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 thereof as an active ingredient. The composition or capsule can effectively treat hepatitis C, and the preparation process is simple, safe, stable, and has rapid dissolution.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and more specifically, to compositions for treating hepatitis C and methods for preparing the same. Background Technology

[0002] 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, HCV infection is often asymptomatic, 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.

[0003] 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.

[0004] 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%).

[0005] Therefore, developing more and more effective drugs for the treatment of hepatitis C as soon as possible is the unremitting goal of drug researchers.

[0006] Example 5 of Chinese Patent CN105968101A discloses a compound represented by the following formula (I), which, as a drug-resistant pangenotypic HCV inhibitor, has a significant effect on the treatment of hepatitis C virus (HCV) infection or hepatitis C disease.

[0007] Formula (I). Summary of the Invention

[0008] Based on the compound shown in Formula (I), the inventors of this application have developed a pharmaceutical formulation with the compound shown in Formula (I) or its pharmaceutically acceptable salt as the active ingredient through experiments. The compound shown in Formula (I) or its pharmaceutically acceptable salt has low solubility. During the formulation development process, the inventors controlled the particle size of the active pharmaceutical ingredient of the compound shown in Formula (I) or its pharmaceutically acceptable salt (D50 ≤ 15 μm, D90 ≤ 55 μm) to prepare a composition with good dissolution rate. This composition overcomes the rate-limiting step of dissolution and belongs to the category of oral immediate-release formulations. Especially when prepared as a capsule formulation, the preparation process is simple and involves fewer production steps, which can greatly reduce the production cost of new drugs and accelerate the research and development progress of new drugs.

[0009] Based on this, in a first aspect, the present invention provides a composition. According to embodiments of the present invention, the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Formula (I), The particle size of the active ingredient satisfies at least one of the following conditions: D 50 ≤ 15 μm, D 90 ≤ 55μm. The inventors discovered that when the particle size of the active ingredient is within D... 50 ≤ 15 μm, D 90 Within the ≤ 55 μm range, the compositions according to the embodiments of the invention dissolve rapidly. The compositions according to the embodiments of the invention are effective in treating hepatitis C, and are highly safe and have a rapid onset of action.

[0010] According to embodiments of the present invention, the particle size of the active ingredient satisfies at least one of the following conditions: 3 μm ≤ D 50 ≤ 15 μm, 6 μm ≤ D 90 ≤ 55μm.

[0011] According to an embodiment of the present invention, the particle size of the active ingredient satisfies the following condition: D 50 ≤ 14μm, D 90 ≤ 51μm; or D 50 ≤ 11μm, D 90 ≤ 30μm. The inventors discovered that in the direct powder filling granulation process, the particle size of the active ingredient satisfies D 50 ≤ 14μm, D 90 Under conditions ≤ 51 μm, the resulting formulation exhibits a superior dissolution rate; in wet granulation and filling processes, the particle size of the active ingredient satisfies D 50 ≤ 11μm, D 90 The dissolution rate of the resulting formulation is better when the particle size is ≤ 30 μm.

[0012] According to an embodiment of the present invention, the particle size of the active ingredient satisfies the following condition: 3 μm ≤ D 50 ≤ 14μm, 6μm≤D 90 ≤ 51μm; or 6 μm≤D 50 ≤ 11μm, 10 μm≤D 90 ≤ 30μm.

[0013] According to an embodiment of the present invention, the particle size of the active ingredient further satisfies: D 10 ≤ 4 μm, D is preferred 10 ≤3 μm.

[0014] According to an embodiment of the present invention, the particle size of the active ingredient further satisfies: 1 μm ≤ D 10 ≤ 4 μm or 2 μm ≤ D 10 ≤ 3 μm.

[0015] According to embodiments of the present invention, the above composition may further include at least one of the following additional technical features: According to embodiments of the present invention, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt.

[0016] According to embodiments of the present invention, the inorganic acid salt or organic acid salt is a single salt or a disalt.

[0017] According to a specific embodiment of the present invention, the inorganic acid salt is selected from hydrohalides, halogen-series oxygen-containing inorganic acid salts, carbon-series oxygen-containing inorganic acid salts, nitrogen-series oxygen-containing inorganic acid salts, boron-series oxygen-containing inorganic acid salts, silicon-series oxygen-containing inorganic acid salts, phosphorus-series oxygen-containing inorganic acid salts, or sulfur-series inorganic acid salts; the organic acid salt is selected from carboxylates, sulfonates, sulfinates, or thiocarboxylates.

[0018] According to another specific embodiment of the present invention, the inorganic acid salt is selected from hydrochloride, sulfate, hydrogen sulfate, nitrate, borate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, perchlorate, persulfate, hemisulfate, disulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, or metaphosphate; 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(hydroxynaphthyl)ate, and salicylate. Galactobionate, glucono-disulfonate, mandelate, gluconate, 1,2-ethanedisulfonate, 2-naphthalenesulfonate, oxalate, trifluoroacetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethylsulfonate, glyceryl phosphate, heptaate, hexanoate, 2-hydroxy-ethanesulfonate, laurate, lauryl sulfate, nicotinate, oleate, palmitate, pyrate, pectate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, undecanoate, or pentanoate.

[0019] According to an embodiment of the present invention, the inorganic acid salt is a phosphate.

[0020] According to an embodiment of the present invention, the inorganic acid salt is a diphosphate.

[0021] According to an embodiment of the present invention, the pharmaceutically acceptable salt is a phosphate, and the phosphate of the compound shown in formula (I) has the structure shown in formula (II). Equation (II).

[0022] During the development of this pharmaceutical formulation, the inventors discovered that when the pharmaceutically acceptable salt is selected from phosphates, the composition of this invention, in addition to having greater solubility, has a more stable dissolution rate and is more suitable for drug preparation. This discovery can further accelerate the research and development of new drugs.

[0023] According to embodiments of the present invention, based on the total weight of the composition, the pharmaceutically acceptable mass fraction of the salt of the compound represented by formula (I) or formula (I) is 10%~45%, or 11%~44%, or 12%~43%, or 13%~42%, or 11%~42%, or 12%~39%, or 13%~38%, or 14%~37%, or 15%~36%, 16%~35%, or 17%~34%, or 18%~33%, or 19%~32%, or 20%~31%, or 21%~30%, 22%~29%, 23%~28%, or 24%~27%, or 25%~26%, or about 13%, or about 30%. The inventors have found that the mass fraction of the compound represented by formula (II) in the composition of the present invention within the above range has good flowability, increasing the feasibility of production and effectively ensuring the stability, efficacy, and safety of the composition in treating hepatitis C.

[0024] According to embodiments of the present invention, the composition further comprises a pharmaceutically acceptable excipient, said excipient comprising at least one selected from fillers, disintegrants, flow aids and lubricants, and optionally includes a binder.

[0025] According to an embodiment of the present invention, the filler comprises one or more selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose.

[0026] According to embodiments of the present invention, the filler includes one or more selected from microcrystalline cellulose, mannitol, and lactose. The inventors have found that in direct powder filling processes, using lactose as a filler results in a better dissolution rate of the composition; and in wet granulation filling processes, using a combination of lactose and microcrystalline cellulose as fillers results in a better dissolution rate of the composition.

[0027] According to embodiments of the present invention, the filler includes lactose Granulac 200 and one or more selected from microcrystalline cellulose, mannitol, lactose Flowlac 100, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose. The inventors have found that using lactose Granulac 200 and one or more other fillers as fillers results in a superior dissolution rate of the composition.

[0028] According to embodiments of the present invention, the filler includes one or more of lactose Granulac 200, lactose Flowlac 100, and microcrystalline cellulose. The inventors have found that using a combination of lactose Flowlac 100 and lactose Granulac 200 as fillers results in a better dissolution rate in direct powder filling processes, while using lactose Granulac 200 and microcrystalline cellulose as fillers results in a better dissolution rate in wet granulation filling processes.

[0029] According to an embodiment of the present invention, the microcrystalline cellulose is microcrystalline cellulose 101.

[0030] According to embodiments of the present invention, the disintegrant includes one or more of crospovidone, low-substituted hydroxypropyl cellulose, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch. The inventors have found that using one or more of crospovidone, low-substituted hydroxypropyl cellulose, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch as the disintegrant results in a superior dissolution rate of the composition.

[0031] According to embodiments of the present invention, the disintegrant is crospovidone. The inventors have discovered that, in direct powder filling processes, crospovidone, as a disintegrant, results in a superior dissolution rate of the composition.

[0032] According to embodiments of the present invention, the disintegrant is cross-linked sodium carboxymethyl cellulose or sodium carboxymethyl starch. The inventors have found that in wet granulation and filling processes, using cross-linked sodium carboxymethyl cellulose or sodium carboxymethyl starch as a disintegrant results in a better dissolution rate and a higher dissolution plateau in the composition, especially sodium carboxymethyl starch, which exhibits a superior dissolution rate.

[0033] According to an embodiment of the present invention, the cross-linked polyvinylpyrrolidone is cross-linked polyvinylpyrrolidone XL.

[0034] According to an embodiment of the present invention, the sodium carboxymethyl starch is sodium carboxymethyl starch (DST).

[0035] According to an embodiment of the present invention, the flow aid is colloidal silica or talc.

[0036] According to an embodiment of the present invention, the colloidal silica is colloidal silica (anhydrous) A200.

[0037] According to an embodiment of the present invention, the lubricant is magnesium stearate or glyceryl behenate.

[0038] According to an embodiment of the present invention, the lubricant is magnesium stearate. The inventors have discovered that using magnesium stearate as a lubricant results in a better dissolution rate and improved fluidity of the composition.

[0039] According to an embodiment of the present invention, the magnesium stearate is magnesium stearate MF-2-V.

[0040] According to an embodiment of the present invention, the adhesive is hydroxypropyl methylcellulose or hydroxypropyl cellulose.

[0041] According to an embodiment of the present invention, the adhesive is hydroxypropyl methylcellulose. The inventors have discovered that using hydroxypropyl methylcellulose as the adhesive results in a better dissolution rate of the composition.

[0042] According to an embodiment of the present invention, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5LV.

[0043] According to an embodiment of the present invention, the mass fraction of the active ingredient is 10-35% based on the total weight of the composition.

[0044] According to embodiments of the present invention, the filler has a mass fraction of 50-90% based on the total weight of the composition. This further improves the dissolution rate of the formulation.

[0045] Optionally, the mass ratio of the lactose Granulac 200 and one or more selected from microcrystalline cellulose, mannitol, lactose Flowlac 100, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose is 1:3 to 3:1.

[0046] According to embodiments of the present invention, the disintegrant has a mass fraction of 2% to 6% based on the total weight of the composition. This further improves the dissolution rate of the formulation.

[0047] According to an embodiment of the present invention, the mass fraction of the gliding agent is 0.5% to 1.5% based on the total weight of the composition. This further improves the dissolution rate of the formulation.

[0048] According to embodiments of the present invention, the mass fraction of the lubricant is 0.5% to 3% based on the total weight of the composition. The inventors have found that too low a dosage of lubricant can lead to problems such as rod sticking, unstable dosage, and uneven content during mass production, while too high a dosage can result in excessive lubrication of particles during mass production, and the hydrophobicity of the lubricant can significantly slow down the dissolution rate. Therefore, a lubricant mass fraction within the range of 0.5% to 3% can further improve the stability and uniformity during mass production, and further improve the dissolution rate of the formulation.

[0049] According to embodiments of the present invention, the mass fraction of the binder is 0% to 3% based on the total weight of the composition. For example, in a direct powder filling process, no binder may be added; in a wet granulation filling process, the mass fraction of the binder is 0.5% to 3% based on the total weight of the composition.

[0050] According to an embodiment of the present invention, in the powder direct filling process, the excipients include fillers, disintegrants, flow aids and lubricants.

[0051] According to an embodiment of the present invention, in the powder direct filling process, the mass fraction of the filler is 55% to 90%, preferably 65% ​​to 85%, based on the total weight of the composition.

[0052] According to an embodiment of the present invention, in the direct powder filling process, the mass ratio of lactose Granulac 200 to lactose Flowlac 100 is 1:3.

[0053] According to an embodiment of the present invention, in the direct powder filling process, the mass fraction of the disintegrant is 2% to 4%, preferably 3%, based on the total weight of the composition.

[0054] According to an embodiment of the present invention, in the powder direct filling process, the mass fraction of the flow aid is 0.5% to 1.5%, preferably 1%, based on the total weight of the composition.

[0055] According to an embodiment of the present invention, in the powder direct filling process, the mass fraction of the lubricant is 0.5% to 1%, preferably 0.6% to 1%, and more preferably 0.8%, based on the total weight of the composition.

[0056] This can further improve the dissolution rate of formulations prepared in the direct powder filling process.

[0057] According to an embodiment of the present invention, in the wet granulation and filling process, the excipients include fillers, disintegrants, flow aids, lubricants, and binders.

[0058] According to an embodiment of the present invention, in the wet granulation and filling process, the mass fraction of the filler is 55% to 65% based on the total weight of the composition.

[0059] According to an embodiment of the present invention, in the wet granulation and filling process, the mass ratio of lactose Granulac 200 to microcrystalline cellulose is 1.4:1 to 3:1, preferably 1.4:1 to 2.5:1, and more preferably 2:1.

[0060] According to an embodiment of the present invention, the microcrystalline cellulose is microcrystalline cellulose 101.

[0061] According to an embodiment of the present invention, the mass fraction of the disintegrant is 4% to 6%, preferably 5% to 6%, and more preferably 5%, based on the total weight of the composition.

[0062] According to an embodiment of the present invention, the mass fraction of the gliding agent is 0.5% to 1.5%, preferably 1%, based on the total weight of the composition.

[0063] According to an embodiment of the present invention, the mass fraction of the lubricant is 1% to 2.5%, preferably 1.5%, based on the total weight of the composition.

[0064] According to an embodiment of the present invention, the adhesive has a mass fraction of 0.5% to 3%, preferably 1.5%, based on the total weight of the composition.

[0065] This can further improve the dissolution rate of formulations prepared by wet granulation and filling processes.

[0066] According to an embodiment of the present invention, in the composition prepared by the direct powder filling process, the mass ratio of the active ingredient, the filler, the disintegrant, the flow aid, and the lubricant is (10~35):(55~90):(2~4):(0.5~1.5):(0.5~1). This further improves the dissolution rate of the composition prepared by the direct powder filling process.

[0067] According to embodiments of the present invention, in the composition prepared by the direct powder filling process, the mass ratio of the active ingredient, the filler, the disintegrant, the flow aid, and the lubricant is (13~14):(81~82):3:1:(0.5~1), for example, 13.6:81.6:3:1:0.8. This further improves the dissolution rate of the composition prepared by the direct powder filling process.

[0068] According to embodiments of the present invention, in the composition prepared by the direct powder filling process, the mass ratio of the active ingredient, the filler, the disintegrant, the flow aid, and the lubricant is (29~30):(65~66):3:1:(0.5~1), for example 29.36:65.87:3:1:0.8. This further improves the dissolution rate of the composition prepared by the direct powder filling process.

[0069] According to an embodiment of the present invention, in the composition prepared by the wet granulation and filling process, the mass ratio of the active ingredient, the filler, the binder, the disintegrant, the flow aid, and the lubricant is (10~35):(55~65):(0.5~3):(4~6):(0.5~1.5):(1~2.5). This further improves the dissolution rate of the composition prepared by the wet granulation and filling process.

[0070] According to embodiments of the present invention, in the composition prepared by the wet granulation and filling process, the mass ratio of the active ingredient, the filler, the binder, the disintegrant, the flow aid, and the lubricant is (30~31):(60~61):1.5:5:1:1.5, for example, 30.76:60.24:1.5:5:1:1.5. This further improves the dissolution rate of the composition prepared by the wet granulation and filling process.

[0071] According to an embodiment of the present invention, the dosage form of the composition is an oral formulation.

[0072] According to an embodiment of the present invention, the dosage form of the composition is a solid oral dosage form.

[0073] According to embodiments of the present invention, the dosage form of the composition is capsule, tablet, pellet, powder, sustained-release agent, aqueous suspension, ointment, paste, emulsion, lotion, gel, solution, spray, inhaler, or patch.

[0074] In a second aspect, the present invention provides a capsule filled with contents comprising the composition described above. The capsule according to embodiments of the present invention can be used for the effective treatment of hepatitis C, and exhibits good stability and rapid dissolution.

[0075] In a third aspect, the present invention provides a capsule filled with contents. According to embodiments of the invention, the contents comprise: a compound of formula (II) and a filler, a disintegrant, a flow aid, a lubricant, and optionally a binder, wherein the compound of formula (II) comprises 10% to 45% by mass based on the total weight of the contents, and the particle size of the compound of formula (II) satisfies at least one of the following conditions: D 50 ≤ 15 μm, D 90 ≤ 55μm, Equation (II).

[0076] The capsules according to embodiments of the present invention can be used to effectively treat hepatitis C, and have good stability, rapid dissolution, and high safety.

[0077] According to embodiments of the present invention, the capsule may further include at least one of the following additional technical features: According to an embodiment of the present invention, in the capsule described in the third aspect, the compound represented by formula (II) is used in an amount of 10 to 35 parts by weight, the filler is used in an amount of 55 to 90 parts by weight, the disintegrant is used in an amount of 2 to 4 parts by weight, the gliding agent is used in an amount of 0.5 to 1.5 parts by weight, and the lubricant is used in an amount of 0.5 to 1 part by weight.

[0078] According to an embodiment of the present invention, in the capsule described in the third aspect, the compound represented by formula (II) is used in an amount of 10 to 35 parts by weight, the filler is used in an amount of 55 to 65 parts by weight, the binder is used in an amount of 0.5 to 3 parts by weight, the disintegrant is used in an amount of 4 to 6 parts by weight, the gliding agent is used in an amount of 0.5 to 1.5 parts by weight, and the lubricant is used in an amount of 1 to 2.5 parts by weight.

[0079] According to a specific embodiment of the present invention, in the capsule described in the third aspect, the filler comprises one or more selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose.

[0080] According to another specific embodiment of the present invention, in the capsule described in the third aspect, the filler comprises lactose Granulac 200 and one or more selected from microcrystalline cellulose, mannitol, lactose Flowlac 100, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose.

[0081] According to another specific embodiment of the present invention, in the capsule described in the third aspect, preferably, the filler comprises one or more of lactose Granulac 200, lactose Flowlac 100, and microcrystalline cellulose.

[0082] According to another specific embodiment of the present invention, in the capsule described in the third aspect, preferably, the filler comprises one or more of lactose Granulac 200, lactose Flowlac 100, and microcrystalline cellulose 101.

[0083] According to another specific embodiment of the present invention, in the capsule described in the third aspect, the disintegrant includes one or more of crospovidone, low-substituted hydroxypropyl cellulose, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

[0084] According to yet another specific embodiment of the present invention, in the capsule described in the third aspect, the disintegrant is croscarmellose sodium.

[0085] According to yet another specific embodiment of the present invention, in the capsule described in the third aspect, the disintegrant is sodium carboxymethyl starch.

[0086] According to another specific embodiment of the present invention, in the capsule described in the third aspect, the disintegrant is sodium carboxymethyl starch (DST).

[0087] According to another specific embodiment of the present invention, in the capsule described in the third aspect, the flow aid is colloidal silica or talc.

[0088] According to another specific embodiment of the present invention, in the capsule described in the third aspect, the gliding agent is colloidal silica (anhydrous) A200.

[0089] According to yet another embodiment of the invention, in the capsule described in the third aspect, the lubricant is magnesium stearate. According to yet another embodiment of the invention, in the capsule described in the third aspect, the lubricant is magnesium stearate MF-2V.

[0090] According to yet another specific embodiment of the invention, in the capsule described in the third aspect, the lubricant is glyceryl behenate.

[0091] According to yet another specific embodiment of the present invention, in the capsule described in the third aspect, the adhesive is hydroxypropyl methylcellulose.

[0092] According to another specific embodiment of the present invention, in the capsule described in the third aspect, the adhesive is hydroxypropyl methylcellulose E5LV.

[0093] According to another specific embodiment of the present invention, in the capsule described in the third aspect, the amount of lactose Granulac 200 used is 10 to 45 parts by weight.

[0094] According to another specific embodiment of the present invention, in the capsule described in the third aspect, the amount of one or more selected from microcrystalline cellulose, mannitol, lactose Flowlac 100, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose is 10 to 70 parts by weight.

[0095] According to another specific embodiment of the present invention, the filler contains lactose Granulac 200 and one or more selected from microcrystalline cellulose, mannitol, lactose Flowlac 100, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose in a mass ratio of 1:3 to 3:1.

[0096] According to another specific embodiment of the present invention, the microcrystalline cellulose is microcrystalline cellulose 101.

[0097] According to a specific embodiment of the present invention, the capsule is a single-dose formulation or a multi-dose formulation. A single-dose formulation means that the capsule is suitable for administering one capsule once daily to the patient to achieve the desired therapeutic effect; a multi-dose formulation means that the capsule is suitable for administering multiple capsules daily to the patient to achieve the desired therapeutic effect.

[0098] According to specific embodiments of the present invention, the capsule is a 10mg, 50mg, or 100mg formulation. It should be noted that, in this application, a 10mg capsule means that the mass of the compound represented by formula (I) in the capsule is approximately 10mg, with a fluctuation of no more than 5mg from approximately 10mg; a 50mg capsule means that the mass of the compound represented by formula (I) in the capsule is approximately 50mg, with a fluctuation of no more than 5mg from approximately 50mg; and a 100mg capsule means that the mass of the compound represented by formula (I) in the capsule is approximately 100mg, with a fluctuation of no more than 5mg from approximately 100mg.

[0099] According to another specific embodiment of the present invention, the capsule is a 100mg formulation.

[0100] In a fourth aspect, the present invention provides a capsule filled with contents. According to an embodiment of the invention, the capsule is a 10 mg formulation, the contents comprising 10-15 parts by weight of the compound of formula (II), 70-85 parts by weight of the filler, 2-4 parts by weight of the disintegrant, 0.5-1.5 parts by weight of the gliding agent, and 0.5-1 parts by weight of the lubricant, wherein the particle size of the compound of formula (II) satisfies at least one of the following conditions: D 50 ≤ 14μm, D 90 ≤ 51μm, Equation (II).

[0101] According to a specific embodiment of the present invention, in the capsule described in the fourth aspect, the capsule is a 10 mg formulation, the contents comprising 13-14 parts by weight of the compound represented by formula (II), 81-82 parts by weight of the filler, 3 parts by weight of the disintegrant, 1 part by weight of the gliding agent, and 0.5-1 part by weight of the lubricant, wherein the particle size of the compound represented by formula (II) satisfies at least one of the following conditions: D 50 ≤ 14μm, D 90 ≤ 51μm, Equation (II).

[0102] The capsules according to embodiments of the present invention are used to effectively treat hepatitis C, and have good stability, rapid dissolution, and high safety.

[0103] In a fifth aspect, the present invention provides a capsule filled with contents. According to embodiments of the invention, the capsule is a 50 mg or 100 mg formulation, the contents comprising 25-30 parts by weight of the compound of formula (II), 55-80 parts by weight of the filler, 2-4 parts by weight of the disintegrant, 0.5-1.5 parts by weight of the gliding agent, and 0.5-1 parts by weight of the lubricant, wherein the particle size of the compound of formula (II) satisfies at least one of the following conditions: D 50 ≤ 14μm, D 90 ≤ 51μm, Equation (II).

[0104] According to a specific embodiment of the present invention, in the capsule described in the fifth aspect, the capsule is a 50 mg formulation or a 100 mg formulation, the contents comprising 29-30 parts by weight of the compound represented by formula (II), 65-66 parts by weight of the filler, 3 parts by weight of the disintegrant, 1 part by weight of the gliding agent, and 0.5-1 part by weight of the lubricant, wherein the particle size of the compound represented by formula (II) satisfies at least one of the following conditions: D 50 ≤14μm, D 90 ≤ 51μm, Equation (II).

[0105] The capsules according to embodiments of the present invention are used to effectively treat hepatitis C, and have good stability, rapid dissolution, and high safety.

[0106] According to specific embodiments of the present invention, in the capsules described in the fourth and fifth aspects of the present invention, the filler includes lactose Granulac 200 and lactose Flowlac 100.

[0107] According to specific embodiments of the present invention, in the capsules described in the fourth and fifth aspects of the present invention, the mass ratio of lactose Granulac 200 to lactose Flowlac 100 is 1:3.

[0108] According to specific embodiments of the present invention, in the capsules described in the fourth and fifth aspects of the present invention, the disintegrant is crospovidone.

[0109] According to specific embodiments of the present invention, in the capsules described in the fourth and fifth aspects of the present invention, the disintegrant is crospovidone XL.

[0110] According to specific embodiments of the present invention, in the capsules described in the fourth and fifth aspects of the present invention, the flow aid is colloidal silica.

[0111] According to specific embodiments of the present invention, in the capsules described in the fourth and fifth aspects of the present invention, the gliding agent is colloidal silica (anhydrous) A200.

[0112] According to specific embodiments of the present invention, in the capsules described in the fourth and fifth aspects of the present invention, the lubricant is magnesium stearate.

[0113] According to specific embodiments of the present invention, in the capsules described in the fourth and fifth aspects of the present invention, the lubricant is magnesium stearate MF-2V.

[0114] In a sixth aspect, the present invention provides a capsule filled with contents. According to an embodiment of the invention, the capsule is a 100mg formulation, the contents comprising 30-35 parts by weight of the compound of formula (II), 60-65 parts by weight of a filler, 0.5-3 parts by weight of a binder, 4-6 parts by weight of a disintegrant, 0.5-1 parts by weight of a gliding agent, and 1-2.5 parts by weight of a lubricant, wherein the particle size of the compound of formula (II) satisfies at least one of the following conditions: D 50 ≤ 11μm, D 90 ≤ 30μm, Equation (II).

[0115] According to a specific embodiment of the present invention, in the capsule described in the sixth aspect, the capsule is a 100mg formulation, the contents comprising 30-31 parts by weight of the compound represented by formula (II), 60-61 parts by weight of the filler, 1.5 parts by weight of the binder, 5 parts by weight of the disintegrant, 1 part by weight of the gliding agent, and 1.5 parts by weight of the lubricant, wherein the particle size of the compound represented by formula (II) satisfies at least one of the following conditions: D 50 ≤ 11μm, D 90 ≤ 30μm Equation (II).

[0116] The capsules according to embodiments of the present invention have high stability in terms of dosage, can be used to effectively treat hepatitis C, and have good stability, rapid dissolution, and high safety.

[0117] According to a specific embodiment of the present invention, in the capsule of the sixth aspect of the present invention, the filler comprises lactose Granulac 200 and microcrystalline cellulose.

[0118] According to a specific embodiment of the present invention, in the capsule described in the sixth aspect of the present invention, the mass ratio of lactose Granulac 200 to microcrystalline cellulose is 1.4:1 to 3:1, preferably 2:1.

[0119] According to a specific embodiment of the present invention, in the capsule described in the sixth aspect of the present invention, the microcrystalline cellulose is microcrystalline cellulose 101.

[0120] According to a specific embodiment of the present invention, in the capsule described in the sixth aspect of the present invention, the disintegrant is sodium carboxymethyl starch.

[0121] According to a specific embodiment of the present invention, in the capsule of the sixth aspect of the present invention, the disintegrant is sodium carboxymethyl starch (DST).

[0122] According to a specific embodiment of the present invention, in the capsule described in the sixth aspect of the present invention, the flow aid is colloidal silica.

[0123] According to a specific embodiment of the present invention, in the capsule described in the sixth aspect of the present invention, the gliding agent is colloidal silica (anhydrous) A200.

[0124] According to a specific embodiment of the present invention, in the capsule described in the sixth aspect of the present invention, the lubricant is magnesium stearate.

[0125] According to a specific embodiment of the present invention, in the capsule described in the sixth aspect of the present invention, the lubricant is magnesium stearate MF-2-V.

[0126] In a seventh aspect, the present invention provides a method for preparing capsules. According to an embodiment of the present invention, the method includes: (1) premixing an active ingredient with a filler, a disintegrant, and a flow aid to obtain a first mixture; (2) second mixing the first mixture with a lubricant to obtain a second mixture; and (3) capsule filling the second mixture to obtain the capsule, wherein the particle size of the active ingredient satisfies at least one of the following conditions: D 50 ≤ 14μm, D 90 ≤ 51 μm. The capsules prepared by the method according to embodiments of the present invention can be used to effectively treat hepatitis C, and have good stability, rapid dissolution, and high safety.

[0127] In an eighth aspect of the invention, a method for preparing capsules is provided. According to an embodiment of the invention, the method includes: (1) subjecting an active ingredient to a first premixing treatment with a filler, a binder, and a first disintegrant; (2) subjecting the first premixing product to wet granulation; (3) subjecting the wet granulation product to drying treatment and a second premixing treatment with a second disintegrant and a flow aid; (4) subjecting the second premixing mixture to a total mixing treatment with a lubricant; and (5) subjecting the total mixing product to capsule filling treatment to obtain the capsules; wherein the particle size of the active ingredient satisfies at least one of the following conditions: D 50 ≤ 11μm, D 90 ≤ 30μm. The method according to embodiments of the present invention exhibits no sticking during the filling process, stable fill volume, and the prepared capsules can be used for the effective treatment of hepatitis C, demonstrating good stability, rapid dissolution, and high safety. Attached Figure Description

[0128] Figure 1 The results are for the dissolution rate of 10mg capsules according to Example 1 of the present invention; Figure 2The results are for the dissolution rate of the 50mg capsules according to Example 1 of the present invention; Figure 3 The results are the dissolution rate of 100mg capsules according to Example 1 of the present invention; Figure 4 The results are for the dissolution rate of 100mg capsules according to Example 2 of the present invention. 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] "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.

[0133] 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.

[0134] 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.

[0135] 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, powders, oral powders, pills, capsules, and / or granules. In some embodiments, a solid oral dosage form is a capsule.

[0136] 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 Granulac 200 and one or more selected from microcrystalline cellulose, mannitol, lactose Flowlac 100, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose. In some embodiments, the microcrystalline cellulose is microcrystalline cellulose 101.

[0137] The term "disintegrant" includes, but is not limited to, corn starch, CMC-Ca, CMC-Na, crospovidone, low-substituted hydroxypropyl cellulose, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, microcrystalline cellulose, crospovidone polyvinylpyrrolidone (PVP) (e.g., as known and available by trademark from ISP or XL), 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.

[0138] 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. In some embodiments of the present invention, the flow aid is colloidal silica (anhydrous) A200.

[0139] The term "lubricant" includes, but is not limited to: magnesium stearate, aluminum stearate or calcium stearate, PEG 4000-8000, talc, sodium benzoate, glyceryl monostearate (e.g., having a molecular weight of 200 to 800 Daltons, such as glyceryl monostearate (e.g., Danisco, UK)), glyceryl dibenzene (e.g., Compritol ATO888™, Gattefossé France), glyceryl palmitate stearate (e.g., Precirol™, Gattefossé France), polyethylene glycol (PEG, BASF), hydrogenated cottonseed oil (Lubitrab™, Edward Mendell Ltd.), and castor oil (Cutina™ HR, Henkel). In some embodiments of the invention, the lubricant is magnesium stearate. In some embodiments of the invention, the lubricant is magnesium stearate MF-2-V.

[0140] In this invention, the term "10 mg, 50 mg, or 100 mg formulation" refers to the fact that the 10 mg, 50 mg, or 100 mg unit formulations of this invention contain approximately 10 mg, approximately 50 mg, or approximately 100 mg of the compound represented by formula (I), respectively; the 10 mg, 50 mg, or 100 mg unit formulation can be, but is not limited to, one capsule, one tablet, or one packet of pills. Preferably, the 10 mg, 50 mg, or 100 mg unit formulation of this invention is one capsule containing approximately 10 mg, approximately 50 mg, or approximately 100 mg of the compound represented by formula (I), respectively.

[0141] In this invention, "dosage" refers to mass dosage, and "%" refers to mass percentage.

[0142] The "angle of repose" mentioned in this invention has been widely used in multiple 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 by the free inclined plane of powder accumulation with the horizontal plane in a static equilibrium state.

[0143] The method for determining the angle of repose in this invention is as follows: The entire apparatus consists of a feeding funnel, an electric stirrer, a fixed-diameter receiving base with an octet of 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 testing funnel must be dry, and its bottom outlet should be plugged with a movable lever. Place the weighed, uncompressed test sample into the funnel. After opening the bottom of the funnel, allow the powder to flow naturally from the funnel opening using its own fluidity. Then, carefully adjust the height of the receiving base until the tip of the powder cone is level with the funnel opening, taking care not to allow 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 corresponding 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.

[0144] Evaluation of powder flowability using angle of repose

[0145] (Reference: Public Notice on the Draft Standard for the Determination of Powder Flowability (Second Time), January 2024) The present invention proposes a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Formula (I), The particle size of the active ingredient satisfies at least one of the following conditions: D 50 ≤ 15 μm, D 90 ≤ 55μm; Optionally, the particle size of the active ingredient satisfies at least one of the following conditions: 3 μm ≤ D 50 ≤ 15 μm, 6 μm ≤ D 90 ≤ 55μm; Preferably, the particle size of the active ingredient meets the following conditions: D 50 ≤ 14μm, D 90 ≤ 51μm; or D 50 ≤ 11μm, D 90 ≤ 30μm; Preferably, the particle size of the active ingredient meets the following conditions: 3 μm ≤ D 50 ≤ 14μm, 6 μm≤D 90 ≤ 51μm; or 6 μm≤D 50 ≤ 11μm, 10 μm≤D 90 ≤ 30μm; Optionally, the particle size of the active ingredient further satisfies: D 10 ≤ 4 μm, D is preferred 10 ≤ 3 μm; Preferably, the particle size of the active ingredient further satisfies: 1 μm ≤ D 10 ≤ 4 μm or 2 μm ≤ D 10 ≤ 3 μm.

[0146] The composition of the present invention is effective in treating hepatitis C and has a high safety profile.

[0147] In some embodiments of the present invention, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt.

[0148] In some embodiments of the present invention, the inorganic acid salt or organic acid salt is a single salt or a disalt.

[0149] In some embodiments of the present invention, the inorganic acid salt is selected from hydrogen halide salts, halogen series oxygen-containing inorganic acid salts, carbon series oxygen-containing inorganic acid salts, nitrogen series oxygen-containing inorganic acid salts, boron series oxygen-containing inorganic acid salts, silicon series oxygen-containing inorganic acid salts, phosphorus series oxygen-containing inorganic acid salts, or sulfur series inorganic acid salts.

[0150] In some embodiments of the present invention, the inorganic acid salt is selected from hydrochloride, sulfate, hydrogen sulfate, nitrate, borate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, perchlorate, persulfate, hemisulfate, bisulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, or metaphosphate.

[0151] In some embodiments of the present invention, the organic acid salt is selected from carboxylates, sulfonates, sulfinates, or thiocarboxylates.

[0152] In some embodiments of the present invention, 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(hydroxynaphthyl)ate, salicylate, galactobionate, glucono-2-ethylhexanoate, mandelate, gluconate, 1,2-ethanedisulfonate, 2-naphthalenesulfonate, and oxalate. Trifluoroacetate, 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.

[0153] In some embodiments of the present invention, the pharmaceutically acceptable salt is a phosphate.

[0154] In some embodiments of the present invention, the phosphate of the compound shown in formula (I) has the structure shown in formula (II). Equation (II).

[0155] In some embodiments of the present invention, based on the total weight of the composition, the mass fraction of the compound of formula (I) or formula (II) or its pharmaceutically acceptable salt in the composition of the present invention is 10% to 45%, or 11% to 44%, or 12% to 43%, or 13% to 42%, or 11% to 42%, or 12% to 39%, or 13% to 38%, or 14% to 37%, or 15% to 36%, 16% to 35%, or 17% to 34%, or 18% to 33%, or 19% to 32%, or 20% to 31%, or 21% to 30%, 22% to 29%, 23% to 28%, or 24% to 27%, or 25% to 26%, or about 13%, or about 30%.

[0156] In some embodiments of the invention, the composition further comprises a pharmaceutically acceptable excipient, which includes at least one of fillers, disintegrants, flow aids, and lubricants, and optionally includes a binder.

[0157] In some embodiments of the present invention, the filler includes one or more selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose.

[0158] In some embodiments of the present invention, the filler includes lactose Granulac 200 and one or more selected from microcrystalline cellulose, mannitol, lactose Flowlac 100, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose.

[0159] In some embodiments of the present invention, the filler includes one or more of lactose Granulac 200, lactose Flowlac 100, and microcrystalline cellulose.

[0160] In some embodiments of the present invention, the microcrystalline cellulose is microcrystalline cellulose 101.

[0161] In some embodiments of the present invention, the disintegrant includes one or more of crospovidone, low-substituted hydroxypropyl cellulose, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch. In some embodiments of the present invention, the disintegrant is crospovidone; in some embodiments of the present invention, the disintegrant is crospovidone sodium carboxymethyl cellulose; and in some embodiments of the present invention, the disintegrant is sodium carboxymethyl starch.

[0162] In some embodiments of the present invention, the cross-linked polyvinylpyrrolidone is cross-linked polyvinylpyrrolidone XL.

[0163] In some embodiments of the present invention, the sodium carboxymethyl starch is sodium carboxymethyl starch (DST).

[0164] In some embodiments of the present invention, the flow aid is colloidal silica or talc. In some embodiments of the present invention, the flow aid is colloidal silica. In some embodiments of the present invention, the flow aid is colloidal silica (anhydrous) A200.

[0165] In some embodiments of the present invention, the lubricant is magnesium stearate. In some embodiments of the present invention, the magnesium stearate is magnesium stearate MF-2-V.

[0166] In some embodiments of the present invention, the lubricant is glyceryl behenate.

[0167] In some embodiments of the present invention, the adhesive is hydroxypropyl methylcellulose or hydroxypropyl cellulose. In some embodiments of the present invention, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5LV.

[0168] Embodiments of the invention are illustrated below. These embodiments are exemplary and intended to explain the invention, and should not be construed as limiting the invention.

[0169] Example 1: Investigation of the particle size range of active ingredients in the direct powder filling process The capsules were designed in three sizes: 10mg, 50mg, and 100mg (based on the mass of the compound shown in formula (I) being 10mg, 50mg, and 100mg, respectively). The effect of the particle size of the active pharmaceutical ingredient (API) of different compounds shown in formula (II) on the formulation was investigated using dissolution behavior as an indicator, so as to determine the range of API particle size.

[0170] In this embodiment, the prescription used is shown in Table 1 below: Table 1:

[0171] The powder direct filling process steps are as follows: The compound shown in formula (II) and excipients (filler, disintegrant, glidant, lubricant) are prepared according to the dosage requirements in Table 1, premixed after passing through a 40-mesh sieve (without adding lubricant), and then lubricant is added for total mixing to obtain a uniform powder. The powder is then filled according to the target filling amount to obtain capsules.

[0172] Dissolution method: The dissolution medium is 0.1M HCl, basket method, 900 mL, 100 rpm, medium temperature: 37.0±0.5℃. Dissolution sampling is carried out at different time points in Table 3. The dissolution sampling volume is 5 mL. Dissolution test sample sampling operation: the syringe is used to directly sample at the midpoint between the liquid surface and the top of the rotating basket, and 10 mm away from the inner wall of the dissolution cup. Acceptable standard: the amount dissolved at 30 min shall not be less than 80% of the labeled amount (Q).

[0173] Table 2. Particle size of active ingredients and corresponding formulation information

[0174] The dissolution results are shown in Table 3 below. Figures 1-3 As shown.

[0175] Table 3. Dissolution curves of capsules (active ingredients of different particle sizes) in 0.1 M HCl.

[0176] Table 3 shows that there was no significant difference in the dissolution curves of active ingredients of different particle sizes in 0.1 M HCl for 10 mg capsules (batch numbers 1-1, 2-1, 3-1, 4-1, 50 mg capsules (batch numbers 1-2, 2-2, 3-2, 4-2, 100 mg capsules (batch numbers 1-3, 2-3, 3-3, 4-3, 1 ...

[0177] The inventors further designed the capsules to be 100 mg in size and used dissolution behavior as an indicator to examine the effect of large-particle-size active ingredients on the formulation in order to determine the particle size range of the active pharmaceutical ingredient.

[0178] Table 4. Information related to large particle size active ingredients

[0179] The dissolution results are shown in Table 5 below: Table 5. Dissolution curves of the capsules in 0.1M HCl

[0180] Table 5 shows that when the active ingredient has a larger particle size, the 100 mg capsules dissolve more slowly in 0.1 M HCl, and the SD is larger, with significant differences in the dissolution rate of the prepared capsules.

[0181] In summary, in the direct powder filling process, the particle size control range for capsule active pharmaceutical ingredients is: D50≤14μm, D90≤51μm.

[0182] Example 2: Investigation of the particle size range of active pharmaceutical ingredients in wet granulation capsule filling process Using active ingredients with different particle size distributions, 10 batches of samples were obtained by wet granulation and capsule filling according to the target formulation process.

[0183] In this embodiment, the prescription used is shown in Table 6 below: Table 6:

[0184] Wet granulation capsule filling process steps: The compound shown in formula (II) and excipients (filler, binder, disintegrant, glidant, lubricant) are prepared according to the dosage requirements in Table 6. After adding the internal raw materials and excipients to the granulation pot, they are premixed 1. Then, the batch amount of purified water is added to make wet granules. After wet granulation, they are dried and dry granulated. The external excipients (external disintegrant, glidant) are sieved through a 30-mesh sieve and added to the mixing tank for premixing 2. Then, the lubricant is sieved through a 30-mesh sieve and added to the mixing tank for total mixing to obtain uniform granules. The capsules are then filled according to the target filling amount.

[0185] Dissolution method: The dissolution medium is pH 3.0 phosphate buffer + 0.2% Tween 80, 900 mL, paddle method, 75 rpm, medium temperature: 37.0±0.5℃. Dissolution samples are taken at different time points. The dissolution sample volume is 5 mL. Dissolution sample sampling operation: take the sample at the midpoint between the liquid surface and the upper edge of the paddle, and 10 mm away from the wall of the dissolution vessel. Acceptable standard: the amount dissolved at 30 min shall not be less than 80% of the labeled amount (Q).

[0186] Table 7. Correspondence between particle size of formulation (100 mg formulation) and active ingredient.

[0187] Note: In Table 7, batches 3, 5, and 8 of the formulation were prepared using two batches of active pharmaceutical ingredient (API). A 100mg formulation refers to a formulation in which the mass of the compound represented by formula (I) is 100mg.

[0188] The acceptable particle size range of raw materials was determined by comparing the dissolution rates of the capsules. Batch numbers 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 were examined to study the effect of different raw material particle size distributions on the dissolution of the formulation. The results are shown in Table 8 below. Figure 4 As shown.

[0189] Table 8 Dissolution data of capsules (100mg) containing active ingredients of different particle sizes

[0190] The results showed that the dissolution rates of batches 1 and 2 were significantly lower than those of other batches of formulation products. Therefore, considering the overall particle size distribution of the formulation process, in vitro dissolution data, and the fluctuation of particle size detection, the particle size distribution of the active pharmaceutical ingredient should be controlled within D90≤30μm and D50≤11μm.

[0191] Example 3 Development of Powder Direct Filling Process In the process of direct powder filling of the previous formulation, the inventors screened the excipients and optimized the preparation process under the condition of the appropriate particle size of the active ingredient determined in Example 1, in order to obtain a formulation that is suitable for large-scale industrial production and has a higher dissolution rate of the active ingredient.

[0192] By screening the types and ratios of excipients and measuring the dissolution rate of the product, the inventors determined the optimal formulation of the preparation containing the compound shown in formula (II) as the active substance, as shown in Tables 9 and 10 below.

[0193] Table 9 Optimized Formula for 10mg Specification

[0194] Table 10 Optimized Prescription for 50mg / 100mg Specifications

[0195] Through investigation of the dissolution medium, dissolution device, and rotation speed, the inventors determined the following dissolution test method for the above-mentioned formulation: using 0.1 mol / L hydrochloric acid solution as the dissolution medium, employing the basket method, and rotating at 100 rpm. The limit is set at 30 minutes, during which the amount dissolved must not be less than 80% of the labeled amount (Q).

[0196] Example 4 Development of Wet Granulation and Filling Process The direct powder filling process formulation for the capsules consists of the compounds shown in Formula (II), lactose Flowlac 100, lactose Granulac 200, crospovidone XL, colloidal silica (anhydrous) A200, and magnesium stearate MF-2-V. When changing the formulation process, the principle of not introducing too many new excipients is followed. Based on the suitable particle size of the active ingredient determined in Example 2, and considering the types of excipients, microcrystalline cellulose 101 was added as a filler to improve the feasibility of wet granulation; hydroxypropyl methylcellulose E5LV was selected as a binder to improve the granulation effect; sodium carboxymethyl starch DST was added as a disintegrant; colloidal silica (anhydrous) A200 and magnesium stearate MF-2-V remained unchanged.

[0197] The capsules were developed to a specification of 100 mg (based on the mass of the compound shown in formula (I) being 100 mg). An initial formulation was designed and investigated based on the results of raw material and excipient compatibility tests and the range of excipient dosages. The main focus was on screening the types of fillers, disintegrants, and binders that affect the process and dissolution rate, aiming to obtain capsules with higher dissolution rates.

[0198] The formulations containing the compound shown in formula (II) as the active substance are shown in Table 11 below. Table 11:

[0199] Through investigation of the dissolution medium, dissolution device, and rotation speed, the inventors determined the dissolution test method for the above-mentioned formulation as follows: a pH 3.0 disodium hydrogen phosphate-citric acid buffer solution + 0.2% Tween 80 is used as the dissolution medium; the method is the paddle method at a rotation speed of 75 rpm. The acceptable dissolution limit is set at 45 min, where the amount dissolved must not be less than 80% of the labeled amount (Q).

[0200] Example 5 Prepare capsules containing the compound shown in formula (II) as the active ingredient according to the following prescription, and determine the dissolution rate.

[0201] Capsules were prepared according to the powder direct filling process developed in Example 3: Particle size D 50 =9.04μm, D 90 The compound of formula (II) with a particle size of 28.4 μm and excipients (filler, disintegrant, glidant, lubricant) are prepared according to the dosage requirements in Tables 12, 13 or 14. After passing through a 40-mesh sieve, they are premixed (without adding lubricant). Then, lubricant is added and the mixture is fully mixed to obtain a uniform powder. The powder is then filled according to the target filling amount to obtain capsules.

[0202] Table 12 (Prescription 1):

[0203] Table 13 (Prescription 2):

[0204] Table 14 (Prescription 3):

[0205] Dissolution testing was performed using the method described in General Chapter 0931, Method I of the current edition of the Chinese Pharmacopoeia. 0.1M HCl was used as the dissolution medium at a temperature of 37.0 ± 0.5℃, employing the basket method at 100 rpm. Dissolution of the capsules was determined after 0 months and after 12, 24, and 36 months of storage at 30℃ and 65% humidity. Samples were taken at the midpoint between the liquid surface and the top of the rotating basket, 10 mm from the inner wall of the dissolution vessel, for 30 minutes, with a sample volume of 5 mL. The acceptable standard for dissolution was that the amount dissolved after 30 minutes should not be less than 80% of the labeled amount (Q). The results are shown in Table 15.

[0206] Table 15:

[0207] Example 6 Prepare capsules containing the compound shown in formula (II) as the active ingredient according to the following prescription, and determine the dissolution rate.

[0208] Capsules were prepared according to the wet granulation and filling process developed in Example 4: Particle size D 50 =7μm / D 90 =17μm, D 50 =8μm / D 90 The compound shown in formula (II) with a particle size of 23 μm and excipients (filler, binder, disintegrant, glidant, lubricant) are prepared according to the dosage requirements in Table 16. After adding the internal raw materials and excipients to the granulation pot, premixing is performed 1. Then, purified water of the batch amount is added to make wet granules. After wet granulation, the granules are dried and then dry granulated. The external excipients (external disintegrant, glidant) are sieved through a 30-mesh sieve and added to the mixing tank for premixing 2. Then, the lubricant is sieved through a 30-mesh sieve and added to the mixing tank for total mixing to obtain uniform granules. The capsules are then filled according to the target filling amount.

[0209] Table 16 (Prescription 4):

[0210] Dissolution was determined using the method (General Chapter 0931, Method II, current edition of the Chinese Pharmacopoeia). The dissolution medium was a disodium hydrogen phosphate-citric acid buffer solution (pH 3.0) containing 0.2% Tween 80. The medium temperature was 37.0 ± 0.5 °C. The dissolution method was a paddle method at 75 rpm. Dissolution was measured after 0 months, and after 12 months, 24 months, and 36 months of storage at 30 °C and 65% humidity. Sampling was taken at the midpoint between the liquid surface and the upper edge of the paddle, 10 mm from the wall of the dissolution vessel, for 45 minutes, with a sample volume of 5 mL. The acceptable dissolution standard was 80% of the labeled amount (Q) after 45 minutes. The results are shown in Table 17.

[0211] Table 17:

[0212] Example 7: Investigation of fillers in direct powder filling process 7.1 Investigation of Single Filler Prepare capsules containing the compound shown in formula (II) as the active ingredient according to the following prescription, and determine the dissolution rate.

[0213] Particle size D 50 =7.735μm, D 90 The compound shown in formula (II) with a particle size of 25.706 μm and excipients (filler, gliding agent, lubricant) are prepared according to the dosage requirements in Table 18. After passing through a 40-mesh sieve, they are premixed (without adding lubricant). Then, lubricant is added and the mixture is fully mixed to obtain a uniform powder. The powder is then filled according to the target fill weight to obtain capsules.

[0214] Table 18 Prescription Information for 100 mg Specification

[0215] Note: In Table 18, "N / A" indicates none.

[0216] The dissolution rate of the capsules was determined using the method of General Chapter 0931, Method II, of the current edition of the Chinese Pharmacopoeia, with 0.1 M HCl as the dissolution medium, 900 mL of solution, a medium temperature of 37.0 ± 0.5℃, using the paddle method at 50 rpm. Samples were taken at the midpoint between the liquid surface and the upper edge of the paddle, 10 mm from the inner wall of the dissolution vessel, at different time points, with a sample volume of 5 mL. The acceptable standard for dissolution was that the amount dissolved at 45 min should not be less than 80% of the labeled amount (Q). The results are shown in Table 19.

[0217] Table 19 Dissolution curves of capsules in 0.1 M HCl

[0218] The results of the investigation of the above-mentioned different single filler types showed that the capsules of Formula 7-1 and Formula 7-2 had faster dissolution rates and could dissolve completely. Therefore, water-soluble excipients lactose Flowlac 100 and mannitol 200SD were selected as the main fillers.

[0219] 7.2 Investigation of Combined Fillers Using dissolution rate as an indicator, we investigated the combined fillers of lactose Flowlac100 + lactose Granulac200 and mannitol 100SD + mannitol 200SD.

[0220] Prepare capsules containing the compound shown in formula (II) as the active ingredient according to the following prescription, and determine the dissolution rate.

[0221] Particle size D 50 =8.965μm, D 90 The compound shown in formula (II) with a particle size of 32.120 μm and excipients (fillers, disintegrants, glidants) are prepared according to the dosage requirements in Table 20, passed through a 40-mesh sieve, and mixed to obtain a uniform powder. The powder is then filled to the target fill weight to obtain capsules.

[0222] Table 20 Prescription Information for 10 mg Specification

[0223] Note: In Table 20, "N / A" indicates none.

[0224] The dissolution rate of the capsules was determined using the method of General Chapter 0931, Method I, in the current edition of the Chinese Pharmacopoeia. The dissolution medium was 0.1 M HCl, 900 mL, at a temperature of 37.0 ± 0.5 °C, using the basket method at 100 rpm. Samples were taken at the midpoint between the liquid surface and the rotating basket, 10 mm from the inner wall of the dissolution vessel, at different time points, with a sample volume of 5 mL. The acceptable standard for dissolution was that the amount dissolved at 30 min should not be less than 80% of the labeled amount (Q). The results are shown in Table 21.

[0225] Table 21 Dissolution curves of capsules in 0.1M HCl

[0226] The results of the evaluation of different filler combinations, such as lactose Flowlac100 + lactose Granulac200 and mannitol 100SD + mannitol 200SD, showed that the capsules in formulation 7-5 had a fast dissolution rate and were completely dissolved. This indicates that the formulation using lactose Flowlac100 + lactose Granulac200 as fillers has a better dissolution effect.

[0227] Example 8: Investigation of disintegrants in direct powder filling process Using dissolution rate as an indicator, the disintegrants crospovidone and crospovidone sodium carboxymethyl cellulose were examined.

[0228] Prepare capsules containing the compound shown in formula (II) as the active ingredient according to the following prescription, and determine the dissolution rate.

[0229] Particle size D 50 =6.364μm, D 90 The compound shown in formula (II) with a particle size of 24.540 μm and excipients (filler, disintegrant, glidant) are prepared according to the dosage requirements in Table 22, premixed after passing through a 40-mesh sieve (without adding lubricant), and then lubricant is added for total mixing to obtain a uniform powder. The powder is then filled according to the target fill amount to obtain capsules.

[0230] Table 22 Prescription information for 10 mg and 100 mg strengths

[0231] Note: In Table 22, "N / A" indicates none.

[0232] The dissolution rate of the capsules was determined using the method of General Chapter 0931, Method I, in the current edition of the Chinese Pharmacopoeia. 0.1 M HCl was used as the dissolution medium, 900 mL was dispensed, the medium temperature was 37.0 ± 0.5℃, and the basket method was employed at 100 rpm. Samples were taken at the midpoint between the liquid surface and the rotating basket, 10 mm from the inner wall of the dissolution vessel, at different time points, with a sample volume of 5 mL. The acceptable standard for dissolution was that the amount dissolved at 30 min should not be less than 80% of the labeled amount (Q). The results are shown in Table 23.

[0233] Table 23 Dissolution curves of capsules in 0.1M HCl

[0234] Dissolution studies using different disintegrants (crospovidone and crospovidone sodium carboxymethyl cellulose) showed the following results: In the 10mg formulation, the dissolution rate of crospovidone (Formulation 8-1) was not significantly different from that of crospovidone sodium (Formulation 8-2); in the 100mg formulation, the dissolution rate of crospovidone (Formulation 8-3) was faster than that of crospovidone sodium (Formulation 8-4) before 15 minutes. Therefore, formulations using crospovidone as a disintegrant have better dissolution performance.

[0235] Example 9: Investigation of Lubricants in Direct Powder Filling Process Using the angle of repose and dissolution rate as indicators, the lubricants glyceryl behenate and magnesium stearate were investigated as follows.

[0236] Prepare capsules containing the compound shown in formula (II) as the active ingredient according to the following prescription, and determine the dissolution rate.

[0237] Particle size D 50 =6.364μm, D 90 The compound shown in formula (II) with a particle size of 24.540 μm and excipients (filler, disintegrant, glidant) are prepared according to the dosage requirements in Table 24. After passing through a 40-mesh sieve, they are premixed (without adding lubricant). Then, lubricant is added and the mixture is fully mixed to obtain a uniform powder. The powder is then filled according to the target fill weight to obtain capsules.

[0238] Table 24 Prescription information for 10 mg and 100 mg strengths

[0239] Note: In Table 24, "N / A" indicates none.

[0240] The dissolution rate of the capsules was determined using the method of General Chapter 0931, Method I, in the current edition of the Chinese Pharmacopoeia, with 0.1 M HCl as the dissolution medium, 900 mL of solution, a medium temperature of 37.0 ± 0.5 °C, using the basket method, and at 100 rpm. Samples were taken at the midpoint between the liquid surface and the rotating basket, 10 mm from the inner wall of the dissolution vessel, at different time points, with a sample volume of 5 mL. The acceptable standard for dissolution rate was that the amount dissolved at 30 min should not be less than 80% of the labeled amount (Q). The results are shown in Table 25.

[0241] Table 25 Dissolution curves of capsules in 0.1M HCl

[0242] The results in Table 25 show that the dissolution rate of magnesium stearate (Formula 9-1, Formula 9-3) is faster than that of glyceryl behenate (Formula 9-2, Formula 9-4), and the former can be completely dissolved.

[0243] The liquidity results are shown in Table 26 below: Table 26 Overall Powder Flowability

[0244] The results of the study in Table 26 show that the formulations containing magnesium stearate (Formulation 9-1 and Formulation 9-3) have a smaller angle of repose, which means they have better flowability.

[0245] Example 10: Investigation of fillers in wet granulation and filling process When changing from a direct powder filling process to a wet granulation filling process, based on the excipients used in the direct powder filling process and adhering to the principle of not introducing too many new excipients, we investigated the effect of the combination of the fillers used in the direct powder filling process, namely lactose Flowlac 100: lactose Granulac 200 (3:1, corresponding to formulation 10-1 in Table 27 below) and lactose Granulac 200: microcrystalline cellulose 101 (2:1, corresponding to formulation 10-2 in Table 27 below), on the dissolution of 100mg capsules prepared by the wet granulation filling process.

[0246] Prepare capsules containing the compound shown in formula (II) as the active ingredient according to the following prescription, and determine the dissolution rate.

[0247] Particle size D 50 =13μm, D 90The compound shown in formula (II) with a particle size of 35 μm and excipients (filler, binder, disintegrant, glidant, lubricant) are prepared according to the dosage requirements in Table 27. After adding the internal raw materials and excipients to the granulation pot, premixing is performed 1. Then, the batch amount of purified water is added (the amount of purified water in formula 10-1 is 14% of the amount of internal materials, and the amount of purified water in formula 10-2 is 20% of the amount of internal materials, both of which are removed in the subsequent drying process) to make wet granules. After wet granulation, drying and dry granulation are performed. The external excipients (external disintegrant, glidant) are passed through a 30-mesh sieve and added to the mixing tank for premixing 2. Then, the lubricant is passed through a 30-mesh sieve and added to the mixing tank for total mixing to obtain uniform granules. The capsules are then filled according to the target filling amount.

[0248] Table 27 Prescription Information for 100mg Strengths Containing Different Fillers

[0249] Note: In Table 27, "N / A" indicates none.

[0250] Dissolution testing was performed using the method described in General Chapter 0931, Method II of the current edition of the Chinese Pharmacopoeia. The dissolution medium was 0.1 M HCl, 900 mL, at a temperature of 37.0 ± 0.5 °C. The dissolution was determined using the slurry method (with a settling basket) at 75 rpm. Samples were taken at the midpoint between the liquid surface and the upper edge of the slurry, 10 mm from the inner wall of the dissolution vessel. Samples were taken at different time points, with a sample volume of 5 mL. The acceptable standard for dissolution was that the amount dissolved at 45 min should not be less than 80% of the labeled amount (Q). The results are shown in Table 28.

[0251] Table 28 Dissolution results of 100mg atenitamivir phosphate capsules

[0252] Based on the dissolution results in Table 28, the dissolution rate of formulation 10-1, which corresponds to the combination of filler lactose Flowlac 100 and lactose Granulac 200 (3:1), is relatively slow, while the dissolution rate of formulation 10-2, which corresponds to the combination of filler lactose Granulac 200 and microcrystalline cellulose 101 (2:1), is relatively fast. Therefore, the formulation containing the combination of lactose Granulac 200 and microcrystalline cellulose 101 (2:1) as a filler has a better dissolution effect.

[0253] Example 11 Investigation of disintegrants in wet granulation and filling process The effects of disintegrants crospovidone XL-10, crospovidone sodium carboxymethyl cellulose, or sodium carboxymethyl starch DST on the dissolution of 100 mg capsules prepared by wet granulation and filling process were investigated.

[0254] Prepare capsules containing the compound shown in formula (II) as the active ingredient according to the following prescription, and determine the dissolution rate.

[0255] Particle size D 50 =13μm, D 90 The compound shown in formula (II) with a particle size of 35 μm and excipients (filler, binder, disintegrant, glidant, lubricant) are prepared according to the dosage requirements in Table 29. After adding the internal raw materials and excipients to the granulation pot, premixing is performed 1. Then, the batch amount of purified water is added (the amount of purified water in formula 11-1 is 20% of the amount of internal materials, the amount of purified water in formula 11-2 is 23% of the amount of internal materials, and the amount of purified water in formulas 11-3 and 11-4 is 24% of the amount of internal materials, all of which are removed in the subsequent drying process) to make wet granules. After wet granulation, drying and dry granulation are performed. The external excipients (external disintegrant, glidant) are added to the mixing tank after passing through a 30-mesh sieve and premixed 2. Then, the lubricant is added to the mixing tank after passing through a 30-mesh sieve and mixed to obtain uniform granules. The capsules are then filled according to the target filling amount.

[0256] Table 29 Prescription Information for 100mg Strengths Containing Different Disintegrants

[0257] Note: In Table 29, "N / A" indicates none.

[0258] Dissolution testing was performed using the method described in General Chapter 0931, Method II of the current edition of the Chinese Pharmacopoeia. The dissolution medium was 0.1 M HCl, 900 mL, at a temperature of 37.0 ± 0.5 °C. The dissolution rate was determined using the slurry method (with a settling basket) at 75 rpm. Samples were taken at the midpoint between the liquid surface and the upper edge of the slurry, 10 mm from the inner wall of the dissolution vessel. Samples were taken at different time points, with a sample volume of 5 mL. The acceptable standard for dissolution was that the amount dissolved at 45 min should not be less than 80% of the labeled amount (Q). The results are shown in Table 30.

[0259] Table 30 Dissolution results of 100mg atenitamivir phosphate capsules

[0260] Based on the dissolution results, Formulation 11-1, with crospovidone XL-10 as the disintegrant, exhibited a slower dissolution rate and a relatively larger SD value. Formulation 11-2, with an increased proportion of crospovidone XL-10, showed a faster dissolution rate but still had a relatively large SD value. Observation of the dissolution phenomenon revealed that batches of capsules using crospovidone XL-10 as the disintegrant tended to clump together during dissolution. Compared to Formulation 11-3, which used sodium carboxymethyl cellulose as the disintegrant, Formulation 11-4, which used sodium carboxymethyl starch (DST) as the disintegrant, showed a relatively faster dissolution rate and a higher dissolution plateau. Therefore, formulations using sodium carboxymethyl starch (DST) as the disintegrant exhibited better dissolution performance.

[0261] Example 12 Investigation of binders in wet granulation and filling processes Using dissolution rate as an indicator, hydroxypropyl methylcellulose E5 LV and hydroxypropyl cellulose EXF were used as binders for evaluation.

[0262] Prepare capsules containing the compound shown in formula (II) as the active ingredient according to the following prescription, and determine the dissolution rate.

[0263] Particle size D 50 =11.1μm, D 90 The compound shown in formula (II) with a particle size of 35.9 μm and excipients (filler, binder, disintegrant, glidant, lubricant) are prepared according to the dosage requirements in Table 31. After adding the internal raw materials and excipients to the granulation pot, premixing is performed 1. Then, the batch amount of purified water (the amount of purified water is 32% of the amount of internal materials, which will be removed in the subsequent drying process) is added to make wet granules. After wet granulation, drying and dry granulation are performed. The external excipients (external disintegrant, glidant) are passed through a 30-mesh sieve and added to the mixing tank for premixing 2. Then, the lubricant is passed through a 30-mesh sieve and added to the mixing tank for total mixing to obtain uniform granules. The capsules are then filled according to the target filling amount.

[0264] Table 31 Prescription Information for 100mg Strengths Containing Different Adhesives

[0265] Note: In Table 31, "N / A" indicates none.

[0266] The dissolution rate of the capsules was determined using the method of General Chapter 0931, Method II, of the current edition of the Chinese Pharmacopoeia, with 0.1 M HCl as the dissolution medium, 900 mL of solution, a medium temperature of 37.0 ± 0.5 °C, and the slurry method (with a settling basket) at 75 rpm. Samples were taken at the midpoint between the liquid surface and the upper edge of the slurry, 10 mm from the inner wall of the dissolution vessel, at different time points, with a sample volume of 5 mL. The acceptable standard for dissolution was that the amount dissolved at 45 min should not be less than 80% of the labeled amount (Q). The results are shown in Table 32.

[0267] Table 32 Dissolution results of 100mg atenitamivir phosphate capsules

[0268] Based on the dissolution results, formulation 12-1, with hydroxypropyl cellulose EXF as the binder, exhibited a slower dissolution rate and a relatively larger SD value; formulation 12-2, with hydroxypropyl methylcellulose E5 LV as the binder, showed a faster dissolution rate and a smaller SD. Therefore, formulations using hydroxypropyl methylcellulose E5 LV as the binder demonstrate better dissolution performance.

[0269] Example 13: Investigation of surfactants in direct powder filling process Capsules containing the compound shown in formula (II) as the active ingredient were prepared according to the following prescription, and the degree of absorption in dogs was compared.

[0270] Particle size D 50 =7.479μm, D 90 The compound shown in formula (II) with a particle size of 26.944 μm and the excipients are prepared according to the dosage requirements in Table 33, premixed after passing through a 40-mesh sieve (without adding lubricant), and then lubricant is added for total mixing to obtain a uniform powder. The powder is then filled according to the target filling amount to obtain capsules.

[0271] Table 33 Prescription information for 100 mg strength

[0272] Note: In Table 33, "N / A" indicates none.

[0273] Dissolution testing was performed using the method described in General Chapter 0931, Method II of the current edition of the Chinese Pharmacopoeia. The dissolution medium was 0.1 M HCl, 900 mL, at a temperature of 37.0 ± 0.5 °C, using the paddle method at 50 rpm. Samples were taken at the midpoint between the liquid surface and the upper edge of the paddle, 10 mm from the inner wall of the dissolution vessel. Samples were taken at different time points, with a sample volume of 5 mL. The acceptable standard for dissolution was that the amount dissolved at 45 min should not be less than 80% of the labeled amount (Q). The results are shown in Table 34.

[0274] Table 34 Dissolution curves of different formulation capsules in 0.1 M HCl

[0275] Table 34 shows that formulation 13-4, which does not contain surfactants and uses lactose Flowlac100 + lactose Granulac200 as fillers, has the best dissolution effect.

[0276] In addition, the differences in absorption of the different prescription capsules in beagle dogs were compared: Beagle dogs were orally administered different prescription capsules, with 3 animals in each group, at a dose of 100 mg / animal (1 capsule), administered once daily. Blood samples were collected venously at time points (0.5, 1, 2, 4, 6, 8, 10, and 24 hours after administration and collected in anticoagulant tubes containing EDTA-K2. After centrifugation, the supernatant from the plasma samples was quantitatively analyzed by LC-MS / MS, and pharmacokinetic parameters were calculated using the non-compartmental model method in WinNonlin 6.3 software. The results are shown in Table 35 below: Table 35 Pharmacokinetic parameters of different prescription capsules

[0277] The results of the investigation of the above different formulations showed that the in vivo exposure of the formulations containing surfactants (Formula 13-1 and Formula 13-2) was lower than that of the formulations without surfactants (Formula 13-3 and Formula 13-4). 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.

[0278] 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 thereof as an active ingredient. Equation (I), The particle size of the active ingredient satisfies at least one of the following conditions: D 50 ≤ 15 μm,D 90 ≤ 55μm; Optionally, the particle size of the active ingredient satisfies at least one of the following conditions: 3 μm ≤ D 50 ≤ 15 μm,6 μm≤D 90 ≤ 55μm; Preferably, the particle size of the active ingredient meets the following conditions: D 50 ≤ 14μm,D 90 ≤ 51μm; or D 50 ≤ 11μm,D 90 ≤ 30μm; Preferably, the particle size of the active ingredient meets the following conditions: 3 μm ≤ D 50 ≤ 14μm,6μm≤D 90 ≤ 51μm;or6μm≤D 50 ≤ 11μm,10μm≤D 90 ≤ 30μm; Optionally, the particle size of the active ingredient further satisfies: D 10 ≤ 4 μm, D is preferred 10 ≤ 3 μm; Preferably, the particle size of the active ingredient further satisfies: 1 μm ≤ D 10 ≤ 4 μm or 2 μm ≤ D 10 ≤ 3 μm.

2. The composition according to claim 1, characterized in that, The pharmaceutically acceptable salts are inorganic acid salts or organic acid salts; Optionally, the inorganic acid salt or organic acid salt is a single salt or a disalt; Optionally, the inorganic acid salt is selected from hydrohalides, halogen-based oxygen-containing inorganic acid salts, carbon-based oxygen-containing inorganic acid salts, nitrogen-based oxygen-containing inorganic acid salts, boron-based oxygen-containing inorganic acid salts, silicon-based oxygen-containing inorganic acid salts, phosphorus-based oxygen-containing inorganic acid salts, or sulfur-based inorganic acid salts. Optionally, the organic acid salt is selected from carboxylates, sulfonates, sulfinates, or thiocarboxylates; Optionally, the inorganic acid salt is selected from hydrochloride, sulfate, hydrogen sulfate, nitrate, borate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, perchlorate, persulfate, hemisulfate, disulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, or metaphosphate. Optionally, 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(hydroxynaphthyl)ate, salicylate, galactobionate, gluconate, mandelate, gluconate, 1,2-ethanedisulfonate, 2-naphthalenesulfonate, oxalate, trifluoroacetate, etc. Salts, adipates, alginates, ascorbic acid salts, aspartate salts, benzenesulfonates, butyrates, camphorates, camphor sulfonates, cyclopentylpropionate, digluconate, dodecyl sulfate, ethyl sulfonate, glyceryl phosphate, heptate, hexanoate, 2-hydroxy-ethanesulfonate, laurate, lauryl sulfate, nicotinate, oleate, palmitate, pyrate, pectate, 3-phenylpropionate, picrates, pentanoate, propionate, stearate, thiocyanate, undecanoate, or pentanoate.

3. The composition according to any one of claims 1-2, characterized in that, The pharmaceutically acceptable salt is a phosphate, and the phosphate of the compound shown in formula (I) has the structure shown in formula (II). Equation (II).

4. The composition according to any one of claims 1 to 3, characterized in that, The mass fraction of the active ingredient is 10%~45%, or 11%~44%, or 12%~43%, or 13%~42%, or 11%~42%, or 12%~39%, or 13%~38%, or 14%~37%, or 15%~36%, 16%~35%, or 17%~34%, or 18%~33%, or 19%~32%, or 20%~31%, or 21%~30%, 22%~29%, 23%~28%, or 24%~27%, or 25%~26%, or about 13%, or about 30%.

5. The composition according to any one of claims 1-4, characterized in that, Further includes pharmaceutically acceptable excipients, said excipients including at least one of fillers, disintegrants, glidants and lubricants, and optionally includes binders; Optionally, the filler includes one or more selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose; Preferably, the filler includes lactose Granulac 200 and one or more selected from microcrystalline cellulose, mannitol, lactose Flowlac 100, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose; Preferably, the filler comprises one or more of lactose Granulac 200, lactose Flowlac 100, and microcrystalline cellulose; Optionally, the disintegrant includes one or more of crospovidone, low-substituted hydroxypropyl cellulose, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch; Optionally, the flow aid is colloidal silica or talc. Optionally, the lubricant is magnesium stearate or glyceryl behenate; Optionally, the adhesive is hydroxypropyl methylcellulose or hydroxypropyl cellulose.

6. The composition according to claim 5, characterized in that, Based on the total weight of the composition, the mass fraction of the active ingredient is 10-35%; Optionally, the filler has a mass fraction of 50-90% based on the total weight of the composition; Optionally, the mass ratio of the lactose Granulac 200 and one or more selected from microcrystalline cellulose, mannitol, lactose Flowlac 100, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose is 1:3 to 3:

1. Optionally, the disintegrant has a mass fraction of 2% to 6% based on the total weight of the composition; Optionally, the gliding agent has a mass fraction of 0.5% to 1.5% based on the total weight of the composition; Optionally, the mass fraction of the lubricant is 0.5% to 3% based on the total weight of the composition; Optionally, the adhesive has a mass fraction of 0-3% based on the total weight of the composition; Optionally, the adhesive has a mass fraction of 0.5% to 3% based on the total weight of the composition.

7. The composition according to claim 6, characterized in that, The excipients include fillers, disintegrants, flow aids, and lubricants. Based on the total weight of the composition, the mass fraction of the fillers is 55% to 90%, preferably 65% ​​to 85%. Optionally, the mass ratio of lactose Granulac 200 to lactose Flowlac 100 is 1:3; Optionally, based on the total weight of the composition, the mass fraction of the disintegrant is 2% to 4%, preferably 3%; Optionally, the gliding agent has a mass fraction of 0.5% to 1.5%, preferably 1%, based on the total weight of the composition; Optionally, based on the total weight of the composition, the mass fraction of the lubricant is 0.5% to 1%, preferably 0.6% to 1%, and more preferably 0.8%.

8. The composition according to claim 6, characterized in that, The excipients include fillers, disintegrants, flow aids, lubricants, and binders, and the mass fraction of the fillers is 55% to 65% based on the total weight of the composition; Optionally, the mass ratio of lactose Granulac 200 to microcrystalline cellulose is 1.4:1 to 3:1, preferably 1.4:1 to 2.5:1, and more preferably 2:1; Optionally, based on the total weight of the composition, the mass fraction of the disintegrant is 4% to 6%, preferably 5% to 6%, more preferably 5%; Optionally, the gliding agent has a mass fraction of 0.5% to 1.5%, preferably 1%, based on the total weight of the composition; Optionally, based on the total weight of the composition, the mass fraction of the lubricant is 1% to 2.5%, preferably 1.5%; Optionally, the adhesive has a mass fraction of 0.5% to 3%, preferably 1.5%, based on the total weight of the composition.

9. The composition according to claim 7, characterized in that, In the composition, the mass ratio of the active ingredient, the filler, the disintegrant, the flow aid, and the lubricant is (10~35):(55~90):(2~4):(0.5~1.5):(0.5~1); or, in the composition, the mass ratio of the active ingredient, the filler, the disintegrant, the flow aid, and the lubricant is (13~14):(81~82):3:1:(0.5~1); or, in the composition, the mass ratio of the active ingredient, the filler, the disintegrant, the flow aid, and the lubricant is (29~30):(65~66):3:1:(0.5~1).

10. The composition according to claim 8, 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 (10~35):(55~65):(0.5~3):(4~6):(0.5~1.5):(1~2.5); or, in the composition, the mass ratio of the active ingredient, the filler, the binder, the disintegrant, the flow aid, and the lubricant is (30~31):(60~61):1.5:5:1:1.

5.

11. The composition according to any one of claims 1-10, 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, pellet, powder, sustained-release formulation, aqueous suspension, ointment, paste, emulsion, lotion, gel, solution, spray, inhaler, or patch.

12. A capsule filled with contents, characterized in that, The contents include the composition according to any one of claims 1-10.

13. A capsule filled with contents, characterized in that, The contents comprise: a compound of formula (II) and fillers, disintegrants, flow aids, lubricants, and optionally binders, wherein the compound of formula (II) comprises 10% to 45% by mass based on the total weight of the contents, and the particle size of the compound of formula (II) satisfies at least one of the following conditions: D 50 ≤ 15 μm, D 90 ≤ 55μm, Equation (II).

14. The capsule according to claim 13, characterized in that, The compound shown in formula (II) is used in an amount of 10 to 35 parts by weight, the filler is used in an amount of 55 to 90 parts by weight, the disintegrant is used in an amount of 2 to 4 parts by weight, the gliding agent is used in an amount of 0.5 to 1.5 parts by weight, and the lubricant is used in an amount of 0.5 to 1 part by weight. or The compound shown in formula (II) is used in an amount of 10 to 35 parts by weight, the filler is used in an amount of 55 to 65 parts by weight, the adhesive is used in an amount of 0.5 to 3 parts by weight, the disintegrant is used in an amount of 4 to 6 parts by weight, the gliding agent is used in an amount of 0.5 to 1.5 parts by weight, and the lubricant is used in an amount of 1 to 2.5 parts by weight.

15. The capsule according to claim 13 or 14, characterized in that, The filler includes one or more selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose; Preferably, the filler includes lactose Granulac 200 and one or more selected from microcrystalline cellulose, mannitol, lactose Flowlac 100, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose; Preferably, the filler comprises one or more of lactose Granulac 200, lactose Flowlac 100, and microcrystalline cellulose; Optionally, the disintegrant includes one or more of crospovidone, low-substituted hydroxypropyl cellulose, crospovidone sodium carboxymethyl cellulose, and sodium carboxymethyl starch; Optionally, the flow aid is colloidal silica or talc. Optionally, the lubricant is magnesium stearate or glyceryl behenate; Optionally, the adhesive is hydroxypropyl methylcellulose or hydroxypropyl cellulose. Optionally, the amount of lactose Granulac 200 used is 10 to 45 parts by weight; Optionally, the amount of one or more selected from microcrystalline cellulose, mannitol, lactose Flowlac 100, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose is 10 to 70 parts by weight. Optionally, the filler contains lactose Granulac 200 and one or more selected from microcrystalline cellulose, mannitol, lactose Flowlac 100, pregelatinized starch, sorbitol, dicalcium phosphate, starch, and sucrose in a mass ratio of 1:3 to 3:

1.

16. The capsule according to claim 13 or 14, characterized in that, The capsules may be single-dose or multi-dose formulations; Optionally, the capsule is a 10mg, 50mg, or 100mg formulation; Preferably, the capsule is a 100mg formulation.

17. A capsule filled with contents, characterized in that, The capsule is a 10mg formulation, the contents of which include 10-15 parts by weight of the compound of formula (II), 70-85 parts by weight of the filler, 2-4 parts by weight of the disintegrant, 0.5-1.5 parts by weight of the gliding agent, and 0.5-1 parts by weight of the lubricant. The particle size of the compound of formula (II) satisfies at least one of the following conditions: D 50 ≤ 14μm, D 90 ≤51μm; or, the contents comprise 13-14 parts by weight of the compound of formula (II), 81-82 parts by weight of the filler, 3 parts by weight of the disintegrant, 1 part by weight of the gliding agent, and 0.5-1 parts by weight of the lubricant, wherein the particle size of the compound of formula (II) satisfies at least one of the following conditions: D 50 ≤ 14μm, D 90 ≤ 51μm, Equation (II).

18. A capsule filled with contents, characterized in that, The capsule is a 50mg or 100mg formulation, the contents comprising 25-30 parts by weight of the compound of formula (II), 55-80 parts by weight of the filler, 2-4 parts by weight of the disintegrant, 0.5-1.5 parts by weight of the gliding agent, and 0.5-1 parts by weight of the lubricant, and the particle size of the compound of formula (II) satisfies at least one of the following conditions: D 50 ≤14μm, D 90 ≤ 51 μm; or, the contents comprise 29-30 parts by weight of the compound of formula (II), 65-66 parts by weight of the filler, 3 parts by weight of the disintegrant, 1 part by weight of the gliding agent, and 0.5-1 part by weight of the lubricant, wherein the particle size of the compound of formula (II) satisfies at least one of the following conditions: D 50 ≤ 14μm, D 90 ≤ 51μm, Equation (II).

19. The capsule according to claim 17 or 18, characterized in that, The filler includes lactose Granulac 200 and lactose Flowlac 100; Preferably, the mass ratio of lactose Granulac 200 to lactose Flowlac 100 is 1:3; Preferably, the disintegrant is crospovidone; Preferably, the flow aid is colloidal silica; Preferably, the lubricant is magnesium stearate.

20. A capsule filled with contents, characterized in that, The capsule is a 100mg formulation, and the contents include 30-35 parts by weight of the compound of formula (II), 60-65 parts by weight of the filler, 0.5-3 parts by weight of the binder, 4-6 parts by weight of the disintegrant, 0.5-1 parts by weight of the gliding agent, and 1-2.5 parts by weight of the lubricant. The particle size of the compound of formula (II) satisfies at least one of the following conditions: D 50 ≤ 11μm, D 90 ≤ 30 μm; or, the contents comprise 30-31 parts by weight of the compound of formula (II), 60-61 parts by weight of the filler, 1.5 parts by weight of the binder, 5 parts by weight of the disintegrant, 1 part by weight of the glidant, and 1.5 parts by weight of the lubricant, wherein the particle size of the compound of formula (II) satisfies at least one of the following conditions: D 50 ≤ 11μm, D 90 ≤ 30μm, Formula (II); Preferably, the filler comprises lactose Granulac 200 and microcrystalline cellulose; Preferably, the mass ratio of lactose Granulac 200 to microcrystalline cellulose is 1.4:1 to 3:1, more preferably 2:1; Preferably, the disintegrant is sodium carboxymethyl starch; Preferably, the flow aid is colloidal silica; Preferably, the lubricant is magnesium stearate.

21. A method for preparing capsules, comprising: (1) The active ingredient is premixed with filler, disintegrant and gliding agent to obtain a first mixture; (2) The first mixture is subjected to a second mixing treatment with a lubricant to obtain a second mixture; (3) and the second mixture is subjected to capsule filling to obtain the capsules. Wherein, the particle size of the active ingredient satisfies at least one of the following conditions: D 50 ≤ 14μm,D 90 ≤ 51μm.

22. A method for preparing capsules, comprising: (1) The active ingredient is subjected to a first premixing treatment with filler, binder and first disintegrant; (2) The first premixed product is subjected to wet granulation; (3) The wet granulation product is dried and then premixed with the second disintegrant and the glidant. (4) The second premixed mixture is then mixed with the lubricant. (5) The total mixture product is subjected to capsule filling treatment to obtain the capsules; Wherein, the particle size of the active ingredient satisfies at least one of the following conditions: D 50 ≤ 11μm,D 90 ≤ 30μm。

Images