CN117427143A

CN117427143A - Pharmaceutical composition containing peptidomimetic compounds and application thereof

Info

Publication number: CN117427143A
Application number: CN202310899186.8A
Authority: CN
Inventors: 任军乐; 孙晓伟; 何影; 安立鑫; 刘娜; 杜晓俐; 吕高星; 董丹丹
Original assignee: CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Current assignee: CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Priority date: 2022-07-22
Filing date: 2023-07-21
Publication date: 2024-01-23

Abstract

The application provides a pharmaceutical composition containing a compound shown in a formula (I), a solvate or pharmaceutically acceptable salt thereof and application thereof, and the pharmaceutical composition provides a pharmaceutical preparation with excellent performance and good pharmacokinetics, satisfies oral administration, can improve bioavailability, thereby reducing or avoiding the use of a powerful CYP enzyme inhibitor and having good patent medicine potential.

Description

Pharmaceutical composition containing peptidomimetic compounds and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a pharmaceutical composition containing a peptidomimetic compound and application of the pharmaceutical composition.

Background

Among specific anti-novel coronavirus small molecule inhibitors targeting the viral replication cycle, inhibitors of the main protease Mpro (also known as 3 CLpro) are most widely studied, one of which is a peptidomimetic inhibitor mimicking a natural polypeptide substrate, and is mainly obtained by modification of the substrate polypeptide sequence of the main protease Mpro.

The anti-new coronavirus oral drug PAXLOVID was announced by the company of the 11 th of 2021 to reduce the probability of hospitalization or death of adults at risk of serious diseases by 89%, and the main active ingredient is PF-07321332, and the proliferation of viruses is restricted by inhibiting 3CL protease. The current clinical trial dose of PAXLOVID is twice daily, 300 mg PF-07321332 each time taken with 100 milligram ritonavir.

The pharmaceutical compounds have the following drawbacks: 1. the medicine is required to be taken twice every day, and the medicine compliance is required to be further improved; 2. the combined use increases the risk of adverse reactions; PF-07321332 is required to be administered simultaneously with ritonavir, a potent CYP3A4 inhibitor, limiting the range of use of other drugs. The high dosage and ritonavir can easily cause various adverse reactions, the strong CYP enzyme inhibition effect also limits the use of a large amount of CYP enzyme metabolism substrate medicines, various limits are brought to a treatment method, and the risk of patients is greatly increased.

Patent application CN202210600047.6 describes a compound of formula I, a preparation method and application thereof, and the compound is a 3CL protease inhibitor of a deuterated peptoid structure.

Disclosure of Invention

The present application provides a pharmaceutical composition comprising a compound of formula I, a solvate or a pharmaceutically acceptable salt thereof, having excellent formulation properties, on the basis of a compound of formula I.

In a first aspect of the present application, there is provided a pharmaceutical composition comprising: a compound of formula I or a pharmaceutically acceptable salt, solvate thereof as an active ingredient; and (3) an excipient.

In a second aspect of the present application, there is provided a pharmaceutical composition comprising: a crystalline form of a compound of formula I as active ingredient; and (3) an excipient.

In some embodiments, the crystalline form is form a, using Cu-ka radiation, having an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 11.8,12.7,15.6,18.3.

In some embodiments of the present application, the crystalline form a, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 11.8,12.7,15.6,18.3,20.4.

In some embodiments of the present application, the crystalline form a, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 11.8,12.7,15.6,18.3,19.8,20.4.

In some embodiments of the present application, the crystalline form a, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 11.8,12.7,15.6,17.3,18.3,19.8,20.4.

In some embodiments of the present application, the crystalline form a, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 11.8,12.7,15.6,17.3,18.3,19.8,20.4,22.2.

In some embodiments of the present application, the crystalline form a, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 7.6,9.7,11.8,12.7,15.6,17.3,18.3,19.8,20.4,22.2.

In some embodiments of the present application, the crystalline form a, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 7.6,9.7,11.8,12.7,15.6,17.3,18.3,19.8,20.4,20.9,22.2.

In some embodiments of the present application, the crystalline form a, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 7.6,9.7,11.8,12.7,15.6,17.3,17.8,18.3,19.8,20.4,20.9,21.6,22.2.

In some embodiments of the present application, the crystalline form a, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 7.6,9.7,11.4,11.8,12.1,12.7,15.6,17.3,17.8,18.3,19.8,20.4,20.9,21.6,22.2.

In some embodiments of the present application, the crystalline form a, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 7.6,9.7,11.4,11.8,12.1,12.7,15.6,17.3,17.8,18.3,19.8,20.4,20.9,21.6,22.2,23.5,24.6.

In some embodiments of the present application, the crystalline form a, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 7.6,9.7,11.4,11.8,12.1,12.7,15.6,17.3,17.8,18.3,18.7,19.8,20.4,20.9,21.6,22.2,23.5,24.6.

In some embodiments of the present application, the crystalline form a, using Cu-ka radiation, has an X-ray powder diffraction pattern substantially as shown in figure 1.

In some embodiments of the present application, the crystalline form a has a differential scanning calorimetry curve with an endothermic peak at 196±5 ℃.

In some embodiments of the present application, the form a, its differential scanning calorimetric curve, begins to exhibit an endothermic signal at 192±5 ℃.

In some embodiments of the present application, the form a, the differential scanning calorimetry curve, has an endothermic peak at 196±5 ℃, and an exothermic peak occurs at 336±5 ℃.

In some embodiments of the present application, the crystalline form a has a DSC profile substantially as shown in figure 2.

In some embodiments of the present application, the crystalline form a, having a chemical purity of ≡96%; preferably, it has a chemical purity of ≡97%; further preferably, it has a chemical purity of ≡98%; further preferably, it has a chemical purity of 99% or more; further preferably, it has a chemical purity of 99.5% or more.

In some embodiments, the crystalline form is form B, using Cu-ka radiation, whose X-ray powder diffraction pattern comprises diffraction peaks (±0.2°): 7.2,12.6,16.9,18.5.

In some embodiments of the present application, the crystalline form B, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 7.2,11.8,12.6,16.9,18.5.

In some embodiments of the present application, the crystalline form B, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 7.2,11.8,12.6,14.2,16.9,18.5.

In some embodiments of the present application, the crystalline form B, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 7.2,11.8,12.6,14.2,16.0,16.9,18.5.

In some embodiments of the present application, the crystalline form B, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 7.2,11.8,12.6,14.2,16.0,16.9,18.5,19.2.

In some embodiments of the present application, the crystalline form B, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 7.2,11.4,11.8,12.6,14.2,16.0,16.9,18.5,19.2,23.7.

In some embodiments of the present application, the crystalline form B, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 7.2,10.5,11.4,11.8,12.6,14.2,16.0,16.9,18.5,19.2,22.2,23.7,25.3.

In some embodiments of the present application, the crystalline form B, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 7.2,10.5,11.4,11.8,12.6,14.2,16.0,16.9,18.5,19.2,19.9,20.8,22.2,23.7,25.3.

In some embodiments of the present application, form B uses Cu-ka radiation having an X-ray powder diffraction pattern substantially as shown in figure 3.

In some embodiments of the present application, the form B, the differential scanning calorimetry curve, exhibits a peak of endotherm at 131±5 ℃.

In some embodiments of the present application, the crystalline form B, the differential scanning calorimetry curve of which begins to develop an endothermic signal at 117±5 ℃.

In some embodiments of the present application, the crystalline form B has a differential scanning calorimetry curve that peaks for endotherms at 131±5 ℃ and peaks for exotherms at 335±5 ℃.

In some embodiments of the present application, the excipient comprises a filler and a lubricating excipient, optionally further comprising a disintegrant and/or a binder.

In some embodiments of the present application, the excipient comprises a filler, a lubricating excipient, and a disintegrant, optionally, further comprising a binder.

In some embodiments of the present application, the excipient comprises a filler, a lubricating excipient, a disintegrant.

In some embodiments of the present application, the lubricating adjuvant is a lubricant, optionally, further comprising a glidant.

In some embodiments of the present application, the lubricating adjuvants are lubricants and glidants.

In some embodiments of the present application, the filler is selected from one or more of starch, powdered sugar, magnesium oxide, pregelatinized starch, lactose monohydrate, microcrystalline cellulose, silicified microcrystalline cellulose, sugar alcohols, inorganic calcium salts; preferably, the sugar alcohol filler is selected from one or more of mannitol, sorbitol and xylitol, and the inorganic calcium salt filler is selected from one or more of calcium phosphate, calcium hydrogen phosphate, calcium sulfate and calcium carbonate; preferably, the filler is selected from one or more of pregelatinized starch, lactose monohydrate, microcrystalline cellulose, mannitol, sorbitol, anhydrous dibasic calcium phosphate, dibasic calcium sulfate dihydrate, and calcium carbonate; further preferably, the filler is selected from one or more of pregelatinized starch, lactose monohydrate, microcrystalline cellulose, mannitol, anhydrous dibasic calcium phosphate, and calcium carbonate; further preferably, the filler is selected from one or more of pregelatinized starch, lactose monohydrate, microcrystalline cellulose, anhydrous dibasic calcium phosphate, or mannitol; further preferably, the filler is selected from one or more of pregelatinized starch, lactose monohydrate, microcrystalline cellulose, or mannitol.

In some embodiments of the present application, the filler is selected from one of pregelatinized starch, anhydrous dibasic calcium phosphate, calcium carbonate, microcrystalline cellulose, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose monohydrate, or a combination of pregelatinized starch and anhydrous dibasic calcium phosphate, or a combination of pregelatinized starch and calcium carbonate, or a combination of pregelatinized starch and lactose monohydrate; preferably, the filler is selected from one of pregelatinized starch, anhydrous calcium hydrogen phosphate and microcrystalline cellulose, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose monohydrate, or a combination of pregelatinized starch and anhydrous calcium hydrogen phosphate, or a combination of pregelatinized starch and calcium carbonate; further preferably, the filler is selected from: one of pregelatinized starch or microcrystalline cellulose, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose monohydrate, or a combination of pregelatinized starch and anhydrous dibasic calcium phosphate, or a combination of pregelatinized starch and calcium carbonate; further preferably, the filler is selected from: one of pregelatinized starch or microcrystalline cellulose, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose monohydrate.

In some embodiments of the present application, the weight ratio of the two fillers in the combination of pregelatinized starch and mannitol, microcrystalline cellulose and lactose monohydrate, pregelatinized starch and anhydrous dibasic calcium phosphate, pregelatinized starch and lactose monohydrate, or pregelatinized starch and calcium carbonate is 1:10 to 10:1; or 1:7 to 7:1; or 1:6-6:1, or 1:5-5:1; or 1:4-4:1; or 1:3 to 3:1; or 1:2-2:1; or 2:1.

In some embodiments of the present application, the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, silica, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate, or polyethylene glycols; preferably one or more of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, sodium benzoate, sodium lauryl sulfate, talc, silica, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulfate or magnesium lauryl sulfate; further preferred are one or more of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, sodium benzoate, sodium lauryl sulfate, talc, silica, zinc stearate, sodium stearyl fumarate, magnesium stearyl fumarate or magnesium lauryl sulfate; further preferred is one or more of talc, magnesium stearate, calcium stearate or sodium stearyl fumarate; still more preferred is sodium stearyl fumarate.

In some embodiments of the present application, the glidant is selected from one or more of colloidal silicon dioxide, talc or aluminum hydroxide; preferably colloidal silica.

In some embodiments of the present application, the lubricating auxiliary material is a combination of a lubricant and a glidant, wherein the weight ratio of the glidant to the lubricant is 1:6-6:1; or 1:5-5:1; or 1:4-4:1; or 1:3 to 3:1; or 1:2-2:1; or 1:1, 1:2, 1:1.5, 2:1, 2:3, 3:1, 3:2, 4:3 or 5:3.

In some embodiments of the present application, the pharmaceutical composition comprises a disintegrant selected from one or more of dry starch, carboxymethyl cellulose, microcrystalline cellulose, powdered cellulose, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate, polyvinylpyrrolidone, maltodextrin, magnesium aluminum silicate, corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, effervescent disintegrant, sodium carboxymethyl starch, or croscarmellose sodium; preferably one or more of dry starch, pregelatinized starch, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, croscarmellose sodium or crospovidone; preferably one or more of crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch or croscarmellose sodium; further preferred are crospovidone, sodium carboxymethyl starch or croscarmellose sodium; more preferably crospovidone or croscarmellose sodium.

In some embodiments of the present application, the pharmaceutical composition comprises a binder selected from one or more of starch slurry, copovidone, sugar powder, syrup, polyvinylpyrrolidone, cellulose derivative, cement, polyethylene glycol 4000, and dextrin; preferably, the cellulose derivative is selected from methylcellulose, hydroxypropyl cellulose, ethylcellulose, and sodium carboxymethylcellulose; further preferred are copovidone, powdered sugar, polyvinylpyrrolidone, hydroxypropyl methylcellulose and sodium carboxymethylcellulose; further preferred are copovidone VA64 and polyvinylpyrrolidone.

In some embodiments of the present application, the filler is selected from one of pregelatinized starch, microcrystalline cellulose, anhydrous dibasic calcium phosphate, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose monohydrate, or a combination of pregelatinized starch and anhydrous dibasic calcium phosphate, or a combination of pregelatinized starch and calcium carbonate; the lubricating auxiliary material is a lubricant and/or a glidant, wherein the lubricant is sodium stearyl fumarate, and the glidant is colloidal silicon dioxide; optionally, the disintegrant is selected from croscarmellose sodium.

In some embodiments of the present application, the pharmaceutical composition comprises an active ingredient, a filler, a lubricant, and a glidant, wherein the filler is pregelatinized starch or microcrystalline cellulose; preferably, the glidant is colloidal silicon dioxide; further preferably, the lubricant is magnesium stearate; further preferably, the pharmaceutical composition further comprises a disintegrant selected from sodium carboxymethyl starch or croscarmellose sodium.

In some embodiments of the present application, the pharmaceutical composition comprises an active ingredient, a filler, a lubricant, and a glidant, wherein the filler is pregelatinized starch and mannitol; preferably, the glidant is colloidal silicon dioxide; further preferably, the lubricant is magnesium stearate.

In some embodiments of the present application, the pharmaceutical composition comprises an active ingredient, a filler, and a lubricant, wherein the filler is microcrystalline cellulose; preferably, the lubricant is magnesium stearate.

In some embodiments of the present application, the pharmaceutical composition comprises an active ingredient, a filler, a lubricant, a glidant, and a disintegrant, wherein the filler is microcrystalline cellulose and lactose monohydrate; preferably, the glidant is selected from colloidal silicon dioxide; further preferably, the disintegrant is selected from crospovidone or croscarmellose sodium; still more preferably, the lubricant is magnesium stearate or sodium stearyl fumarate.

In some embodiments of the present application, the pharmaceutical composition comprises an active ingredient, a filler, a lubricant, and a glidant, wherein the filler is anhydrous dibasic calcium phosphate or a combination of anhydrous dibasic calcium phosphate and pregelatinized starch; preferably, the glidant is selected from colloidal silicon dioxide; further preferably, the lubricant is magnesium stearate; still further preferably, the pharmaceutical composition further comprises a disintegrant selected from sodium carboxymethyl starch or croscarmellose sodium.

In some embodiments of the present application, the pharmaceutical composition comprises an active ingredient, a filler, a lubricant, and a glidant, wherein the filler is calcium carbonate or a combination of calcium carbonate and pregelatinized starch; preferably, the glidant is selected from colloidal silicon dioxide; further preferably, the lubricant is magnesium stearate; still further preferably, the pharmaceutical composition further comprises a disintegrant selected from sodium carboxymethyl starch or croscarmellose sodium; still further preferably, the pharmaceutical composition further comprises a binder selected from copovidone.

In some embodiments of the present application, the pharmaceutical composition comprises the following components in percentage by weight:

The active ingredients are 0.5-90 wt%; or 1% -90%; or 0.5% -85%; or 5% -80%; or 5% -75%; or 5% -70%; or 10% -70%; or 5% -65%; or 5% -60%; or 5% -55%; or 5% -50%; or 5% -45%; or 5% -40%; or 10% -65%; or 10% -60%; or 15% -55%; or 15% -45%; or 15% -40%; or 15% -30%;

5-99% of filler; or 10% -95%; or 15% -95%; or 15% -90%; or 15% -85%; or 15% -80%; or 20% -80%; or 25% -80%; or 25% -75%; or 30% -75%; or 35% -90%; or 35% -75%; or 40% -90%; or 40% -75%; or 45% -75%; or 50% -90%; or 50% -75%; or 55% -75%;

0 to 20 weight percent of disintegrating agent; or 0% -15%; or 0% -10%; or 0% -8%; or 0% -6%; or 0% -5%; or 0% -4%; or 0.5% -4%; or 1% -4%; or 1.5% -4%; or 2% -4%; or 3% -4%;

Lubricating auxiliary materials, the weight percentage of which is 0-18%; or 0.1% -18%; or 0% -15%; or 0.1% -15%; or 0% -10%; or 0.1% -10%; or 0% -8%; or 0% -7%; or 0% -6%; or 1% -6%; or 0.5% -6%; or 0% -5%; or 1% -5%; or 1.5% -4.5%; or 2% -4%; or 2% -3%; or 2.5% -5%; or 3% -4%;

other excipients, the weight percentage of which is 0-25%; or 0% -20%; or 0% -15%; or 0% -10%; or 0% -5%; and is also provided with

The sum of the weight percentages of the components is 100 percent.

the active ingredients comprise 1-90 wt%, preferably 5-80 wt%, 5-65 wt%, 5-55 wt%, 15-45 wt% or 15-30 wt%;

10-95% of filler, preferably 25-90%, 35-85%, 40-80% or 50-80% of filler by weight;

0 to 15 weight percent of disintegrating agent, preferably 0 to 10 weight percent, 0 to 6 weight percent, 0 to 5 weight percent or 0 to 4 weight percent;

The lubricating auxiliary material comprises, by weight, 0% -18%, preferably 0.1% -18%, 0% -15%, 0% -10%, 0% -6%, 0% -5%, 0.1% -15%, 0.1% -10%, 0.5% -0%, 1% -5%, 2.5% -4.5% or 3% -4%;

other excipients, the weight percentage of which is 0-25%, preferably 0-20%, 0-15%, 0-10% or 0-5%; and the sum of the weight percentages of the components is 100 percent.

In some embodiments of the present application, the lubricating adjuvant is a lubricant.

0.5 to 90 percent of active ingredient, 5 to 99 percent of filling agent, 0 to 20 percent of disintegrating agent, 0 to 10 percent of adhesive, 0.1 to 15 percent of lubricating auxiliary material and 0 to 25 percent of other excipient; or alternatively

5 to 80 percent of active ingredient, 10 to 95 percent of filling agent, 0 to 15 percent of disintegrating agent, 0 to 6 percent of adhesive, 0.50 to 10 percent of lubricating auxiliary material and 0 to 15 percent of other excipient; or alternatively

5 to 80 percent of active ingredient, 15 to 85 percent of filler, 0 to 5 percent of disintegrating agent, 0 to 4 percent of adhesive, 0 to 7 percent of lubricating auxiliary material and 0 to 10 percent of other excipient; or alternatively

5 to 80 percent of active ingredient, 15 to 80 percent of filler, 0 to 4 percent of disintegrating agent, 0 to 3 percent of adhesive, 1 to 6 percent of lubricating auxiliary material and 0 to 5 percent of other excipient; the sum of the weight percentages of the components is 100 percent.

In some aspects of the present application, the aforementioned pharmaceutical composition comprises the following components in percentage by weight:

5 to 90 percent of active ingredient, 5 to 90 percent of filler, 0 to 5 percent of disintegrating agent, 0 to 5 percent of adhesive, 1 to 7 percent of lubricating auxiliary material and 0 to 5 percent of other excipient; or alternatively

10% -90% of active ingredient, 15% -90% of filler, 0% -5% of disintegrating agent, 0% -4% of adhesive, 1% -6% of lubricating auxiliary material and 0% -5% of other excipient; or alternatively

10% -80% of active ingredient, 15% -85% of filler, 0% -5% of disintegrating agent, 0% -4% of adhesive, 3% -5% of lubricating auxiliary material and 0% -5% of other excipient; or alternatively

10 to 80 percent of active ingredient, 15 to 85 percent of filling agent, 0 to 5 percent of disintegrating agent, 0 to 4 percent of adhesive, 3.5 to 6 percent of lubricating auxiliary material and 0 to 5 percent of other excipient; or alternatively

10% -80% of active ingredient, 15% -85% of filler, 0% -5% of disintegrating agent, 0% -4% of adhesive, 4% -6% of lubricating auxiliary material and 0% -5% of other excipient; or alternatively

25% -60% of active ingredient, 35% -70% of filler, 0% -4% of disintegrating agent, 0% -3% of adhesive, 5% -6% of lubricating auxiliary material and 0% -5% of other excipient; or alternatively

The sum of the weight percentages of the components is 100 percent.

In some embodiments of the present application, the filler is selected from the group consisting of: one of pregelatinized starch, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and calcium carbonate, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose monohydrate, or a combination of pregelatinized starch and anhydrous calcium hydrogen phosphate, or a combination of pregelatinized starch and calcium carbonate; the lubricating auxiliary material is a lubricant and/or a glidant, wherein the lubricant is sodium stearate fumarate, and the glidant is colloidal silicon dioxide; the disintegrating agent is selected from crospovidone and croscarmellose sodium; the binder is selected from copovidone; preferably copovidone VA64 and/or copovidone VA64Fine.

In some embodiments of the present application, the filler is selected from the group consisting of a combination of pregelatinized starch and mannitol, microcrystalline cellulose and lactose monohydrate, a combination of pregelatinized starch and anhydrous dibasic calcium phosphate, a combination of pregelatinized starch and lactose monohydrate, or a combination of pregelatinized starch and calcium carbonate, where the weight ratio of the two fillers is from 1:10 to 10:1, preferably from 1:7 to 7:1, more preferably from 1:6 to 6:1, more preferably from 1:5 to 5:1, more preferably from 1:4 to 4:1, more preferably from 1:3 to 3:1, more preferably from 1:2 to 2:1, and even more preferably 2:1.

0.5 to 90 percent of active ingredient, 5 to 99 percent of filler, 0 to 20 percent of disintegrating agent, 0 to 10 percent of adhesive, 0 to 10 percent of lubricant, 0 to 10 percent of glidant and 0 to 25 percent of other excipient; or alternatively

5 to 80 percent of active ingredient, 10 to 95 percent of filling agent, 0 to 10 percent of disintegrating agent, 0 to 6 percent of adhesive, 0 to 5 percent of lubricant, 0 to 5 percent of glidant and 0 to 25 percent of other excipient; or alternatively

5 to 80 percent of active ingredient, 15 to 85 percent of filler, 0 to 6 percent of disintegrating agent, 0 to 5 percent of adhesive, 1 to 4 percent of lubricant, 0 to 4 percent of glidant and 0 to 15 percent of other excipient; or alternatively

5 to 80 percent of active ingredient, 15 to 80 percent of filler, 0 to 5 percent of disintegrating agent, 0 to 4 percent of adhesive, 1 to 3.50 percent of lubricant, 0 to 3.50 percent of glidant and 0 to 10 percent of other excipient; or alternatively

5 to 80 percent of active ingredient, 15 to 80 percent of filler, 0 to 4 percent of disintegrating agent, 0 to 3 percent of adhesive, 1 to 3 percent of lubricant, 0 to 3 percent of glidant and 0 to 5 percent of other excipient; the sum of the weight percentages of the components is 100 percent.

5 to 90 percent of active ingredient, 5 to 90 percent of filler, 0 to 5 percent of disintegrating agent, 0 to 5 percent of adhesive, 1 to 5 percent of lubricant, 0 to 5 percent of glidant and 0 to 5 percent of other excipient; or alternatively

5 to 90 percent of active ingredient, 5 to 90 percent of filler, 0 to 5 percent of disintegrating agent, 0 to 5 percent of adhesive, 1 to 4 percent of lubricant, 0 to 4 percent of glidant and 0 to 5 percent of other excipient; or alternatively

10% -90% of active ingredient, 15% -90% of filler, 0% -5% of disintegrating agent, 0% -4% of adhesive, 1% -3% of lubricant, 0% -3% of glidant and 0% -5% of other excipient; or alternatively

10% -90% of active ingredient, 15% -90% of filler, 0% -4% of disintegrating agent, 0% -3% of adhesive, 1% -3% of lubricant, 0% -3% of glidant and 0% -5% of other excipient; or alternatively

The sum of the weight percentages of the components is 100 percent.

In some embodiments of the present application, the filler is selected from the group consisting of: one of pregelatinized starch, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and calcium carbonate, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose monohydrate, or a combination of pregelatinized starch and anhydrous calcium hydrogen phosphate, or a combination of pregelatinized starch and calcium carbonate; the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate; the glidant is colloidal silicon dioxide; the disintegrating agent is selected from carboxymethyl starch sodium and cross-linked sodium carboxymethyl cellulose; the binder is copovidone, preferably copovidone VA64.

In some embodiments of the present application, the filler is selected from the group consisting of a combination of pregelatinized starch and mannitol, microcrystalline cellulose and lactose monohydrate, a combination of pregelatinized starch and anhydrous dibasic calcium phosphate, a combination of pregelatinized starch and lactose monohydrate, or a combination of pregelatinized starch and calcium carbonate, preferably, the weight ratio of the two fillers is 1:10 to 10:1, preferably 1:7 to 7:1, more preferably 1:6 to 6:1, more preferably 1:5 to 5:1, more preferably 1:4 to 4:1, more preferably 1:3 to 3:1, more preferably 1:2 to 2:1, and even more preferably 1:1.

5 to 45 percent of active ingredient, 50 to 90 percent of filler, 0 to 5 percent of disintegrating agent, 0 to 5 percent of adhesive, 1 to 5 percent of lubricant, 0 to 5 percent of glidant and 0 to 5 percent of other excipient; or alternatively

5 to 40 percent of active ingredient, 50 to 90 percent of filler, 0 to 5 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 4 percent of lubricant, 1 to 4 percent of glidant and 0 to 5 percent of other excipient; or alternatively

5 to 40 percent of active ingredient, 50 to 90 percent of filler, 0 to 5 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 1 to 3 percent of glidant and 0 to 5 percent of other excipient; or alternatively

5 to 40 percent of active ingredient, 50 to 90 percent of filler, 0 to 5 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 1 to 2 percent of glidant and 0 to 5 percent of other excipient; or alternatively

20 to 45 percent of active ingredient, 50 to 75 percent of filler, 0 to 5 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 1 to 2 percent of glidant and 0 to 5 percent of other excipient; or alternatively

20 to 40 percent of active ingredient, 50 to 75 percent of filler, 0 to 4 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 1 to 2 percent of glidant and 0 to 5 percent of other excipient; or alternatively

20 to 40 percent of active ingredient, 50 to 75 percent of filling agent, 0 to 4 percent of disintegrating agent, 2 to 3 percent of lubricant, 1 to 2 percent of glidant and 0 to 5 percent of other excipient; or alternatively

20-40% of active ingredient, 50-75% of filler, 2-4% of disintegrating agent, 2-3% of lubricant and 1-2% of glidant;

The sum of the weight percentages of the components is 100 percent.

In some embodiments of the present application, the filler is selected from the group consisting of: pregelatinized starch or microcrystalline cellulose, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose monohydrate; the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate; the glidant is colloidal silicon dioxide; the disintegrating agent is selected from carboxymethyl starch sodium and cross-linked sodium carboxymethyl cellulose; the binder is copovidone, preferably copovidone VA64.

In some embodiments of the present application, the filler is selected from the group consisting of a combination of pregelatinized starch and mannitol, a combination of microcrystalline cellulose and lactose monohydrate, preferably, the weight ratio of the two fillers is 1:10 to 10:1, preferably 1:7 to 7:1, more preferably 1:6 to 6:1, more preferably 1:5 to 5:1, more preferably 1:4 to 4:1, more preferably 1:3 to 3:1, more preferably 1:2 to 2:1, and even more preferably 1:1.

15 to 45 percent of active ingredient, 50 to 75 percent of filler, 1 to 5 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 4 percent of lubricant, 3 to 4 percent of glidant and 0 to 5 percent of other excipient; or alternatively

20 to 40 percent of active ingredient, 50 to 75 percent of filler, 2 to 4 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 2 to 4 percent of glidant and 0 to 5 percent of other excipient; or alternatively

20-40% of active ingredient, 50-75% of filler, 2-4% of disintegrating agent, 2-3% of lubricant and 2-4% of glidant;

the sum of the weight percentages of the components is 100 percent.

In some embodiments of the present application, the filler is selected from the group consisting of: a combination of microcrystalline cellulose and lactose monohydrate; preferably, the weight ratio of the two fillers is 1:10 to 10:1, preferably 1:7 to 7:1, more preferably 1:6 to 6:1, more preferably 1:5 to 5:1, more preferably 1:4 to 4:1, more preferably 1:3 to 3:1, more preferably 1:2 to 2:1, more preferably 2:1; the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate; the glidant is colloidal silicon dioxide; the disintegrating agent is selected from carboxymethyl starch sodium and cross-linked sodium carboxymethyl cellulose; the binder is copovidone, preferably copovidone VA64.

10% -90% of active ingredient, 5% -90% of filler, 0% -5% of disintegrating agent, 0% -5% of adhesive, 1% -4% of lubricant, 1% -4% of glidant and 0% -5% of other excipient; or alternatively

10% -90% of active ingredient, 5% -90% of filler, 0% -5% of disintegrating agent, 0% -4% of adhesive, 1% -3% of lubricant, 1% -3% of glidant and 0% -5% of other excipient; or alternatively

15 to 70 percent of active ingredient, 20 to 80 percent of filling agent, 0 to 5 percent of disintegrating agent, 0 to 4 percent of adhesive, 1 to 3 percent of lubricant, 1 to 3 percent of glidant and 0 to 5 percent of other excipient; or alternatively

15 to 70 percent of active ingredient, 20 to 80 percent of filling agent, 0 to 4 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 1 to 2 percent of glidant and 0 to 5 percent of other excipient; or alternatively

15-70% of active ingredient, 20-80% of filler, 0-4% of disintegrating agent, 0-3% of adhesive, 2-3% of lubricant and 1-2% of glidant;

The sum of the weight percentages of the components is 100 percent.

In some embodiments of the present application, the filler is selected from the group consisting of: anhydrous dibasic calcium phosphate or calcium carbonate, or a combination of pregelatinized starch and anhydrous dibasic calcium phosphate, or a combination of pregelatinized starch and calcium carbonate; the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate; the glidant is colloidal silicon dioxide; the disintegrating agent is selected from carboxymethyl starch sodium and cross-linked sodium carboxymethyl cellulose; the binder is copovidone, preferably copovidone VA64.

In some embodiments of the present application, the filler is selected from the group consisting of a combination of pregelatinized starch and anhydrous dibasic calcium phosphate, or a combination of pregelatinized starch and calcium carbonate, preferably, the weight ratio of the two fillers is 1:10 to 10:1, preferably 1:7 to 7:1, more preferably 1:6 to 6:1, more preferably 1:5 to 5:1, more preferably 1:4 to 4:1, more preferably 1:3 to 3:1, more preferably 1:2 to 2:1, and even more preferably 1:1.

5 to 80 percent of active ingredient, 15 to 80 percent of filler, 0 to 4 percent of disintegrating agent, 0 to 3 percent of adhesive, 1 to 3 percent of lubricant, 0 to 3 percent of glidant and 0 to 5 percent of other excipient; or alternatively

5 to 80 percent of active ingredient, 15 to 80 percent of filler, 0 to 4 percent of disintegrating agent, 0 to 3 percent of adhesive, 1 to 3 percent of lubricant, 1 to 5 percent of glidant and 0 to 5 percent of other excipient; or alternatively

5 to 80 percent of active ingredient, 15 to 80 percent of filler, 0 to 4 percent of disintegrating agent, 0 to 3 percent of adhesive, 1 to 3 percent of lubricant, 1 to 3 percent of glidant and 0 to 5 percent of other excipient; or alternatively

The sum of the weight percentages of the components is 100 percent; wherein the filler is pregelatinized starch; the lubricant is magnesium stearate; the glidant is colloidal silicon dioxide; the disintegrating agent is selected from sodium carboxymethyl starch and/or croscarmellose sodium; the binder is copovidone.

20 to 45 percent of active ingredient, 40 to 80 percent of filler, 0 to 5 percent of disintegrating agent, 0 to 5 percent of adhesive, 2 to 5 percent of lubricant, 1 to 5 percent of glidant and 0 to 5 percent of other excipient; or alternatively

20 to 45 percent of active ingredient, 40 to 80 percent of filler, 0 to 3 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 4 percent of lubricant, 1 to 4 percent of glidant and 0 to 5 percent of other excipient; or alternatively

20 to 45 percent of active ingredient, 40 to 80 percent of filler, 0 to 3 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 2 to 4 percent of glidant and 0 to 5 percent of other excipient; or alternatively

20 to 45 percent of active ingredient, 40 to 80 percent of filler, 0 to 3 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 3 to 4 percent of glidant and 0 to 5 percent of other excipient; or alternatively

25 to 40 percent of active ingredient, 50 to 75 percent of filler, 0 to 3 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 3 to 4 percent of glidant and 0 to 5 percent of other excipient; or alternatively

25 to 40 percent of active ingredient, 50 to 70 percent of filler, 0 to 3 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 3 to 4 percent of glidant and 0 to 5 percent of other excipient; or alternatively

In some embodiments of the present invention, the pharmaceutical composition comprises the following components in percentage by weight:

5 to 65 percent of active ingredient, 35 to 90 percent of pregelatinized starch, 0 to 6 percent of disintegrating agent, 0.1 to 5 percent of lubricant, 1 to 5 percent of glidant and 0 to 25 percent of other excipient; or alternatively

5 to 55 percent of active ingredient, 40 to 90 percent of pregelatinized starch, 0 to 5 percent of disintegrating agent, 0.1 to 4 percent of lubricant, 1 to 5 percent of glidant and 0 to 20 percent of other excipient; or alternatively

5 to 40 percent of active ingredient, 50 to 90 percent of pregelatinized starch, 0 to 3 percent of disintegrating agent, 1 to 3 percent of lubricant, 1 to 5 percent of glidant and 0 to 15 percent of other excipient; or 5% -40% of active ingredient, 50% -90% of pregelatinized starch, 0% -3% of disintegrating agent, 1% -3% of lubricant, 1% -5% of colloidal silicon dioxide and 0% -10% of other excipient; or 5 to 40 percent of active ingredient, 50 to 90 percent of pregelatinized starch, 0 to 3 percent of disintegrating agent, 1 to 3 percent of magnesium stearate, 1 to 5 percent of colloidal silicon dioxide and 0 to 5 percent of other excipient; or alternatively

5 to 40 percent of active ingredient, 50 to 90 percent of pregelatinized starch, 0 to 3 percent of carboxymethyl starch sodium or cross-linked sodium carboxymethyl cellulose, 1 to 3 percent of magnesium stearate and 1 to 5 percent of colloidal silicon dioxide;

the sum of the weight percentages of the components is 100 percent.

20 to 45 percent of active ingredient, 40 to 80 percent of pregelatinized starch, 0 to 5 percent of disintegrating agent, 0 to 5 percent of adhesive, 2 to 5 percent of lubricant, 1 to 5 percent of glidant and 0 to 5 percent of other excipient; or alternatively

20 to 45 percent of active ingredient, 40 to 80 percent of pregelatinized starch, 0 to 3 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 4 percent of lubricant, 1 to 4 percent of glidant and 0 to 5 percent of other excipient; or alternatively

20 to 45 percent of active ingredient, 40 to 80 percent of pregelatinized starch, 0 to 3 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 2 to 4 percent of colloidal silicon dioxide and 0 to 5 percent of other excipient; or alternatively

20 to 45 percent of active ingredient, 40 to 80 percent of pregelatinized starch, 0 to 3 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 3 to 4 percent of colloidal silicon dioxide and 0 to 5 percent of other excipient; or alternatively

25 to 40 percent of active ingredient, 50 to 75 percent of pregelatinized starch, 0 to 3 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 3 to 4 percent of colloidal silicon dioxide and 0 to 5 percent of other excipient; or alternatively

25% -40% of active ingredient, 50% -70% of pregelatinized starch 0% -3% of disintegrating agent, 0% -3% of adhesive, 2% -3% of lubricant and 3% -4% of colloidal silicon dioxide; the sum of the weight percentages of the components is 100 percent;

preferably, the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate; preferably, the glidant is selected from colloidal silicon dioxide; preferably, the disintegrant is selected from one or both of sodium carboxymethyl starch and croscarmellose sodium; preferably, the binder is copovidone, more preferably copovidone VA64.

5 to 65 percent of active ingredient, 10 to 95 percent of filler (pregelatinized starch and mannitol), 0 to 6 percent of disintegrating agent, 0.1 to 5 percent of lubricant, 1 to 5 percent of glidant and 0 to 25 percent of other excipient; or alternatively

5 to 65 percent of active ingredient, 5 to 30 percent of pregelatinized starch, 5 to 65 percent of mannitol, 0 to 6 percent of disintegrating agent, 0.1 to 5 percent of lubricant, 1 to 5 percent of glidant and 0 to 20 percent of other excipient; or alternatively

5 to 55 percent of active ingredient, 5 to 30 percent of pregelatinized starch, 5 to 65 percent of mannitol, 0 to 5 percent of disintegrating agent, 0.1 to 4 percent of lubricant, 1 to 5 percent of glidant and 0 to 15 percent of other excipient; or alternatively

5 to 40 percent of active ingredient, 5 to 30 percent of pregelatinized starch, 5 to 65 percent of mannitol, 0 to 3 percent of disintegrating agent, 1 to 3 percent of lubricant, 1 to 5 percent of glidant and 0 to 10 percent of other excipient; or alternatively

5 to 40 percent of active ingredient, 5 to 30 percent of pregelatinized starch, 5 to 65 percent of mannitol, 0 to 3 percent of disintegrating agent, 1 to 3 percent of lubricant, 1 to 5 percent of colloidal silicon dioxide and 0 to 10 percent of other excipient; or alternatively

5 to 40 percent of active ingredient, 5 to 30 percent of pregelatinized starch, 5 to 65 percent of mannitol, 0 to 3 percent of disintegrating agent, 1 to 3 percent of magnesium stearate, 1 to 5 percent of colloidal silicon dioxide and 0 to 5 percent of other excipient; or alternatively

5 to 40 percent of active ingredient, 5 to 30 percent of pregelatinized starch, 5 to 65 percent of mannitol, 0 to 3 percent of carboxymethyl starch sodium or cross-linked carboxymethyl cellulose sodium, 1 to 3 percent of magnesium stearate and 1 to 5 percent of colloidal silicon dioxide;

The sum of the weight percentages of the components is 100 percent;

preferably, the weight ratio of pregelatinized starch to mannitol is 1:10 to 10:1, preferably 1:7 to 7:1, more preferably 1:6 to 6:1, more preferably 1:5 to 5:1, more preferably 1:4 to 4:1, more preferably 1:3 to 3:1, more preferably 1:2 to 2:1.

5 to 45 percent of active ingredient, 50 to 90 percent of filler (pregelatinized starch and mannitol), 0 to 3 percent of disintegrating agent, 0 to 4 percent of adhesive, 2 to 4 percent of lubricant, 2.5 to 5 percent of glidant and 0 to 5 percent of other excipient; or alternatively

5 to 45 percent of active ingredient, 5 to 60 percent of pregelatinized starch, 5 to 65 percent of mannitol, 0 to 3 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 4 percent of lubricant, 2.5 to 5 percent of glidant and 0 to 5 percent of other excipient; or alternatively

25% -45% of active ingredient, 5% -55% of pregelatinized starch, 5% -65% of mannitol, 0% -3% of disintegrating agent, 0% -3% of adhesive, 2% -4% of lubricant, 3% -4% of glidant and 0% -5% of other excipient; the sum of the weight percentages of the components is 100 percent;

Preferably, the weight ratio of pregelatinized starch to mannitol is 1:10-10:1, preferably 1:7-7:1, more preferably 1:6-6:1, more preferably 1:5-5:1, more preferably 1:4-4:1, more preferably 1:3-3:1, more preferably 1:2-2:1; preferably, the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate; preferably, the glidant is selected from colloidal silicon dioxide; preferably, the disintegrant is selected from one or both of sodium carboxymethyl starch and croscarmellose sodium; preferably, the binder is copovidone, preferably copovidone VA64.

5 to 65 percent of active ingredient, 10 to 95 percent of filling agent (microcrystalline cellulose and lactose monohydrate), 0 to 6 percent of disintegrating agent, 0.1 to 5 percent of lubricant, 0.5 to 5 percent of glidant and 0 to 25 percent of other excipient; or alternatively

5 to 65 percent of active ingredient, 5 to 50 percent of microcrystalline cellulose, 5 to 45 percent of lactose monohydrate, 0 to 6 percent of disintegrating agent, 0.1 to 5 percent of lubricant, 0.5 to 5 percent of glidant and 0 to 20 percent of other excipient; or alternatively

5 to 55 percent of active ingredient, 15 to 50 percent of microcrystalline cellulose, 10 to 45 percent of lactose monohydrate, 0 to 5 percent of disintegrating agent, 0.1 to 4 percent of lubricant, 0.5 to 5 percent of glidant and 0 to 15 percent of other excipient; or alternatively

5 to 40 percent of active ingredient, 15 to 50 percent of microcrystalline cellulose, 10 to 45 percent of lactose monohydrate, 0 to 4 percent of disintegrating agent, 1 to 2 percent of lubricant, 0.5 to 5 percent of glidant and 0 to 10 percent of other excipient; or alternatively

5 to 40 percent of active ingredient, 15 to 50 percent of microcrystalline cellulose, 10 to 45 percent of lactose monohydrate, 0 to 4 percent of disintegrating agent, 1 to 2 percent of lubricant, 0.5 to 5 percent of colloidal silicon dioxide and 0 to 10 percent of other excipient; or alternatively

5 to 40 percent of active ingredient, 15 to 50 percent of microcrystalline cellulose, 10 to 45 percent of lactose monohydrate, 0 to 4 percent of disintegrating agent, 1 to 2 percent of sodium stearyl fumarate, 0.5 to 5 percent of colloidal silicon dioxide and 0 to 5 percent of other excipient; or alternatively

5 to 40 percent of active ingredient, 20 to 50 percent of microcrystalline cellulose, 10 to 45 percent of lactose monohydrate, 0 to 4 percent of crospovidone or croscarmellose sodium, 1 to 2 percent of sodium stearyl fumarate and 0.5 to 5 percent of colloidal silicon dioxide;

5 to 40 percent of active ingredient, 20 to 50 percent of microcrystalline cellulose, 10 to 30 percent of lactose monohydrate, 1 to 4 percent of crospovidone or croscarmellose sodium, 1 to 2 percent of sodium stearyl fumarate and 0.5 to 3 percent of colloidal silicon dioxide;

the sum of the weight percentages of the components is 100 percent;

preferably, the weight ratio of microcrystalline cellulose to lactose monohydrate is from 1:10 to 10:1, preferably from 1:7 to 7:1, more preferably from 1:6 to 6:1, more preferably from 1:5 to 5:1, more preferably from 1:4 to 4:1, more preferably from 1:3 to 3:1, more preferably from 1:2 to 2:1.

20 to 45 percent of active ingredient, 50 to 75 percent of filling agent (microcrystalline cellulose and lactose monohydrate), 0 to 5 percent of disintegrating agent, 0 to 5 percent of adhesive, 2 to 4 percent of lubricant, 2 to 4 percent of glidant and 0 to 5 percent of other excipient; or alternatively

20 to 45 percent of active ingredient, 50 to 75 percent of filling agent (microcrystalline cellulose and lactose monohydrate), 1 to 4 percent of disintegrating agent, 0 to 4 percent of adhesive, 2 to 3 percent of lubricant, 3 to 4 percent of glidant and 0 to 5 percent of other excipient; or alternatively

20 to 45 percent of active ingredient, 15 to 50 percent of microcrystalline cellulose, 15 to 45 percent of lactose monohydrate, 1 to 4 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 3 to 4 percent of glidant and 0 to 5 percent of other excipient; or alternatively

25% -45% of active ingredient, 15% -50% of microcrystalline cellulose, 15% -45% of lactose monohydrate, 1% -3% of disintegrating agent, 0% -3% of adhesive, 2% -3% of lubricant, 3% -4% of glidant and 0% -5% of other excipient; or the sum of the weight percentages of the components is 100 percent;

preferably, the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate; preferably, the glidant is selected from colloidal silicon dioxide; preferably, the disintegrant is selected from one or both of sodium carboxymethyl starch and croscarmellose sodium; preferably, the binder is copovidone, preferably copovidone VA64.

10 to 90 percent of active ingredient, 5 to 85 percent of anhydrous calcium hydrophosphate, 0 to 3 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 1 to 3 percent of glidant and 0 to 5 percent of other excipient; or alternatively

10 to 80 percent of active ingredient, 15 to 85 percent of anhydrous calcium hydrophosphate, 0 to 3 percent of disintegrating agent, 0 to 3 percent of adhesive, 2 to 3 percent of lubricant, 1 to 3 percent of glidant and 0 to 5 percent of other excipient; and the sum of the weight percentages of the components is 100 percent;

15 to 80 percent of active ingredient, 5 to 20 percent of anhydrous calcium hydrophosphate, 5 to 60 percent of pregelatinized starch, 0 to 3 percent of disintegrating agent, 0 to 3 percent of adhesive, 1.5 to 3 percent of lubricant, 2 to 3 percent of glidant and 0 to 5 percent of other excipient;

and the sum of the weight percentages of the components is 100 percent;

10% -80% of active ingredient, 15% -75% of calcium carbonate, 0% -5% of disintegrating agent, 0% -3% of adhesive, 2% -3% of lubricant, 2% -3% of glidant and 0% -5% of other excipient; or alternatively

10% -80% of active ingredient, 15% -75% of calcium carbonate, 0.5% -4% of disintegrating agent, 0% -3% of adhesive, 2% -3% of lubricant, 2% -3% of glidant and 0% -5% of other excipient;

and the sum of the weight percentages of the components is 100 percent;

10% -80% of active ingredient, 5% -40% of calcium carbonate, 5% -60% of pregelatinized starch, 0% -2% of disintegrating agent, 0% -3% of adhesive, 2% -3% of lubricant, 2% -3% of glidant and 0% -5% of other excipient; or alternatively

10 to 80 percent of active ingredient, 5 to 40 percent of calcium carbonate, 5 to 60 percent of pregelatinized starch, 0 to 2 percent of disintegrating agent, 0 to 2 percent of adhesive, 2 to 3 percent of lubricant, 2 to 3 percent of glidant and 0 to 5 percent of other excipient;

and the sum of the weight percentages of the components is 100 percent;

5 to 65 percent of active ingredient, 10 to 95 percent of microcrystalline cellulose, 0 to 6 percent of disintegrating agent, 0.1 to 5 percent of lubricant, 0 to 10 percent of glidant and 0 to 25 percent of other excipient; or alternatively

5 to 55 percent of active ingredient, 20 to 85 percent of microcrystalline cellulose, 0 to 5 percent of disintegrating agent, 0.1 to 4 percent of lubricant, 0 to 8 percent of glidant and 0 to 20 percent of other excipient; or alternatively

5% -45% of active ingredient, 30% -75% of microcrystalline cellulose, 0% -4% of disintegrating agent, 1% -3% of lubricant, 0% -3% of glidant and 0% -10% of other excipient;

the sum of the weight percentages of the components is 100 percent.

In some embodiments of the present application, the pharmaceutical compositions of the above (first, second aspects) may further contain other excipients in addition to the type of excipient. The other excipients are selected from: binders, flavoring agents, bacteriostats, pH adjusters, pigments, thickeners, dispersants, colorants, antioxidants, stabilizers, fragrances, coating materials, and the like. In embodiments of the present application, the weight percentage of other excipients in the pharmaceutical composition is 0% to 25%, preferably 0% to 20%, 0% to 15%, 0% to 10% or 0% to 5%.

In some aspects of the present application, when the pharmaceutical composition of the present invention is a solid preparation in unit dosage form (e.g., a tablet, powder, dry suspension, granule or capsule), the pharmaceutical composition comprises 1mg to 750mg, alternatively 1 to 500mg, alternatively 10mg to 300mg of the active ingredient (i.e., the drug substance of the present invention) per unit dose; or 25-300mg; or 25-200mg; or 25-150mg; or 25-125mg; or 50-125mg; or 25mg; or 50mg; or 75mg; or 100mg; or 125mg; or 150mg; or 200mg. The dosage of the active ingredient is calculated as the free base; the solid preparation can be applied in single dose or divided dose.

In some aspects of the present application, a method is provided, the method comprising: the method comprises the step of administering to a patient a daily dose of 1-1800 mg/day of compound I, or 1-600 mg/day of compound of formula (I), or 25-600 mg/day of compound of formula (I), or 50-600 mg/day of compound of formula (I), or 100-500 mg/day of compound of formula (I), or 100-400 mg/day of compound of formula (I), or 200-600 mg/day of compound of formula (I), or 200-500 mg/day of compound of formula (I), or 200-400 mg/day of compound of formula (I), or 100-300 mg/day of compound of formula (I), or 300-1800 mg/day of compound of formula (I), or 600-1350 mg/day of compound of formula (I), or 100 mg/1350 mg/day of compound of formula (I).

Preferably, the daily dose is administered at 50mg; or 75mg; or 100mg; or 125mg; or 150mg; or 200mg; or 300mg; or 400mg; or 500mg; or 600mg; or 900mg; or 1350mg; or 1800mg of the compound of formula (I).

The preferred embodiments of the present invention may be arbitrarily combined.

In a third aspect of the present application, there is provided a pharmaceutical composition which is a sustained release composition comprising: a compound of formula I or a pharmaceutically acceptable salt, solvate thereof as an active ingredient; polymeric carriers, solubilizing agents, and other excipients; the excipient includes one or more of filler, binder, glidant and lubricant.

In some aspects of the present application, the coating further comprises a coating layer, preferably a film coating.

In some embodiments of the present application, the compound of formula I is in its crystalline form; the compound of the formula I is in the form of a crystal form A or a crystal form B; preferred are crystalline form a of the compound of formula I. Form a and form B are as described in the first and second aspects of the invention.

In some aspects of the present application, the active ingredient of the compound of formula I comprises 5.0% to 65.0% by weight of the pharmaceutical composition, or 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0%, 50.0%, 55.0%, 60.0% or 65.0%.

In some aspects of the present application, the polymeric carrier is selected from one or more of polyethylene glycol, copovidone (PVP/VA), hypromellose (e.g., K4M or K100 Lv), hypromellose acetate succinate (HPMCAS), hypromellose phthalate (HPMCP), polyvinyl acetate povidone mixture, poloxamer and carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, polyacrylic resin, ethylcellulose, carbomer, stearic acid, polyoxyethylene, polyvinyl acetate povidone mixture, glyceryl monostearate, glyceryl distearate, glyceryl behenate, cetyl alcohol, stearyl alcohol, beeswax, hydrogenated castor oil, carnauba wax, paraffin wax, white wax and microcrystalline wax.

In some aspects of the present application, the polymeric carrier comprises 5.0% to 80.0%, alternatively 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0%,50.0%,60.0%,70.0% or 80.0% by weight of the pharmaceutical composition.

In some embodiments of the present application, the filler may be a filler known in the art, preferably one or more of microcrystalline cellulose, pregelatinized starch, lactose monohydrate, mannitol, dibasic calcium phosphate, and silicified microcrystalline cellulose; for example, one or more of starch, lactose monohydrate, and mannitol.

When the polymer carrier adopts a hydrophilic gel framework material, water-soluble auxiliary materials such as lactose monohydrate, mannitol, starch and the like are preferably used as the filling agent, and the water-soluble auxiliary materials have the advantages that when the insoluble medicine is released, the water-soluble auxiliary materials are dissolved (such as lactose monohydrate, mannitol, starch and the like) to improve the porosity, and serve as a pore-forming agent to control the release performance together with the polymer carrier.

In some aspects of the present application, the filler comprises 10.0% to 60.0% by weight of the pharmaceutical composition, alternatively 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0%, 50.0%, 55.0% or 60.0%.

In some embodiments of the present application, the binder may be a tacky substance known in the art, preferably one or more of povidone (also known as polyvinylpyrrolidone, PVP), methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, copovidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, and sodium alginate.

In some aspects of the present application, the binder comprises 5.0% to 30.0% by weight of the pharmaceutical composition, alternatively 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 20.0%, 25.0% or 30.0%.

In some aspects of the present application, the solubilizing agent comprises 0.5% to 20.0% by weight of the pharmaceutical composition, alternatively 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0% or 20.0%.

In some embodiments of the present application, the solubilizing agent may be a solubilizing agent known in the art, preferably one or more of poloxamer, sodium lauryl sulfate, medium chain triglycerides, tween 80, polyoxyethylene hydrogenated castor oil, and propylene glycol monocaprylate.

In some embodiments of the present application, the lubricant may be a lubricating substance, preferably one or more of calcium stearate, magnesium stearate, zinc stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, starch, talc, and paraffin wax, and more preferably one or more of magnesium stearate, calcium stearate, and stearic acid.

In some aspects of the present application, the lubricant comprises 0% to 5%, such as 0.1%, 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, or 5.0% by weight of the pharmaceutical composition; wherein the content refers to the weight percentage of the lubricant in the total weight of the pharmaceutical composition.

In some embodiments of the present application, the additional adjuvant comprises 30.0% -80.0% by weight of the pharmaceutical composition, such as 30.0%, 35.0%, 40.0%, 45.0%, 50.0%, 55.0%, 6.0%, 65.0%, 70.0%, 75.0% or 80.0%.

In some aspects of the present application, when the pharmaceutical composition of the present application is a solid sustained-release preparation (such as a tablet, powder, dry suspension, granule or capsule) in unit dosage form, the pharmaceutical composition comprises 1mg to 600mg, or 10mg to 500mg, of the active ingredient (i.e., the drug substance described herein) per unit dosage; or 25-500mg; or 25-400mg; or 25-300mg; or 50-500mg; or 50-400mg; or 50-300mg; or 50-200mg; or 25mg; or 50mg; or 75mg; or 100mg; or 125mg; or 150mg; or 200mg; or 300mg; or 400mg; or 500mg; or 600mg. The dosage of the active ingredient is calculated as the free base.

In some aspects of the present application, a method is provided, the method comprising: the patient is administered a daily dose of 1-1800 mg/day of compound I, or 1-600 mg/day of compound I, or 25-600 mg/day of compound I, or 50-600 mg/day of compound I, or 100-500 mg/day of compound I, or 100-400 mg/day of compound I, or 200-600 mg/day of compound I, or 200-500 mg/day of compound I, or 200-400 mg/day of compound I, or 100-300 mg/day of compound I, or 300-1800 mg/day of compound I, or 600-1500 mg/day of compound I, or 600-1350 mg/day of compound I, or 600-1200 mg/day of compound I, or 900-1350 mg/day of compound I, or 1350 mg/day of compound I.

Preferably, the daily dose is administered at 50mg; or 75mg; or 100mg; or 125mg; or 150mg; or 200mg; or 300mg; or 400mg; or 500mg; or 600mg; or 900mg; or 1350mg; or 1800mg of Compound I.

In some aspects of the present application, the (first, second or third) pharmaceutical composition described above further comprises an additional component selected from one, two or more of the following additional therapeutic agents, wherein the additional therapeutic agents are selected from the group consisting of: PLpro (papin-like protease) inhibitors, master protease (Mpro/3 CLpro) inhibitors, rdR-p (RNA-dependent RNA polymerase) inhibitors, CYP3A4 inhibitors, and the like.

In some aspects of the present application, the PLpro inhibitor is selected from the group consisting of: apilimod, EIDD-2801, ribavirin, valacyclovir, beta-thymidine, aspartame, oxprenolol, doxycycline, perphenazine, iopromide, riboflavin, rapalotil, 2' -cyciocytidine, chloramphenicol, chlorglycerate, levodropropizine, cefamandole, floxuridine, tigecycline, pemetrexed, L (+) -ascorbic acid, glutathione, hesperetin, adenomethionine, madol, isotretinoin, dantrolene, sulfasalazine antibacterial agents, silibinin, nicardipine, sildenafil, platycodin, chrysin, neohesperidin baicalin, sugetriol-3, 9-diacetate, (-) -epigallocatechin gallate, phaitanin D, 2- (3, 4-dihydroxyphenyl) -2- [ [2- (3, 4-dihydroxyphenyl) -3, 4-dihydro-5, 7-dihydroxy-2H-1-benzopyran-3-yl ] oxy ] -3, 4-dihydro-2H-1-benzopyran-3, 4,5, 7-tetrol, 2-bis (3-indolyl) -3-indolone, (S) - (1S, 2R,4aS,5R,8 aS) -1-formylamino-1, 4 a-dimethyl-6-methylene-5- ((E) -2- (2-oxo-2, 5-dihydrofuran-3-yl) vinyl) decahydronaphthalen-2-yl-2-amino-3-phenylpropionate, piceatannol (Piceatannol), rosmarinic acid, and magnolol.

In some aspects of the present application, the 3CLpro inhibitor is selected from the group consisting of: lisocycloxine, chlorhexidine, alfuzosin, cilostatin, famotidine, amitraz, pra Luo Jiaan, nepafenac (Nepafenac), carvedilol, amprenavir, tigcycline, montelukast, carminic acid, mimosa, flavins, lutein, cefpiramide, fenescillin, candesaqu, nicardipine, estradiol valerate, pioglitazone, colpitan, telmisartan, doxycycline, terramycin, 5- ((1, 2-dithiolan-3-yl) valeric acid (1S, 2R,4aS,5R,8 aS) -1-formylamino-1, 4 a-dimethyl-6-methylene-5- ((E) -2- (2-oxo-2, 5-dihydrofuran-3-yl) vinyl) decahydronaphthalen-2-yl ester, tunal, white pigment-7-O-beta-glucuronide, andrographolide, 2S-2, 5- ((2S, 5-dimethyl-2-oxo-5S-2, 5-methyl-4 aS-2-methyl-5-methyl-2-formyloxy) -2-nitro-2-methyl-4-E-5-methyl-2-lactone, 2 beta-hydroxy-3, 4-seco-friedelane lactone-27-acid (S) - (1S, 2r,4as,5r,8 as) -1-formylamino-1, 4 a-dimethyl-6-methylene-5- ((E) -2- (2-oxo-2, 5-dihydrofuran-3-yl) vinyl) decahydronaphthalen-2-yl-2-amino-3-phenylpropionate, isoodendrinol, beer sterol, hesperidin, neohesperidin, andropanin, benzoic acid 2- ((1 r,5r,6r,8 as) -6-hydroxy-5- (hydroxymethyl) -5,8 a-dimethyl-2-methylenedecahydronaphthalen-1-yl) ethyl ester, cosmosstin, cleistolone a, 2-di (3-indolyl) -3-indolone, biobin, genistein, phyllamol, 3' -dio, face, berkokurtide, berkovic, norubicine, or other than 5-acetyl-5-acetyl-pterocarcinol.

In some aspects of the present application, the RdRp inhibitor is selected from the group consisting of: deuterium bromelain, valacyclovir, chlorhexidine, ceftibuzene, fenoterol, fludarabine, itraconazole, cefuroxime, atovaquone, chenodeoxycholic acid, cromolyn, panturonium bromide, cortisone, tibolone, novobiocin, silybin, idarubicin bromocriptine, diphenoxylate, benzyl penicillium G (Benzylpenicilloyl G), dabigatran etexilate, betulonal, genidilin, 2β,30β -dihydroxy-3, 4-seco-friedelane lactone-27-lactone, 14-deoxy-11, 12-didehydroandrographolide, gniditrin, 3' -di-O-gallic acid theaflavin ester, (R) - ((1R, 5as,6R,9 as) -1,5 a-dimethyl-7-methylene-3-oxo-6- ((E) -2- (2-oxo-2, 5-dihydrofuran-3-yl) vinyl) decahydro-1H-benzo [ c ] azepin-1-yl) methyl 2-amino-3-phenylpropionate, 2β -hydroxy-3, 4-seco-friedel-27-oic acid, 2- (3, 4-dihydroxyphenyl) -2- [ [2- (3, 4-dihydroxyphenyl) -3, 4-dihydro-5, 7-dihydroxy-2H-1-benzopyran-3-yl ] oxy ] -3, 4-dihydro-2H-1-benzopyran-3, 4,5, 7-tetraol, phyllaemamicin B, 14-hydroxycinnone (14-hydroxyperotodone), andrographolide, 2- ((1R, 5R,6R,8 aS) -6-hydroxy-5- (hydroxymethyl) -5,8 a-dimethyl-2-methylenedeca-naphthalen-1-yl) ethylbenzoate, andrographolide, sugetriol-3, 9-diacetate, baicalin, 5- ((1, 2-dithiolan-3-yl) pentanoic acid (1S, 2R,4aS,5R,8 aS) -1-formylamino-1, 4 a-dimethyl-6-methylene-5- ((E) -2- (2-oxo-2, 5-dihydrofuran-3-yl) vinyl) deca-hydronaphthalen-2-yl ester, 1, 7-dihydroxy-3-methoxyxanthone, 1,2, 6-trimethoxy-8- [ (6-O-beta-D-xylopyranosyl-beta-D-oxo ] -9-beta-xylopyranosyl ] -9-H-beta-xylopyranosyl-9-beta-xylo-9-xylo-6-xylo-beta-6-xylo-xanthone, 9-beta-xylo-6-xanthone, 8- (. Beta. -D-glucopyranosyloxy) -1,3, 5-trihydroxy-9H-xanthen-9-one.

In some aspects of the present application, the additional therapeutic agent is ritonavir.

In a fourth aspect of the invention, there is provided the use of a pharmaceutical composition according to the invention in the manufacture of a medicament for the prevention and/or treatment of viral diseases.

In some aspects of the present application, the medicament is for preventing and/or treating a symptom or disease caused by a virus having a 3C-like protease.

In some aspects of the present application, the medicament is for preventing and/or treating a symptom or disease caused by a virus having the major protease Mpro.

In some aspects of the present application, the medicament is for preventing and/or treating symptoms or diseases caused by SARS-CoV-2 infection.

In some aspects of the present application, the symptom or disease caused by SARS-CoV-2 is selected from the group consisting of: cold-like symptoms associated with fever, chills, headache, hypogeusia, muscle aches, general malaise, or sore throat, runny nose, nasal obstruction, cough, inflammation of the respiratory tract with sputum, gastrointestinal symptoms of abdominal pain, vomiting, diarrhea, inflammatory reactions characterized by deep airway and alveolar lesions, pulmonary fibrosis, pulmonary exudative reactive pneumonia symptoms, and further acute encephalopathy, kidney injury, liver injury, heart failure, or myocarditis complications.

In a fifth aspect of the invention, there is provided a process for preparing a pharmaceutical composition comprising formula I, comprising:

1) Preparing the bulk drugs and part of excipients into solid particles;

2) Uniformly mixing the solid particles with the rest excipient;

3) Pressing the mixed granules into a pharmaceutical composition;

optionally, the above pharmaceutical composition is coated.

The preparation method of the pharmaceutical composition containing the formula I is characterized by dry granulation.

In some embodiments of the present application, the method for preparing a pharmaceutical composition comprising formula I, comprises:

1) Rolling the crude drug and part of excipients into strips by a dry granulator, and crushing the strips into solid particles;

2) Uniformly mixing the crushed solid particles with the rest excipient;

3) And pressing the mixed granules into tablets.

Optionally, the above tablet is coated to prepare film coated tablet.

The pharmaceutical composition of the invention has the following advantages: good stability, high dissolution, excellent pharmacokinetic properties. The pharmaceutical composition provides a pharmaceutical preparation with excellent performance and good pharmacokinetics, satisfies the requirement of oral administration, and can improve the bioavailability, thereby reducing or avoiding the use of a powerful CYP enzyme inhibitor and greatly reducing the risk of patients.

Definition of the definition

The term "drug substance" refers to a drug substance used for producing various preparations, which is an active ingredient (also referred to as an active ingredient) in the preparation, is prepared by a chemical synthesis or biotechnology method and is used as a medicinal powder, crystal or the like, but cannot be directly taken by a subject.

The "compound represented by formula (I) in crystalline form" referred to herein refers to a compound represented by formula (I) in crystalline form, and includes anhydrous and solvent-free forms, hydrate forms, and solvate forms of the compound represented by formula (I). The crystalline form is preferably anhydrous and solvent-free or a hydrate form; further preferred is an anhydrous and solvent-free form.

In an X-ray powder diffraction pattern, the term "substantially" or "substantially as shown" refers to a substantially pure crystalline form in which at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks in the powder X-ray diffraction pattern appear in the given pattern. Further, as the content of a certain crystal form in a product gradually decreases, some diffraction peaks ascribed to the crystal form in the X-ray powder diffraction pattern thereof may be reduced due to factors of the detection sensitivity of the instrument. Furthermore, there may be slight errors in the position of the peaks for any given crystal form, which is also well known in the crystallography arts. For example, the position of the peak may be shifted due to a change in temperature at the time of analyzing the sample, a shift in the sample, calibration of the instrument, or the like, and a measurement error of the 2θ value is sometimes about ±0.3°, typically about ±0.2°. Thus, this error should be taken into account when determining each crystal structure, and the term "substantially" or "substantially as shown in the drawings" is also intended to cover such differences in diffraction peak positions, meaning ± 0.3 °, preferably ± 0.2 °.

In a DSC profile, the term "substantially" or "substantially as shown" means that for an isomorphous form of an isomorphous compound, the errors in the thermal transition onset temperature, endothermic peak temperature, exothermic peak temperature, melting point, etc., are typically within about 8 ℃, usually within about 5 ℃, usually within about 3 ℃ in successive assays. When describing a compound as having a given thermal transition onset temperature, endothermic peak temperature, exothermic peak temperature, melting point, etc., this temperature is referred to as + -5 deg.c.

The term "preventing" as used herein refers to a compound or drug that, when used in a disease or disorder (e.g., a viral disease), reduces the frequency of symptoms of a medical disorder or delays the onset of the disease or disorder in a subject as compared to a subject not administered the compound or drug (e.g., a combination product as claimed herein).

The term "treating" as used herein refers to alleviating, alleviating or ameliorating a symptom of a disease or disorder, ameliorating a symptom of underlying metabolism, inhibiting a disease or symptom, e.g., preventing the development of a disease or disorder, alleviating a disease or disorder, causing regression of a disease or disorder, alleviating a condition caused by a disease or disorder, or preventing a symptom of a disease or disorder.

The words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.

Within the scope of this application, the various options of any feature may be combined with the various options of other features to form a number of different embodiments. This application is intended to cover all possible embodiments consisting of the various options of all technical features.

The term "excipient" as used herein, which may also be referred to as "pharmaceutically acceptable excipients", "adjuvants" or "additives", refers to the general term for all additional materials used in formulating prescriptions and producing medicaments, generally pharmaceutically acceptable inert ingredients, in addition to the active ingredients, which have been reasonably evaluated in terms of safety. Examples of excipients include, without limitation, binders, disintegrants, lubricating adjuvants (lubricants, glidants, anti-adherents), stabilizers, fillers (or diluents), and flavoring agents, thickening agents, dispersing agents, colorants, bacteriostats, antioxidants, pH adjusters, surfactants, fragrances, and coating materials (plasticizers, opacifiers, pigments), among others. For example, excipients can enhance the handling characteristics of a pharmaceutical formulation, for example, by increasing flowability and/or adhesiveness to make the formulation acceptable for processing. Further, the "excipient" should have good compatibility with the active ingredient, i.e., the excipient itself or the impurities contained therein do not chemically react with the structural groups in the active ingredient or cause degradation of the active ingredient, resulting in a decrease in the content of the active ingredient.

As used herein, "filler" or "diluent" refers to excipients used to increase the weight and volume of a pharmaceutical composition to facilitate shaping and dosing. The filler described herein may be a single filler or a mixture of two or more fillers. In some embodiments of the present application, the filler is selected from one or more of starch, pregelatinized starch, powdered sugar, magnesium oxide, lactose monohydrate, microcrystalline cellulose, sugar alcohols, or inorganic calcium salts; preferably, the sugar alcohol is selected from one or more of xylitol, sorbitol and mannitol; preferably, the inorganic calcium salt is selected from one or more of calcium phosphate, calcium hydrogen phosphate, calcium carbonate and calcium sulfate. In one embodiment, the filler is selected from one of pregelatinized starch, anhydrous dibasic calcium phosphate, calcium carbonate, microcrystalline cellulose, mannitol, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose monohydrate, or a combination of pregelatinized starch and anhydrous dibasic calcium phosphate, or a combination of pregelatinized starch and calcium carbonate. In one embodiment, the filler is a combination of pregelatinized starch and mannitol, microcrystalline cellulose and lactose monohydrate, a combination of pregelatinized starch and anhydrous dibasic calcium phosphate, or pregelatinized starch and calcium carbonate.

As used herein, "binder" or "adhesive" refers to a tacky excipient that can aggregate and bind non-tacky or less tacky materials or excipients into particles or compression form, and can be a solid powder or a viscous liquid. In some embodiments of the present application, the binder is selected from one or more of starch slurry, copovidone, cellulose derivative, sugar powder, syrup, polyvinylpyrrolidone, mucilage, polyethylene glycol 4000, and dextrin; the cellulose derivative comprises methyl cellulose, hydroxypropyl cellulose, ethyl cellulose or sodium carboxymethyl cellulose; the dextrin comprises maltodextrin; the polyvinylpyrrolidone, also called povidone, includes povidone K30, povidone K25, povidone K90, etc.; the copovidone comprises copovidone VA64, copovidone VA64Fine and the like; the mucilage comprises acacia mucilage, gelatin mucilage and the like.

As used herein, "disintegrant" refers to an excipient used to promote disintegration of a pharmaceutical composition in the gastrointestinal tract and to increase the dissolution rate of an active ingredient. In some embodiments of the present application, no disintegrant is included in the pharmaceutical composition. In some embodiments of the present application, the pharmaceutical composition comprises a disintegrant, and the disintegrant is selected from one or more of dry starch, sodium carboxymethyl cellulose, microcrystalline cellulose, powdered cellulose, methylcellulose, potassium polacrilin, sodium alginate, sodium starch glycolate, polyvinylpyrrolidone, maltodextrin, magnesium aluminum silicate, corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, effervescent disintegrants, sodium carboxymethyl starch, and croscarmellose sodium. Preferably, the disintegrant is selected from one or more of dry starch, pregelatinized starch, crospovidone, low substituted hydroxypropyl cellulose, sodium carboxymethyl starch and croscarmellose sodium. In one embodiment, the disintegrant is preferably one or more of pregelatinized starch, crospovidone, low substituted hydroxypropylcellulose, sodium carboxymethyl starch, or croscarmellose sodium; further preferred are crospovidone, sodium carboxymethyl starch or croscarmellose sodium; more preferably croscarmellose sodium. The crospovidone includes crospovidone CL-M, crospovidone CL-SF, crospovidone CL-F, crospovidone CL and the like.

As used herein, "flavoring agent" or "flavoring agent" refers to a pharmaceutical adjuvant for improving or masking the unpleasant odor and taste of a drug, making it difficult for the user to perceive the odor or taste of the drug, and may be further classified into sweetener (or sweetener), flavoring agent, mucilage, effervescent agent, etc. In some embodiments of the present application, the flavoring agent comprises one or more of a sweetener, a flavoring agent, a mucilage, or an effervescent agent.

The term "lubricating excipient" as used herein is a broad term lubricant, and refers to an excipient used to reduce the inter-particle and inter-die friction forces of a pharmaceutical composition and to improve force transmission and distribution. The lubricating auxiliary materials are divided into a lubricant, a glidant and an anti-adhesion agent according to the three functions of reducing friction, improving particle mobility and resisting adhesion between a die hole and drug particles.

The coating material, the coating powder, the coating agent or the coating premix are the mixture of various medicinal auxiliary materials, and have the main functions of coloring, masking smell, avoiding light, prolonging the shelf life, improving the appearance and the like. As used herein, "film-coated tablet" or "film-coated tablet" refers to a tablet having a film (coating) coating over the core (which is made from the pharmaceutical composition of the present application by compression). The film coating may be prepared using coating materials and methods commonly used in the art. For example, film coating materials typically comprise one or more of film forming agents (or polymeric materials), plasticizers, porogens, colorants, opacifiers, and certain solid materials; further, the coating material can be dissolved in a solvent to prepare a coating liquid. Wherein the polymer material is selected from one or more of hypromellose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, acrylic resin, ethyl cellulose, cellulose acetate phthalate, polyvinyl alcohol phthalate, cellulose acetate trimellitate, hypromellose phthalate, polyvinyl alcohol, etc.; the plasticizer is selected from glycerol, propylene glycol, polyethylene glycol, monoacetin, triacetin, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, castor oil, silicone oil, corn oil, liquid paraffin, etc.; the porogen (also called release rate modifier) may be selected from sucrose, sodium chloride, surfactants, etc.; the solid material can be selected from talcum powder, magnesium stearate, colloidal silicon dioxide, etc.; the opacifier comprises titanium dioxide; colorants conventional in the art, such as one or more selected from amaranth, carmine, lemon yellow, soluble indigo, orange G, eosin, fuchsin, mery, sudan yellow, or mercuric may also be optionally used. The coating material can also be directly selected from commercially available premixed coating powders, for example Series of coating powders, < - > Create>Series of coating powders, < - > Create>Series of coating powders, < - > Create>Series of coating powders, < - > Create>Coating powder series, etc. The coating material can be a gastric-soluble coating material or an enteric coating material. The weight of the film coating is 1-5%, preferably 1.5-4%, more preferably 1.5% -3% of the weight of the tablet core. The coating solvent is selected from water and ethanol, preferably water, which can be removed during drying without remaining in the final product. For example, a->The series of coating powder comprises the following components: opamp 85G64788, 85F18422, 0366507, 8568918, 85F12252, 03F58908, and the like.

The term "sustained release formulation" as used herein includes any pharmaceutical composition capable of slowly releasing a drug over an extended period of time, including both extended release and controlled release formulations.

The beneficial effects of the invention are as follows:

Drawings

Fig. 1: x-ray powder diffraction pattern of crystalline form a of preparation example 2.

Fig. 2: DSC profile of crystalline form a of preparation 2.

Fig. 3: x-ray powder diffraction pattern of crystalline form B of preparative example 1.

Fig. 4: DSC profile of crystalline form B of preparation example 1.

Detailed Description

1. X-ray powder diffraction (X-ray powder diffractometer, XRPD)

Instrument model: d2 PHASER Bruker powder X-ray diffraction

The testing method comprises the following steps: about 100 samples for XRPD detection

The detailed XRPD parameters are as follows:

x-ray generator: cu, K alpha,

light pipe voltage: 30kV, light pipe current: 10mA

Scanning range: 5 ° -60 ° (2θ) (example 3); 5 ° -50 ° (2θ) (examples 1 and 2)

Scanning step length: 0.02 degree

Sample tray: zero background sample tray.

2. Differential scanning calorimetric analysis (Differential Scanning Calorimeter, DSC)

Instrument model: DSC3500 NETZSCH differential scanning calorimeter

The testing method comprises the following steps: the sample was placed in a perforated aluminum crucible and heated to the final temperature at a ramp rate of 10 ℃/min after equilibration at 25 ℃.

Sample amount: 5mg of

Type of air flow: nitrogen gas

Flow rate: 20mL/min

Heating initiation temperature: 30 DEG C

Termination temperature: 400 ℃.

3. Thermogravimetric analysis (Thermal Gravimetric Analyzer, TGA)

Instrument model: TGA2 Metrele thermogravimetric analyzer

The testing method comprises the following steps: the sample was placed in an aluminum crucible peeled in advance, and after the sample mass was automatically weighed in a TGA furnace, the sample was heated to the final temperature at a rate of 10 ℃/min.

Sample amount: 10mg of

Type of air flow: nitrogen gas

Sample cell airflow rate: 20mL/min

Heating initiation temperature: 40 DEG C

Termination temperature: 700 ℃.

4. Nuclear magnetic resonance spectrum (Nuclear Magnetic Resonance Spectroscopy NMRS)

Instrument model: AVANCE III 600MHz nuclear magnetic resonance spectrometer

Content and test solvent: ¹ H-NMR, test solvent DMSO-d ₆ 。

Test temperature: 25 DEG C

5. High Performance Liquid Chromatography (HPLC)

Instrument model: agilent1260 Infinicity II high performance liquid chromatograph (Agilent, US)

Chromatographic column: agilent SB-C18, 4.6mm.times.150mm, 5 μm

Test conditions: a wavelength of 210nm; column temperature 50 DEG C

Sample injection volume: 10 mu L.

6. Moisture permeability

The method in Chinese pharmacopoeia is adopted for determination, and the specific test method is as follows:

1) The dried glass weighing bottle with plug (with the outer diameter of 50mm and the height of 15 mm) is taken, placed in a proper constant temperature drying box (with ammonium chloride or ammonium sulfate saturated solution placed at the lower part) or a climatic box (with the set temperature of 25 ℃ +/-1 ℃ and the relative humidity of 80% +/-2%) at the temperature of 25 ℃ +/-1 ℃ for one day before the test, and precisely weighed (m ₁ )；

2) Spreading the sample in the weighing bottle, wherein the sample is about 1mm thick, and precisely weighing (m ₂ )；

3) The weighing bottle is opened, and the bottle cap is placed under the constant temperature and humidity condition for 24 hours;

4) The lid of the weighing flask was closed, and the weight (m ₃ )；

Percentage of weight gain= (m ₃ -m ₂ )/(m ₂ -m ₁ )×100％；

5) Characterization of hygroscopicity and definition of the weight gain by hygroscopicity:

characteristic of moisture absorption	Weight gain ratio
		Has very good moisture permeability	The weight gain of the wet-induced hair is not less than 15 percent
Having moisture-permeability	The weight gain of the wet-induced weight is less than 15 percent but not less than 2 percent
		Slightly moisture-absorbing property	The weight gain of the wet-drawing is less than 2 percent but not less than 0.2 percent
No or almost no hygroscopicity	The weight gain of the wet-induced weight is less than 0.2 percent

7. Crystal form stability test in water and biological media

The preparation process of the biological medium is shown in the following table. Samples of different crystal forms were added to 4.0mL of water and biological medium (FaSSIF, feSSIF, faSSGF, faSSIF/FeSSIF/FaSSGF powder manufacturer Biorelevant) respectively to prepare suspensions, and the suspensions were shaken at 37 ℃ for 24h, the supernatants at 24h time points were tested for pH, and XRPD testing was performed on the remaining solids.

Remarks: faSSIF: simulating intestinal fluid in the small intestine in a human pre-meal hunger state; feSSIF: simulating intestinal fluid in the small intestine in a postprandial satiety state of a human; faSSGF: simulating gastric juice when the human is empty in a hunger state.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials are presented herein for illustrative purposes only.

The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).

The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.

Preparation example 1: preparation of Compound of formula (I) Crystal form B

To the reaction flask were added compound I-1 (5.3 g), dichloromethane (50 mL) and N-methylmorpholine (4.1 g), and trifluoroacetic anhydride (4.3 g) was added dropwise with stirring, followed by stirring at room temperature for 2 hours. The reaction was quenched with purified water (80 mL), the organic phase was washed with saturated aqueous sodium chloride after phase separation, and the organic phase was concentrated to dryness under reduced pressure to give a concentrate (4.5 g).

To the reaction flask was added a mixed solvent (ethyl acetate: methyl tert-butyl ether=1:10 (v/v), total volume 20 mL) and concentrate (2 g), heated to 50 ℃, stirred for 1h, then cooled to room temperature, stirred for 2h, filtered with suction, dried in vacuo at 50 ℃ to give a solid (1.3 g, hplc purity 98.8%).

Preparation example 2: preparation of Compound of formula (I) Crystal form A

Isopropyl acetate (7 mL) and the concentrate from example 1 (2.2 g) were added to the reaction flask, and the mixture was stirred until dissolved at 65℃and continued to be stirred. N-heptane (27 mL) was added to the flask, stirring was continued for 1.5h, cooling to room temperature, stirring was performed for 20min, cooling to 5℃and stirring was performed at this temperature, maintaining stirring for 2h, suction filtration and vacuum drying at 60℃to give a solid (1.5 g, HPLC purity 99.9%).

Preparation example 3: amorphous preparation of the Compound of formula (I)

The concentrate (2 g) was obtained in accordance with example 1, and the mixture was subjected to flash column chromatography on a silica gel column, gradient elution of petroleum ether/ethyl acetate/methanol, and concentration under reduced pressure to give a solid (1.6 g, HPLC purity 95.5%).

Example 1: preparation of tablets of the Compound of formula (I)

(1) Uniformly mixing a bulk drug (a compound crystal form A of the formula (I)) containing the compound of the formula (I) with colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate and microcrystalline cellulose;

(2) Adding the mixture obtained in the step (1) into a granulator for granulating, wherein the pore diameter of a screen is 1.0mm;

(3) Adding sodium stearyl fumarate (internal addition) into the mixture obtained in the step (2), and uniformly mixing;

(4) Granulating the mixture obtained in the step (3) by using a dry granulator, wherein the aperture of a screen is 1.0mm;

(5) Uniformly mixing the particles obtained in the step (4) with sodium stearyl fumarate (additionally);

(6) Tabletting the mixture obtained in the step (5), and controlling the average weight difference to +/-5%, thereby obtaining tablets with the following specifications;

(7) And (3) coating the tablet core obtained in the step (6) by adopting a gastric-soluble film coating.

Example 2: preparation of tablets of the Compound of formula (I)

With reference to the preparation method of example 1, only the active ingredient is adjusted to form B of the compound of formula (I), and the remaining components and proportions are unchanged, resulting in 50mg (mg/tablet), 75mg (mg/tablet), 100mg (mg/tablet), 125mg (mg/tablet), 150mg (mg/tablet) and 250mg (mg/tablet) of the pharmaceutical composition.

Example 3: preparation of tablets of the Compound of formula (I)

With reference to the preparation method of example 1, the following pharmaceutical composition can be obtained by adjusting the disintegrant to be crospovidone.

Example 4: preparation of tablets of the Compound of formula (I)

With reference to the preparation method of example 3, only the active ingredient is adjusted to form B of the compound of formula (I), the remaining components and proportions being unchanged, 100mg (mg/tablet) and 250mg (mg/tablet) of the pharmaceutical composition are obtained.

Example 5: preparation of tablets of the Compound of formula (I)

With reference to the preparation method of example 1, the following pharmaceutical compositions were obtained by adjusting the amounts of the fillers lactose monohydrate and microcrystalline cellulose.

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Example 6:

with reference to the preparation method of example 5, only the active ingredient is adjusted to form B of the compound of formula (I), the remaining components and proportions are unchanged, resulting in 100mg (mg/tablet) and 250mg (mg/tablet) of the pharmaceutical composition.

Example 7:

with reference to the preparation method of example 1, the following pharmaceutical compositions were obtained by adjusting the types of fillers and the amounts of fillers and glidants.

Example 8: preparation of tablets of the Compound of formula (I)

With reference to the preparation method of example 7, only the active ingredient is adjusted to form B of the compound of formula (I), the remaining components and proportions are unchanged, resulting in 100mg (mg/tablet) and 250mg (mg/tablet) of the pharmaceutical composition.

Experimental example 9: preparation of sustained release tablets of the Compound of formula (I)

Step 1: adding bulk drugs containing a compound of formula (I), poloxamer, lactose, microcrystalline cellulose, hypromellose (L100 LVCR) and hypromellose (K4M CR) into a wet granulation pan for premixing;

step 2: adding a proper amount of purified water or absolute ethyl alcohol into the materials in the step 1 for wet granulation, and drying after granulating;

Step 3: finishing the granules dried in the step 2, wherein the aperture of a screen is 1.5mm-2.0mm;

step 4: adding the granules, the colloidal silicon dioxide and the magnesium stearate of the whole granules obtained in the step 3 into a mixer for uniform mixing;

step 5: placing the material obtained in the step 4 on a rotary tablet press, and pressing into a tablet core with single 700mg and 100N-260N hardness;

step 6: and (3) coating the plain tablet obtained in the step (5) with a gastric-soluble film coating premix (Opadry) to obtain a film coated tablet.

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Experimental example 10: preparation of sustained release tablets of the Compound of formula (I)

Step 1: adding bulk drugs containing a compound of formula (I), poloxamer, lactose, microcrystalline cellulose, hypromellose (L100 LVCR) and hypromellose (K4M CR) into a mixer for premixing;

step 2: adding the mixture obtained in the step 1 into a granulator for granulating, wherein the aperture of a screen is 1.0mm;

step 3: adding the granules obtained in the step (2) and the magnesium stearate (added internally) into a mixer for uniform mixing;

step 4: granulating the granules mixed in the step 3 by a dry method, wherein the aperture of a screen is 1.5mm-2.0mm;

step 5: adding the granules granulated in the step 4, colloidal silicon dioxide and magnesium stearate (added) into a mixer for uniform mixing;

Step 6: placing the material obtained in the step 5 on a rotary tablet press, and pressing into a tablet core with single 700mg and 100N-260N hardness;

step 7: and (3) coating the plain tablet obtained in the step (6) with a gastric-soluble film coating premix (Opadry) to obtain a film coated tablet.

Comparative example 1: preparation of PF-07321332 Compound tablet

With reference to the preparation method of example 1, the following pharmaceutical composition was obtained by adjusting the active ingredient to PF-07321332.

Component (A)	Action	100mg tablet (mg/tablet)	100mg tablet (% w/w)
				PF-07321332	Active ingredient	100.00	20.00
Colloidal silica	Glidant	5.00	1.00
				Croscarmellose sodium	Disintegrating agent	15.00	4.00
Lactose monohydrate	Filler (B)	123.50	24.70
				Microcrystalline cellulose	Filler (B)	241.5	48.30
Sodium stearyl fumarate (internal)	Lubricant	5.00	1.00
				Sodium stearyl fumarate (plus)	Lubricant	5.00	1.00
Tablet core		500.00	100.00
				Gastric soluble type Opadry film coat	Coating material	15.00	3.00

The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.

Test example 1: hygroscopicity study of crystalline forms of the Compound of formula (I)

Weighing a proper amount of a crystal form of the compound of the formula (I), performing a hygroscopicity test, and taking a sample after DVS for X-ray powder diffraction.

Experimental results:

table 1: results of the wettability test of the crystalline forms

Table 2: results of hygroscopicity test for form B

Test example 2: solid stability experiments of the crystalline form of the Compound of formula (I)

Placing a proper amount of crystal form samples of the compound of the formula (I) into a weighing bottle, respectively placing the crystal form samples for 7 days and 15 days under the conditions of high temperature (60 ℃), high humidity (25 ℃/92.5% RH), illumination (25 ℃/4500 lux) and acceleration (40 ℃/75% RH) in an open mode, respectively performing X-ray powder diffraction on the samples, and examining the stability of the crystal form of the compound of the formula (I) under different conditions.

Table 3: solid stability test results of crystalline forms

Test example 3: physical stability of the crystalline form of the Compound of formula (I)

Taking a proper amount of crystal form samples of the compound of the formula (I), respectively placing the crystal form samples in a mortar, grinding for 5-10 minutes, taking the ground powder for X-ray powder diffraction, and examining the physical stability of the powder.

Table 4: XRPD results after grinding of crystalline forms

Examples and initial crystalline forms	Post-grinding crystalline forms
		PREPARATION EXAMPLE 2/Crystal form A	The crystal form is unchanged

Test example 4: stability experiments of the crystalline form of the Compound of formula (I) in a biological Medium

The stability of the crystalline form of the compound of formula (I) in pure water and three biological solvent media (FaSSIF, feSSIF and FaSSGF) was examined.

Table 5: results of stability experiments of the crystalline form in biological solvent Medium

Test example 5, stability test

The stability of the compound tablet of formula (I) was tested according to the high performance liquid chromatography of the chinese pharmacopoeia.

Instrument device: high performance liquid chromatograph Waters 2695-2489.

The results are shown in the following table:

TABLE 6 stability results for tablets of examples 1-100mg

The results show that the pharmaceutical composition of the invention has good stability.

Test example 6 dissolution test

The dissolution rates of the tablets produced in examples 1, 3 and 5 were tested according to the test methods described in the dissolution and release rate assays of the chinese pharmacopoeia.

Instrument device: auto-sampling dissolution apparatus 708-DS.

The dissolution method comprises the following steps: a basket rotating method; dissolution medium: phosphate buffer, pH6.8, 0.2% SDS; volume of medium: 900ml; medium temperature: 37 plus or minus 0.5 ℃; rotational speed: 75rpm; sampling time points: 45min; the content was checked by HPLC.

The results are shown in the following table:

TABLE 7 dissolution results

The result shows that the medicine composition has high dissolution rate and meets the preparation requirement.

Test example 7 chip friability detection substrate

The tablets produced in examples 1, 3 and 5 were tested for average friability according to the test method described in the tablet friability test method of the chinese pharmacopoeia.

Instrument device: friability tester CS-2.

The inspection method comprises the following steps: the weight of the tablet is 0.65g or less, and a plurality of tablets are taken, so that the total weight of the tablet is about 6.5g; the weight of the tablet is greater than 0.65g, and 10 tablets are taken. The powder falling off from the tablets is blown off by a blower, weighed precisely, placed in a cylinder and rotated 100 times. Taking out, removing powder by the same method, precisely weighing, reducing weight by less than 1%, and detecting fracture, crack and crushed tablet.

The results are shown in the following table:

TABLE 8 friability results

Sample of	Examples 1-100mg tablets	Examples 3-100mg tablets	Examples 5-100mg tablets
				Friability degree of friability	0.4％	0.5％	0.4％

Test example 8, content uniformity test

The uniformity of the tablets produced in examples 1, 3 and 5 was tested according to the test method described in the content uniformity inspection method of chinese pharmacopoeia.

Instrument device: high performance liquid chromatograph Waters 2695-2489.

The testing method comprises the following steps: taking 10 pieces of test sample, and respectively measuring the relative content X of each single dose with the marked amount being 100 by adopting a high performance liquid chromatography method, and solving the mean value X and standard deviation S and the absolute value A (A= |100-X|) of the difference between the marked amounts and the mean value; if A+2.2S is less than or equal to 15.0, the content uniformity of the sample meets the regulation.

The results are shown in the following table:

Table 9 uniformity results

Sample of	Examples 1-100mg tablets	Examples 3-100mg tablets	Examples 5-100mg tablets
				Sheet 1	97.4％	99.1％	97.1％
Sheet 2	98.5％	98.6％	99.1％
				Sheet 3	95.8％	96.2％	97.5％
Sheet 4	98.4％	100.8％	96.3％
				Sheet 5	97.1％	96.7％	96.5％
Sheet 6	100.4％	98.7％	98.8％
				Sheet 7	99.9％	99.7％	100.2％
Sheet 8	99.6％	98.6％	99.5％
				Sheet 9	96.8％	97.9％	97.7％
Sheet 10	99.4％	101.7％	102.2％
				Mean value of	98.3％	98.8％	98.5％
Standard deviation of	1.5	1.7	1.8
				A+2.2S	5.0	4.9	5.6

The results show that the pharmaceutical composition provided by the invention has good uniformity and meets the preparation requirements.

Test example 9, pharmacokinetic test

(1) The purpose is as follows:

this experiment evaluates the metabolic stability of the compounds of formula I in rats and cynomolgus monkeys, as well as the evaluation of in vivo pharmacokinetics after oral administration.

(2) Reagent and test animal:

waters ACQUITY UPLC ultra high performance liquid systems (Waters company);

Xex-TQ XS triple quadrupole mass spectrometer (Waters);

phenix Winnolin pharmacokinetic software (V8.0, certara Inc., USA);

r320 low speed cryocentrifuge (beijing ocean medical device);

TGL-16M high speed bench refrigerated centrifuge (Hunan instruments Co., ltd.);

MS105 electronic analytical balance (mertrel-tolido (Shanghai) limited);

tween 80 (Tween 80), purchased from Sigma Co;

methylcellulose (MC), purchased from Sigma;

SD rats were purchased from Beijing Vitolihua test animal technologies Co., ltd;

cynomolgus monkey is purchased from Hainan New positive biotechnology Co.

(3) In vivo pharmacokinetic experiment method for rat

(3.1) preparation of a liquid medicine:

2% Tween 80:98%0.5% MC aqueous solution (V: V).

(3.2) dosing regimen:

6 healthy adult male SD rats (3 animals per group) were fed with PF07321332 and deuterated drug (7) at a dose of 10mg/kg by gavage overnight (free drinking water) and a dose of 10mL/kg. Blood is collected from jugular vein for 0.2mL at 0.5, 1, 2, 4, 6, 8, 12 and 24h before and after administration, and centrifuged at 4deg.C for 5min to separate blood plasma, and stored at-20deg.C for testing. And (3) establishing an LC/MS/MS method to measure the original drug concentration in the blood plasma, drawing a blood drug concentration-time curve, and calculating main pharmacokinetic parameters by adopting WinNonlin 7.2 software.

Table 10 pharmacokinetic parameters of rats (po)

Note that: t (T) _max * Expressed in terms of median (minimum, maximum)

From the above table it can be seen that the compound of formula I has a higher peak plasma concentration and higher plasma exposure after intragastric administration compared to the non-deuterated compound PF-07321332, indicating that the compound of formula I has a more excellent pharmacokinetic behavior in vivo. The application potential of the ritonavir combined dosage is lower than that of PF-07321332 or reduced so as not to be combined with ritonavir, so that the clinical use population can be enlarged, and adverse reactions can be reduced.

(4) In vivo pharmacokinetic studies in cynomolgus monkeys

(4.1) preparation of a liquid medicine:

2% Tween 80:98%0.5% MC aqueous solution (V: V).

(4.2) dosing regimen:

8 healthy adult cynomolgus monkeys, each half of which is fasted overnight (free drinking water), are randomly divided into 4 groups, and are respectively subjected to single-drug gavage and combined Ritonavir (Ritonavir) gavage administration, and 5mL/kg of the drug is administrated [ solvent is 2% Tween 80:98%0.5% MC aqueous solution (V: V) ]; after 0.25, 0.5, 1, 2, 4, 8, 10, 24, 32 and 48 hours of administration, 1mL of blood is taken from four limbs of a monkey and placed in a K2-EDTA anticoagulation tube respectively, placed in wet ice, centrifugally separated into plasma at 4 ℃, transferred and split into a 2.0mL centrifuge tube, and immediately placed in a refrigerator at-80 ℃ for preservation. The concentration of the test compound in the plasma was determined by LC-MS/MS.

Table 11 cynomolgus monkey pharmacokinetic parameters (po)

After oral gavage, the exposure of the group alone of the compound of the formula I is obviously higher than that of the group alone of PF-07321332, C _max And AUC _last 7.32 and 3.31 times PF-07321332, respectively; the exposure of the single group of the compound of the formula I is higher than that of the PF-07321332 +ritonavir combined group, C _max And AUC _last 1.40 and 1.76 times, respectively. The exposure of the compound of formula I is significantly increased after the combination with ritonavir, as a single use group4.47 times Meter (AUC) _last Meter).

The results show that the compounds of the present invention have good in vivo pharmacokinetics, and have the potential to be administered at lower doses or without ritonavir combination.

Claims

1. A pharmaceutical composition, in the form of a capsule,

comprising as active ingredient a compound of formula (I) or a pharmaceutically acceptable salt, solvate or excipient thereof;

the active ingredient is a compound of formula (I) in crystalline form, which crystalline form is form a, using Cu-ka radiation, the X-ray powder diffraction pattern of which comprises diffraction peaks (±0.2°): 11.8,12.7,15.6,18.3.

2. The pharmaceutical composition of claim 1, wherein the crystalline form a, using Cu-ka radiation, has an X-ray powder diffraction pattern comprising diffraction peaks (±0.2°): 11.8,12.7,15.6,18.3,20.4;

alternatively, using Cu-ka radiation, its X-ray powder diffraction pattern comprises diffraction peaks (±0.2°): 11.8,12.7,15.6,18.3,19.8,20.4;

alternatively, using Cu-ka radiation, its X-ray powder diffraction pattern comprises diffraction peaks (±0.2°): 11.8,12.7,15.6,17.3,18.3,19.8,20.4;

alternatively, using Cu-ka radiation, its X-ray powder diffraction pattern comprises diffraction peaks (±0.2°): 11.8,12.7,15.6,17.3,18.3,19.8,20.4,22.2;

Alternatively, using Cu-ka radiation, its X-ray powder diffraction pattern comprises diffraction peaks (±0.2°): 7.6,9.7,11.8,12.7,15.6,17.3,18.3,19.8,20.4,22.2;

alternatively, using Cu-ka radiation, its X-ray powder diffraction pattern comprises diffraction peaks (±0.2°): 7.6,9.7,11.8,12.7,15.6,17.3,18.3,19.8,20.4,20.9,22.2;

alternatively, using Cu-ka radiation, its X-ray powder diffraction pattern comprises diffraction peaks (±0.2°): 7.6,9.7,11.8,12.7,15.6,17.3,17.8,18.3,19.8,20.4,20.9,21.6,22.2;

alternatively, using Cu-ka radiation, its X-ray powder diffraction pattern comprises diffraction peaks (±0.2°): 7.6,9.7,11.4,11.8,12.1,12.7,15.6,17.3,17.8,18.3,19.8,20.4,20.9,21.6,22.2;

alternatively, using Cu-ka radiation, its X-ray powder diffraction pattern comprises diffraction peaks (±0.2°): 7.6,9.7,11.4,11.8,12.1,12.7,15.6,17.3,17.8,18.3,19.8,20.4,20.9,21.6,22.2,23.5,24.6;

alternatively, using Cu-ka radiation, its X-ray powder diffraction pattern comprises diffraction peaks (±0.2°): 7.6,9.7,11.4,11.8,12.1,12.7,15.6,17.3,17.8,18.3,18.7,19.8,20.4,20.9,21.6,22.2,23.5,24.6;

Alternatively, it has an X-ray powder diffraction pattern substantially as shown in figure 1.

3. The pharmaceutical composition of any one of claims 1-2, wherein the crystalline form a has a differential scanning calorimetry curve with an endotherm at 196 ± 5 ℃; alternatively, it has a DSC profile substantially as shown in figure 2.

4. A pharmaceutical composition according to any one of claims 1-3, wherein the excipient comprises a filler and a lubricating excipient, optionally further comprising a disintegrant and/or a binder; preferably, the excipient comprises a filler, a lubricating auxiliary material and a disintegrating agent, wherein the lubricating auxiliary material is a lubricant and a glidant.

5. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition comprises the following components in percentage by weight:

The sum of the weight percentages of the components is 100 percent.

6. The pharmaceutical composition according to any one of claims 4-5, wherein the filler is selected from one of pregelatinized starch or microcrystalline cellulose, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose monohydrate, or a combination of pregelatinized starch and anhydrous dibasic calcium phosphate, or a combination of pregelatinized starch and calcium carbonate; further preferably, the filler is selected from: one of pregelatinized starch or microcrystalline cellulose, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose monohydrate; the weight ratio of the two fillers in the combination of pregelatinized starch and mannitol, microcrystalline cellulose and lactose monohydrate, pregelatinized starch and anhydrous calcium hydrophosphate, pregelatinized starch and lactose monohydrate or pregelatinized starch and calcium carbonate is 1:10-10:1; or 1:7 to 7:1; or 1:6-6:1, or 1:5-5:1; or 1:4-4:1; or 1:3 to 3:1; or 1:2-2:1; or 2:1;

the lubricating auxiliary material is a combination of a lubricant and a glidant, wherein the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talcum powder, silicon dioxide, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, sodium dodecyl sulfate, magnesium dodecyl sulfate or polyethylene glycol; preferably one or more of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, sodium benzoate, sodium lauryl sulfate, talc, silica, zinc stearate, sodium stearyl fumarate, magnesium lauryl sulfate, polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulfate or magnesium lauryl sulfate; further preferred are one or more of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, sodium benzoate, sodium lauryl sulfate, talc, silica, zinc stearate, sodium stearyl fumarate, magnesium stearyl fumarate or magnesium lauryl sulfate; further preferred is one or more of talc, magnesium stearate, calcium stearate or sodium stearyl fumarate; still more preferably sodium stearyl fumarate, the glidant is selected from one or more of colloidal silicon dioxide, talc or aluminum hydroxide; preferably colloidal silica;

The weight ratio of the glidant to the lubricant is 1:6-6:1; or 1:5-5:1; or 1:4-4:1; or 1:3 to 3:1; or 1:2-2:1; or 1:1, 1:2, 1:1.5, 2:1, 2:3, 3:1, 3:2, 4:3 or 5:3.

7. The pharmaceutical composition according to claim 6, wherein the disintegrant is selected from one or more of dry starch, carboxymethyl cellulose, microcrystalline cellulose, powdered cellulose, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate, polyvinylpyrrolidone, maltodextrin, magnesium aluminum silicate, corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, effervescent disintegrant, sodium carboxymethyl starch or croscarmellose sodium; preferably one or more of dry starch, pregelatinized starch, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, croscarmellose sodium or crospovidone; preferably one or more of crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch or croscarmellose sodium; further preferred are crospovidone, sodium carboxymethyl starch or croscarmellose sodium; more preferably crospovidone or croscarmellose sodium.

8. The pharmaceutical composition according to any one of claims 1-7, wherein the pharmaceutical composition comprises 1-750mg, alternatively 1-500mg, alternatively 10-300mg of active ingredient per unit dose of the pharmaceutical composition when the pharmaceutical composition is in solid form in unit dose form; or 25-300mg; or 25-200mg; or 25-150mg; or 25-125mg; or 50-125mg; or 25mg; or 50mg; or 75mg; or 100mg; or 125mg; or 150mg; or 200mg; the solid preparation can be applied in single dose or divided dose.

9. The pharmaceutical composition of any one of claims 1-8, further comprising an additional component selected from one, two or more of the following additional therapeutic agents, wherein the additional therapeutic agents are selected from the group consisting of: PLpro inhibitors, major protease Mpro inhibitors, rdRp inhibitors, CYP3A4 inhibitors, and the like.

10. Use of a pharmaceutical composition according to any one of claims 1-9 as a medicament or in the preparation of a medicament; preferably, the medicament has an antiviral effect; alternatively, the medicament is for the prevention and/or treatment of viral diseases; alternatively, the medicament is for the prevention and/or treatment of symptoms or diseases caused by viruses having the major protease Mpro; alternatively, the medicament is used for preventing and/or treating symptoms or diseases caused by SARS-CoV-2 infection.