Dry suspension, preparation method therefor, and use thereof

Abstract

A dry suspension, a preparation method therefor, and use thereof. The dry suspension comprises: A) a solid dispersion, wherein the solid dispersion comprises: (1) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and (2) a polymer carrier, wherein the polymer carrier comprises one or more of copovidone, povidone, and hypromellose; and B) an excipient.

Description

Dry suspensions, their preparation methods and applications

[0001] This application claims priority to Chinese patent application 202510386978.4, filed on March 28, 2025, and Chinese patent application 202610348230.X, filed on March 20, 2026. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to a dry suspension, its preparation method, and its application. Background Technology

[0003] Compound (I) is a cap-dependent endonuclease inhibitor that targets a novel target and is independently developed. It is effective in treating influenza A and B, with high safety and low resistance rate. It is described in patent document WO2019141179A1. Its chemical name is (((R)-12'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiaheptazone-11-yl)-6',8'-dioxo-6',8',12',12a'-tetrahydro-1'H,4'H-spiro[cyclopropane-1,3'-[1,4]oxazin[3,4-c]pyrido[2,1-f][1,2,4]triazine]-7'-yl)oxy)methyl carbonate, and its structure is shown in Formula (I).

[0004] Compound (I) is a poorly soluble drug, almost insoluble in water. Conventional solid dosage forms show less than 15% dissolution within 60 minutes. The inventors have tried various solubilization methods, such as air jet milling and microemulsion preparation, but none have yielded effective results. Furthermore, tablet administration has poor compliance and low adherence for patients with swallowing difficulties or children. There is an urgent need to develop formulations that can improve these problems, such as dry suspensions.

[0005] Solid dispersions (SDs) are solid substances formed by highly dispersing drugs in suitable materials using specific methods. They are a technical strategy for improving dissolution and bioavailability. However, currently only a few solid dispersion formulations are on the market, and even fewer are dry suspensions. The main reasons hindering their widespread commercialization are numerous limiting factors and shortcomings, such as:

[0006] (1) Selecting a suitable polymer dispersion carrier for a solid dispersion is usually difficult, time-consuming and unpredictable: because little is known about drug-polymer interactions, which are unique, and different drugs interact differently with different polymer dispersion carriers. The drug dispersion state, molecular migration rate, dissolution and crystallization rate in the solid dispersion are different. Some polymer dispersion carriers not only fail to inhibit the crystallization of amorphous drugs, but also promote crystal growth. Some may accelerate drug dissolution rather than increase drug concentration. Combining drugs with polymer dispersion carriers does not necessarily improve solubility or properties.

[0007] (2) Storage is prone to aging: Solid dispersions are usually physically unstable. When stored, especially under elevated temperature and humidity, the drugs in the dispersion often revert to a more stable crystalline form, thus losing their advantages.

[0008] (3) Gastrointestinal / Dissolution crystallization: During use, solid dispersions may cause the drug to rapidly reach a supersaturated state in the gastrointestinal tract / dissolution medium. This unstable system can cause the drug to spontaneously crystallize from the supersaturated solution into a stable form.

[0009] (4) It is difficult to simultaneously take into account the properties of the formulation: solid dispersion particles are usually uneven in size and shape, with generally small particle size. Some are in powder form, have poor flowability, are not easy to mix with other excipients, and have inconsistent content and delivery dosage, which is not conducive to the formulation.

[0010] (5) Problems such as moisture absorption and microbial contamination are prone to occur: solid dispersions are prone to moisture absorption and microbial contamination, which increases the amount of related substances and affects product quality;

[0011] (6) Increased difficulty in dry suspension formulation: When preparing dry suspensions using solid dispersions, more factors need to be considered compared to preparing solid dispersions using a single API.

[0012] Therefore, for solid dispersion formulations, especially solid dispersion dry suspensions, it is not enough to only focus on dissolution or solubility. The key to achieving widespread application lies in how to improve dissolution or solubility while taking into account storage stability, reducing recrystallization, formulation processability, dry suspension properties, product quality, bioavailability, etc. Summary of the Invention

[0013] This invention provides a solid dispersion, a dry suspension, a method for preparing the same, and its applications.

[0014] In a first aspect, the present invention provides a solid dispersion comprising: (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (2) a polymer carrier comprising one or more of copovidone, povidone and hydroxypropyl methylcellulose.

[0015] In some embodiments, the polymer carrier in the solid dispersion comprises copovidone and / or hydroxypropyl methylcellulose. Preferably, the polymer carrier comprises copovidone; more preferably, the polymer carrier is copovidone.

[0016] In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and the polymer carrier. Preferably, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and copovidone.

[0017] In some embodiments, the weight ratio of the compound represented by formula (I) or its pharmaceutically acceptable salt to the polymer carrier in the solid dispersion is 1:(0.5-10), preferably 1:(0.7-8), more preferably 1:(1-6), and even more preferably 1:(1-4), for example 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0018] In some embodiments, the polymer carrier in the solid dispersion comprises copovidone, wherein the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the copovidone is 1:(0.5-10), preferably 1:(0.7-8), more preferably 1:(1-6), and even more preferably 1:(1-4), for example 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0019] In some embodiments, the solid dispersion further includes a substrate, namely, the solid dispersion comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate.

[0020] In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate.

[0021] In some embodiments, the substrate in the solid dispersion comprises one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, corn starch, and low-substituted hydroxypropyl cellulose; preferably, the substrate comprises crospovidone and / or crospovidone sodium carboxymethyl cellulose; more preferably, the substrate comprises crospovidone; and even more preferably, the substrate is crospovidone.

[0022] In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the substrate comprises crospovidone. Preferably, the polymer carrier is copovidone, and the substrate is crospovidone. More preferably, the solid dispersion consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, copovidone, and crospovidone.

[0023] In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the substrate comprises croscarmellose sodium. Preferably, the polymer carrier is copovidone, and the substrate is croscarmellose sodium. More preferably, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, copovidone, and croscarmellose sodium.

[0024] In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the substrate comprises sodium carboxymethyl starch. Preferably, the polymer carrier is copovidone, and the substrate is sodium carboxymethyl starch. More preferably, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, copovidone, and sodium carboxymethyl starch.

[0025] In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the substrate comprises corn starch. Preferably, the polymer carrier is copovidone, and the substrate is corn starch. More preferably, the solid dispersion consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, copovidone, and corn starch.

[0026] In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the substrate comprises low-substituted hydroxypropyl cellulose. Preferably, the polymer carrier is copovidone, and the substrate is low-substituted hydroxypropyl cellulose. More preferably, the solid dispersion consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, copovidone, and low-substituted hydroxypropyl cellulose.

[0027] In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises povidone and the substrate comprises crospovidone. Preferably, the polymer carrier is povidone and the substrate is crospovidone. More preferably, the solid dispersion consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, povidone, and crospovidone.

[0028] In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises hydroxypropyl methylcellulose and the substrate comprises crospovidone. Preferably, the polymer carrier is hydroxypropyl methylcellulose and the substrate is crospovidone. More preferably, the solid dispersion consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose, and crospovidone.

[0029] In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the substrate is 1:(0.5-10), preferably 1:(0.7-8), more preferably 1:(1-6), and even more preferably 1:(1-4), for example 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0030] In some embodiments, the solid dispersion comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), and even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0031] In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the copovidone, and the substrate is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0032] In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, the substrate comprises crospovidone, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the copovidone, and the crospovidone is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0033] In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the substrate comprises croscarmellose sodium, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the copovidone, and the croscarmellose sodium is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0034] In some embodiments, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the substrate comprises sodium carboxymethyl starch, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the copovidone, and the sodium carboxymethyl starch is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0035] In some embodiments, the polymer carrier comprises copovidone, the substrate comprises corn starch, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the copovidone, and the corn starch is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), and even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0036] In some embodiments, the polymer carrier comprises copovidone, the substrate comprises low-substituted hydroxypropyl cellulose, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the copovidone, and the low-substituted hydroxypropyl cellulose is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), and even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0037] In some embodiments, the polymer carrier comprises povidone, the substrate comprises cross-linked povidone, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the povidone, and the cross-linked povidone is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), and even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0038] In some embodiments, the polymer carrier comprises hydroxypropyl methylcellulose, the substrate comprises crospovidone, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the hydroxypropyl methylcellulose and the crospovidone is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0039] In some embodiments, the solid dispersion does not include a surfactant.

[0040] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof exists in an amorphous state in the solid dispersion. In this invention, amorphous means that it does not exhibit crystalline characteristics as detected by conventional methods such as X-ray powder diffraction, differential scanning calorimetry, or thermogravimetric analysis.

[0041] In some embodiments, the solubility of the solid dispersion is more than three times, preferably more than five times, more preferably more than seven times, and more preferably more than eight times, the solubility of the compound represented by formula (I) or its pharmaceutically acceptable salt (e.g., pH 6.8 phosphate buffer, 0.1 M hydrochloric acid solution, 0.01 M hydrochloric acid solution, pH 4.5 acetate buffer or purified water).

[0042] In some embodiments, the solid dispersion is prepared by solvent extraction; preferably, the solid dispersion is prepared by solvent evaporation, freeze drying, spray drying or fluidized bed process; more preferably, the solid dispersion is prepared by spray drying or fluidized bed process.

[0043] Secondly, the present invention also provides a method for preparing a solid dispersion as described above, wherein the method for preparing the solid dispersion is a solvent method, the solvent method comprising: dispersing the compound represented by formula (I) or its pharmaceutically acceptable salt with a polymer carrier in a solvent, removing the solvent, and forming a solid dispersion.

[0044] In some embodiments, the solvent method is a spray drying method, which includes: dispersing the compound of formula (I) or its pharmaceutically acceptable salt and polymer carrier in a solvent and spray drying.

[0045] In some embodiments, the solvent in the spray drying method may be one or more of methanol, acetone and dichloromethane, or a mixture thereof with water, preferably acetone.

[0046] In some embodiments, the amount of solvent used in the spray drying method may be 5 to 80 times the weight of the compound represented by formula (I) or its pharmaceutically acceptable salt, preferably 10 to 50 times, for example 45 times.

[0047] In some embodiments, the inlet air temperature of the spray drying method can be 80-100°C, for example, 90°C.

[0048] In some embodiments, the outlet air temperature of the spray drying method can be 50-80°C, for example, 60-67°C.

[0049] In some embodiments, the feed flow rate of the spray drying process can be 200-300 g / h, for example 252 g / h.

[0050] In some embodiments, the spray drying method may further include a drying step after the spray drying is completed. The drying temperature is preferably 50-80°C, more preferably 60-65°C; the drying time is preferably 1-50 hours, more preferably 10-40 hours, for example 22 hours; the drying is preferably vacuum drying; and the drying equipment is preferably a vacuum drying oven.

[0051] In some embodiments, the solid dispersion further includes a substrate, and the solvent method is a fluidized bed method, in which the compound of formula (I) or its pharmaceutically acceptable salt and polymer carrier are dispersed in a solvent and sprayed onto the surface of the substrate in a fluidized state.

[0052] In some embodiments, in the fluidized bed process, the solvent may be one or more of methanol, acetone, and dichloromethane, or a mixture thereof with water; preferably, the solvent is an acetone-water mixture or an acetone-methanol mixture.

[0053] In some embodiments, the solvent in the fluidized bed process is an acetone-water mixture. In the acetone-water mixture, the weight ratio of acetone to water can be (1-4):1, for example, 4:1 or 3:1.

[0054] In some embodiments, the solvent in the fluidized bed process is an acetone-methanol mixture. In the acetone-methanol mixture, the weight ratio of acetone to methanol can be (1-4):1, for example, 2:1.

[0055] In some embodiments, the amount of solvent used in the fluidized bed process may be 5-80 times the weight of the compound represented by formula (I) or its pharmaceutically acceptable salt, preferably 10-50 times, more preferably 20-40 times, for example 25 times, 31.25 times or 37.5 times.

[0056] In some implementations, the fluidized bed method involves adjusting the airflow rate to fluidize the substrate.

[0057] In some embodiments, during the liquid spraying process, the inlet air temperature is controlled to be 50-80°C, for example, 65-75°C, 65-80°C, 55-80°C, or 50-70°C.

[0058] In some embodiments, during the fluidized bed process, the material temperature is controlled at 25-50°C, for example, 30-46°C or 36-44°C.

[0059] In some implementations, the fluidized bed method may involve top spraying or bottom spraying, preferably top spraying.

[0060] In some embodiments, the fluidized bed method may further include a drying step after the liquid spraying is completed.

[0061] In some embodiments, during the drying process in the fluidized bed method, the inlet air temperature is controlled at 50-80°C, for example, 65-75°C, 65-80°C, or 50-70°C.

[0062] In some embodiments, during the drying process in the fluidized bed method, the material temperature is controlled at 25-60°C, for example, 35-45°C, 40-53°C, 35-47°C, or 40-56°C.

[0063] In some embodiments, the drying time is 0.5-24 hours, preferably 1-10 hours, for example 1-2 hours.

[0064] Thirdly, the present invention also provides a dry suspension comprising:

[0065] A. A solid dispersion; said solid dispersion comprising: (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (2) a polymer carrier comprising one or more of copovidone, povidone and hydroxypropyl methylcellulose;

[0066] B, excipients (i.e., additives other than solid dispersions);

[0067] solid dispersions

[0068] In some embodiments, the polymer carrier in the solid dispersion of the dry suspension comprises copovidone and / or hydroxypropyl methylcellulose. Preferably, the polymer carrier comprises copovidone; more preferably, the polymer carrier is copovidone.

[0069] In some embodiments, the solid dispersion in the dry suspension comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and the polymer carrier. Preferably, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and copovidone.

[0070] In some embodiments, the weight ratio of the compound of formula (I) or its pharmaceutically acceptable salt to the polymer carrier in the solid dispersion of the dry suspension is 1:(0.5-10), preferably 1:(0.7-8), more preferably 1:(1-6), and even more preferably 1:(1-4), for example 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0071] In some embodiments, the polymer carrier in the solid dispersion of the dry suspension comprises copovidone, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the copovidone is 1:(0.5-10), preferably 1:(0.7-8), more preferably 1:(1-6), and even more preferably 1:(1-4), for example 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0072] In some embodiments, the solid dispersion in the dry suspension further includes a substrate, namely, the solid dispersion comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate.

[0073] In some embodiments, the solid dispersion in the dry suspension consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate.

[0074] In some embodiments, the substrate in the solid dispersion of the dry suspension includes one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, corn starch, and low-substituted hydroxypropyl cellulose; preferably, the substrate includes crospovidone and / or crospovidone sodium carboxymethyl cellulose; more preferably, the substrate includes crospovidone; and even more preferably, the substrate is crospovidone.

[0075] In some embodiments, the solid dispersion in the dry suspension comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the substrate comprises crospovidone. Preferably, the polymer carrier is copovidone, and the substrate is crospovidone. More preferably, the solid dispersion consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, copovidone, and crospovidone.

[0076] In some embodiments, the solid dispersion in the dry suspension comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the substrate comprises croscarmellose sodium. Preferably, the polymer carrier is copovidone, and the substrate is croscarmellose sodium. More preferably, the solid dispersion consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, copovidone, and croscarmellose sodium.

[0077] In some embodiments, the solid dispersion in the dry suspension comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the substrate comprises sodium carboxymethyl starch. Preferably, the polymer carrier is copovidone, and the substrate is sodium carboxymethyl starch. More preferably, the solid dispersion consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, copovidone, and sodium carboxymethyl starch.

[0078] In some embodiments, the solid dispersion in the dry suspension comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the substrate comprises corn starch. Preferably, the polymer carrier is copovidone, and the substrate is corn starch. More preferably, the solid dispersion consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, copovidone, and corn starch.

[0079] In some embodiments, the solid dispersion in the dry suspension comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the substrate comprises low-substituted hydroxypropyl cellulose. Preferably, the polymer carrier is copovidone, and the substrate is low-substituted hydroxypropyl cellulose. More preferably, the solid dispersion consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, copovidone, and low-substituted hydroxypropyl cellulose.

[0080] In some embodiments, the solid dispersion in the dry suspension comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises povidone, and the substrate comprises crospovidone. Preferably, the polymer carrier is povidone, and the substrate is crospovidone. More preferably, the solid dispersion consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, povidone, and crospovidone.

[0081] In some embodiments, the solid dispersion in the dry suspension comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises hydroxypropyl methylcellulose and the substrate comprises crospovidone. Preferably, the polymer carrier is hydroxypropyl methylcellulose and the substrate is crospovidone. More preferably, the solid dispersion consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose, and crospovidone.

[0082] In some embodiments, the solid dispersion in the dry suspension comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the substrate is 1:(0.5-10), preferably 1:(0.7-8), more preferably 1:(1-6), and even more preferably 1:(1-4), for example 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0083] In some embodiments, the solid dispersion in the dry suspension comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), and even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0084] In some embodiments, the solid dispersion in the dry suspension comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the copovidone, and the substrate is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0085] In some embodiments, the solid dispersion in the dry suspension comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, the substrate comprises crospovidone, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the copovidone, and the crospovidone is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0086] In some embodiments, the solid dispersion in the dry suspension comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, a polymer carrier, and a substrate, wherein the polymer carrier comprises copovidone, and the substrate comprises croscarmellose sodium, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the copovidone, and the croscarmellose sodium is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0087] In some embodiments, the solid dispersion in the dry suspension comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the substrate, wherein the polymer carrier comprises copovidone, and the substrate comprises sodium carboxymethyl starch, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the copovidone, and the sodium carboxymethyl starch is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0088] In some embodiments, the polymer carrier in the dry suspension comprises copovidone, the substrate comprises corn starch, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the copovidone, and the corn starch is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), and even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0089] In some embodiments, the polymer carrier in the dry suspension comprises copovidone, the substrate comprises low-substituted hydroxypropyl cellulose, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the copovidone, and the low-substituted hydroxypropyl cellulose is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), and even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0090] In some embodiments, the polymer carrier in the dry suspension comprises povidone, the substrate comprises crospovidone, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the povidone, and the crospovidone is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), and even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0091] In some embodiments, the polymer carrier in the dry suspension comprises hydroxypropyl methylcellulose, the substrate comprises crospovidone, and the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the hydroxypropyl methylcellulose and the crospovidone is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), further preferably 1:(1-4):(1-4), even more preferably 1:(1-4):4, for example 1:4:4 or 1:1:4.

[0092] In some embodiments, the solid dispersion in the dry suspension does not include a surfactant.

[0093] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is present in an amorphous state in the solid dispersion of the dry suspension. In this invention, amorphous means that it does not exhibit crystalline characteristics as detected by conventional methods such as X-ray powder diffraction, differential scanning calorimetry, or thermogravimetric analysis.

[0094] In some embodiments, the solubility of the solid dispersion in the dry suspension is more than three times, preferably more than five times, more preferably more than seven times, and more preferably more than eight times, the solubility of the compound represented by formula (I) or its pharmaceutically acceptable salt (e.g., pH 6.8 phosphate buffer, 0.1 M hydrochloric acid solution, 0.01 M hydrochloric acid solution, pH 4.5 acetate buffer or purified water).

[0095] In some embodiments, the solid dispersion in the dry suspension is prepared by a solvent method, which includes: dispersing the compound represented by formula (I) or its pharmaceutically acceptable salt with a polymer carrier in a solvent, removing the solvent, and forming a solid dispersion; preferably, the solid dispersion is prepared by solvent evaporation, freeze drying, spray drying or fluidized bed process; more preferably, the solid dispersion is prepared by spray drying or fluidized bed process.

[0096] In some embodiments, the solvent method is a spray drying method, which includes: dispersing the compound of formula (I) or its pharmaceutically acceptable salt and polymer carrier in a solvent and spray drying.

[0097] In some embodiments, the solvent in the spray drying method may be one or more of methanol, acetone, and dichloromethane, or a mixture thereof with water, preferably acetone.

[0098] In some embodiments, the amount of solvent used in the spray drying method may be 5 to 80 times the weight of the compound represented by formula (I) or its pharmaceutically acceptable salt, preferably 10 to 50 times, for example 45 times.

[0099] In some embodiments, the inlet air temperature of the spray drying method can be 80-100°C, for example, 90°C.

[0100] In some embodiments, the outlet air temperature of the spray drying method can be 50-80°C, for example, 60-67°C.

[0101] In some embodiments, the feed flow rate of the spray drying process can be 200-300 g / h, for example 252 g / h.

[0102] In some embodiments, the spray drying method may further include a drying step after the spray drying is completed. The drying temperature is preferably 50-80°C, more preferably 60-65°C; the drying time is preferably 1-50 hours, more preferably 10-40 hours, for example 22 hours; the drying is preferably vacuum drying; and the drying equipment is preferably a vacuum drying oven.

[0103] In some embodiments, the solid dispersion in the dry suspension further includes a substrate, and the solvent method is a fluidized bed method, in which the compound of formula (I) or its pharmaceutically acceptable salt and polymer carrier are dispersed in a solvent and sprayed onto the surface of the substrate in a fluidized state.

[0104] In some embodiments, in the fluidized bed process, the solvent may be one or more of methanol, acetone, and dichloromethane, or a mixture thereof with water; preferably, the solvent is an acetone-water mixture or an acetone-methanol mixture.

[0105] In some embodiments, the solvent in the fluidized bed process is an acetone-water mixture. In the acetone-water mixture, the weight ratio of acetone to water can be (1-4):1, for example, 4:1 or 3:1.

[0106] In some embodiments, the solvent in the fluidized bed process is an acetone-methanol mixture. In the acetone-methanol mixture, the weight ratio of acetone to methanol can be (1-4):1, for example, 2:1.

[0107] In some embodiments, the amount of solvent used in the fluidized bed process may be 5 to 80 times the weight of the compound represented by formula (I) or its pharmaceutically acceptable salt, preferably 10 to 50 times, more preferably 20 to 40 times, for example 25, 31.25 or 37.5 times.

[0108] In some implementations, the fluidized bed method involves adjusting the airflow rate to fluidize the substrate.

[0109] In some embodiments, during the liquid spraying process, the inlet air temperature is controlled to be 50-80°C, for example, 65-75°C, 65-80°C, 55-80°C, or 50-70°C.

[0110] In some embodiments, during the fluidized bed process, the material temperature is controlled at 25-50°C, for example, 30-46°C or 36-44°C.

[0111] In some implementations, the fluidized bed method may involve top spraying or bottom spraying, preferably top spraying.

[0112] In some embodiments, the fluidized bed method may further include a drying step after the liquid spraying is completed.

[0113] In some embodiments, during the drying process in the fluidized bed method, the inlet air temperature is controlled at 50-80°C, for example, 65-75°C, 65-80°C, or 50-70°C.

[0114] In some embodiments, during the drying process in the fluidized bed method, the material temperature is controlled at 25-60°C, for example, 35-45°C, 40-53°C, 35-47°C, or 40-56°C.

[0115] In some embodiments, the drying time is 0.5-24 hours, preferably 1-10 hours, for example 1-2 hours.

[0116] excipient

[0117] In some embodiments, the excipients in the dry suspension include one or more of diluents, suspending agents, flow aids, lubricants, sweeteners, and flavorings.

[0118] In some embodiments, the excipients in the dry suspension include diluents and suspending agents.

[0119] In some embodiments, the excipients in the dry suspension include diluents, suspending agents, and sweeteners.

[0120] In some embodiments, the excipients include diluents, suspending agents, flow aids, lubricants, sweeteners, and flavorings.

[0121] dry suspension

[0122] In some implementations, the dry suspension does not include a stabilizer.

[0123] In some embodiments, the dry suspension contains 0.1%-30% by weight of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, preferably 0.5%-20%, more preferably 1%-10%, and even more preferably 1%-5%, for example 0.1%, 0.3%, 0.5%, 0.7%, 1%, 2%, 3%, 3.3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, or 30%.

[0124] In some embodiments, the weight percentage of the solid dispersion in the dry suspension may be 0.2%-70%, preferably 1%-50%, more preferably 5%-30% or 20%-40%, and even more preferably 10%-20% or 25%-35%, for example 5%, 10%, 15%, 18%, 20%, 25%, 30% or 40%.

[0125] In some embodiments, the weight percentage of the diluent (e.g., including mannitol and / or maltitol) in the dry suspension is 40%-80%, preferably 40%-65% or 70%-80%; more preferably 50%-65% or 75%-80%; and even more preferably 50%-62% or 75%-80%.

[0126] In some embodiments, the diluent in the dry suspension includes mannitol; the mannitol accounts for 30%-65% by weight of the dry suspension, preferably 35%-45%, more preferably 35%-40%, for example 35.3% or 36.3%.

[0127] In some embodiments, the diluent in the dry suspension includes mannitol and maltitol; the mannitol and maltitol account for 70%-80% by weight of the dry suspension, preferably 75%-80%, more preferably 75%-80%, for example 75.3% or 76.3%.

[0128] In some embodiments, the weight percentage of the suspending agent (e.g., hydroxypropyl methylcellulose) in the dry suspension is 1%-14%, preferably 1%-12%, more preferably 1%-5% or 2%-12%, and even more preferably 1%-3% or 3%-10%, such as 2%, 3.3% or 13.3%.

[0129] In some embodiments, the weight percentage of the flow aid (e.g., colloidal silica) in the dry suspension is 0.5%-5%, preferably 1%-4% or 0.5%-3%, more preferably 2%-4% or 0.5%-1%, for example 1% or 3.3%.

[0130] In some embodiments, the weight percentage of the lubricant (e.g., sodium stearate fumarate) in the dry suspension is 0.1%-5%, preferably 0.1%-2%, and more preferably 0.1%-1%.

[0131] In some embodiments, the sweetener (e.g., sucralose) in the dry suspension has a weight percentage of 0.1%-5%, preferably 0.5%-3%, more preferably 1%-3% or 0.5%-1%, for example 2%.

[0132] In some embodiments, the flavoring agent (e.g., strawberry powder flavoring) in the dry suspension has a weight percentage of 0.1%-3%, preferably 0.1%-1%, and more preferably 0.1%-0.5%.

[0133] In some embodiments, the dry suspension comprises 1%-50% solid dispersion, 40%-80% diluent, and 1%-12% suspending agent.

[0134] In some embodiments, the dry suspension comprises 1%-50% solid dispersion, 40%-80% diluent, 1%-12% suspending agent, 0.5%-5% flow aid, 0.1%-5% lubricant, 0.1%-5% sweetener and 0.1%-3% flavoring agent.

[0135] In some embodiments, the dry suspension comprises 1%-50% solid dispersion, 40%-65% diluent, and 1%-12% suspending agent.

[0136] In some embodiments, the dry suspension comprises 1%-50% solid dispersion, 40%-65% diluent, 1%-12% suspending agent, 0.5%-5% flow aid, 0.1%-5% lubricant, 0.1%-5% sweetener and 0.1%-3% flavoring agent.

[0137] In some embodiments, the dry suspension comprises 20%-40% solid dispersion, 50%-65% diluent, and 2%-12% suspending agent.

[0138] In some embodiments, the dry suspension comprises 20%-40% solid dispersion, 50%-65% diluent, 2%-12% suspending agent, 1%-4% flow aid, 0.1%-2% lubricant, 0.5%-3% sweetener and 0.1%-1% flavoring agent.

[0139] In some embodiments, the dry suspension comprises 25%-35% solid dispersion, 50%-62% diluent, and 3%-10% suspending agent.

[0140] In some embodiments, the dry suspension comprises 25%-35% solid dispersion, 50%-62% diluent, 3%-10% suspending agent, 2%-4% flow aid, 0.1%-1% lubricant, 0.5%-1% sweetener and 0.1%-0.5% flavoring agent.

[0141] In some embodiments, the dry suspension comprises 1%-50% solid dispersion, 70%-80% diluent, and 1%-5% suspending agent.

[0142] In some embodiments, the dry suspension comprises 1%-50% solid dispersion, 70%-80% diluent, 1%-5% suspending agent, 0.5%-5% flow aid, 0.1%-5% lubricant, 1%-5% sweetener and 0.1%-3% flavoring agent.

[0143] In some embodiments, the dry suspension comprises 5%-30% solid dispersion, 75%-80% diluent, and 1%-3% suspending agent.

[0144] In some embodiments, the dry suspension comprises 5%-30% solid dispersion, 75%-80% diluent, 1%-3% suspending agent, 0.5%-3% flow aid, 0.1%-2% lubricant, 1%-3% sweetener and 0.1%-1% flavoring agent.

[0145] In some embodiments, the dry suspension comprises 10%-20% solid dispersion, 75%-80% diluent, and 1%-2% suspending agent.

[0146] In some embodiments, the dry suspension comprises 10%-20% solid dispersion, 75%-80% diluent, 1%-2% suspending agent, 0.5%-1% flow aid, 0.1%-1% lubricant, 2%-3% sweetener and 0.1%-0.5% flavoring agent.

[0147] In some embodiments, the diluent in the dry suspension includes one or more of isomalt, mannitol, maltitol, corn starch, lactose, microcrystalline cellulose, sucrose, and sorbitol, preferably one or more of mannitol, maltitol, corn starch, lactose, microcrystalline cellulose, sucrose, and sorbitol, and more preferably mannitol and / or maltitol.

[0148] In some embodiments, when the dry suspension contains more than 700 mg, the diluent is not mannitol alone.

[0149] In some embodiments, the dry suspension comprises mannitol and maltitol in a ratio of 1:5-5:1, preferably 1:4-4:1, more preferably 1:3-3:1, and even more preferably 1:2-2:1, such as 1:1, 35.3:40, or 36.3:40.

[0150] In some embodiments, the maltitol is one or more of maltitol P35, maltitol P90, and maltitol P200, preferably maltitol P35 and / or maltitol P90.

[0151] In some implementations, the mannitol is 100 SD.

[0152] In some implementations, the isomalt is galenlQ721.

[0153] In some embodiments, the suspending agent in the dry suspension includes one or more of xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose, preferably including hydroxypropyl methylcellulose, and more preferably hydroxypropyl methylcellulose.

[0154] In some embodiments, the ratio of the solid dispersion to the suspending agent (e.g., hydroxypropyl methylcellulose) in the dry suspension is 18:1-18:8. Preferably, the ratio is 18:1.5-18:7.5, for example, a ratio of 18:1.1, 18:1.2, etc. 18:1.3, 18:1.4, 18:1.5, 18:1.6, 18:1.7, 18:1.8, 18:1.9, 18:2, 18:3, 18:4, 18:5, 18:6, 18:7, 18:7.1, 18:7.2, 18:7.3, 18:7.4, 18:7.5, 18:7.6, 18:7.7, 18:7.8, or 18:7.9.

[0155] In some embodiments, the flow aid in the dry suspension includes one or more of colloidal silica, micronized silica gel, and talc, preferably colloidal silica, and more preferably colloidal silica.

[0156] In some embodiments, the lubricant in the dry suspension includes one or more of magnesium stearate, talc, sodium stearate fumarate, and stearic acid, preferably sodium stearate fumarate, and more preferably sodium stearate fumarate.

[0157] In some embodiments, the sweetener in the dry suspension includes one or more of xylitol, sucrose, sucralose, and mannitol, preferably sucralose, and more preferably sucralose.

[0158] In some embodiments, the fragrance in the dry suspension includes one or more of strawberry powder flavoring, grape flavoring and sweet orange powder flavoring, preferably strawberry powder flavoring, and more preferably strawberry powder flavoring.

[0159] In some embodiments, the dry suspension comprises 1%-50% solid dispersion, 40%-65% mannitol, and 1%-12% hydroxypropyl methylcellulose; preferably, the dry suspension comprises 20%-40% solid dispersion, 50%-65% mannitol, and 2%-12% hydroxypropyl methylcellulose; more preferably, the dry suspension comprises 25%-35% solid dispersion, 50%-62% mannitol, and 3%-10% hydroxypropyl methylcellulose.

[0160] In some embodiments, the dry suspension comprises 1%-50% solid dispersion, 40%-65% mannitol, 1%-12% hydroxypropyl methylcellulose, 0.5%-5% colloidal silica, 0.1%-5% sodium stearate fumarate, 0.1%-5% sucralose, and 0.1%-3% strawberry powder flavoring; preferably, the dry suspension comprises 20%-40% solid dispersion, 50%-65% mannitol, 2%-12% hydroxypropyl methylcellulose, 1%-5% hydroxypropyl methylcellulose, and 0.1%-3% strawberry powder flavoring. The dry suspension comprises 25%-35% colloidal silica, 50%-62% mannitol, 3%-10% hydroxypropyl methylcellulose, 2%-4% colloidal silica, 0.1%-1% sodium stearate, 0.5%-1% sucralose, and 0.1%-0.5% strawberry powder flavoring.

[0161] In some embodiments, the dry suspension comprises 1%-50% solid dispersion, 70%-80% mannitol and maltitol, and 1%-5% hydroxypropyl methylcellulose; preferably, the dry suspension comprises 5%-30% solid dispersion, 75%-80% mannitol and maltitol, and 1%-3% hydroxypropyl methylcellulose; more preferably, the dry suspension comprises 10%-20% solid dispersion, 75%-80% mannitol and maltitol, and 1%-2% hydroxypropyl methylcellulose.

[0162] In some embodiments, the dry suspension comprises 1%-50% solid dispersion, 70%-80% mannitol and maltitol, 1%-5% hydroxypropyl methylcellulose, 0.5%-5% colloidal silica, 0.1%-5% sodium stearate fumarate, 1%-5% sucralose, and 0.1%-3% strawberry powder flavoring; preferably, the dry suspension comprises 5%-30% solid dispersion, 75%-80% mannitol and maltitol, 1%-3% hydroxypropyl methylcellulose, The dry suspension comprises 0.5%-3% colloidal silica, 0.1%-2% sodium stearate fumarate, 1%-3% sucralose, and 0.1%-1% strawberry powder flavoring; more preferably, the dry suspension comprises 10%-20% solid dispersion, 75%-80% mannitol and maltitol, 1%-2% hydroxypropyl methylcellulose, 0.5%-1% colloidal silica, 0.1%-1% sodium stearate fumarate, 2%-3% sucralose, and 0.1%-0.5% strawberry powder flavoring.

[0163] In some embodiments, the ratio of mannitol to maltitol in the dry suspension is 1:5-5:1, preferably 1:4-4:1, more preferably 1:3-3:1, and even more preferably 1:2-2:1, for example 1:1, 35.3:40 or 36.3:40.

[0164] In some embodiments, the dry suspension comprises 18.0% solid dispersion, 35.3% mannitol, 40.0% maltitol, 2.0% hydroxypropyl methylcellulose, 1.0% colloidal silica, 0.4% sodium stearate fumarate, 3.0% sucralose, and 0.3% strawberry powder flavoring. Preferably, the dry suspension is 500 mg / bag or 1000 mg / bag.

[0165] In some embodiments, the dry suspension comprises 18.0% solid dispersion, 36.3% mannitol, 40.0% maltitol, 2.0% hydroxypropyl methylcellulose, 1.0% colloidal silica, 0.4% sodium stearate fumarate, 2.0% sucralose, and 0.3% strawberry powder flavoring. Preferably, the dry suspension is 500 mg / bag or 1000 mg / bag.

[0166] In some embodiments, the dry suspension comprises 30.0% solid dispersion, 62.0% mannitol, 3.3% hydroxypropyl methylcellulose, 3.3% colloidal silica, 0.3% sodium stearate fumarate, 0.8% sucralose and 0.2% strawberry powder flavoring, preferably, the dry suspension weighs 600 mg per bag.

[0167] In some embodiments, the dry suspension comprises 30.0% solid dispersion, 60.3% mannitol, 5.0% hydroxypropyl methylcellulose, 3.3% colloidal silica, 0.3% sodium stearate fumarate, 0.8% sucralose and 0.2% strawberry powder flavoring, preferably, the dry suspension is 600 mg / bag.

[0168] In some embodiments, the dry suspension comprises 30.0% solid dispersion, 58.7% mannitol, 6.7% hydroxypropyl methylcellulose, 3.3% colloidal silica, 0.3% sodium stearate fumarate, 0.8% sucralose and 0.2% strawberry powder flavoring, preferably, the dry suspension is 600 mg / bag.

[0169] In some embodiments, the dry suspension comprises 30.0% solid dispersion, 55.3% mannitol, 10.0% hydroxypropyl methylcellulose, 3.3% colloidal silica, 0.3% sodium stearate fumarate, 0.8% sucralose and 0.2% strawberry powder flavoring, preferably, the dry suspension is 600 mg / bag.

[0170] In some embodiments, the sum of the components in the dry suspension is equal to 100%.

[0171] In some embodiments, the dry suspension is 300-1500 mg / bag, preferably 400-1200 mg / bag, and more preferably 500-1000 mg / bag, such as 500 mg / bag, 600 mg / bag or 1000 mg / bag.

[0172] In this invention, the amount of the compound represented by formula (I) or its pharmaceutically acceptable salt in each bag of the dry suspension can be selected according to the actual situation.

[0173] In some embodiments, the amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in each sachet of the dry suspension is 1-80 mg, preferably 5-40 mg, and more preferably 10 mg or 20 mg.

[0174] Fourthly, the present invention also provides a method for preparing the dry suspension as described above, comprising the following steps:

[0175] The solid dispersion is prepared by uniformly mixing the solid dispersion and the excipient (i.e., uniformly mixing the solid dispersion and the excipient as dry powder); optionally, the mixed particles are sieved and then uniformly mixed.

[0176] In this invention, all excipients used in the preparation of solid dispersions and dry suspensions are pharmaceutical excipients conventionally used in the field, and can be found in the Chinese Pharmacopoeia (2020 edition).

[0177] Fifthly, the present invention also provides applications, specifically:

[0178] The present invention also provides the use of the dry suspension prepared by the aforementioned method or the dry suspension prepared by the aforementioned method in the preparation of drugs for the prevention and / or treatment of influenza.

[0179] The present invention also provides a method for preventing and / or treating influenza, comprising administering to a patient a therapeutically effective amount of the dry suspension as described above or a dry suspension prepared by the method described above.

[0180] The present invention also provides a dry suspension as described above for the prevention and / or treatment of influenza.

[0181] In some implementations, the influenza is either influenza A or influenza B.

[0182] In some implementations, the influenza may be uncomplicated influenza or high-risk influenza with influenza-related complications.

[0183] In some implementations, the influenza patients may be children (e.g., children aged 3 months and older, 6 months and older, 1 year and older, 2 years and older, or 5 years and older), adolescents, or adults.

[0184] In some implementations, the influenza patients may be children (e.g., children aged 2 or 5 years and older), adolescents, or adults.

[0185] In some implementations, the influenza refers to uncomplicated influenza A or B in adults, children aged 3 months or older, children aged 6 months or older, children aged 1 year or older, children aged 2 years or older, children aged 5 years or older, or high-risk influenza in adults with influenza-related complications.

[0186] In some implementations, the influenza refers to uncomplicated influenza A or B in adults, children aged 2 or 5 years and older, adolescents, or high-risk adults with influenza-related complications.

[0187] In some implementations, the dosing regimen based on the compound represented by formula (I) is as follows: for adults, 40 mg once daily; for children and adolescents aged 2 years and older, the recommended dosage is based on weight: 40 mg once daily for those weighing ≥32 kg, and 20 mg once daily for those weighing <32 kg.

[0188] The present invention also provides the use of the dry suspension prepared by the aforementioned method, or the dry suspension prepared by the aforementioned method, in combination with oseltamivir in the preparation of drugs for the prevention and / or treatment of influenza.

[0189] The present invention also provides a method for preventing and / or treating influenza, comprising administering to a patient a therapeutically effective amount of the dry suspension as described above, or a combination of the dry suspension prepared by the method described above and oseltamivir.

[0190] The present invention also provides a combination of the dry suspension as described above or the dry suspension prepared by the method described above with oseltamivir, which is used as a drug.

[0191] The present invention also provides a combination of the dry suspension prepared by the aforementioned method and oseltamivir for the prevention and / or treatment of influenza.

[0192] In the above embodiments, the dry suspension containing the dry suspension or the dry suspension prepared by the preparation method described above, and the pharmaceutical composition containing oseltamivir can be taken simultaneously or sequentially.

[0193] In some implementations, the influenza is either influenza A or influenza B.

[0194] In some implementations, the influenza may be uncomplicated influenza or high-risk influenza with influenza-related complications.

[0195] In some implementations, the influenza patients may be children (e.g., children aged 3 months and older, 6 months and older, 1 year and older, 2 years and older, or 5 years and older), adolescents, or adults.

[0196] In some implementations, the influenza patients may be children (e.g., children aged 2 or 5 years and older), adolescents, or adults.

[0197] In some implementations, the influenza refers to uncomplicated influenza A or B in adults, children aged 3 months or older, children aged 6 months or older, children aged 1 year or older, children aged 2 years or older, children aged 5 years or older, or high-risk influenza in adults with influenza-related complications.

[0198] In some implementations, the influenza refers to uncomplicated influenza A or B in adults, children aged 2 or 5 years and older, adolescents, or high-risk adults with influenza-related complications.

[0199] In some implementations, the dosing regimen based on the compound represented by formula (I) is as follows: for adults, 40 mg once daily; for children and adolescents aged 2 years and older, the recommended dosage is based on weight: 40 mg once daily for those weighing ≥32 kg, and 20 mg once daily for those weighing <32 kg.

[0200] The present invention also provides the application of the dry suspension prepared by the aforementioned method or the dry suspension prepared by the aforementioned method in the preparation of drugs for the prevention and / or treatment of influenza, wherein the influenza is caused by avian influenza or influenza virus resistant to NAIs inhibitors (e.g., oseltamivir) or influenza virus resistant to PB2 inhibitors (e.g., VX787).

[0201] The present invention also provides a method for preventing and / or treating influenza, comprising administering to a patient a therapeutically effective amount of the dry suspension as described above or a dry suspension prepared by the method described above, wherein the influenza is avian influenza, influenza caused by a NAIs inhibitor-resistant mutant influenza virus, or influenza caused by a PB2 inhibitor-resistant mutant influenza virus.

[0202] The present invention also provides a dry suspension as described above or a dry suspension prepared by the method described above, which is used for the prevention and / or treatment of influenza, wherein the influenza is avian influenza, influenza caused by a NAIs inhibitor-resistant mutant influenza virus, or influenza caused by a PB2 inhibitor-resistant mutant influenza virus.

[0203] In some implementations, the avian influenza is highly pathogenic avian influenza.

[0204] In some embodiments, the avian influenza virus strain is one or more of A / Anhui / 1 / 2005(H5N1), A / Shenzhen / TH002 / 2016(H5N6), A / Taiwan / 1 / 2013(H6N1), A / Jiangsu / 1 / 2018(H7N4), A / Anhui / 1 / 2013(H7N9)-WT-egg1, A / Hong Kong / 2108 / 2003(H9N2), and A / Jiangxi-Donghu / 346-1 / 2013(H10N8).

[0205] In some implementations, the influenza caused by the NAIs inhibitor-resistant mutant influenza virus is the influenza caused by the oseltamivir-resistant mutant influenza virus.

[0206] In some implementations, the influenza caused by the PB2 inhibitor-resistant mutant influenza virus is the influenza caused by the VX787-resistant mutant influenza virus.

[0207] In some implementations, the drug-resistant influenza may be uncomplicated influenza or high-risk influenza with influenza-related complications.

[0208] In some implementations, the patients with drug-resistant influenza may be children (e.g., children aged 3 months and older, 6 months and older, 1 year and older, 2 years and older, or 5 years and older), adolescents, or adults.

[0209] In some implementations, the patients with drug-resistant influenza may be children (e.g., children aged 2 or 5 years and older), adolescents, or adults.

[0210] In some implementations, the drug-resistant influenza refers to uncomplicated influenza A or B in adults, children aged 3 months or older, children aged 6 months or older, children aged 1 year or older, children aged 2 years or older, children aged 5 years or older, or high-risk influenza in adults with influenza-related complications.

[0211] In some implementations, the drug-resistant influenza refers to uncomplicated influenza A or B in adults, children aged 2 or 5 years and older, adolescents, or high-risk adults with influenza-related complications.

[0212] In some implementations, the dosing regimen based on the compound represented by formula (I) is as follows: for adults, 40 mg once daily; for children and adolescents aged 2 years and older, the recommended dosage is based on weight: 40 mg once daily for those weighing ≥32 kg, and 20 mg once daily for those weighing <32 kg.

[0213] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0214] The reagents and raw materials used in this invention are all commercially available.

[0215] The positive and progressive effects of this invention are as follows:

[0216] The solid dispersion of the present invention and the dry suspension prepared therefrom not only effectively improve solubility and dissolution, but also have one or more of the following effects: (1) good long-term storage stability, with no significant changes in appearance, content, related substances, dissolution, etc. after long-term storage; (2) good ability to maintain supersaturation and inhibit recrystallization; (3) uniform particle size; (4) good flowability; (5) high chemical stability and low related substances; (6) good suspension effect; (7) good content uniformity; (8) low adhesion; (9) simple preparation and high safety; (10) robust process and large-scale industrial production; (11) good bioavailability and pharmacokinetic characteristics, which can effectively relieve influenza symptoms and have good safety. Attached Figure Description

[0217] Figure 1 is a photograph of the solid dispersion prepared in Example 1.

[0218] Figure 2 is a photograph of the solid dispersion prepared in Example 2.

[0219] Figure 3 is a photograph of the solid dispersion prepared in Example 3.

[0220] Figure 4 is a photograph of the solid dispersion prepared in Example 4.

[0221] Figure 5 is a photograph of the solid dispersion prepared in Example 5.

[0222] Figure 6 is a photograph of the solid dispersion prepared in Example 6.

[0223] Figure 7 is a photograph of the solid dispersion prepared in Example 7.

[0224] Figure 8 is a photograph of the solid dispersion prepared in Example 8.

[0225] Figure 9 is a photograph of the solid dispersion prepared in Example 9.

[0226] Figure 10 is a photograph of the solid dispersion prepared in Example 10.

[0227] Figure 11 shows the XRD pattern of the solid dispersion prepared in Example 1; where A represents day 0 and B represents the solid dispersion after storage at 60°C for 10 days.

[0228] Figure 12 shows the XRD pattern of the solid dispersion prepared in Example 4.

[0229] Figure 13 shows the XRD pattern of the solid dispersion prepared in Example 5; where A represents day 0 and B represents the solid dispersion after storage at 60°C for 10 days.

[0230] Figure 14 shows the XRD pattern of the active pharmaceutical ingredient. Detailed Implementation

[0231] The present invention is further illustrated below, but is not intended to limit the invention to the scope of the described embodiments. Experimental methods not specifically described in the following embodiments are performed according to conventional methods and conditions, or as selected in the product manual.

[0232] The main reagents and instruments used in the following preparation and effect examples are shown in the table below.

[0233] (I) Preparation Example

[0234] Preparation Example 1: Preparation of a solid dispersion of active ingredient and polymer carrier copolyvinyl ketone at a ratio of 1:4 using a fluidized bed process. a Removed during the process, for a formulation of 400 units.

[0235] Add acetone and water to a suitable container and stir to form an acetone-water solution. Add copovidone to the acetone-water solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0236] The fluidized bed was first preheated without air. Then, cross-linked polyvinylpyrrolidone was added to the material container, and the air flow rate was adjusted to ensure good fluidization of the cross-linked polyvinylpyrrolidone. The drug solution was then sprayed into the fluidized bed in an atomized state through a spray gun. During the spraying process, the inlet air temperature was 65-75℃, and the material temperature was 36-44℃. After spraying, the material was dried in the fluidized bed. During drying, the inlet air temperature was 65-75℃, and the material temperature was 35-45℃, and the drying time was 1 hour. Subsequently, the material was cooled to room temperature, discharged, and a solid dispersion was obtained (appearance photo shown in Figure 1).

[0237] Preparation Example 2: Preparation of a solid dispersion with an active ingredient and polymer carrier polyvinyl ketone in a 1:4 ratio using a fluidized bed process. a Removed during the process, for a formulation of 400 units.

[0238] Add acetone and methanol to a suitable container and stir to form an acetone-methanol solution. Add povidone to the acetone-methanol solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0239] The fluidized bed was first preheated without air. Then, cross-linked polyvinyl acetate (CRVPA) was added to the material container. The air flow rate was adjusted to ensure good fluidization of the CRVPA. The drug solution was then sprayed into the fluidized bed in an atomized state through a spray gun. During the spraying process, the inlet air temperature was 65-75℃, and the material temperature was 36-44℃. After spraying, the material was dried in the fluidized bed. During drying, the inlet air temperature was 65-75℃, and the material temperature was 35-45℃, for 1 hour. Subsequently, the material was cooled to room temperature, discharged, and a solid dispersion was obtained (appearance photo shown in Figure 2).

[0240] Preparation Example 3: Preparation of a solid dispersion of active ingredient and hydroxypropyl methylcellulose in a 1:4 ratio using a fluidized bed process. a Removed during the process, for a formulation of 400 units.

[0241] Add acetone and methanol to a suitable container and stir to form an acetone-methanol solution. Add hydroxypropyl methylcellulose to the acetone-methanol solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0242] The fluidized bed was first preheated without air. Then, cross-linked polyvinyl acetate (CRVPA) was added to the material container. The air flow rate was adjusted to ensure good fluidization of the CRVPA. The drug solution was then sprayed into the fluidized bed in an atomized state through a spray gun. During the spraying process, the inlet air temperature was 65-75℃, and the material temperature was 36-44℃. After spraying, the material was dried in the fluidized bed. During drying, the inlet air temperature was 65-75℃, and the material temperature was 35-45℃, for 1 hour. Subsequently, the material was cooled to room temperature, discharged, and a solid dispersion was obtained (appearance photo shown in Figure 3).

[0243] Preparation Example 4: Preparation of a solid dispersion of active ingredient and polyethylene glycol in a 1:4 ratio using a fluidized bed process. a Removed during the process, for a formulation of 400 units.

[0244] Add acetone and water to a suitable container and stir to form an acetone-water solution. Add polyethylene glycol to the acetone-water solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0245] The fluidized bed was first preheated without air. Then, cross-linked polyvinyl acetate (CRVPA) was added to the material container. The air flow rate was adjusted to ensure good fluidization of the CRVPA. The drug solution was then sprayed into the fluidized bed in an atomized state through a spray gun. During the spraying process, the inlet air temperature was 65-75℃, and the material temperature was 36-44℃. After spraying, the material was dried in the fluidized bed. During drying, the inlet air temperature was 65-75℃, and the material temperature was 35-45℃, for 1 hour. Subsequently, the material was cooled to room temperature, discharged, and a solid dispersion was obtained (appearance photo shown in Figure 4).

[0246] Preparation Example 5: Preparation of a solid dispersion of active ingredient and copovidone at a ratio of 1:0.5 using a fluidized bed process. a Removed during the process, for a formulation of 400 units.

[0247] Add acetone and water to a suitable container and stir to form an acetone-water solution. Add copovidone to the acetone-water solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0248] The fluidized bed was first preheated without air. Then, cross-linked polyvinyl acetate (CRVPA) was added to the material container. The air flow rate was adjusted to ensure good fluidization of the CRVPA. The drug solution was then sprayed into the fluidized bed in an atomized state through a spray gun. During the spraying process, the inlet air temperature was 65-75℃, and the material temperature was 36-44℃. After spraying, the material was dried in the fluidized bed. During drying, the inlet air temperature was 65-75℃, and the material temperature was 35-45℃, for 1 hour. Subsequently, the material was cooled to room temperature, discharged, and a solid dispersion was obtained (appearance photo shown in Figure 5).

[0249] Preparation Example 6: Preparation of a solid dispersion of active ingredient and copovidone in a 1:1 ratio using a fluidized bed process. a Removed during the process, for a formulation of 400 units.

[0250] Add acetone and water to a suitable container and stir to form an acetone-water solution. Add copovidone to the acetone-water solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0251] The fluidized bed was first preheated without air. Then, cross-linked polyvinyl acetate (CRPA) was added to the material container. The air flow rate was adjusted to ensure good fluidization of the CRPA. The drug solution was then sprayed into the fluidized bed in an atomized state through a spray gun. During the spraying process, the inlet air temperature was 65-75℃, and the material temperature was 36-44℃. After spraying, the material was dried in the fluidized bed. During drying, the inlet air temperature was 65-75℃, and the material temperature was 35-45℃, for 1 hour. Subsequently, the material was cooled to room temperature, discharged, and a solid dispersion was obtained (appearance photo shown in Figure 6).

[0252] Preparation Example 7: Fluidized bed process for preparing a solid dispersion of croscarmellose sodium cellulose as substrate. a Removed during the process, for a formulation of 400 units.

[0253] Add acetone and water to a suitable container and stir to form an acetone-water solution. Add copovidone to the acetone-water solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0254] The fluidized bed was first preheated without air. Then, croscarmellose sodium was added to the material container. The air flow rate was adjusted to ensure good fluidization of the croscarmellose sodium. The drug solution was then sprayed into the fluidized bed in an atomized state through a spray gun. During the spraying process, the inlet air temperature was 65-75℃ and the material temperature was 36-44℃. After spraying, the material was dried in the fluidized bed. During drying, the inlet air temperature was 65-75℃ and the material temperature was 35-45℃ for 1 hour. Subsequently, the material was cooled to room temperature, discharged, and a solid dispersion was obtained (appearance photo shown in Figure 7).

[0255] Preparation Example 8: Preparation of a solid dispersion of sodium carboxymethyl starch substrate using a fluidized bed process. a Removed during the process, for a formulation of 400 units.

[0256] Add acetone and water to a suitable container and stir to form an acetone-water solution. Add copovidone to the acetone-water solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0257] The fluidized bed was first preheated without air. Then, sodium carboxymethyl starch was added to the material container. The air flow was adjusted to achieve good fluidization of the sodium carboxymethyl starch. The drug solution was then sprayed into the fluidized bed in an atomized state through a spray gun. During spraying, the inlet air temperature was 65-75℃, and the material temperature was 36-44℃. After spraying, the material was dried in the fluidized bed. During drying, the inlet air temperature was 65-75℃, and the material temperature was 35-45℃, for 1 hour. The material was then cooled to room temperature, discharged, and a solid dispersion was obtained (appearance photo shown in Figure 8).

[0258] Preparation Example 9: Preparation of a solid dispersion of corn starch substrate using a fluidized bed process a Removed during the process, for a formulation of 400 units.

[0259] Add acetone and water to a suitable container and stir to form an acetone-water solution. Add copovidone to the acetone-water solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0260] The fluidized bed is first preheated without air. Then, corn starch is added to the material pot, and the air flow is adjusted to achieve a good fluidization state. The drug solution is then sprayed into the fluidized bed in an atomized state through a spray gun. During the spraying process, the inlet air temperature is 65-75℃, and the material temperature is 36-44℃. After spraying, the material is dried in the fluidized bed. During drying, the inlet air temperature is 65-75℃, and the material temperature is 35-45℃, for 1 hour. Subsequently, the material is cooled to room temperature, discharged, and a solid dispersion is obtained (appearance photo shown in Figure 9).

[0261] Preparation Example 10: Preparation of a solid dispersion of low-substituted hydroxypropyl cellulose substrate using a fluidized bed process. a Removed during the process, for a formulation of 400 units.

[0262] Add acetone and water to a suitable container and stir to form an acetone-water solution. Add copovidone to the acetone-water solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0263] The fluidized bed was first preheated without air. Then, low-substituted hydroxypropyl cellulose was added to the material container, and the air flow rate was adjusted to achieve a good fluidization state for the low-substituted hydroxypropyl cellulose. The drug solution was then sprayed into the fluidized bed in an atomized state through a spray gun. During the spraying process, the inlet air temperature was 65-75℃, and the material temperature was 36-44℃. After spraying, the material was dried in the fluidized bed. During drying, the inlet air temperature was 65-75℃, and the material temperature was 35-45℃, and the drying time was 1 hour. Subsequently, the material was cooled to room temperature, discharged, and a solid dispersion was obtained (appearance photo shown in Figure 10).

[0264] Preparation Example 11: Preparation of a solid dispersion of active ingredient and copovidone in a 1:4 ratio using a fluidized bed process. a Removed during the process, for a formulation of 400 units, the active ingredient was prepared in the second batch.

[0265] Add acetone and water to a suitable container and stir to form an acetone-water solution. Add copovidone to the acetone-water solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0266] The fluidized bed is first preheated without air. Then, cross-linked polyvinyl acetate (CRPA) is added to the material container. The air flow rate is adjusted to ensure good fluidization of the CRPA. The drug solution is then sprayed into the fluidized bed in an atomized state through a spray gun. During spraying, the inlet air temperature is 50-75℃, and the material temperature is 27-35℃. After spraying, the material is dried in the fluidized bed. During drying, the inlet air temperature is 50-60℃, and the material temperature is 29-44℃, for 2 hours. Subsequently, the material is cooled to room temperature, discharged, and a solid dispersion is obtained.

[0267] Preparation Example 12: Preparation of a solid dispersion of active ingredient and copovidone in a 1:4 ratio using spray drying. a Removed during the process, for a 500-unit formulation, the active ingredient is prepared in the second batch.

[0268] Add acetone to a suitable container, then add copovidone to the acetone while stirring until completely dissolved. Next, add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0269] Using a spray dryer, the drug solution is atomized and sprayed into the dryer through a spray gun. The inlet air temperature is 90℃, the outlet air temperature is 60-67℃, and the feed flow rate is approximately 252 g / h. The spray-dried product is collected and further dried in a vacuum drying oven at 60-65℃ for 22 hours. The material is then collected to obtain a solid dispersion.

[0270] Preparation Example 13: A solid dispersion of active ingredient and copovidone in a 1:22 ratio was prepared using a hot melt extrusion process.

[0271] For the 90-unit formulation, the active ingredient was prepared in the second batch.

[0272] The active ingredient and copovidone were mixed evenly. The mixed powder was melt-extruded using a hot melt extruder at a temperature of 180°C and a screw speed of 200 rpm to obtain a transparent and bright yellow extrudate. The extrudate was then pulverized and passed through an 80-mesh sieve to obtain a solid dispersion.

[0273] Preparation Example 14: Preparation of a solid dispersion of active ingredient and copovidone at a ratio of 1:4 using a fluidized bed process (pilot-scale formulation of 4000 units). a Removed during the process, for a formulation of 4000 units.

[0274] Add acetone and water to a suitable container and stir to form an acetone-water solution. Add copovidone to the acetone-water solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0275] The fluidized bed is first preheated without air. Then, cross-linked polyvinyl acetate (CRPA) is added to the material container. The air flow rate is adjusted to ensure good fluidization of the CRPA. The drug solution is then sprayed into the fluidized bed in an atomized state through a spray gun. During spraying, the inlet air temperature is 65-80℃, and the material temperature is 30-46℃. After spraying, the material is dried in the fluidized bed. During drying, the inlet air temperature is 65-80℃, and the material temperature is 40-53℃, for 2 hours. Subsequently, the material is cooled to room temperature, discharged, and a solid dispersion is obtained.

[0276] Preparation Example 15: A solid dispersion of active ingredient and copovidone at a ratio of 1:4 was prepared using a fluidized bed process (pilot-scale formulation of 10,000 units). a Removed during the process, for a formulation of 10,000 units.

[0277] Add acetone and water to a suitable container and stir to form an acetone-water solution. Add copovidone to the acetone-water solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0278] The fluidized bed is first preheated without air. Then, cross-linked polyvinyl acetate (CRPA) is added to the material container. The air flow rate is adjusted to ensure good fluidization of the CRPA. The drug solution is then sprayed into the fluidized bed in an atomized state through a spray gun. During spraying, the inlet air temperature is 65-80℃, and the material temperature is 30-46℃. After spraying, the material is dried in the fluidized bed. During drying, the inlet air temperature is 65-80℃, and the material temperature is 35-47℃, for 2 hours. Subsequently, the material is cooled to room temperature, discharged, and a solid dispersion is obtained.

[0279] Preparation Example 16: Fluidized bed process for preparing a solid dispersion of active ingredient and copovidone at a ratio of 1:4 (production scale of 25,000 units). a Removed during the process, targeting a formulation of 25,000 units.

[0280] Add acetone to a suitable container, then add the active ingredient while stirring until completely dissolved. Add purified water and stir until completely dissolved. Add copovidone to the above solution while stirring until completely dissolved to obtain a drug solution for later use.

[0281] The fluidized bed is first preheated without air. Then, cross-linked polyvinyl acetate (CRPA) is added to the material container. The air flow rate is adjusted to ensure good fluidization of the CRPA. The drug solution is then sprayed into the fluidized bed in an atomized state through a spray gun. During spraying, the inlet air temperature is 50-70℃, and the material temperature is 30-46℃. After spraying, the material is dried in the fluidized bed. During drying, the inlet air temperature is 50-70℃, and the material temperature is 40-56℃, for 2 hours. Subsequently, the material is cooled to room temperature, discharged, and a solid dispersion is obtained.

[0282] Preparation Example 17: Fluidized bed process for preparing a solid dispersion of active ingredient and copovidone at a ratio of 1:4 (production scale of 100,000 units). a Removed during the process, for a formulation of 100,000 units.

[0283] Add acetone to a suitable container, then add the active ingredient while stirring until completely dissolved. Add purified water and stir until completely dissolved. Add copovidone to the above solution while stirring until completely dissolved to obtain a drug solution for later use.

[0284] The fluidized bed is first preheated without air. Then, cross-linked polyvinyl acetate (CRPA) is added to the material container. The air flow rate is adjusted to ensure good fluidization of the CRPA. The drug solution is then sprayed into the fluidized bed in an atomized state through a spray gun. During spraying, the inlet air temperature is 55-80℃, and the material temperature is 36-44℃. After spraying, the material is dried in the fluidized bed. During drying, the inlet air temperature is 65-75℃, and the material temperature is 35-45℃, for 2 hours. Subsequently, the material is cooled to room temperature, discharged, and a solid dispersion is obtained.

[0285] Preparation Example 18: Preparation of a solid dispersion of active ingredient and polymer carrier copolyvinyl ketone in a 1:4 ratio using a fluidized bed process. a Removed during the process, for a formulation of 4000 units.

[0286] Add acetone and water to a suitable container and stir to form an acetone-water solution. Add copovidone to the acetone-water solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0287] The fluidized bed is first preheated without air. Then, cross-linked polyvinyl acetate (CRPA) is added to the material container. The air flow rate is adjusted to ensure good fluidization of the CRPA. The drug solution is then sprayed into the fluidized bed in an atomized state through a spray gun. During spraying, the inlet air temperature is 65-75℃, and the material temperature is 36-44℃. After spraying, the material is dried in the fluidized bed. During drying, the inlet air temperature is 65-75℃, and the material temperature is 35-45℃, for 1 hour. Subsequently, the material is cooled to room temperature, discharged, and a solid dispersion is obtained.

[0288] Preparation Example 19: Preparation of a dry suspension without using a suspending agent

[0289] For a 50-unit formulation.

[0290] First, the solid dispersion and the prescribed amounts of mannitol, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a PE bag and mixed for 5 minutes. After passing through a 40-mesh sieve once, the mixture is further mixed in the PE bag for 10 minutes to obtain total mixed granules. The total mixed granules are packaged in a polyester / aluminum / polyethylene pharmaceutical composite film bag and heat-sealed. The contents weigh 600 mg per bag, and each bag contains 20 mg of active ingredient.

[0291] Preparation Example 20: Preparation of a dry suspension with xanthan gum as the suspending agent.

[0292] For a 50-unit formulation.

[0293] First, the solid dispersion and the prescribed amounts of mannitol, xanthan gum, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a PE bag and mixed for 5 minutes. After passing through a 40-mesh sieve once, the mixture is further mixed in the PE bag for 10 minutes to obtain the total mixed granules. The total mixed granules are packaged in a polyester / aluminum / polyethylene pharmaceutical composite film bag and heat-sealed. The contents weigh 600 mg per bag, and each bag contains 20 mg of active ingredient.

[0294] Preparation Example 21: Preparation of a dry suspension with hydroxyethyl cellulose as the suspending agent.

[0295] For a 50-unit formulation.

[0296] First, the solid dispersion and the prescribed amounts of mannitol, hydroxyethyl cellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a PE bag and mixed for 5 minutes. After passing through a 40-mesh sieve once, the mixture is further mixed in the PE bag for 10 minutes to obtain the total mixed granules. The total mixed granules are packaged in a polyester / aluminum / polyethylene pharmaceutical composite film bag and heat-sealed. The contents weigh 600mg per bag, and each bag contains 20mg of active ingredient.

[0297] Preparation Example 22: Preparation of a dry suspension with sodium carboxymethyl cellulose as the suspending agent.

[0298] For a 50-unit formulation.

[0299] First, the solid dispersion and the prescribed amounts of mannitol, sodium carboxymethyl cellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a PE bag and mixed for 5 minutes. After passing through a 40-mesh sieve once, the mixture is further mixed in the PE bag for 10 minutes to obtain the total mixed granules. The total mixed granules are packaged in a polyester / aluminum / polyethylene pharmaceutical composite film bag and heat-sealed. The contents weigh 600 mg per bag, and each bag contains 20 mg of active ingredient.

[0300] Preparation Example 23: Preparation of a dry suspension with hydroxypropyl methylcellulose (10 mg per sachet) as the suspending agent.

[0301] For a 50-unit formulation.

[0302] First, the solid dispersion and the prescribed amounts of mannitol, hydroxypropyl methylcellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a PE bag and mixed for 5 minutes. After passing through a 40-mesh sieve once, the mixture is further mixed in the PE bag for 10 minutes to obtain the total mixed granules. The total mixed granules are packaged in a polyester / aluminum / polyethylene pharmaceutical composite film bag and heat-sealed. The contents weigh 600 mg per bag, and each bag contains 20 mg of active ingredient.

[0303] Preparation Example 24: Preparation of a dry suspension with hydroxypropyl methylcellulose (20 mg per sachet) as the suspending agent.

[0304] For a 50-unit formulation.

[0305] First, the solid dispersion and the prescribed amounts of mannitol, hydroxypropyl methylcellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a PE bag and mixed for 5 minutes. After passing through a 40-mesh sieve once, the mixture is further mixed in the PE bag for 10 minutes to obtain the total mixed granules. The total mixed granules are packaged in a polyester / aluminum / polyethylene pharmaceutical composite film bag and heat-sealed. The contents weigh 600 mg per bag, and each bag contains 20 mg of active ingredient.

[0306] Preparation Example 25: Preparation of a dry suspension with hydroxypropyl methylcellulose (30 mg per sachet) as the suspending agent.

[0307] For a 50-unit formulation.

[0308] First, the solid dispersion and the prescribed amounts of mannitol, hydroxypropyl methylcellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a PE bag and mixed for 5 minutes. After passing through a 40-mesh sieve once, the mixture is further mixed in the PE bag for 10 minutes to obtain the total mixed granules. The total mixed granules are packaged in a polyester / aluminum / polyethylene pharmaceutical composite film bag and heat-sealed. The contents weigh 600 mg per bag, and each bag contains 20 mg of active ingredient.

[0309] Preparation Example 26: Preparation of a dry suspension with hydroxypropyl methylcellulose (40 mg per sachet) as the suspending agent.

[0310] For a 25-unit formulation.

[0311] First, the solid dispersion and the prescribed amounts of mannitol, hydroxypropyl methylcellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a PE bag and mixed for 5 minutes. After passing through a 40-mesh sieve once, the mixture is further mixed in the PE bag for 10 minutes to obtain the total mixed granules. The total mixed granules are packaged in a polyester / aluminum / polyethylene pharmaceutical composite film bag and heat-sealed. The contents weigh 600 mg per bag, and each bag contains 20 mg of active ingredient.

[0312] Preparation Example 27: Preparation of a dry suspension with hydroxypropyl methylcellulose (60 mg per sachet) as the suspending agent.

[0313] For a 25-unit formulation.

[0314] First, the solid dispersion and the prescribed amounts of mannitol, hydroxypropyl methylcellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a PE bag and mixed for 5 minutes. After passing through a 40-mesh sieve once, the mixture is further mixed in the PE bag for 10 minutes to obtain the total mixed granules. The total mixed granules are packaged in a polyester / aluminum / polyethylene pharmaceutical composite film bag and heat-sealed. The contents weigh 600 mg per bag, and each bag contains 20 mg of active ingredient.

[0315] Preparation Example 28: Preparation of a dry suspension with hydroxypropyl methylcellulose (80 mg per sachet) as the suspending agent.

[0316] For a 25-unit formulation.

[0317] First, the solid dispersion and the prescribed amounts of mannitol, hydroxypropyl methylcellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a PE bag and mixed for 5 minutes. After passing through a 40-mesh sieve once, the mixture is further mixed in the PE bag for 10 minutes to obtain the total mixed granules. The total mixed granules are packaged in a polyester / aluminum / polyethylene pharmaceutical composite film bag and heat-sealed. The contents weigh 600 mg per bag, and each bag contains 20 mg of active ingredient.

[0318] Preparation Example 29: Preparation of a dry suspension with a content weight of 600 mg / bag

[0319] For a formulation of 750 units.

[0320] First, the solid dispersion and the prescribed amounts of mannitol, maltitol, hydroxypropyl methylcellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a mixer and mixed. After mixing, the mixture is sieved once in a granulator and then transferred to a mixer for further mixing. The final mixture is then collected as total granules. These granules are packaged in polyester / aluminum / polyethylene pharmaceutical composite film bags, heat-sealed, with a content weight of 600mg / bag, each bag containing 20mg of active ingredient.

[0321] Preparation Example 30: A dry suspension with a content weight of 1000 mg / bag was prepared.

[0322] For a formulation of 450 units.

[0323] First, the solid dispersion and the prescribed amounts of mannitol, maltitol, hydroxypropyl methylcellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a mixer and mixed. After mixing, the mixture is sieved once in a granulator and then transferred to a mixer for further mixing. The final mixture is then collected as total granules. These granules are packaged in polyester / aluminum / polyethylene pharmaceutical composite film bags, heat-sealed, with a content weight of 1000 mg / bag, each bag containing 20 mg of active ingredient.

[0324] Preparation Example 31: Preparation of a dry suspension containing maltitol P200

[0325] For a 400-unit formulation.

[0326] First, the solid dispersion and the prescribed amounts of mannitol, maltitol, hydroxypropyl methylcellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a mixer and mixed. After mixing, the mixture is sieved twice in a granulator and then transferred to a mixer for further mixing. The final mixture is then collected as total granules. These granules are packaged in polyester / aluminum / polyethylene pharmaceutical composite film bags, heat-sealed, with a content weight of 1000 mg / bag, each bag containing 20 mg of active ingredient.

[0327] Preparation Example 32: Preparation of a dry suspension containing maltitol P90

[0328] For a 400-unit formulation.

[0329] First, the solid dispersion and the prescribed amounts of mannitol, maltitol, hydroxypropyl methylcellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a mixer and mixed. After mixing, the mixture is sieved twice in a granulator and then transferred to a mixer for further mixing. The final mixture is then collected as total granules. These granules are packaged in polyester / aluminum / polyethylene pharmaceutical composite film bags, heat-sealed, with a content weight of 1000 mg / bag, each bag containing 20 mg of active ingredient.

[0330] Preparation Example 33: Preparation of a dry suspension containing maltitol P35

[0331] For a 500-unit formulation.

[0332] First, the solid dispersion and the prescribed amounts of mannitol, maltitol, hydroxypropyl methylcellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring are added to a mixer and mixed. After mixing, the mixture is sieved twice in a granulator and then transferred to a mixer for further mixing. The final mixture is then collected as total granules. These granules are packaged in polyester / aluminum / polyethylene pharmaceutical composite film bags, heat-sealed, with a content weight of 1000 mg / bag, each bag containing 20 mg of active ingredient.

[0333] Preparation Example 34: Preparation of a dry suspension containing talc.

[0334] For a 25-unit formulation.

[0335] First, the solid dispersion and the prescribed amounts of mannitol, maltitol, hydroxypropyl methylcellulose, talc, sucralose, and strawberry powder flavoring are added to a PE bag and mixed for 5 minutes. After passing through a 40-mesh sieve once, the mixture is further mixed in the PE bag for 10 minutes to obtain the total mixed granules. The total mixed granules are packaged in a polyester / aluminum / polyethylene pharmaceutical composite film bag and heat-sealed. The contents weigh 1000mg per bag, and each bag contains 20mg of active ingredient.

[0336] Preparation Example 35: Preparation of a dry suspension of a solid dispersion of active ingredient and copovidone in a 1:4 ratio (pilot-scale 4000 bags). a Removed during the process, for a formulation of 4000 units.

[0337] The solid dispersion was prepared according to Preparation Example 18. The solid dispersion and the prescribed amounts of mannitol, maltitol, hydroxypropyl methylcellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring were then added to a mixer. After mixing, the mixture was sieved twice in a granulator and then transferred to a mixer for further mixing. The resulting total granules were collected after mixing. The total granules were packaged in polyester / aluminum / polyethylene pharmaceutical composite film bags, heat-sealed, with a content weight of 1000 mg / bag, each bag containing 20 mg of active ingredient.

[0338] Preparation Example 36: Preparation of a mixture of active ingredient and different excipients

[0339] For a 25-unit formulation.

[0340] First, the solid dispersion and the prescribed amount of excipient are added to a PE bag and mixed for 5 minutes. After passing through a 40-mesh sieve once, the mixture is further mixed in the PE bag for 5 minutes to obtain total mixed granules. The total mixed granules are packaged in a polyester / aluminum / polyethylene pharmaceutical composite film bag and heat-sealed. The contents weigh 360 mg / bag, and each bag contains 20 mg of active ingredient.

[0341] Preparation Example 37: Preparation of a dry suspension of a solid dispersion of active ingredient and copovidone in a 1:4 ratio (production scale: 30,000 bags). a Removed during the process, for a formulation of 30,000 units.

[0342] Add acetone and water to a suitable container and stir to form an acetone-water solution. Add copovidone to the acetone-water solution while stirring until completely dissolved. Then add the active ingredient while stirring until completely dissolved to obtain a drug solution for later use.

[0343] The fluidized bed is first preheated without air. Then, cross-linked polyvinyl alcohol (CRVA) is added to the material container. The air flow rate is adjusted to ensure good fluidization of the CRVA. The drug solution is then sprayed into the fluidized bed in an atomized state through a spray gun. During spraying, the inlet air temperature is 55-80℃, and the material temperature is 36-44℃. After spraying, the material is dried in the fluidized bed. During drying, the inlet air temperature is 65-75℃, and the material temperature is 58-61℃, for 2 hours. Subsequently, the material is cooled to room temperature, discharged, and a solid dispersion is obtained.

[0344] Subsequently, the solid dispersion and the prescribed amounts of mannitol, maltitol, hydroxypropyl methylcellulose, colloidal silica, sodium stearate fumarate, sucralose, and strawberry powder flavoring were added to a mixer. After mixing, the mixture was sieved twice in a granulator and then transferred to a mixer for further mixing. The resulting total granules were collected after mixing. The total granules were then packaged in polyester / aluminum / polyethylene pharmaceutical composite film bags, heat-sealed, with a content weight of 1000 mg / bag, each bag containing 20 mg of active ingredient.

[0345] (II) Examples of Results

[0346] Example 1: Solubility of solid dispersion

[0347] The solubility of the solid dispersions and active pharmaceutical ingredients (active ingredients, compounds represented by formula (I)) prepared in Preparation Examples 1-10 and 12 was tested.

[0348] Testing instruments: constant temperature water bath shaker, high performance liquid chromatograph;

[0349] Medium: pH 6.8 phosphate buffer: Take 6.805g of potassium dihydrogen phosphate and 0.9g of sodium hydroxide, dissolve them in 1L of water, mix well, and the solution is ready.

[0350] The determination was performed according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512), and the determination method included the following steps:

[0351] (1) Preparation of test solution: Take an appropriate amount of the sample to be tested, place it in a vial, add an appropriate amount of pH 6.8 phosphate buffer to make a supersaturated solution, place it in a 37℃ constant temperature water bath shaker and shake at 150 rpm, take a sample after 1 hour, filter it through a 0.45 μm PES membrane, and take the filtrate to obtain the test solution.

[0352] (2) Preparation of reference solution: Weigh about 20 mg of reference standard (raw material) accurately, place it in a 100 mL brown volumetric flask, add acetonitrile to dissolve and dilute to the mark, shake well, accurately measure 5 mL, place it in a 50 mL brown volumetric flask, dilute to the mark with diluent (acetonitrile-water), shake well, and use as reference solution.

[0353] (3) Accurately measure the reference solution and the test solution, inject them separately into the high-performance liquid chromatograph, and record the chromatograms. Calculate the solubility using the external standard method.

[0354] The test results are listed in Table 1.

[0355] Table 1. Solubility of solid dispersions and active pharmaceutical ingredients obtained in Preparation Examples 1-10 and 12

[0356] Solid dispersions prepared by using copovidone, povidone, and hydroxypropyl methylcellulose as polymer carriers can significantly improve the solubility of active ingredients, with copovidone and hydroxypropyl methylcellulose showing better results when used as polymer carriers; the solubility of active ingredients and polymer carriers can be improved even at low dosage ratios within various dosage ranges.

[0357] Solid dispersions prepared using crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, corn starch, and low-substituted hydroxypropyl cellulose as substrates can all significantly improve the solubility of active ingredients, with crospovidone and crospovidone sodium carboxymethyl cellulose showing better results when used as substrates.

[0358] Solid dispersions prepared by fluidized bed and spray drying methods can effectively improve solubility.

[0359] Example 2: Study on the crystalline state of solid dispersions

[0360] The solid dispersions and active pharmaceutical ingredients (active ingredients, compounds represented by formula (I)) prepared in Examples 1-10 and 12 were studied for their crystalline state.

[0361] The crystalline morphology of the solid dispersions and active pharmaceutical ingredients prepared in Examples 1-10 and 12 was determined using X-ray powder diffraction (XRD). The changes in the crystalline morphology of the active ingredient in the solid dispersions were investigated after 0 days in aluminum foil packaging and after 10 days of storage at 60°C. The test results are shown in Table 2 and Figures 11-14.

[0362] Table 2. Crystalline states of the active ingredients and the active pharmaceutical ingredient in the solid dispersions obtained in Preparation Examples 1-10 and 12. d The "amorphous" in Table 2 indicates that no crystal form peak of the active pharmaceutical ingredient was detected.

[0363] Solid dispersions prepared using copovidone, povidone, and hydroxypropyl methylcellulose as polymer carriers, as well as solid dispersions prepared using cross-linked povidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, corn starch, and low-substituted hydroxypropyl cellulose as substrates, were all amorphous after 0 days and 10 days of storage at 60°C. Taking Preparation Example 1 as an example, the XRD pattern of the newly prepared solid dispersion is shown in Figure 11A, and the XRD pattern after 10 days of storage at 60°C is shown in Figure 11B; neither showed any crystalline peaks.

[0364] When the ratio of active ingredient to copovidone is 1:0.5, the solid dispersion prepared is amorphous on day 0 (as shown in Figure 13A). After being stored at 60°C for 10 days, a small amount of crystallization occurs, as shown in Figure 13B.

[0365] The crystal form of the active pharmaceutical ingredient (API) was detected in the solid dispersion prepared using polyethylene glycol as the polymer carrier, as shown in Figure 12. Additionally, Figure 14 shows the XRD pattern of the API, which contains peaks indicating the API's crystal form, serving as a control.

[0366] Both fluidized bed and spray drying methods can produce amorphous solid dispersions.

[0367] Example 3: Study on the ability of solid dispersions to maintain supersaturation

[0368] The ability of the solid dispersions and drug substance (active ingredient, compound represented by formula (I)) prepared in Examples 1-10 and 12 to maintain supersaturation was studied.

[0369] Testing instruments: constant temperature water bath shaker, high performance liquid chromatograph;

[0370] Medium: pH 6.8 phosphate buffer: Take 6.805g of potassium dihydrogen phosphate and 0.9g of sodium hydroxide, dissolve them in 1L of water, mix well, and the solution is ready.

[0371] The determination was performed according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512), and the determination method included the following steps:

[0372] (1) Preparation of test solution: Take an appropriate amount of the sample to be tested, place it in a vial, add an appropriate amount of pH 6.8 phosphate buffer to make a supersaturated solution, place it in a 37℃ constant temperature water bath shaker and shake at 150 rpm, and take samples at 1h, 2h and 4h, filter it through a 0.45μm PES membrane, and take the filtrate to obtain the test solution.

[0373] (2) Preparation of reference solution: Weigh about 20 mg of reference standard (raw material) accurately, place it in a 100 mL brown volumetric flask, add acetonitrile to dissolve and dilute to the mark, shake well, accurately measure 5 mL, place it in a 50 mL brown volumetric flask, dilute to the mark with diluent (acetonitrile-water), shake well, and use as reference solution.

[0374] Accurately measure the reference solution and test solution, and inject them separately into the high-performance liquid chromatograph (HPLC), recording the chromatograms. Calculate the solution concentration at each time point using the external standard method.

[0375] The test results are listed in Table 3.

[0376] Table 3. Solubility of solid dispersions and active pharmaceutical ingredients obtained in Preparation Examples 1-10 and 12

[0377] The solubility of solid dispersions prepared using hydroxypropyl methylcellulose as a polymer carrier decreased over time, possibly due to supersaturation crystallization. Solid dispersions prepared using copovidone, povidone, and polyethylene glycol as polymer carriers exhibited better supersaturation maintenance capabilities. Among them, solid dispersions prepared using copovidone as a polymer carrier showed the best effect, with high solubility and the best ability to maintain supersaturation. The supersaturation ability could be maintained within various dosage ratios of the active ingredient and polymer carrier, as well as when using crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, corn starch, and low-substituted hydroxypropyl cellulose as substrates.

[0378] Solid dispersions prepared by fluidized bed and spray drying methods both have good ability to maintain supersaturation.

[0379] Example 4: Study on the particle morphology of solid dispersions

[0380] The particle morphology of the solid dispersions prepared in Examples 1-10 was investigated. The appearance of the solid dispersions prepared in Examples 1-10 is shown in Figures 1-10.

[0381] Solid dispersions prepared using copovidone and hydroxypropyl methylcellulose as polymer carriers exhibit better particle size uniformity; solid dispersions prepared using povidone as a polymer carrier are relatively finer than powders and are prone to agglomeration; solid dispersions prepared using polyethylene glycol as a polymer carrier are relatively harder and have a small amount of caking.

[0382] Solid dispersions prepared using crospovidone and crospovidone sodium carboxymethyl cellulose as substrates exhibit better particle size uniformity; solid dispersions prepared using sodium carboxymethyl starch, corn starch, and low-substituted hydroxypropyl cellulose as substrates have relatively fine particles and are prone to agglomeration.

[0383] Example 5: Study on the Flowability of Solid Dispersions

[0384] The flowability of the solid dispersions prepared in Examples 1-10 was studied.

[0385] Testing instrument: Powder comprehensive property tester;

[0386] The determination method includes the following steps: Take about 10g of solid dispersion and place it in the funnel of the powder comprehensive property tester. Open the baffle at the bottom of the funnel and turn on the vibration to make the powder fall to the platform below. After all the powder has fallen, use a protractor to measure the angle between the inclined plane of the powder accumulation and the platform from two different angles. This is the angle of repose. Record the values ​​and calculate the average value. Take the average value as the angle of repose of the solid dispersion. The results are listed in Table 4.

[0387] Table 4 Angles of repose of the solid dispersions prepared in Examples 1-10

[0388] Solid dispersions prepared using copovidone, hydroxypropyl methylcellulose, and polyethylene glycol as polymer carriers have smaller angles of repose, with solid dispersions prepared using povidone as a polymer carrier being the next smallest.

[0389] Solid dispersions prepared using crospovidone and crospovidone sodium carboxymethyl cellulose as substrates have smaller angles of repose; solid dispersions prepared using sodium carboxymethyl starch, corn starch, and low-substituted hydroxypropyl cellulose as substrates are the next smaller.

[0390] Example 6: Study on total impurities in solid dispersions

[0391] Total impurities were studied in the solid dispersions and drug substances (active ingredients, compounds represented by formula (I)) prepared in Examples 11-13.

[0392] Testing instrument: High Performance Liquid Chromatography (HPLC)

[0393] The determination was performed according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512), and the determination method included the following steps:

[0394] (1) Preparation of test solution: Take an appropriate amount of fine powder of the sample to be tested, accurately weigh it, add an appropriate amount of diluent (acetonitrile-water) and sonicate for 10 minutes to dissolve it, cool it, dilute it with diluent to prepare a solution containing about 1 mg per 1 mL, centrifuge at 8000 rpm for 10 minutes, and take the supernatant.

[0395] (2) Preparation of reference solution: Weigh about 20 mg of reference standard (raw material) accurately, place it in a 100 mL brown volumetric flask, add acetonitrile to dissolve and dilute to the mark, shake well, accurately measure 5 mL, place it in a 50 mL brown volumetric flask, dilute to the mark with diluent (acetonitrile-water), shake well, and use as reference solution.

[0396] (3) Accurately measure the reference solution and the test solution, inject them separately into the high-performance liquid chromatograph, and record the chromatograms. The total impurity content is obtained by subtracting the content of the main component from the chromatogram of the test solution. The results are listed in Table 5.

[0397] Table 5 Total impurity content of solid dispersions and active pharmaceutical ingredients prepared by different processes

[0398] The total impurity content in the solid dispersions prepared by fluidized bed process and spray drying method did not increase significantly, with fluidized bed process being superior. The total impurity content in the solid dispersions prepared by hot melt extrusion method increased significantly.

[0399] Example 7: Study on the suspension effect of dry suspensions

[0400] The total mixed particles obtained in Preparation Examples 19-28 were used to prepare suspensions with a certain amount of purified water, and their suspension effect was evaluated. The results are listed in Table 6.

[0401] Table 6 Evaluation Results of Suspension Agent Types and Dosages

[0402] Xanthan gum or sodium carboxymethyl cellulose provide good suspension, but they do not disperse easily when shaken and require stirring. Hydroxypropyl cellulose provides slightly less effective suspension, but it disperses easily and evenly during preparation. Hydroxypropyl methyl cellulose is easy to prepare and reduces suspended particles on the liquid surface when used within the preferred dosage range.

[0403] Example 8: Study on the overall mixing uniformity and dosage uniformity of dry suspensions

[0404] The mixing uniformity and loading uniformity of the total mixed particles prepared in Examples 29-33 were evaluated, and the results are listed in Tables 7 and 8.

[0405] Table 7 Results of overall mixing homogeneity

[0406] The 600mg and 1000mg dry suspensions of this invention can both meet the requirements for mixing uniformity (RSD≤5%), and the dry suspensions provided by this invention have excellent uniformity of dosage.

[0407] Table 8 Results of overall mixing homogeneity

[0408] All three types of maltitol met the requirements for uniform mixing (RSD≤5%), with P90 and P35 being the better ones.

[0409] Example 9: Evaluation of the Adhesion Effect of Dry Suspension

[0410] 1.00 g of the total mixed particles prepared in Preparation Examples 33, 34 and 37 were added to a 5 mL vial. The vial was inverted three times, and the adhesion at the bottom was observed. The results are listed in Table 9.

[0411] Table 9. Adhesion test results of the formulation

[0412] Adhesion was acceptable, with sodium stearate fumarate and colloidal silica providing superior anti-adhesion properties.

[0413] Example 10: Study on the stability of different types of excipients

[0414] The mixtures of different solid dispersions and excipients in Preparation Example 36 were placed at 40°C, and samples were taken after 7 days to detect impurities and calculate the amount of impurity growth.

[0415] Table 3. Stability results of different excipients (40℃, 7 days)

[0416] Example 11: Process robustness and stability studies

[0417] The properties of the pilot-scale dry suspension (Preparation Example 35) were investigated to assess process robustness, batch-to-batch variability, and feasibility for scale-up production, while also conducting long-term stability studies.

[0418] (1) Appearance test

[0419] The dry suspension prepared using the method in Preparation Example 35 was stored for 6 months at a temperature of 25℃±2℃ and a humidity of 60%±5% RH, and its appearance was continuously tested to observe changes in appearance. The results are shown in Table 10. There was no difference in properties between batches, and the appearance did not change significantly after 6 months of storage at room temperature.

[0420] Table 10 Appearance Changes of Dry Suspension

[0421] (2) Content testing

[0422] The dry suspension prepared using the method in Preparation Example 35 was stored for 6 months at a temperature of 25℃±2℃ and a humidity of RH 60%±5%. The API content in the dry suspension was continuously tested to examine the changes in API content. The results are shown in Table 11. The requirements were met; there was almost no difference in API content between batches, and the API content in the dry suspension did not change significantly after 6 months of storage at room temperature.

[0423] Table 11 API Content of Dry Suspensions

[0424] (3) Isomer content test

[0425] The dry suspension prepared using the method in Preparation Example 35 was stored for 6 months at a temperature of 25℃±2℃ and a humidity of RH 60%±5%. The isomer content of the dry suspension was continuously tested to investigate the changes in isomer content. The results are shown in Table 12. There was no difference between batches. After 6 months of storage at room temperature, no isomers were detected, indicating that the dry suspension was chemically stable.

[0426] Table 12 Isomer Content of Dry Suspension

[0427] (4) Dissolution test

[0428] The dry suspension prepared using the method in Preparation Example 35 was placed in double aluminum blister packaging and stored for 6 months at a temperature of 25℃±2℃ and a humidity of RH 60%±5%. Its dissolution rate (dissolution medium: 0.1% CTAB, pH 6.8 buffer) was continuously tested to observe changes in dissolution rate. The results are shown in Table 13. There was almost no difference in dissolution rate between batches, and no significant change in dissolution rate was observed after 6 months of storage at room temperature, indicating high dissolution stability.

[0429] Table 13 Dissolution rate of dry suspensions

[0430] Preparation Example 37 was tested using the same method. After being stored at room temperature for 6 months, there were no significant changes in appearance, API content, isomer content and dissolution. There was almost no difference in API content and dissolution between batches, and no isomers were detected.

[0431] The dry suspension prepared by the solid dispersion method of the present invention has excellent process robustness and long-term storage stability.

[0432] Pharmacodynamic study of the compound shown in Formula (I) of Example 12

[0433] The compound represented by formula (I) of this invention, upon entering the body, is converted into the compound represented by formula (II), which can specifically inhibit cap-dependent endonuclease activity, thereby effectively inhibiting influenza virus replication and proliferation. Furthermore, cap-dependent endonucleases are only present in influenza viruses and not in normal human cells, and are highly conserved during influenza mutation; therefore, the compound will not affect normal human physiological functions. The following pharmacodynamic studies will be conducted using the compound represented by formula (II).

[0434] (1) In vitro efficacy study of anti-avian influenza virus

[0435] Experimental method: MDCK cells were seeded in 96-well cell culture plates and cultured overnight at 37°C in a 5% CO2 cell incubator. The next day, virus growth medium containing gradient concentrations of the compound shown in formula (II) was mixed with an equal volume of 2000 TCID50. 50 Different avian influenza virus solutions at concentrations of / mL were mixed and added to cell wells washed with PBS, with four replicates per concentration. The treated cell culture plates were then incubated at 37°C in a 5% CO2 incubator for 72 hours. The influenza virus activity in each well was then assessed using a hemagglutination assay, and the EC50 was calculated using the Reed & Muench method. 50 and EC 90 .

[0436] The antiviral activity of the compound represented by formula (II) against seven avian influenza viruses (avian influenza viruses A / Anhui / 1 / 2005(H5N1), A / Shenzhen / TH002 / 2016(H5N6), A / Taiwan / 1 / 2013(H6N1), A / Jiangsu / 1 / 2018(H7N4), A / Anhui / 1 / 2013(H7N9)-WT-egg1, A / Hong Kong / 2108 / 2003(H9N2) and A / Jiangxi-Donghu / 346-1 / 2013(H10N8)) was evaluated, and the test results are shown in Table 14.

[0437] Table 14 shows the results of research on the anti-avian influenza virus activity of the compound represented by formula (II).

[0438] The compound represented by formula (II) exhibited inhibitory activity against all seven highly pathogenic avian influenza virus strains tested, with an average EC50 of [missing information]. 50 The value is 0.90-16.82 nM, EC 90 The range is 2.14-36.50 nM.

[0439] (2) Study on inhibitory activity against drug-resistant mutant influenza virus

[0440] Experimental Methods: MDCK cells were seeded in 96-well cell culture plates and cultured overnight at 37°C in a 5% CO2 incubator. The next day, serially diluted solutions of the compound shown in formula (II) and a virus solution were added. Cells were cultured for 5 days at 37°C in a 5% CO2 incubator until 80-95% cytopathic effect was achieved in the virus-free control wells. Cell viability was then assessed using a CCK8 assay. The antiviral activity of the compound was calculated by its inhibitory effect on the virus-induced cytopathic effect, and the EC50 was calculated. 50 .

[0441] The inhibitory activity of the compound represented by formula (II) against oseltamivir (NAIs inhibitor) resistant A / Weiss / 43 (H1N1) influenza virus strain was tested using the above cytopathic effect assay. The results are shown in Table 15.

[0442] Table 15 shows the inhibitory activity of the compounds (II) against drug-resistant mutants.

[0443] The compound represented by formula (II) exhibited good inhibitory activity against all tested oseltamivir-resistant mutant viral strains. Since oseltamivir belongs to the class of selective ceramide inhibitors (NAIs), there is reason to believe that the compound represented by formula (II) possesses antiviral activity against all NAI-resistant mutant viral strains.

[0444] (3) Evaluation of the efficacy of combined use with oseltamivir

[0445] Experimental Methods: MDCK cells were seeded in 96-well cell culture plates and cultured overnight at 37°C in a 5% CO2 incubator. The next day, seven gradient concentrations of the compound shown in formula (II) and oseltamivir acid were mixed in an orthogonal ratio and added to the wells, followed by influenza virus A / WSN / 33 (H1N1). The experiment was performed in triplicate. Cells were cultured at 37°C in a 5% CO2 incubator for 5 days. Cell viability was detected using the CCK8 reagent, and antiviral activity was calculated. Subsequently, the experimental data were processed using MacSynegy software, and the combined index of the compound shown in formula (II) and oseltamivir acid against influenza virus A / WSN / 33 (H1N1) was calculated. The above experiments were used to evaluate the in vitro antiviral combined effect of the compound shown in formula (II) and the neuraminidase inhibitor oseltamivir. The results showed that in the in vitro activity test against influenza virus A / WSN / 33 (H1N1), the synergistic index of the compound represented by formula (II) in combination with oseltamivir was 364 in the 95% confidence space, which is a high synergistic effect (Prichard MN, et al.), supporting the combined use with oseltamivir.

[0446] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A dry suspension, characterized in that, include: A. Solid dispersion; The solid dispersion comprises: (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (2) A polymer carrier, wherein the polymer carrier comprises one or more of copovidone, povidone, and hydroxypropyl methylcellulose; and B, an excipient; 2. A dry suspension as claimed in claim 1, wherein, The solid dispersion satisfies one or both of the following conditions (a)-(b): (a) The polymer carrier comprises copovidone and / or hydroxypropyl methylcellulose; preferably, the polymer carrier comprises copovidone; (b) The weight ratio of the compound represented by formula (I) or its pharmaceutically acceptable salt to the polymer carrier is 1:(0.5-10), preferably 1:(0.7-8), more preferably 1:(1-6), and even more preferably 1:(1-4); Alternatively, the polymer carrier comprises copovidone, wherein the weight ratio of the compound of formula (I) or its pharmaceutically acceptable salt to the copovidone is 1:(0.5-10), preferably 1:(0.7-8), more preferably 1:(1-6), and even more preferably 1:(1-4).

3. A dry suspension as claimed in claim 1 or 2, characterised in that, The solid dispersion also includes a substrate; Preferably, the substrate comprises one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, corn starch, and low-substituted hydroxypropyl cellulose; More preferably, the substrate comprises crospovidone and / or crospovidone sodium carboxymethyl cellulose; More preferably, the substrate comprises crospovidone.

4. A dry suspension according to any one of claims 1 to 3 wherein, In the solid dispersion, the weight ratio of the compound represented by formula (I) or its pharmaceutically acceptable salt to the substrate is 1:(0.5-10), preferably 1:(0.7-8), more preferably 1:(1-6), and even more preferably 1:(1-4); Alternatively, the substrate may include crospovidone, wherein the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the crospovidone is 1:(0.5-10), preferably 1:(0.7-8), more preferably 1:(1-6), and even more preferably 1:(1-4).

5. A dry suspension as claimed in claim 3, wherein In the solid dispersion, the weight ratio of the compound represented by formula (I) or its pharmaceutically acceptable salt, the polymer carrier, and the substrate is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), and even more preferably 1:(1-4):(1-4); Alternatively, the polymer carrier comprises copovidone, the substrate comprises cross-linked povidone, and the weight ratio of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the copovidone, and the cross-linked povidone is 1:(0.5-10):(0.5-10), preferably 1:(0.7-8):(0.7-8), more preferably 1:(1-6):(1-6), and even more preferably 1:(1-4):(1-4).

6. A dry suspension according to any one of claims 1 to 5 wherein, The solid dispersion is prepared by a solvent method; preferably, it is prepared by solvent evaporation, freeze drying, spray drying or fluidized bed method; more preferably, it is prepared by spray drying or fluidized bed method. The solvent method preferably includes: dispersing the drug and polymer carrier in a solvent, removing the solvent, and forming a solid dispersion; wherein the drug includes the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; More preferably, the solvent method is a spray drying method, comprising: spray drying a drug solution, wherein the drug solution comprises the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and a solvent; Alternatively, more preferably, the solid dispersion further includes a substrate, and the solvent method is a fluidized bed method, comprising: spraying a drug solution onto the surface of the substrate in a fluidized state in a fluidized bed; wherein the drug solution includes the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the polymer carrier, and the solvent.

7. A dry suspension according to any one of claims 1 to 6 wherein, The excipients include one or more of the following: diluents, suspending agents, flow aids, lubricants, sweeteners, and flavorings; Preferably, the excipients include a diluent and a suspending agent; More preferably, the excipients include diluents, suspending agents, and sweeteners; More preferably, the excipients include diluents, suspending agents, flow aids, lubricants, sweeteners, and flavorings.

8. A dry suspension as claimed in claim 7, wherein, The excipient satisfies one or more of the following conditions (a)-(f): (a) The diluent includes one or more of isomalt, mannitol, maltitol, corn starch, lactose, microcrystalline cellulose, sucrose and sorbitol, preferably including one or more of mannitol, maltitol, corn starch, lactose, microcrystalline cellulose, sucrose and sorbitol, more preferably including mannitol and / or maltitol. (b) The suspending agent includes one or more of xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose, preferably including hydroxypropyl methyl cellulose; (c) The flow aid includes one or more of colloidal silica, micronized silica gel and talc, preferably colloidal silica; (d) The lubricant includes one or more of magnesium stearate, talc, sodium stearate fumarate and stearic acid, preferably sodium stearate fumarate; (e) The sweetener comprises one or more of xylitol, sucrose, sucralose and mannitol, preferably sucralose; (f) The fragrance includes one or more of strawberry powder flavoring, grape flavoring and sweet orange powder flavoring, preferably strawberry powder flavoring.

9. A dry suspension as claimed in claim 7 or 8, characterised in that, The dry suspension satisfies one or more of the following conditions (a)-(j): (a) The dry suspension contains 0.1%-30% by weight of the compound represented by formula (I) or its pharmaceutically acceptable salt, preferably 0.5%-20%, more preferably 1%-10%, and even more preferably 1%-5%; (b) The weight percentage of the solid dispersion in the dry suspension is 0.2%-70%, preferably 1%-50%, more preferably 5%-30% or 20%-40%, and even more preferably 10%-20% or 25%-35%; (c) The weight percentage of the diluent in the dry suspension is 40%-80%, preferably 40%-65% or 70%-80%; more preferably 50%-65% or 75%-80%; and even more preferably 50%-62% or 75%-80%. (d) The weight percentage of the suspending agent in the dry suspension is 1%-14%, preferably 1%-12%, more preferably 1%-5% or 2%-12%, and even more preferably 1%-3% or 3%-10%; (e) The weight percentage of the glidant in the dry suspension is 0.5%-5%, preferably 1%-4% or 0.5%-3%, more preferably 2%-4% or 0.5%-1%; (f) The weight percentage of the lubricant in the dry suspension is 0.1%-5%, preferably 0.1%-2%, and more preferably 0.1%-1%; (g) The sweetener in the dry suspension has a weight percentage of 0.1%-5%, preferably 0.5%-3%, more preferably 1%-3% or 0.5%-1%; (h) The weight percentage of the fragrance in the dry suspension is 0.1%-3%, preferably 0.1%-1%, more preferably 0.1%-0.5%; (i) The dry suspension includes a diluent, which includes mannitol and maltitol, wherein the ratio of mannitol to maltitol is 1:5-5:1, preferably 1:4-4:1, more preferably 1:3-3:1, and even more preferably 1:2-2:1; (j) The ratio of the solid dispersion to the suspending agent in the dry suspension is 18:1-18:8, preferably, the ratio of the solid dispersion to the suspending agent is 18:1.5-18:7.

5.

10. A dry suspension according to any one of claims 7 to 9 wherein, The dry suspension comprises 1%-50% solid dispersion, 40%-80% diluent, and 1%-12% suspending agent; preferably, the dry suspension comprises 1%-50% solid dispersion, 40%-80% diluent, 1%-12% suspending agent, 0.5%-5% flow aid, 0.1%-5% lubricant, 0.1%-5% sweetener, and 0.1%-3% flavoring agent.

11. A dry suspension according to claim 10, wherein The dry suspension comprises 1%-50% solid dispersion, 40%-65% mannitol, and 1%-12% hydroxypropyl methylcellulose; preferably, the dry suspension comprises 20%-40% solid dispersion, 50%-65% mannitol, and 2%-12% hydroxypropyl methylcellulose; more preferably, the dry suspension comprises 25%-35% solid dispersion, 50%-62% mannitol, and 3%-10% hydroxypropyl methylcellulose. Alternatively, the dry suspension comprises 1%-50% solid dispersion, 70%-80% mannitol and maltitol, and 1%-5% hydroxypropyl methylcellulose; preferably, the dry suspension comprises 5%-30% solid dispersion, 75%-80% mannitol and maltitol, and 1%-3% hydroxypropyl methylcellulose; more preferably, the dry suspension comprises 10%-20% solid dispersion, 75%-80% mannitol and maltitol, and 1%-2% hydroxypropyl methylcellulose.

12. A dry suspension according to claim 10 or 11, wherein The dry suspension comprises 1%-50% solid dispersion, 40%-65% mannitol, 1%-12% hydroxypropyl methylcellulose, 0.5%-5% colloidal silica, 0.1%-5% sodium stearate fumarate, 0.1%-5% sucralose, and 0.1%-3% strawberry powder flavoring; preferably, the dry suspension comprises 20%-40% solid dispersion, 50%-65% mannitol, 2%-12% hydroxypropyl methylcellulose, and 1%-4%... The dry suspension comprises colloidal silica, 0.1%-2% sodium stearate fumarate, 0.5%-3% sucralose, and 0.1%-1% strawberry powder flavoring; more preferably, the dry suspension comprises 25%-35% solid dispersion, 50%-62% mannitol, 3%-10% hydroxypropyl methylcellulose, 2%-4% colloidal silica, 0.1%-1% sodium stearate fumarate, 0.5%-1% sucralose, and 0.1%-0.5% strawberry powder flavoring; Alternatively, the dry suspension comprises 1%-50% solid dispersion, 70%-80% mannitol and maltitol, 1%-5% hydroxypropyl methylcellulose, 0.5%-5% colloidal silica, 0.1%-5% sodium stearate fumarate, 1%-5% sucralose, and 0.1%-3% strawberry powder flavoring; preferably, the dry suspension comprises 5%-30% solid dispersion, 75%-80% mannitol and maltitol, 1%-3% hydroxypropyl methylcellulose, and 0.5%... -3% colloidal silica, 0.1%-2% sodium stearate fumarate, 1%-3% sucralose and 0.1%-1% strawberry powder flavoring; more preferably, the dry suspension comprises 10%-20% solid dispersion, 75%-80% mannitol and maltitol, 1%-2% hydroxypropyl methylcellulose, 0.5%-1% colloidal silica, 0.1%-1% sodium stearate fumarate, 2%-3% sucralose and 0.1%-0.5% strawberry powder flavoring.

13. The method for preparing the dry suspension according to any one of claims 1-12, characterized in that, Includes the following steps: The solid dispersion is mixed evenly with the excipient; optionally, the resulting granules are sieved and then mixed evenly.

14. The use of a dry suspension prepared by any one of claims 1-12 or by the method of preparing the dry suspension of claim 13 in the preparation of a medicament for the prevention and / or treatment of influenza.

15. The use of a combination of a dry suspension prepared by any one of claims 1-12 or the dry suspension prepared by the method of claim 13 with oseltamivir in the preparation of a drug for the prevention and / or treatment of influenza.

16. The use of a dry suspension prepared by any one of claims 1-12 or by the method of preparing the dry suspension of claim 13 in the preparation of a drug for the prevention and / or treatment of influenza, wherein the influenza is caused by avian influenza or influenza virus resistant to NAIs inhibitors (e.g., oseltamivir) or influenza virus resistant to PB2 inhibitors (e.g., VX787).

17. The application as described in any one of claims 14-16, characterized in that, The influenza referred to is either influenza A or influenza B.

18. The application as described in any one of claims 14-16, characterized in that, The influenza referred to is uncomplicated influenza A or B in adults, children (e.g., 3 months and older, 6 months and older, 1 year and older, 2 years and older, or 5 years and older), adolescents, or high-risk adults with influenza-related complications.

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