablets in pH 4.5 (acetate buffer) + 0.5% SDS medium

[0212] The experimental results of formulations 9-1 to 9-6 in Tables 11-1 and 11-2 show that when the proportion of sodium stearate fumarate as a lubricant is 0.5% to 2%, the composition of the present invention exhibits good flowability and good dissolution. Furthermore, the use of sodium stearate fumarate as a lubricant is effective in the preparation of the tablets, and no sticking or punching phenomenon occurred during tablet compression.

[0213] Example 10: Investigation of the effect of glidant dosage on dissolution Prepare tablets of compound (I) according to the formulation shown below, and determine the dissolution rate.

[0214] Preparation method: (1) According to the formulas in formulas 10-1 to 10-3, the compound of formula (I) and the added material are added to the wet granulation pot for premixing. The stirring speed of the premixing impeller is set to 190 rpm, the cutting speed of the premixing blade is set to 1500 rpm, and the premixing time is 300 s; (2) After the premixing is completed, the premixed product is wet granulated. The stirring speed of the liquid addition / granulation impeller is set to 190 / 190 rpm, the cutting speed of the liquid addition / granulation blade is set to 2500 / 2500 rpm, and the liquid addition time is controlled to 275±35 s. Granulation is carried out. Time 180s; (3) After granulation, the wet granulation product is sieved and then put into a fluidized bed for drying. The air inlet temperature is set to 65±15℃; (4) The granulator parameters are set to 1442±6rpm. The dried granules and all the added excipients are put into the granulator for granulation; (5) The granulated granules are put into a mixing tank and mixed at 10rpm for 15min to obtain total mixed granules; (6) The total mixed granules are put into a tablet press and pressed into tablets that meet the requirements. Finally, the tablets are coated with coating liquid by spraying coating liquid to obtain the finished product.

[0215] Prescription 10-1: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 36.94%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 0.5%, and sodium fumarate stearate 1.0%.

[0216] Prescription 10-2: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 36.44%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1%, and sodium fumarate stearate 1.5%.

[0217] Prescription 10-3: Prescription dosage 300 mg, total tablets 720 mg, containing 41.67% of compound (I), internal additives: lactose 35.94%, microcrystalline cellulose 7.39%, hydroxypropyl methylcellulose 1%, and croscarmellose sodium 3%, external additives: microcrystalline cellulose 5%, croscarmellose sodium 3%, colloidal silica 1.5%, and sodium fumarate stearate 1.5%.

[0218] Table 12 Angle of repose of granules and dissolution data of tablets in pH 4.5 (acetate buffer solution) + 0.25% SDS medium for formulations 10⁻¹ to 10⁻³.

[0219] The experimental results of formulations 10-1 to 10-3 in Table 12 show that when the proportion of colloidal silica as a flow aid is 0.5% to 1.5%, the composition of the present invention has good flowability and good dissolution.

[0220] Example 11: Investigation of the effect of adhesive type on dissolution and flowability Prepare tablets of compound (I) according to the formulation shown in Table 13 below, and determine the dissolution rate.

[0221] Table 13. Prescription Information for Screening Adhesive Types in 400mg Dosage Formulations

[0222] Note: "N / A" indicates that it is not added or not added.

[0223] Preparation method of prescription 11-1: (1) According to prescription 11-1 in the above prescription table, the compound of formula (I) and the added material are premixed in a granulation pot. The stirring speed of the premixing impeller is set to 200 rpm and the cutting speed of the premixing blade is set to 1500 rpm. The premixing time is 10 min. (2) After the premixing is completed, the stirring speed of the liquid addition / granulation impeller is set to 200 / 200 rpm and the cutting speed of the liquid addition / granulation blade is set to 3000 / 3000 rpm. The liquid addition time is controlled to be 275±35 s and the granulation time is 300 s. (3) After granulation, the wet granules are sieved and then put into a fluidized bed for drying. The air inlet temperature is set to 6 rpm. 5±15℃; (4) Set the granulator parameters to 1442±6rpm and put the dried granules into the granulator for granulation; (5) Put the granulated granules and other additives except sodium stearate fumarate into the mixing tank and mix at 10rpm for 10min; (6) Take 3 times the amount of mixed granules of sodium stearate, mix them with sodium stearate fumarate, pass them through a 30-mesh sieve, and put them into the mixing tank. Mix at 10rpm for 5min to obtain total mixed granules; (7) Put the total mixed granules into the tablet press and press them into uncoated tablets that meet the requirements. Finally, use a coating machine to spray coating liquid to coat the uncoated tablets with a film to obtain the finished product.

[0224] Preparation method of prescription 11-2: (1) According to prescription 11-2 in the above prescription table, the compound of formula (I) and the added material are premixed in a granulation pot. The stirring speed of the premixing impeller is set to 200 rpm and the cutting speed of the premixing blade is set to 1500 rpm. The premixing time is 10 min. (2) After the premixing is completed, the stirring speed of the liquid addition / granulation impeller is set to 200 / 120 rpm and the cutting speed of the liquid addition / granulation blade is set to 3000 / 3000 rpm. The liquid addition time is controlled to be 275±35 s and the granulation time is 180 s. (3) After granulation, the wet granules are sieved and then put into a fluidized bed for drying. The air inlet temperature is set to 6 rpm. 5±15℃; (4) Set the granulator parameters to 1442±6rpm and put the dried granules into the granulator for granulation; (5) Put the granulated granules and other additives except sodium stearate fumarate into the mixing tank and mix at 10rpm for 10min; (6) Take 3 times the amount of mixed granules of sodium stearate, mix them with sodium stearate fumarate, pass them through a 30-mesh sieve, and put them into the mixing tank. Mix at 10rpm for 5min to obtain total mixed granules; (7) Put the total mixed granules into the tablet press and press them into uncoated tablets that meet the requirements. Finally, use a coating machine to spray coating liquid to coat the uncoated tablets with a film to obtain the finished product.

[0225] Table 14 Angle of repose of total mixed particles of formulations 11-1 and 11-2 and dissolution data of tablets in purified water + 0.5% SDS medium

[0226] The formulation using hydroxypropyl methylcellulose as a binder (Formulation 11-1) has a smaller angle of repose than the formulation using hydroxypropyl cellulose as a binder (Formulation 11-2), exhibiting relatively better flowability. Furthermore, Formulation 11-2 shows sticking and punching during tableting. Dissolution results show no significant difference in dissolution between the tablets prepared using the two binders. Therefore, hydroxypropyl methylcellulose is preferred as the binder.

[0227] Example 12 Investigation of Disintegrant Types Prepare tablets of compound (I) according to the formulations shown in Tables 15-1 and 15-2 below, and determine the dissolution rate.

[0228] Table 15-1 Prescription Information for Screening Disintegrant Types in 500mg Dosage Formulations

[0229] Note: "N / A" indicates that it is not added or not added.

[0230] Table 15-2 Information on the Selection of Disintegrant Types for 500mg Dosage Formulations

[0231] Note: "N / A" indicates that it is not added or not added.

[0232] Preparation method: Weigh the added materials into PE bags according to the prescriptions 15-1 and 15-2 in Table 15-1 and prescriptions 15-3 and 15-4 in Table 15-2. Mix the API with all the added excipients in the PE bag for 5 minutes, pass through a 40-mesh sieve, mix for another 5 minutes, add an appropriate amount of purified water until the material is in a state where it "can be formed into a ball when squeezed by hand, but can be easily dispersed when lightly pressed", pass through a 20-mesh sieve, and dry in a forced-air drying oven at 50°C to obtain dry granules. Pass through a 20-mesh sieve again, and mix the weighed added excipients with the granulated granules after passing through a 20-mesh sieve for 5 minutes. Use a die to compress and coat the granules to obtain the finished product.

[0233] Table 16 Dissolution data of formulations 15-1 to 15-4 tablets in pH 4.5 (acetate buffer solution) + 0.5% SDS medium

[0234] Tables 15-1 and 16 show that when the filler is a combination of lactose and microcrystalline cellulose, and the disintegrants are crospovidone and crospovidone sodium, respectively, the formulation using crospovidone sodium as the disintegrant has a faster dissolution rate compared to the formulation using crospovidone sodium as the disintegrant. Furthermore, in the determination of tablet disintegration time, it was found that the formulation using crospovidone sodium as the disintegrant had a shorter disintegration time than the formulation using crospovidone sodium as the disintegrant.

[0235] Tables 15-2 and 16 show that when the filler is a combination of mannitol and microcrystalline cellulose, and the disintegrants are sodium carboxymethyl starch and croscarmellose sodium, respectively, the formulation using croscarmellose sodium as the disintegrant has a faster dissolution rate, a relatively lower dissolution endpoint, and a smaller overall dissolution SD compared to the formulation using sodium carboxymethyl starch. Furthermore, in the determination of tablet disintegration time, it was found that the formulation using croscarmellose sodium as the disintegrant had a shorter disintegration time than the formulation using sodium carboxymethyl starch.

[0236] In summary, croscarmellose sodium has the best formulation effect as a disintegrant.

[0237] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0238] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A composition, characterized in that, The composition comprises a compound of formula (I) or a pharmaceutically acceptable salt or crystal form thereof as an active ingredient. Equation (I), The particle size of the active ingredient satisfies the following conditions: D V (90) ≤ 60 μm; or D V (90) ≤ 35 μm; or D V (90) ≤ 30 μm; or D V (90) ≤ 25 μm; or D V (90) ≤ 24 μm; or D V (90) ≤ 23 μm; or D V (90) ≤ 22 μm; or D V (90) ≤ 21 μm; Optionally, the particle size of the active ingredient satisfies the condition: D V (90) ≥ 5 μm.

2. The composition according to claim 1, characterized in that, The particle size of the active ingredient meets the following conditions: D V (50) ≤ 10 μm, or D V (50) ≤ 4 μm, or D V (50) ≤ 3.5 μm; Optionally, the particle size of the active ingredient satisfies the condition: D V (50) ≥ 2 μm.

3. The composition according to any one of claims 1-2, characterized in that, The X-ray powder diffraction pattern of the compound crystal form shown in formula (I) contains the following diffraction peaks at the 2θ angle: 10.35±0.2°, 10.56±0.2°, 13.39±0.2°, 15.68±0.2°, 15.82±0.2°, 20.42±0.2°, 20.84±0.2° and 21.71±0.2°; Optionally, the X-ray powder diffraction pattern of the crystal form includes the following diffraction peaks at the 2θ angle: 4.28±0.2°, 6.69±0.2°, 10.35±0.2°, 10.56±0.2°, 11.83±0.2°, 12.78±0.2°, 13.39±0.2°, 15.68±0.2°, 15.82±0.2°, 16.79±0.2°, 17.59±0.2°. 0.2°, 17.83±0.2°, 20.00±0.2°, 20.42±0.2°, 20.84±0.2°, 21.71±0.2°, 23.50±0.2°, 24.73±0.2°, 26.36±0.2°, 26.52±0.2°, 27.38±0.2°, 28.18±0.2°, 29.95±0.2° and 31.30±0.2°; Optionally, the X-ray powder diffraction pattern of the crystal form includes diffraction peaks at the following 2θ angles: 4.28±0.2°, 5.58±0.2°, 6.69±0.2°, 8.23±0.2°, 10.35±0.2°, 10.56±0.2°, 11.83±0.2°, 12.78±0.2°, 13.39±0.2°, 15.68±0.2°, 15.82±0.2°, 16.45±0.2°, 16.79±0.2°, and 17.59±0.2°. °, 17.83±0.2°, 18.93±0.2°, 20.00±0.2°, 20.42±0.2°, 20.84±0.2°, 21.71±0.2°, 21.99±0.2°, 23.17±0.2°, 23.50±0.2°, 23.78±0.2°, 24.73±0.2°, 25.71±0.2°, 26.36±0.2°, 26.52±0.2°, 27.38±0.2°, 28.18±0.2°, 29.95±0.2°, 31.30±0.2°, 33.17±0.2° and 34.80±0.2°.

4. The composition according to any one of claims 1-3, characterized in that, Based on the total weight of the composition, the mass fraction of the active ingredient is 25%-60%, 30%-55%, 35%-50%, 35%~45%, 36%~44%, 37%~43%, 38%~42%, 39%~42%, 40%~42%, 41%~42%, about 40%, about 41%, or about 42%.

5. The composition according to any one of claims 1-4, characterized in that, It further includes pharmaceutically acceptable excipients, said excipients including at least one of fillers, disintegrants, binders, flow aids and lubricants; Optionally, the filler comprises one or more selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch, sorbitol, dicalcium phosphate, starch, sucrose, and dextrin; Optionally, the filler includes lactose and one or more selected from microcrystalline cellulose, mannitol, pregelatinized starch, sorbitol, dicalcium phosphate, starch and sucrose; Optionally, the disintegrant includes one or more of crospovidone, low-substituted hydroxypropyl cellulose, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, dry starch, corn starch, pregelatinized starch, microcrystalline cellulose, sodium alginate, calcium carboxymethyl cellulose, and magnesium aluminum silicate. Optionally, the flow aid is one or a combination of colloidal silica, talc; Optionally, the lubricant is one or more of sodium stearate fumarate, magnesium stearate, stearic acid, glyceryl behenate, polyethylene glycol 6000, hydrogenated castor oil, and sodium lauryl sulfate. Optionally, the adhesive is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, starch paste, sodium carboxymethyl cellulose, ethyl cellulose, povidone, and gelatin.

6. The composition according to claim 5, characterized in that, The filler includes at least one of internal filler and external filler, optionally, the weight ratio of the internal filler and external filler is (5~15): 1, (6~13): 1, (7~12): 1, (8~9): 1, 11: 1, 9: 1, 8: 1 or 7: 1; Optionally, the disintegrant includes at least one of an exogenous disintegrant and an endogenous disintegrant; Optionally, the lubricant includes at least one of an external lubricant and an internal lubricant.

7. The composition according to any one of claims 4-6, characterized in that, Based on the total weight of the composition, the mass fraction of the active ingredient is 25%-60%, 30%-55%, 35%-50%, 35-45%, 36%-44%, 37%-43%, 38%-42%, 39%-42%, 40%-42%, or 41%-42%; Optionally, based on the total weight of the composition, the mass fraction of the filler is 30%~65%, 35%~60%, 40%~55%, 44%~50%, or 45%~50%; Optionally, based on the total weight of the composition, the mass fraction of the disintegrant is 4%~10%, 4%~8%, 5%~7%, 4%, 5%, 6%, 7%, 8% or 9%; Optionally, based on the total weight of the composition, the mass fraction of the gliding agent is 0.5%~3%, 0.5%~2.5%, 0.5%~2%, 0.5%~1.5%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5% or 3%; Optionally, based on the total weight of the composition, the mass fraction of the lubricant is 0.5%~5%, 0.5%~4%, 0.5%~3%, 0.5%~2%, 0.5%~1.5%, 0.5%, 1.0%, 1.5%, 2%, 3%, 4% or 5%; Optionally, based on the total weight of the composition, the mass fraction of the adhesive is 0.5%~7%, 0.5%~6.5%, 0.5%~6%, 0.5%~5.5%, 0.5%~5%, 0.5%~4.5%, 0.5%~3.0%, 0.5%~2.5%, 0.5%~2.0%, 0.5%~1.5%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5%, 5.5%, 6%, 6.5%, or 7%.

8. The composition according to claim 6 or 7, characterized in that, Based on the total weight of the composition, the mass fraction of the internal filler is 38%~45%, 39%~45%, 40%~45%, 42.33%, 43.83%, or 44.83%; optionally, based on the total weight of the composition, the mass fraction of the external filler is 3%~8%, 4%~6%, 4%, 5%, or 6%. Optionally, based on the total weight of the composition, the mass fraction of the internally added disintegrant is 2.5%~6.0%, 2.5%-4.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, or 6.0%; Optionally, the mass fraction of the added disintegrant is 2% to 4%, 2%, 2.5%, 3.0%, 3.5%, or 4% based on the total weight of the composition.

9. The composition according to any one of claims 5-8, characterized in that, The filler includes internal fillers and external fillers, wherein the internal filler is selected from at least one of microcrystalline cellulose, lactose, mannitol, and pregelatinized starch; Optionally, the added filler includes lactose and microcrystalline cellulose, lactose and pregelatinized starch, or mannitol and microcrystalline cellulose; Optionally, the added filler includes lactose and microcrystalline cellulose, wherein the weight ratio of lactose to microcrystalline cellulose is 1:1 to 8:1, 2:1 to 7:1, 3:1 to 7:1, 3:1, 4:1, 5:1, 6:1 or 7:

1. Optionally, the internal filler includes mannitol and microcrystalline cellulose, wherein the weight ratio of mannitol to microcrystalline cellulose is 1:1 to 6:1, 1:1 to 5:1, 1:1 to 4:1, 1:1 to 3:1, 1:1 to 2:1 or 1:1 to 1.5:1; Optionally, the added filler includes lactose and pregelatinized starch, wherein the weight ratio of lactose to pregelatinized starch is 1:1 to 5:1 or 2:1 to 5:1; Optionally, the added filler includes microcrystalline cellulose.

10. The composition according to any one of claims 5-9, characterized in that, The disintegrant includes internally added disintegrants and externally added disintegrants; Optionally, the internal or external disintegrant is croscarmellose sodium; Optionally, the ratio of the internally added disintegrant to the externally added disintegrant is 0.7:1 to 3:1, 0.75:1 to 2:1, 0.75:1, 0.8:1, 1:1, 1.3:1, 1.5:1 or 2:1; Optionally, the lubricant includes external lubricants and internal lubricants; Optionally, the lubricant is an external lubricant; Optionally, the added lubricant is magnesium stearate or sodium stearate fumarate; Optionally, the internal lubricant is magnesium stearate or sodium stearate fumarate.

11. The composition according to any one of claims 5-10, characterized in that, In the composition, the mass ratio of the active ingredient, the filler, the binder, the disintegrant, the flow aid, and the lubricant is (35~45):(45~50):(0.5~4.5):(4~10):(0.5~1.5):(0.5~2); optionally, the mass ratio of the active ingredient, the filler, the binder, the disintegrant, the flow aid, and the lubricant is 42:49:1:6:1:1.5 or 42:49:1:6:1:1.

1.

12. The composition according to any one of claims 1-11, characterized in that, The composition is in the form of an oral preparation; Optionally, the dosage form of the composition is a solid oral dosage form; Optionally, the dosage form of the composition is a capsule, tablet, granule, pill, powder, or sustained-release formulation.

13. The composition according to any one of claims 1-12, characterized in that, The dosage form of the composition is capsules, tablets, granules or pills; Optionally, the capsules, tablets, granules, or pills are prepared by dry granulation or wet granulation.

14. The composition according to claim 13, characterized in that, The tablets are single-dose or multi-dose formulations; optionally, the tablets are 50 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg formulations. Preferably, the tablet is a 300 mg formulation.

15. The composition according to claim 14, characterized in that, The tablet contains fillers including internal fillers and external fillers. The internal fillers include microcrystalline cellulose and lactose, and the external fillers include microcrystalline cellulose. Preferably, the mass ratio of microcrystalline cellulose to lactose in the added filler is 1:3 to 1:7; Preferably, the disintegrant is croscarmellose sodium; Preferably, the flow aid is colloidal silica; Preferably, the lubricant is sodium stearate fumarate; Preferably, the adhesive is hydroxypropyl methylcellulose.

16. A method for preparing tablets, characterized in that, include: (1) Premix the active ingredients with the added materials; (2) The premixed product is subjected to wet granulation; (3) The wet granulation product is dried; (4) The dried product is mixed with the added materials; (5) The total mixture product is compressed into tablets to obtain the tablets; The active ingredient includes the compound represented by formula (I) or its pharmaceutically acceptable salt or crystal form. Equation (I), The particle size of the active ingredient satisfies at least one of the following conditions: 2 μm ≤ D V (50) ≤ 10 µm or 5 µm ≤ D V (90) ≤ 60 μm; Preferably, after tableting, the process further includes coating the uncompressed tablets obtained after tableting; Optionally, the added material includes, but is not limited to, added fillers, added adhesives, added disintegrants, added lubricants, or any combination thereof; Optionally, the added materials include, but are not limited to, added fillers, added disintegrants, flow aids, added lubricants, or any combination thereof; Optionally, the filler, binder, disintegrant, filler, flow aid, and lubricant each have the definition as described in any one of claims 5-15.

17. The method according to claim 16, characterized in that, The process of mixing the dried product with the added materials includes: The dried product and the added material are then subjected to a granulation process. The granulation product is subjected to the aforementioned total mixing treatment; Optionally, the total mixing treatment of the dried product with the additives includes: The dried product is then subjected to granulation treatment. The granulated product is mixed with other additives besides the added lubricant. The mixed products are then mixed with an added lubricant.

18. A method for preparing tablets, characterized in that, include: (1) The active ingredient and the first added material are subjected to granulation and premixing treatment in sequence; (2) The first premixed product is subjected to a second premixed treatment with the second added material; (2) The second premixed product is subjected to dry granulation; (4) The dry granulation product is subjected to a third premixing treatment with the first additive; (5) The third premixed product is mixed with the second additive. (6) The total mixture product is compressed into tablets to obtain the tablets; The active ingredient includes the compound represented by formula (I) or its pharmaceutically acceptable salt or crystal form. Equation (I), The particle size of the active ingredient satisfies at least one of the following conditions: 2 μm ≤ D V (50) ≤ 10 µm or 5 µm ≤ D V (90) ≤ 60 μm; Preferably, after tableting, the process further includes coating the uncompressed tablets obtained after tableting; Optionally, the first added material includes, but is not limited to, added fillers, added binders, added disintegrants, or any combination thereof; Optionally, the second added material includes, but is not limited to, an added lubricant; Optionally, the first additive material includes, but is not limited to, additive fillers, additive disintegrants, flow aids, or any combination thereof; Optionally, the second additive material includes, but is not limited to, an additive lubricant; Optionally, the filler, binder, disintegrant, filler, flow aid, and lubricant each have the definition as described in any one of claims 5-15.

19. A tablet, characterized in that, It is prepared by the method described in claim 16 or 17.

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