Solid dispersion, pharmaceutical composition, and preparation method and use therefor

Abstract

A solid dispersion, a pharmaceutical composition, and preparation method and use therefor. The solid dispersion comprises the following components: a compound 1 and a polymer carrier, wherein the polymer carrier is selected from one or more of HPMCAS, Soluplus and PVP-VA. The solid dispersion is more beneficial to dispersing the compound 1 in the polymer carrier in an amorphous or near-amorphous or non-crystalline state, and is beneficial to improving the solubility of the compound 1.

Description

Solid dispersion, pharmaceutical composition, preparation method and use thereof

[0001] This application claims priority from PCT International Patent Application No. PCT / CN2023 / 122859, filed on September 28, 2023. This application incorporates the entire text of the aforementioned PCT International Patent Application. Technical Field

[0002] The present invention relates to a solid dispersion, a pharmaceutical composition, a preparation method and use thereof. Background Art

[0003] Compound 1 (see US10689362B2, Compound 54) is a type III receptor tyrosine kinase inhibitor, a compound that inhibits kinases and is useful for treating diseases or disorders mediated by these kinases. Compound 1 inhibits CSF-1R kinase (IC50 value less than 100 nM). Studies have shown that Compound 1 is poorly soluble in aqueous media, with solubility being pH-dependent. Development of a formulation with high solubility and bioavailability is desirable.

[0004] Many drug development programs present the problem of poor oral bioavailability of new drug molecules. A drug molecule may have low oral bioavailability due to (1) poor dissolution rate, (2) poor solubility, or (3) limited permeation rate. Depending on the etiology, different strategies have been adopted to improve the absorption of oral drugs. The bioavailability of drug substances with limited solubility rates can be improved by various solubilization techniques, such as solid dispersions with polymeric materials, or the use of large amounts of surfactants, cyclodextrins, micelles, polymeric micelles, liposomes, acidic pH modifiers, or dendrimers.

[0005] Solid dispersions, first proposed in 1961, are solid substances formed by highly dispersing poorly soluble drugs in a suitable solid carrier material. A drug's solubility and dispersion state are among the primary factors affecting its in vivo bioavailability. Solid dispersion technology enables the formation of a highly dispersed drug within a polymer carrier, effectively increasing the solubility and dissolution rate of poorly soluble drugs, thereby enhancing their bioavailability.

[0006] There are many methods for preparing solid dispersions, and the optional excipients are also numerous and complex. Although there are many publicly published literatures on solid dispersions, the applicable prescriptions and preparation processes selected for different drug properties vary greatly, and research and testing are needed based on the characteristics of the drug.

[0007] Formula optimization can also improve the solubility and dissolution rate of poorly soluble drugs, thereby increasing their bioavailability. The solubilization mechanism of optimized formulations is complex, and the number and variety of excipients available is also greater. It is necessary to experiment with different mechanisms of action based on the characteristics of the drug and select different excipients for testing and research.

[0008] So far, there has been no report on the solubilization technology of compound 1.

[0009] Chemical name: 6-((3-methoxy-4-((6-methylpyridin-3-yl)-methoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile;

[0010] Molecular formula: C 27 H 26 N6O3.

[0011] Summary of the Invention

[0012] The technical problem to be solved by the present invention is to overcome one or both of the disadvantages of low solubility and low in vivo exposure of Compound 1, and further overcome one or both of the disadvantages of high production cost and poor patient compliance when Compound 1 is used as a pharmaceutical agent, thereby providing a solid dispersion, a pharmaceutical composition, a preparation method thereof, and uses thereof. The pharmaceutical composition of the present invention has one or both of the advantages of good solubility and good in vivo exposure, and further has one or both of the advantages of low production cost and good patient compliance.

[0013] The present invention mainly solves the above technical problems through the following technical solutions.

[0014] The present invention provides a solid dispersion comprising the following components: compound 1 and a polymer carrier;

[0015] Wherein, the polymer carrier is selected from one or more of HPMCAS, Soluplus and PVP-VA.

[0016] In some embodiments, in the solid dispersion, the polymer carrier is selected from HPMCAS.

[0017] In some embodiments, in the solid dispersion, the polymer carrier is selected from Soluplus.

[0018] In some embodiments, in the solid dispersion, the polymer carrier is selected from PVP-VA.

[0019] In some embodiments, in the solid dispersion, the HPMCAS is preferably selected from one or both of HPMCAS-HF and HPMCAS-HG, more preferably HPMCAS-HG. The PVP-VA is preferably PVP-VA64. The PVP-VA64 can be Plasdone TM S-630 or Plasdone TM S-630ULTRA.

[0020] In some embodiments, in the solid dispersion, the weight ratio of Compound 1 to the polymer carrier is about 1:1 to about 1:10.

[0021] In some embodiments, in the solid dispersion, the weight ratio of the compound 1 to the polymer carrier is preferably about 1:2 to about 1:5, for example, 3:7, 1:3 or 1:4, more preferably about 1:3 to about 1:4, more preferably about 1:3.

[0022] In some embodiments, in the solid dispersion, the weight ratio of Compound 1 to the polymer carrier is about 3:7.

[0023] In some embodiments, in the solid dispersion, the weight percentage of the polymer carrier in the solid dispersion is at least about 50%, at least about 60%, at least about 67%, at least about 70%, at least about 75%, at least about 80% or at least about 90%.

[0024] In some embodiments, in the solid dispersion, the weight percentage of Compound 1 in the solid dispersion is about 10% to about 50%, about 20% to about 40%, or about 25% to about 33%.

[0025] In some embodiments, the solid dispersion of the present invention may further comprise other excipients in addition to the polymer carrier, such as surfactants, glidants, plasticizers, and the like.

[0026] In some embodiments, the solid dispersion of the present invention may further comprise a surfactant.

[0027] In some embodiments, in the solid dispersion, Compound 1 is dispersed in the polymer carrier in an amorphous (or nearly amorphous) or substantially non-crystalline state.

[0028] In some embodiments, Compound 1 in the solid dispersion is substantially amorphous.

[0029] In some embodiments, the solid dispersion is obtained by spray drying, hot melt extrusion, or solvent evaporation.

[0030] In some embodiments, the solid dispersion consists of the Compound 1 and the polymer carrier.

[0031] In some embodiments, the solid dispersion is composed of the following components in percentage by mass:

[0032] Scheme 1.1: 25% compound 1 and 75% Soluplus;

[0033] Scheme 1.2: 25% Compound 1 and 75% Plasdone TM S-630ULTRA;

[0034] Scheme 1.3: 20% compound 1 and 80% Soluplus;

[0035] Scheme 1.4: 25% compound 1 and 75% HPMCAS-HG;

[0036] Scheme 1.5: 30% compound 1 and 70% HPMCAS-HG.

[0037] The present invention also provides a method for preparing any of the aforementioned solid dispersions of the present invention, comprising the following steps: mixing the components.

[0038] In some embodiments, the method for preparing the solid dispersion preferably comprises the following steps: dissolving the compound 1 and the polymer carrier in a solvent and mixing them uniformly, and evaporating the solvent to obtain a solid dispersion.

[0039] In some embodiments, the preparation method involves evaporating the solvent by spray drying.

[0040] In some embodiments, the solvent used in the preparation method is an organic solvent.

[0041] In some embodiments, the organic solvent is selected from one or both of halogenated alkane solvents and alcohol solvents, preferably a mixture of dichloromethane and ethanol.

[0042] The present invention also provides a solid dispersion prepared by the above preparation method.

[0043] The present invention also provides a pharmaceutical composition comprising any one of the aforementioned solid dispersions of the present invention, and one or more pharmaceutically acceptable carriers.

[0044] In some embodiments, the excipient in the solid dispersion and the pharmaceutically acceptable carrier in the pharmaceutical composition are different from each other.

[0045] In some embodiments, the pharmaceutical composition is a tablet, capsule, granule, powder, dry suspension, or enteric-coated preparation.

[0046] In some embodiments, in the pharmaceutical composition, the pharmaceutically acceptable carrier is one or more of a solubilizer, an acidic pH regulator, a disintegrant, a glidant, a filler, a lubricant, and a surfactant.

[0047] In some embodiments, the pharmaceutical composition includes the following components in mass percentage:

[0048] 20%-70% of the solid dispersion of any one of the preceding items of the present invention,

[0049] 0%-30% cosolvent,

[0050] 0%-20% acidic pH adjuster,

[0051] 3%-30% disintegrant,

[0052] 0%-10% glidant,

[0053] 0%-50% filler,

[0054] 0%-1% lubricant,

[0055] 0%-20% surfactant.

[0056] In the present invention, one or more of the polymer carrier, the cosolvent, the acidic pH regulator and the surfactant has the function of improving the solubility of Compound 1.

[0057] In the present invention, the solid dispersion has the effect of improving the solubility of Compound 1.

[0058] In some embodiments, when the mass percentage of the co-solvent is 0%, the mass percentage of the acidic pH adjuster is not 0%.

[0059] In some embodiments, in the pharmaceutical composition, the mass percentage of the solid dispersion is 40%, 50%, 64.5% or 66.4%.

[0060] In some embodiments, in the pharmaceutical composition, the mass percentage of the solid dispersion is 30%-60%, preferably 40%-50%.

[0061] In some embodiments, in the pharmaceutical composition, the mass percentage of the co-solvent is, for example, 0%, 5.8%, 6%, 7.5%, 12%, 14%, 17.5% or 24%.

[0062] In some embodiments, in the pharmaceutical composition, the mass percentage of the co-solvent is preferably 0%-24%.

[0063] In some embodiments, in the pharmaceutical composition, the mass percentage of the co-solvent is preferably 4%-14%, for example, 6%, 7.5% or 12%.

[0064] In some embodiments, in the pharmaceutical composition, the mass percentage of the acidic pH regulator is, for example, 0%, 5%, 6.25%, 10%, 15%, 20% or 39.5%.

[0065] In some embodiments, in the pharmaceutical composition, the mass percentage of the acidic pH regulator is preferably 0%-15%, for example, 0%, 5%, 6.25% or 10%.

[0066] In some embodiments, in the pharmaceutical composition, the mass percentage of the acidic pH regulator is more preferably 3%-12%, for example, 5%, 6.25% or 10%.

[0067] In some embodiments, in the pharmaceutical composition, the mass percentage of the disintegrant is, for example, 3%, 8%, 10%, 14%, 26.4% or 27.2%.

[0068] In some embodiments, in the pharmaceutical composition, the mass percentage of the disintegrant is preferably 3%-20%, more preferably 3%-15%, for example 3% or 10%.

[0069] In some embodiments, in the pharmaceutical composition, the mass percentage of the glidant is, for example, 0% or 4%.

[0070] In some embodiments, in the pharmaceutical composition, the mass percentage of the glidant is preferably 1%-10%, for example, 4%.

[0071] In some embodiments, in the pharmaceutical composition, the mass percentage of the filler is, for example, 0%, 13.5%, 16.5%, 17.5%, 18.50%, 19.25%, 19.5%, 21.5%, 22.5%, 25.5%, 26.5%, 28.5%, 29.25%, 29.5%, 30.5%, 34.5%, 35.5%, 36.5%, 39.5% or 40.5%.

[0072] In some embodiments, in the pharmaceutical composition, the mass percentage of the filler is preferably 10%-45%, more preferably 20%-40%, for example, 28.5%, 29.25% or 34.5%.

[0073] In the present invention, in the pharmaceutical composition, the mass percentage of the filler can be increased or decreased accordingly according to the adjustment of other components.

[0074] In some embodiments, in the pharmaceutical composition, the mass percentage of the lubricant is, for example, 0%, 0.4% or 0.5%, preferably 0% or 0.5%.

[0075] In some embodiments, in the pharmaceutical composition, the mass percentage of the surfactant is 0%-12%.

[0076] In some embodiments, in the pharmaceutical composition, the mass percentage of the surfactant is 0%-10%, for example, 0%, 1%, 5% or 10%.

[0077] In some embodiments, in the pharmaceutical composition, the mass percentage of the surfactant is preferably 0%-5%, for example, 0%, 1% or 5%.

[0078] In some embodiments, in the pharmaceutical composition, the mass ratio of the polymer carrier to the compound 1 is 2:1 to 4:1, for example, 2.3:1, 3:1 or 4:1.

[0079] In some embodiments, in the pharmaceutical composition, the mass ratio of the polymer carrier to the compound 1 is preferably 2:1 to 2.5:1, for example, 2.3:1.

[0080] In some embodiments, in the pharmaceutical composition, the mass ratio of the acidic pH regulator to the compound 1 is preferably 1:1 to 1:3, for example, 1:1.2 or 1:2.4.

[0081] In some embodiments, in the pharmaceutical composition, the cosolvent is selected from one or more of PEG, PVP, HPMCAS, HPMC, Eudragit and Soluplus.

[0082] In some embodiments, in the pharmaceutical composition, the co-solvent is selected from one or more of PVP, HPMC and Soluplus, preferably PVP or Soluplus.

[0083] In some embodiments, in the pharmaceutical composition, in the co-solvent, the PEG is selected from one or both of PEG4000 and PEG6000.

[0084] In some embodiments, in the pharmaceutical composition, in the co-solvent, the PVP is selected from one or more of PVPK17, PVPK30, PVP K90 and PVP-VA64, preferably PVP-VA64.

[0085] In some embodiments, in the pharmaceutical composition, the PVP-VA64 may be Plasdone TM S-630 or Plasdone TM S-630ULTRA.

[0086] In some embodiments, in the pharmaceutical composition, in the co-solvent, the HPMC is preferably HPMC E3LV.

[0087] In some embodiments, in the pharmaceutical composition, in the co-solvent, the HPMCAS is selected from one or more of HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LG, HPMCAS-MG, and HPMCAS-HG, preferably HPMCAS-HG.

[0088] In some embodiments, in the pharmaceutical composition, in the co-solvent, the Eudragit is selected from one or more of Eudragit L100-55 and Eudragit S100.

[0089] In some embodiments, in the pharmaceutical composition, the cosolvent is preferably selected from one or more of PVP-VA64, Soluplus, HPMCE3LV and PVP k30, more preferably PVP-VA64 or Soluplus.

[0090] In some embodiments, in the pharmaceutical composition, the acidic pH regulator is selected from one or both of an organic acid and an inorganic acid. The organic acid is, for example, selected from one or more of citric acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid, oxalic acid, aspartic acid, mandelic acid, glutaric acid, and glutamic acid, preferably selected from one or more of fumaric acid, citric acid, tartaric acid, and malic acid, more preferably tartaric acid. The inorganic acid is preferably selected from one or more of hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid.

[0091] In some embodiments, in the pharmaceutical composition, the acidic pH regulator is preferably selected from one or more of citric acid, fumaric acid, malic acid and tartaric acid.

[0092] In some embodiments, in the pharmaceutical composition, the acidic pH adjuster is preferably tartaric acid.

[0093] In some embodiments, in the pharmaceutical composition, when the acidic pH regulator is tartaric acid, the mass percentage of the acidic pH regulator is preferably 3% to 7%, more preferably 4% to 6%, for example, 5%.

[0094] In some embodiments, in the pharmaceutical composition, when the acidic pH regulator is malic acid, the mass percentage of the acidic pH regulator is preferably 3% to 7%, more preferably 4% to 6%, for example, 5%.

[0095] In some embodiments, in the pharmaceutical composition, when the acidic pH regulator is fumaric acid, the mass percentage of the acidic pH regulator is preferably 8% to 12%, more preferably 9% to 11%, for example, 10%.

[0096] In some embodiments, in the pharmaceutical composition, when the acidic pH regulator is citric acid, the mass percentage of the acidic pH regulator is preferably 8% to 12%, more preferably 9% to 11%, for example, 10%.

[0097] In some embodiments, in the pharmaceutical composition, the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and sodium carboxymethyl cellulose, preferably one or both of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch.

[0098] In some embodiments, in the pharmaceutical composition, the disintegrant is preferably sodium carboxymethyl cellulose, or a mixture of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch.

[0099] In some embodiments, in the pharmaceutical composition, when the disintegrant is a mixture of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch, the mass ratio of the cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch is 1:1 to 2:1, preferably 1.5:1.

[0100] In some embodiments, in the pharmaceutical composition, the glidant is, for example, colloidal silicon dioxide.

[0101] In some embodiments, in the pharmaceutical composition, the filler is selected from one or more of mannitol, lactose, compressible starch and microcrystalline cellulose, preferably mannitol.

[0102] In some embodiments, in the pharmaceutical composition, the lubricant is, for example, magnesium stearate.

[0103] In some embodiments, in the pharmaceutical composition, the surfactant is selected from one or more of sodium lauryl sulfate, vitamin E polyethylene glycol succinate, poloxamer 188 and poloxamer 407.

[0104] In some embodiments, the pharmaceutical composition consists of the solid dispersion, the cosolvent, the acidic pH regulator, the disintegrant, the glidant, the filler, the lubricant, and the surfactant.

[0105] In some embodiments, the pharmaceutical composition is composed of the following components in percentage by mass:

[0106] Scheme 2.1: 19.35% compound 1, 45.15% HPMCAS-HG, 5.8% PVPK90, 26.4% CMS-N a , 0.4% magnesium stearate and 2.9% film coating premix (gastric soluble);

[0107] Scheme 2.2: 15% compound 1, 35% HPMCAS-HG, 17.5% PVP-VA64, 4% colloidal silicon dioxide, 19.25% mannitol, 3% sodium carboxymethylcellulose, and 6.25% tartaric acid;

[0108] Scheme 2.3: 15% compound 1, 35% HPMCAS-HG, 7.5% Soluplus, 4% colloidal silicon dioxide, 29.25% mannitol, 3% sodium carboxymethylcellulose, and 6.25% tartaric acid;

[0109] Scheme 2.4: 15% compound 1, 35% HPMCAS-HG, 17.5% Soluplus, 4% colloidal silicon dioxide, 19.25% mannitol, 3% sodium carboxymethylcellulose, and 6.25% tartaric acid;

[0110] Scheme 2.5: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 34.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, and 0.5% magnesium stearate;

[0111] Scheme 2.6: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 39.5% mannitol, 6% CCMC-Na, 4% CMS-Na, and 0.5% magnesium stearate;

[0112] Scheme 2.7: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 29.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 10% tartaric acid, and 0.5% magnesium stearate;

[0113] Scheme 2.8: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 19.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 20% tartaric acid, and 0.5% magnesium stearate;

[0114] Scheme 2.9: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silica, 6% CCMC-Na, 4% CMS-Na, 39.5% tartaric acid, and 0.5% magnesium stearate;

[0115] Scheme 2.10: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 34.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% fumaric acid, and 0.5% magnesium stearate;

[0116] Scheme 2.11: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 34.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% citric acid, and 0.5% magnesium stearate;

[0117] Scheme 2.12: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 34.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% malic acid, and 0.5% magnesium stearate;

[0118] Scheme 2.13: 12% compound 1, 28% HPMCAS-HG, 6% Soluplus, 4% colloidal silicon dioxide, 34.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, and 0.5% magnesium stearate;

[0119] Regimen 2.14: 12% compound 1, 28% HPMCAS-HG, 6% HPMC E3LV, 4% colloidal silicon dioxide, 34.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, and 0.5% magnesium stearate;

[0120] Scheme 2.15: 12% compound 1, 28% HPMCAS-HG, 6% PVP k30, 4% colloidal silicon dioxide, 34.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, and 0.5% magnesium stearate;

[0121] Scheme 2.16: 12% compound 1, 28% HPMCAS-HG, 4% colloidal silicon dioxide, 40.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% citric acid, and 0.5% magnesium stearate;

[0122] Scheme 2.17: 12% compound 1, 28% HPMCAS-HG, 12% PVP-VA64, 4% colloidal silicon dioxide, 28.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% citric acid, and 0.5% magnesium stearate;

[0123] Regimen 2.18: 12% compound 1, 28% HPMCAS-HG, 24% PVP-VA64, 4% colloidal silicon dioxide, 16.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% citric acid, and 0.5% magnesium stearate;

[0124] Scheme 2.19: 12% compound 1, 28% HPMCAS-HG, 14% S0luplus, 4% colloidal silicon dioxide, 26.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, and 0.5% magnesium stearate;

[0125] Scheme 2.20: 12% compound 1, 28% HPMCAS-HG, 4% colloidal silicon dioxide, 35.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, 5% sodium lauryl sulfate, and 0.5% magnesium stearate;

[0126] Scheme 2.21: 12% compound 1, 28% HPMCAS-HG, 14% S o luplus, 25.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, 5% sodium lauryl sulfate, and 0.5% magnesium stearate;

[0127] Scheme 2.22: 12% compound 1, 28% HPMCAS-HG, 14% S oluplus, 4% colloidal silicon dioxide, 26.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% sodium lauryl sulfate, and 0.5% magnesium stearate;

[0128] Scheme 2.23: 19.92% compound 1, 46.48% HPMCAS-HG, 6% PVPk30, 27.2% CMS-Na, and 0.4% magnesium stearate;

[0129] Scheme 2.24: 12% compound 1, 28% HPMCAS-HG, 14% S o luplus, 4% colloidal silicon dioxide, 26.5% mannitol, 10% CMS-Na, 5% tartaric acid, and 0.5% magnesium stearate;

[0130] Scheme 2.25: 12% compound 1, 28% HPMCAS-HG, 14% S o luplus, 4% colloidal silicon dioxide, 21.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, 5% sodium lauryl sulfate, and 0.5% magnesium stearate;

[0131] Scheme 2.26: 12% compound 1, 28% HPMCAS-HG, 14% PVP-VA64, 4% colloidal silicon dioxide, 21.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, 5% sodium lauryl sulfate, and 0.5% magnesium stearate;

[0132] Scheme 2.27: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 29.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, 5% sodium lauryl sulfate, and 0.5% magnesium stearate;

[0133] Scheme 2.28: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 36.5% mannitol, 6% CCMC-Na, 2% CMS-Na, 5% tartaric acid, and 0.5% magnesium stearate;

[0134] Scheme 2.29: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 30.5% mannitol, 6% CCMC-Na, 8% CMS-Na, 5% tartaric acid, and 0.5% magnesium stearate;

[0135] Scheme 2.30: 15% compound 1, 35% HPMCAS-HG, 4% colloidal silicon dioxide, 35.5% mannitol, 6% CCMC-Na, 4% CMS-Na, and 0.5% magnesium stearate;

[0136] Scheme 2.31: 12% compound 1, 28% HPMCAS-HG, 12% Soluplus, 4% colloidal silicon dioxide, 28.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, and 0.5% magnesium stearate;

[0137] Scheme 2.32: 12% compound 1, 28% HPMCAS-HG, 12% PVP-VA64, 4% colloidal silicon dioxide, 22.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 10% tartaric acid, 0.5% magnesium stearate, and 1% poloxamer 407;

[0138] Scheme 2.33: 12% compound 1, 28% HPMCAS-HG, 12% PVP-VA64, 4% colloidal silicon dioxide, 18.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 10% tartaric acid, 0.5% magnesium stearate, and 5% poloxamer 407;

[0139] Regimen 2.34: 12% Compound 1, 28% HPMCAS-HG, 12% PVP-VA64, 4% colloidal silicon dioxide, 13.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 10% tartaric acid, 0.5% magnesium stearate, and 10% poloxamer 407.

[0140] In some embodiments, the pharmaceutical composition comprises the components in mass percentages as shown in any one of Schemes 2.1 to 2.34.

[0141] In some embodiments, in Schemes 2.1 to 2.34, the Compound 1 and the HPMCAS-HG are in the form of solid dispersions as components thereof.

[0142] In some embodiments, in Schemes 2.2 to 2.21, the Compound 1 and the HPMCAS-HG are in the form of solid dispersions as components thereof.

[0143] In some embodiments, the pharmaceutical composition preferably includes the components in mass percentages as shown in any one of Schemes 2.2 to 2.34, and more preferably includes the components in mass percentages as shown in any one of Schemes 2.3, 2.5 and 2.31.

[0144] In some embodiments, the pharmaceutical composition is preferably composed of the components in mass percentages as shown in any one of Schemes 2.2 to 2.34, and more preferably composed of the components in mass percentages as shown in any one of Schemes 2.3, 2.5 and 2.31.

[0145] The present invention also provides a method for preparing any of the aforementioned pharmaceutical compositions of the present invention, comprising the following steps: mixing the components.

[0146] In some embodiments, the preparation method of the pharmaceutical composition comprises wet granulation or dry granulation.

[0147] In some embodiments, when the pharmaceutical composition is a tablet, the method for preparing the pharmaceutical composition may include the following steps:

[0148] (1) wet granulation, wet granulation, drying and dry granulation of the solid dispersion and the cosolvent to obtain granules;

[0149] (2) The granules are mixed uniformly with the remaining ingredients and compressed to obtain tablets.

[0150] In some embodiments, when the pharmaceutical composition is a tablet, the method for preparing the pharmaceutical composition may include the following steps:

[0151] (1) wet granulation, wet granulation, drying and dry granulation of the solid dispersion and the cosolvent to obtain granules;

[0152] (2) The granules are mixed uniformly with the remaining components, compressed and coated to obtain tablets.

[0153] In some embodiments, when the pharmaceutical composition is a tablet, the method for preparing the pharmaceutical composition may include the following steps:

[0154] (1) uniformly mixing the solid dispersion, the cosolvent, the glidant, the filler, the pH regulator, the disintegrant, and the surfactant, and then dry granulating and dry sizing the mixture to obtain granules;

[0155] (2) The granules are mixed with the lubricant and the remaining components and compressed to obtain tablets.

[0156] In some embodiments, when the pharmaceutical composition is a tablet, the method for preparing the pharmaceutical composition may include the following steps:

[0157] (1) uniformly mixing the solid dispersion, the cosolvent, the glidant, the filler, the pH regulator, the disintegrant, and the surfactant, and then dry granulating and dry sizing the mixture to obtain granules;

[0158] (2) The granules are mixed uniformly with the lubricant and the remaining components, compressed and coated to obtain tablets.

[0159] The present invention also provides a use of any of the aforementioned solid dispersions of the present invention in preparing a preparation of Compound 1.

[0160] In some embodiments, the formulation of Compound 1 is preferably any one of the aforementioned pharmaceutical compositions of the present invention.

[0161] The present invention also provides a use of one or more of the polymer carrier of any of the aforementioned inventions, the cosolvent of any of the aforementioned inventions, the acidic pH regulator of any of the aforementioned inventions, the disintegrant of any of the aforementioned inventions, and the surfactant of any of the aforementioned inventions for improving the solubility of Compound 1.

[0162] The present invention also provides a use of any of the aforementioned solid dispersions of the present invention or any of the aforementioned pharmaceutical compositions of the present invention in preparing a drug.

[0163] In one embodiment, the drug is a drug for treating one or more of tumors, pulmonary fibrosis, autoimmune diseases and neurodegenerative diseases, preferably a drug for treating one or more of Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke and neuromyelitis.

[0164] The present invention also provides any of the aforementioned solid dispersions of the present invention or any of the aforementioned pharmaceutical compositions of the present invention for use in treating one or more of tumors, pulmonary fibrosis, autoimmune diseases and neurodegenerative diseases.

[0165] In some embodiments, the solid dispersion or the pharmaceutical composition is preferably used to treat one or more diseases selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and neuromyelitis.

[0166] The present invention also provides a method for treating a subject in need thereof, comprising: administering to the subject an effective amount of any of the aforementioned solid dispersions of the present invention or any of the aforementioned pharmaceutical compositions of the present invention; the subject suffers from one or more of tumors, pulmonary fibrosis, autoimmune diseases and neurodegenerative diseases.

[0167] In some embodiments, the subject preferably suffers from one or more diseases selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and neuromyelitis.

[0168] Definition of terms

[0169] As used herein, the term "solid dispersion" (SD) generally refers to a solid-state system comprising at least two components, wherein one component is substantially uniformly dispersed throughout the other component. For example, a solid dispersion can be a dispersion of one or more active ingredients (e.g., a drug, such as Compound 1 of the present invention) in a polymer carrier, which can be prepared by melt and / or solvent methods. In a solid dispersion, the active ingredient can exist in a molecular state, a colloidal state, a metastable state, or an amorphous state.

[0170] In the present invention, the term "drug substance (DS)" refers to an active pharmaceutical ingredient (API) with pharmaceutical effects that has not been formulated into a final pharmaceutical preparation form, such as the compound itself as the active pharmaceutical ingredient.

[0171] As used herein, the term "active pharmaceutical ingredient (API)" refers to a pharmaceutically active compound, a pharmaceutically acceptable salt thereof, or a mixture thereof. The API or active pharmaceutical ingredient in the solid dispersion of the present invention is Compound 1 (sometimes referred to herein simply as the API).

[0172] The term "amorphous solid dispersion (ASD)" in the present invention refers to a solid dispersion comprising a substantially amorphous active pharmaceutical ingredient.

[0173] The term "amorphous" in the present invention means that the active ingredient has no definite structure, ie, no crystal structure.

[0174] The term "substantially amorphous," "nearly amorphous," or "substantially non-crystalline" as used herein refers to a composition that does not contain a significant amount of crystalline drug, such as a composition having a crystallinity of at most about 5%, such as at most about 2%, or at most about 1%, as observed by X-ray diffraction analysis. In a specific embodiment, "substantially amorphous" may mean that no detectable crystallinity is observed by one or both of X-ray diffraction analysis and polarized light microscopy.

[0175] The term "polymer carrier," also known as a "high molecular weight carrier," refers to a chain or network of macromolecular compounds composed of multiple repeating backbone structural units linked by covalent bonds. In the art, polymer carriers commonly used in solid dispersions include, but are not limited to, polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyacrylic acid resins, and Soluplus (polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer). For example, one or any combination of PEG4000, PEG6000, Eudragit L100-55, Eudragit S100, PVPK17, PVPK30, PVPK90, PVP-VA64, Plasdone S-630, Plasdone S-630 ULTRA, HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG and Soluplus can be used as the polymer carrier in the solid dispersion.

[0176] In the art, solid dispersions may further contain other additives as needed, such as lubricants, fillers, disintegrants, stabilizers (e.g., antioxidants, light stabilizers, free radical scavengers, stabilizers against microbial attack, etc.). The specific selection range and amount of the other additives are routine choices made by those skilled in the art.

[0177] The solid dispersion of the present invention can be prepared using any appropriate method, including but not limited to solvent-assisted methods such as solvent evaporation and solvent precipitation, and solvent-free solid-state methods such as melting and hot-melt extrusion. The solvent evaporation method can specifically be a coating method, rotary evaporation, freeze drying, supercritical fluid method, or spray drying.

[0178] In the solvent evaporation method, the active ingredient (such as compound 1 of the present invention) and the polymer carrier (such as Soluplus) and optional surfactants and / or other excipients can be dissolved in a suitable solvent, and then the solvent is evaporated to obtain a solid dispersion. The solid obtained after solvent evaporation can be further vacuum dried to obtain a solid dispersion. It should be understood that the active ingredient and the polymer carrier and the optional surfactant can be dissolved in a solvent separately and then mixed, or mixed and dissolved in a solvent. When the active ingredient and the polymer carrier are mixed and dissolved in a solvent, any one component can be added first to fully dissolve it, and then another component is added to dissolve, for example, the active ingredient is first dissolved in a solvent, and then the polymer carrier is added to dissolve, or the polymer carrier is first dissolved in a solvent, and then the active ingredient is added to dissolve. When the active ingredient and the polymer carrier are dissolved in a solvent separately, the two can be dissolved in the same solvent or in different solvents.

[0179] The solvent used can be an organic solvent, for example, one or more selected from dichloromethane, anhydrous ethanol, methanol, acetone, and ethyl acetate. In some embodiments, the solvent is a mixture of dichloromethane and ethanol. In some embodiments, the weight percentage of dichloromethane to ethanol in the solvent can be from about 1:1 to about 10:1, for example, from about 2:1 to about 8:1, from about 3:1 to about 5:1, or about 4:1.

[0180] It should be understood that, while it is desirable to remove all solvent as much as possible, a small amount of solvent residue is normal. In some embodiments, the solvent residue in the solid dispersion of the present invention is no more than about 1000 ppm, no more than about 900 ppm, no more than about 800 ppm, no more than about 700 ppm, no more than about 600 ppm, no more than about 500 ppm, or no more than about 400 ppm.

[0181] The pharmaceutical composition of the present invention can be formulated as a solid, semi-solid, liquid or gaseous preparation, for example, an oral preparation or a parenteral preparation, a suppository, etc. Suitable formulations include, but are not limited to, tablets, capsules, granules, powders, suspensions, ointments, solutions, injections, inhalants, gels, etc. In some embodiments, the pharmaceutical composition of the present invention is an enteric-coated tablet, such as an enteric-coated tablet or an enteric-coated capsule (including a hard capsule or a soft capsule).

[0182] The pharmaceutical composition of the present invention can be prepared by methods well known in the pharmaceutical field. For example, methods for preparing pharmaceutical compositions are known to those skilled in the art, for example, see The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000).

[0183] The route of administration of the pharmaceutical composition of the present invention includes but is not limited to oral, topical, transdermal, intramuscular, intravenous, inhalation, parenteral, sublingual, rectal, vaginal and intranasal. The pharmaceutical composition of the present invention is particularly suitable for transmucosal administration to the experimenter's preparation, that is, it can be administered to the mucosa with transmembrane absorption. For this reason, suitable route of administration includes by inhalation, oral, intranasal and rectal administration, particularly preferably oral administration. The dosage form that is suitable for oral administration includes forms such as tablets, capsules, granules, syrups. But, other routes of administration, for example parenteral administration, are not excluded.

[0184] The pharmaceutical composition of the present invention can be prepared from the solid dispersion of the present invention and one or more pharmaceutically acceptable carriers by conventional pharmaceutical methods.

[0185] For example, the solid dispersion of the present invention can be subjected to appropriate treatment and then mixed with one or more pharmaceutically acceptable carriers to prepare a formulation. The appropriate treatment can be to prepare the solid dispersion of the present invention into a powder or granules suitable for preparation, and the treatment method includes, for example, crushing, grinding or grinding.

[0186] The term "pharmaceutically acceptable carrier" refers to any carrier included in a pharmaceutical composition as an inactive ingredient that gives the composition a suitable appearance and properties for administration. Pharmaceutically acceptable carriers, such as stabilizers, diluents, additives, adjuvants, and excipients, have substantially no long-term or permanent adverse effects when administered to a subject. A "pharmaceutically acceptable carrier" should be a pharmaceutically inert material that is substantially biologically inactive and constitutes the majority of the formulation.

[0187] In the present invention, the pharmaceutically acceptable carrier includes but is not limited to a solubilizing agent, an acidic pH regulator, a glidant, a surfactant, a disintegrant, a diluent, a binder, a filler, an antioxidant and a lubricant.

[0188] The weight percentages of the components in the solid dispersions and pharmaceutical compositions of the present invention may fluctuate by about ±2%, about ±1.5%, about ±1%, about ±0.5%, about ±0.2%, about ±0.1%, about ±0.05%, about ±0.02%, or about ±0.01%.

[0189] As used herein, “about” before a numerical value indicates that the numerical value may fluctuate by ±2%, ±1.5%, ±1%, ±0.5%, ±0.2%, ±0.1%, ±0.05%, ±0.02%, or ±0.01%.

[0190] The term "cosolvent" as used herein refers to a compound, an association compound, or a double salt formed between a poorly soluble drug and a third substance in a solvent to increase the solubility of the drug in the solvent. Suitable polymer cosolvents in the art include, for example, one or more of PEG, PVP, HPMCAS, HPMC, Eudragit, and Soluplus.

[0191] As used herein, the term "acidic pH regulator" refers to an excipient used to maintain or alter the pH of a drug. Suitable acidic pH regulators in the art may include, for example, one or both of organic and inorganic acids. The organic acid may be selected from, for example, one or more of citric acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid, oxalic acid, aspartic acid, mandelic acid, glutaric acid, and glutamic acid. The inorganic acid may be selected from, for example, one or more of hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid.

[0192] The term "glidant" in the present invention refers to an auxiliary material that can reduce the friction between particles and improve the flowability of powder (granules). In the art, the glidant can be selected from one or more of colloidal silicon dioxide, animal or plant fats, waxes, etc.

[0193] In the present invention, the term "surfactant" refers to a class of compounds containing fixed hydrophilic and lipophilic groups that, due to their amphiphilic nature, tend to concentrate on the surface of a solution, at the interface of two immiscible liquids, or at the interface of a liquid and a solid, thereby reducing surface tension or interfacial tension. In the art, surfactants can generally further enhance the therapeutic potential of solid dispersions, and can include, for example: anionic surfactants such as sodium lauryl sulfate (sodium lauryl sulfate) and sodium docusate; cationic surfactants such as cetrimide, benzethonium chloride, cetylpyridinium chloride, and lauric acid; nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters (specifically, Tween 80, 60, 40, and 20), polyoxyethylene castor oil derivatives (specifically, Cremophor RH40), polyoxyethylene stearate, vitamin E polyethylene glycol succinate, and poloxamers (poloxamer 188 and poloxamer 407).

[0194] The term "disintegrant" in the present invention refers to an ingredient added to a prescription to promote rapid disintegration of the preparation into small units and to dissolve the drug more quickly. In the art, suitable disintegrants may be, for example, one or more of povidone, crospovidone, carboxymethyl cellulose, methyl cellulose, alginic acid, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, starch (such as corn starch, potato starch), formaldehyde-casein, alginic acid, silicon dioxide, and guar gum.

[0195] The term "diluent" in the present invention is also called "filler", which refers to an ingredient used to increase the volume or weight of a preparation. Diluents usually account for a large proportion in pharmaceutical dosage forms. Their function is not only to ensure a certain volume of the preparation, but also to reduce the dosage deviation of the main drug component and improve the compression moldability of the drug. In the art, suitable diluents can be, for example, one or more of sugars (such as maltose, lactose, fructose, sucrose), cellulose materials (such as microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose), starch (such as pregelatinized corn starch, maltodextrin, dextrin), sugar alcohols (such as mannitol, sorbitol), dextrate, calcium phosphate, gum, acrylate (such as polymethacrylic acid), calcium carbonate, magnesium oxide, and talc.

[0196] In the present invention, the term "binder" refers to a type of solid powder or solution with viscosity that aggregates non-viscous or insufficiently viscous material powders into granules to promote compression molding. In the art, suitable binders may be, for example, one or more of gum arabic, gelatin, carbomer, dextrin, starch (such as corn starch), povidone, copovidone, carboxymethyl cellulose, guar gum, glucose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, polymethacrylate, maltodextrin, and hydroxyethyl cellulose.

[0197] The term "antioxidant" as used herein refers to a class of substances that can effectively prevent or delay auto-oxidation. These substances are an important component of pharmaceutical excipients, primarily used to prevent oxidative deterioration of drugs and their formulations, as well as discoloration, precipitation, and other instabilities caused by oxidation. Suitable antioxidants in the art include, for example, ascorbic acid or sodium ascorbate.

[0198] The term "lubricant" as used herein refers to a substance that reduces friction between the tablet and the wall of the die hole. Suitable lubricants in the art include, for example, polyethylene glycol (e.g., with a molecular weight of 1000 to 6000), magnesium stearate, calcium stearate, sodium stearyl fumarate, and the like.

[0199] The term "glidant" in the present invention refers to a substance that reduces friction between particles and thus improves powder flowability. In the art, suitable glidants can be selected from one or more of colloidal silicon dioxide, animal or vegetable fats, waxes, etc.

[0200] In the present invention, term " plasticizer " refers to a kind of low molecular weight substance, when being added in another material (being generally macromolecular polymer), can make macromolecular material have flexibility and elasticity, and be easy to process.In this area, plasticizer generally can improve the processability of this solid dispersion, for example can be selected from acetyl tributyl citrate, acetyl triethyl citrate, benzyl benzoate, chlorobutanol, dextrin, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, glycerine, glyceryl monostearate, mannitol, mineral oil, lanolin alcohol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, triacetin, tributyl citrate, one or more of triethanolamine and triethyl citrate.

[0201] The term "HPMCAS" in the present invention refers to hydropropyl methylcellulose acetate succinate, for example, HPMCAS-LF, HPMCAS-LG, HPMCAS-MF, HPMCAS-MG, HPMCAS-HF, HPMCAS-HG, etc.

[0202] The term "PVP-VA" in the present invention is a vinyl pyrrolidone-vinyl acetate copolymer (copovidone), for example, PVP-VA64, PVP-VA37, PVP-VA73 and the like.

[0203] The term "PEG" in the present invention refers to polyethylene glycol, for example, PEG4000, PEG6000, etc.

[0204] The term "PVP" in the present invention refers to polyvinylpyrrolidone (Povidone), for example, PVP K17, PVP K30, PVP K90, PVP-VA64, Plasdone S-630, Plasdone S-630 ULTRA and the like.

[0205] The term "HPMC" in the present invention refers to hydroxypropyl methylcellulose, for example, it can be HPMCE3LV, E5LV, E6LV, E15LV, E50LV, E4M, E10M, K100LV, K4M, K15M, L100M, A15LV, A4C, A15C, A4M and other related models.

[0206] The term "Eudragit" in the present invention refers to an acrylic resin, for example, Eudragit L100-55, Eudragit S100, and the like.

[0207] The term "Soluplus" in the present invention is a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0208] The solid dispersion or pharmaceutical composition of the present invention may include a film coating. The film coating can improve taste and provide a refined appearance. If desired, the film coating can be an enteric coating. The film coating typically comprises a polymeric film-forming material, such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and an acrylate or methacrylate copolymer. In addition to the film-forming polymer, the film coating may also include a plasticizer such as polyethylene glycol, a surfactant such as Tween, and an optional pigment such as titanium dioxide or iron oxide. The film coating may also include talc as an anti-adherent. The film coating of the tablet can also contribute to a comfortable coating that can be swallowed.

[0209] Enteric formulations are typically prepared by a film coating process which generally involves accumulating a thin film layer of an acid-insoluble (enteric) polymer onto the surface of a previously prepared dosage form, for example by spraying an aqueous or organic solution or suspension of the enteric polymer onto a tumbling or moving tablet or capsule and depositing the enteric polymer by drying with hot air.

[0210] The solid dispersion or pharmaceutical composition of the present invention can be in a unit dosage form containing a predetermined amount of active ingredient per unit dose. In the solid dosage form of the pharmaceutical composition of the present invention, the dosage of the active ingredient can be 0.1-100 mg / unit dose, or 10-20 mg / unit dose.

[0211] The solid dispersion or pharmaceutical composition of the present invention can be administered to a subject in need thereof in a therapeutically effective amount. As used herein, the term "therapeutically effective amount" refers to an amount that achieves the desired therapeutic effect within a specific dosage and time period. The "therapeutically effective amount" is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the route of administration.

[0212] The dosage for parenteral administration may be 0.1-200 mg active ingredient / kg body weight / day. The dosage for oral administration may be 0.1-1000 mg active ingredient / kg body weight / day, for example 0.1-100 mg active ingredient / kg body weight / day.

[0213] The term "solubility" in the present invention refers to the solubility of the active ingredient in an aqueous medium, such as water, buffer, gastric or intestinal simulated fluid (such as FaSSIF, FeSSIF or SGF), gastric fluid or intestinal fluid.

[0214] The term "bioavailability" as used herein refers to the extent to which a drug is utilized by a target tissue (in this invention, such as the intestine) after administration. For example, "bioavailability" can refer to the fraction of a drug that is absorbed after administration to a subject in a fed or fasted state.

[0215] In certain aspects, following administration of a solid dispersion or pharmaceutical composition of the invention to a subject, whether fasting or fed, the bioavailability of Compound 1 is at least about 15% of the administered dose, but may be greater than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, or 70%.

[0216] The term "fasting" in the present invention may also be referred to as "empty stomach", which generally refers to a period of at least 2 hours before and at least 2 hours after a subject's previous meal.

[0217] The term "meal" in the present invention may also be referred to as "postprandial", which generally refers to the period within 2 hours after a subject has eaten.

[0218] The solid dispersion or pharmaceutical composition of the present invention can be used to treat diseases mediated by CSF-1R kinase.

[0219] The disease mediated by CSF-1R kinase can be selected from multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), prostate cancer, breast cancer, ovarian cancer, melanoma, glioblastoma multiforme, giant cell tumor of bone, non-small cell lung cancer, giant cell tumor of tendon sheath, tumor metastasis, myelofibrosis, villonodular synovitis and gastrointestinal stromal tumor.

[0220] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0221] The reagents and raw materials used in the present invention are commercially available.

[0222] The Chinese equivalents of the English or English abbreviations involved in this invention are as follows:

[0223] The positive progress effect of the present invention is:

[0224] (1) The solid dispersion prepared from the composition of the present invention is more conducive to dispersing Compound 1 in an amorphous (or nearly amorphous) or non-crystalline state in a polymer carrier; further, the solid dispersion prepared from the composition of the present invention is conducive to improving the solubility of Compound 1.

[0225] (2) Forming compound 1 into a solid dispersion significantly improved its solubility and bioavailability. In particular, Soluplus, Plasdone S-630 ULTRA, or HPMCAS-HG showed superior solubilization effects on compound 1 compared to other polymer carriers (e.g., PEG4000, PEG6000, Eudragit L100-55, Eudragit S100, PVPK17, PVPK30, PVPK90, Plasdone S-630, HPMCAS-LF, HPMCAS-MF, and HPMCAS-HF). The solubility of the solid dispersion of compound 1 prepared using Soluplus or Plasdone S-630 ULTRA as a polymer carrier is higher than that of the solid dispersion of compound 1 prepared using other polymer carriers (e.g., PEG4000, PEG6000, Eudragit L100-55, Eudragit S100, PVPK17, PVPK30, PVPK90, Plasdone S-630, HPMCAS-LF, HPMCAS-MF, HPMCAS-HF). Under intestinal and / or gastric fluid conditions, the solubility of compound 1 solid dispersions prepared using Soluplus, Plasdone S-630 ULTRA, or HPMCAS-HG was significantly improved compared to compound 1 itself, and was superior to compound 1 solid dispersions prepared using other polymer carriers (e.g., PEG4000, PEG6000, Eudragit L100-55, Eudragit S100, PVPK17, PVPK30, PVPK90, Plasdone S-630, HPMCAS-LF, HPMCAS-MF, HPMCAS-HF).

[0226] (3) The pharmaceutical composition of the present invention has one or more advantages of improved pharmacokinetics, increased in vivo exposure, and good solubility. In addition, the increased in vivo exposure reduces the amount of compound 1 used, which can significantly reduce the production cost in the drug development stage, such as reducing the tablet size or making it into a dry suspension, and can also improve patient compliance. Therefore, the pharmaceutical composition of the present invention further has one or both advantages of low production cost and good patient compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0227] Figure 1 shows the XRPD results of solid dispersions prepared by spray drying using different polymer carriers in different media after 2 hours; (a) XRPD result of pure API after 2 hours; (b) XRPD result of API + HPMCAS-HG after 2 hours; (c) XRPD result of API + Soluplus after 2 hours; (d) XRPD result of API + Plasdone S-630 ULTRA after 2 hours; from top to bottom, the XRPD results are before solubility test, 2 hours in FaSSiF medium, 2 hours in FeSSiF medium, and 2 hours in SGF medium, respectively.

[0228] Figure 2 shows the drug absorption of a solid dispersion prepared using HPMCAS-HG as a polymer carrier in rats using different administration methods. The bar graphs of AUC and Cmax shown below show the gastric model on the left and the intestinal model on the right.

[0229] Figure 3 shows the effects of different polymer carriers on absorption in a rat gastric model; the three samples from left to right are solid dispersions prepared with HPMCAS-HG, Soluplus, and Plasdone S-630ULTRA as polymer carriers.

[0230] Figure 4 shows the exposure comparison in dogs.

[0231] Figure 5 shows the comparison of dissolution curves in pH 4.5 medium with different acidic pH adjuster contents.

[0232] Figure 6 shows the comparison of the two-stage dissolution curves based on the acidic pH adjuster content.

[0233] Figure 7 shows the comparison of dissolution curves of acidic pH adjusters in pH 4.5 medium.

[0234] Figure 8 shows the comparison of the two-stage dissolution profiles for different types of acidic pH adjusters.

[0235] Figure 9 shows the comparison of dissolution curves in different co-solvent types and pH 4.5 medium.

[0236] Figure 10 shows the comparison of the two-stage dissolution profiles according to the type of co-solvent.

[0237] Figure 11 shows the comparison of dissolution curves in pH 4.5 medium with different co-solvent contents.

[0238] Figure 12 shows the comparison of the two-stage dissolution profiles depending on the co-solvent content. DETAILED DESCRIPTION

[0239] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0240] The following reagents and detection methods will be used in the embodiments of the present invention:

[0241] Chemical name: 6-((3-methoxy-4-((6-methylpyridin-3-yl)-methoxy)phenyl)amino)-3-morpholinoquinoxaline-5-carbonitrile;

[0242] Molecular formula: C 27 H 26 N6O3.

[0243] 1. Reagents

[0244] (1) Compound 1 was obtained from Tianjin Kailiying Pharmaceutical Co., Ltd.

[0245] (2) PEG6000 was obtained from Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd.

[0246] (3) Soluplus is from BASF.

[0247] (4) Plasdone S-630ULTRA from Ashland.

[0248] (5) HPMCAS-HG from Shin-Etsu, viscosity type: 3 mPa.s.

[0249] (6) PVPK30 from BASF

[0250] (7) PVP-VA64 from BASF

[0251] (8) HPMC E3LV from Colorcon

[0252] (9) Anhydrous ethanol and dichloromethane were obtained from Tianjin Tairong Chemical Trading Co., Ltd.

[0253] (10) Fumaric acid from Finar

[0254] (11) Malic acid comes from Alpha

[0255] (12) Fumaric acid from Finar

[0256] (13) Tartaric acid from Hunan Erkang Pharmaceutical

[0257] 2. PLM experimental methods:

[0258] PLM images were collected using a Leica DM750P polarized light microscope (Leica, Germany). A small amount of each sample was placed on a glass slide, a drop of cedarwood oil was applied, and the slide was covered with a glass slide. The sample was observed using polarized light at an appropriate magnification. The instrument was controlled and data were analyzed using LAS (V4.9) software.

[0259] 3. XRPD experimental method:

[0260] Crystalline analysis of the samples was performed using a D8 FOCUS X-ray powder diffractometer (Bruker, Germany) in reflectance mode. The 2θ scanning angle of the samples ranged from 3° to 42°, with a scanning step length of 0.02°, a scanning time of 0.2 s per step, and a temperature of 25°C. The light tube voltage and current were 40 kV and 40 mA, respectively. During sample preparation, an appropriate amount of sample was placed on a polished sample plate and gently flattened with a spoon or glass slide to ensure a smooth surface. XRPD spectra were analyzed using DIFFRAC.EVA (V4.3.1).

[0261] 4. Solvent residue and purity detection method:

[0262] Prepare a 50 mg / mL test solution using 0.25 mg / mL anhydrous ethanol solution and 0.03 mg / mL dichloromethane solution as the reference solution, and 0.01 mg / mL anhydrous ethanol and 0.006 mg / mL dichloromethane as the sensitivity solution. DMSO was used as the solvent for the above solutions. Detection was performed using a gas chromatograph.

[0263] 5. Solubility test method:

[0264] Prepare FaSSIF stock solution with pH buffer: weigh approximately 621 mg of NaCl, approximately 345 mg of NaH2PO4, and approximately 41.9 mg of NaOH into a 100 mL volumetric flask. Dissolve in water to a depth of approximately 5 cm from the scale line. After the solution cools, adjust the pH to volume with water and shake well.

[0265] FeSSIF mother solution: Weigh approximately 866 mg of glacial acetic acid, approximately 406 mg of NaOH, and approximately 1184 mg of NaCl into a 100 mL volumetric flask. Dissolve in water to a depth of approximately 5 cm from the scale line. After the solution cools, adjust the pH to volume with water and shake well.

[0266] SGF solution: Weigh approximately 202 mg of NaCl and approximately 321 mg of pepsin into a 100 mL volumetric flask. Pipette 700 μL of HCl and dissolve in water until the solution is approximately 5 cm from the scale line. After the solution cools, dilute to volume with water and shake well.

[0267] FaSSIF solution: Pipette FaSSIF mother liquor into a 100 mL volumetric flask, weigh approximately 225 mg of FaSSIF powder and add it. Dissolve the FaSSIF mother liquor to a depth of approximately 5 cm from the scale line. After the solution cools, dilute to volume with FaSSIF mother liquor, shake well, and let stand for 2 hours before use.

[0268] FeSSIF solution: Pipette FeSSIF mother liquor into a 100 mL volumetric flask, weigh approximately 1122 mg of FeSSIF powder and add it. Dissolve the FeSSIF mother liquor to a depth of approximately 5 cm from the scale line. After the solution cools, dilute to volume with FeSSIF solution and shake well.

[0269] Experimental process

[0270] Weigh approximately 20 mg of sample into a 4-mL bottle, add 4 mL of different solvents (FaSSIF, FeSSIF, SGF), place in a magnetic separator, and stir at 37°C for 2 h. Sampling was performed at 0.5 h and 2 h, respectively. After filtration, the sample concentration in the filtrate was determined by HPLC, and the pH value of the 2 h filtrate and the crystal form of the remaining solid were determined.

[0271] Example 1 Solid Dispersion

[0272] 1.1. Rotary evaporation pilot experiment 1

[0273] See Table 1 for prescribing information.

[0274] Table 1:

[0275] Note: a indicates that the solvent will be removed during sample preparation.

[0276] The process parameters are shown in Table 2.

[0277] Table 2:

[0278] Analysis results

[0279] When the rotary evaporation method was used and the ratio of API to carrier was 1:3, the samples prepared were not amorphous, and PEG6000 had the worst effect in inhibiting crystallization.

[0280] 1.2. Rotary evaporation test 2

[0281] See Table 3 for prescribing information.

[0282] Table 3:

[0283] Note: a Solvent will be removed during sample preparation

[0284] The process parameters are shown in Table 4.

[0285] Table 4:

[0286] Analysis results:

[0287] When the ratio of API to HPMCAS-HG was 1:3 and the ratio of API to Soluplus was 1:4 using the rotary evaporation method, no completely amorphous samples were obtained, proving that the rotary evaporation method cannot prepare amorphous solid dispersions.

[0288] 1.3 Spray drying test

[0289] See Table 5 for prescribing information.

[0290] Table 5:

[0291] Note: a indicates that the solvent will be removed during sample preparation.

[0292] Preparation process of prescription 8:

[0293] Solution Preparation: Weigh dichloromethane and anhydrous ethanol and add to the solution system. Slowly add HPMCAS-HG to the solution system and stir until the materials are completely dissolved. Slowly add compound 1 to the solution system. After complete addition, rinse the addition funnel with a mixture of dichloromethane and anhydrous ethanol to confirm that compound 1 is completely added. Stir until completely dissolved.

[0294] Spray drying: Nitrogen replacement, preheating. Use blank solvent to stabilize the parameters. After the inlet temperature reaches 70℃±5℃ and the outlet temperature reaches 45.0±5.0℃, switch the solution and start spray drying.

[0295] Double-cone drying: The solid dispersion prepared by spray drying is dried in a double-cone dryer until the residual solvent content is within acceptable limits. Central control sampling is performed to test the content and moisture content.

[0296] The process parameters of Recipe 6 and Recipe 7 are shown in Table 6.

[0297] Table 6:

[0298] Analysis results: Spray drying method can be used to prepare amorphous solid dispersions, polymer carriers HPMCAS-HG, Soluplus and Plasdone TM S-630 ULTRA has a better crystallization inhibitory effect. The results of solvent residue and purity are shown in Table 7.

[0299] Table 7:

[0300] The solubility test results are shown in Table 8.

[0301] Table 8:

[0302] The XRPD results after 2 hours are shown in Figure 1, including (a) the XRPD result of pure API (L321100013) after 2 hours; (b) the XRPD result of API + HPMCAS-HG (R1273430101) after 2 hours; (c) the XRPD result of API + Soluplus (PF127343-01-ZDQ-0103-149-06) after 2 hours; and (d) the XRPD result of API + Plasdone S-630 ULTRA (PF127343-01-ZDQ-0106-151-07) after 2 hours. From top to bottom, the XRPD results are before the solubility test, after 2 hours in FaSSIF medium, after 2 hours in FeSSIF medium, and after 2 hours in SGF medium.

[0303] Solubility results showed that under intestinal and gastric fluid conditions, the solubility of samples using Soluplus or Plasdone S-630 ULTRA as carriers was significantly improved compared to the API. Under intestinal fluid conditions, the solubility of samples using HPMCAS-HG as carriers was significantly improved compared to the API, and the crystal form of samples using Soluplus as carriers was more stable.

[0304] 1.4. Rat PK Study

[0305] Experimental methods:

[0306] 1) 9 SD rats, 3 in each group, clean grade, adult male, 6-8 weeks old, weighing 280-320 g at the beginning of the experiment.

[0307] 2) Prescription: API: Soluplus = 1:3 (Prescription 6), API: Plasdone™ S-630 ULTRA = 1:3 (Prescription 7), API: HPMCAS-HG = 3:7 (Prescription 8).

[0308] 3) Solvent: 0.5% MC (1500cp), pH=1.2.

[0309] 4) Dosage: 60 mg / kg based on API.

[0310] 5) Dosage volume: 10 ml / kg

[0311] 6) Administration: Oral, single dose. Fast for 12 hours before administration. Resume food 2 hours after administration, with free access to water.

[0312] 7) Blood collection points: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 24h

[0313] 8) Sample Collection: Collect 100 μL of blood and place it in a labeled EDTA-2K anticoagulant tube. Gently invert the tube to thoroughly mix the anticoagulant (EDTA-2K) with the blood. Store in an ice-water bath and centrifuge within 1-2 hours of blood collection at 4°C, 8000 rpm, for 5 minutes to separate the plasma. After centrifugation, place the separated plasma in a labeled EP tube and store in a -80°C freezer as soon as possible until analysis.

[0314] 9) Test results:

[0315] Referring to Figure 2, the reference solid dispersion was administered to rats in different ways (gastric model pH 1.2, intestinal model pH 6-7) to simulate human gastric dissolution (before meal) and enteric dissolution (after meal). In the gastric model pH 1.2, a hydrochloric acid solution containing 5% MC at pH 1.2 was administered to rats by gavage to lower the pH. In the intestinal model pH 6-7, an aqueous solution containing 5% MC was administered to rats by gavage, and no pH increase occurred in the gastrointestinal tract. It was found that the exposure of the drug in the rat intestinal model was greater than that in the gastric model, and the AUC increased by 107%. This result shows that evaluating solid dispersions in the gastric model can better reflect the actual situation in the human body, and it also suggests that changes in the gastrointestinal pH of rats affect the absorption of the reference solid dispersion.

[0316] As shown in Figure 3, because the gastrointestinal pH of rats is relatively high, generally above 3, all three solid dispersions were administered orally with a pH 1.2 hydrochloric acid solution containing 5% MC to lower the pH and simulate the pH changes in the human gastrointestinal tract. According to the rat PK test results, Formulations 6, 7, and 8 showed good in vivo exposure in rats, indicating that the polymer carrier in the solid dispersions enhances the formulation's tolerance to gastrointestinal pH changes and improves in vivo absorption.

[0317] 1.5. Solid Dispersions Used in Subsequent Examples

[0318] prescription:

[0319] Note: *Indicates that the solvent was removed during sample preparation.

[0320] Preparation process:

[0321] 1) Solution Preparation: Weigh dichloromethane and anhydrous ethanol and add to the solution system. Slowly add HPMCAS to the solution system and stir until the materials are completely dissolved. Slowly add Compound 1 to the solution system. After complete addition, rinse the addition funnel with a mixture of dichloromethane and anhydrous ethanol to ensure complete addition of Compound 1. Stir until completely dissolved.

[0322] 2) Spray drying:

[0323] Nitrogen replacement and preheating.

[0324] Spray drying: Use a blank solvent to stabilize the parameters. After the inlet air temperature reaches 70℃±5℃ and the outlet air temperature reaches 45.0±5.0℃, switch the solution and start spray drying.

[0325] Double-cone drying: The solid dispersion prepared by spray drying is dried in a double-cone dryer until the residual solvent content is within acceptable limits. Central control sampling is performed to test the content and moisture content.

[0326] 3) The prepared solid dispersion will be used to prepare the formulations in the subsequent examples.

[0327] Example 2 Tablets

[0328] 2.1. Tablet prescription:

[0329] 2.2. Tablet preparation process:

[0330] 1) Wet granulation

[0331] Weigh povidone K90 and purified water according to the prescription.

[0332] Prepare the adhesive: add weighed povidone K90 (adhesive) into weighed purified water (adhesive solvent), stir and mix to make the solution clear.

[0333] Premixing: Add the weighed povidone K90 (added internally) and solid dispersion into the wet granulation pot in sequence and mix for 2 minutes.

[0334] Add binder: spray the prepared binder into the wet granulation pot.

[0335] Granulation: add water and granulate.

[0336] 2) Wet whole grain

[0337] Use 8-mesh screen of sieving machine to carry out wet granulation.

[0338] 3) Fluidized bed drying

[0339] After preheating the fluidized bed, the wet granulated material is put into the fluidized bed, the inlet air temperature is set to 60°C (55-65°C), and the drying loss is detected. When the drying loss is ≤3.0%, the drying is terminated.

[0340] 4) Dry whole grain

[0341] Use a 12-mesh screen of a sieving machine to perform dry granulation.

[0342] 5) Total Mixing

[0343] Calculation and weighing of the dosage of additional excipients: Calculate sodium starch glycolate and magnesium stearate according to the prescription and weigh the corresponding weights.

[0344] Total mixing: Add the dry granules, sodium starch glycolate, and magnesium stearate into the mixing hopper in sequence, set the mixing speed to 14 rpm, mix for 4 minutes, and take samples to check the mixing uniformity.

[0345] 6) Tablet pressing

[0346] Tablets of 150 mg strength were compressed using an oval die measuring 19.0 mm x 7.6 mm.

[0347] 7) Coating

[0348] Compound 1 (150 mg) was coated as a plain tablet, and the coating was continued until the coating weight gain reached 3%.

[0349] 2.3 In vivo PK study in Beagle dogs

[0350] Experimental methods:

[0351] 1) 3 male dogs, Beagle dogs, ordinary grade, adult males, weighing 10-14kg.

[0352] 2) Administration: Dogs were fasted overnight and given an intramuscular injection of 6 μg / kg pentagastrin (0.25 mg / mL) followed by a timer 20 to 30 minutes after administration.

[0353] 3) Dosage: 300 mg / dog, approximately 30 mg / kg.

[0354] 4) Administration: Oral, single dose.

[0355] 5) Blood collection points: Plasma: 0, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, 48 h, 72 h (the blood collection points for the first in vivo PK test in dogs were 0-48 h, and the blood collection points for the second in vivo PK test in dogs were 0-72 h, with an additional blood collection point of 72 h compared to the first time).

[0356] 6) Sample Collection: Collect 1 mL of blood and place it in a labeled EDTA-2K anticoagulant tube. Gently invert the tube to thoroughly mix the anticoagulant (EDTA-2K) and blood. Centrifuge and store in a freezer immediately until analysis.

[0357] 7) Sample Analysis: Compound 1 was extracted from plasma by protein precipitation and quantitatively analyzed using a triple quadrupole tandem mass spectrometer in multiple reaction monitoring mode. The components of the sample were separated using a chromatographic column and gradient elution with a mobile phase of methanol and 0.1% formic acid in water at a flow rate of 0.6000 mL / min. The quantitative range was 1.00 to 2500 ng / mL. The concentration of compound 1 in the biological samples obtained in this experiment was determined using LC-MS / MS analysis. Corresponding pharmacokinetic parameters were obtained and used to evaluate the pharmacokinetic properties of compound 1 in beagle dogs.

[0358] 8) Pharmacokinetic Parameter Calculation Method: Pharmacokinetic parameters were calculated using a non-compartmental model in Phoenix Win Nonlin 8.3. All calculations and analyses used the same decimal places as the software output. Deviations were calculated using Excel office software. Rounding errors do not affect the authenticity of the data.

[0359] In vivo PK test (first time) results (parallel comparison with Examples 3 and 5):

[0360] In vivo PK test (second time) results (parallel comparison with Examples 5 and 30):

[0361] 2.4. In vitro dissolution test:

[0362] 2.4.1 Dissolution Method 1

[0363] Dissolution results of dissolution method 1:

[0364] 2.4.1 Dissolution Method 2

[0365] Dissolution results of dissolution method 2:

[0366] Example 3 dry suspension

[0367] 3.1. Dry suspension prescription:

[0368] Tablet prescription 1

[0369] Tablet prescription 2

[0370] 3.2 Preparation process:

[0371] 1) Mixing

[0372] According to the prescription, the solid dispersion, copovidone VA64, and colloidal silicon dioxide were weighed and added to the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve. Then, mannitol, tartaric acid, and CMC-Na were weighed according to the prescription, added to the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve.

[0373] 3.3. In vivo PK test in Beagle dogs: The method is as described in 2.3 of Example 2, and the test was conducted in parallel with Examples 2 and 5.

[0374] Results of the in vivo PK test (first trial) of tablet formulation 2:

[0375] Example 4 Dry Suspension

[0376] 4.1. Dry suspension prescription:

[0377] 4.2 Preparation process:

[0378] Mixing

[0379] According to the prescription, the solid dispersion, Soluplus, and colloidal silicon dioxide were weighed and added to the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve. Then, mannitol, tartaric acid, and CMC-Na were weighed according to the prescription, added to the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve.

[0380] Example 5 Tablets (5% tartaric acid)

[0381] 5.1. Tablet Prescription:

[0382] 5.2 Preparation process:

[0383] 1) Premix

[0384] According to the prescription, the solid dispersion, high molecular polymer and colloidal silicon dioxide were weighed and added into the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve. Then, according to the prescription, mannitol, organic acid and cross-linked sodium carboxymethyl cellulose were weighed and added into the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve.

[0385] 2) Dry granulation

[0386] Dry granulation was performed using a dry granulator.

[0387] 3) Dry whole grain

[0388] Use a 12-mesh screen of a granulator to perform dry granulation.

[0389] 4) Total Mixing

[0390] Calculation and weighing of the dosage of additional excipients: Calculate sodium starch glycolate and magnesium stearate according to the prescription and weigh the corresponding weights.

[0391] Total mixing: Add the dry granulated granules, sodium starch glycolate and magnesium stearate into the mixing hopper, set the mixing speed to 15 rpm, the mixing time to 5 min, and take samples to check the mixing uniformity.

[0392] 5) Tablet pressing

[0393] 75 mg tablets were compressed using a 16.31 mm × 8.59 mm oval die.

[0394] 5.3. In vivo PK test in Beagle dogs. The method is as described in 2.3 of Example 2.

[0395] In vivo PK test (first time) results (parallel comparison with Examples 2 and 3):

[0396] In vivo PK test (second time) results (parallel comparison with Examples 2 and 30):

[0397] 5.4. For the in vitro dissolution test method, refer to dissolution method 1 and method 2 in 2.4 of Example 2.

[0398] Dissolution results of dissolution method 1:

[0399] Dissolution results of dissolution method 2:

[0400] Example 6 Tablets (0% tartaric acid)

[0401] 6.1. Tablet Prescription:

[0402] 6.2. Preparation process: see 5.2 of Example 5

[0403] 6.3. For the in vitro dissolution test method, refer to dissolution method 1 and method 2 in 2.4 of Example 2.

[0404] Dissolution results of dissolution method 1:

[0405] Dissolution results of dissolution method 2:

[0406] Example 7 Tablets (10% tartaric acid)

[0407] 7.1. Tablet Prescription:

[0408] 7.2. Preparation process: see 5.2 of Example 5

[0409] 7.3. For the in vitro dissolution test method, refer to dissolution method 1 and method 2 in 2.4 of Example 2.

[0410] Dissolution results of dissolution method 1:

[0411] Dissolution results of dissolution method 2:

[0412] Example 8 Tablets (20% Tartaric Acid)

[0413] 8.1. Tablet Prescription:

[0414] 8.2. Preparation process: see 5.2 of Example 5

[0415] Example 9 Tablets (40% Tartaric Acid)

[0416] 9.1. Tablet Prescription:

[0417] 9.2. Preparation process: see 5.2 of Example 5

[0418] Example 10 Tablets (5% Fumaric Acid)

[0419] 10.1. Tablet Prescription:

[0420] 10.2. Preparation process: see 5.2 of Example 5

[0421] 10.3. For the in vitro dissolution test method, refer to dissolution method 1 and method 2 in 2.4 of Example 2.

[0422] Dissolution results of dissolution method 1:

[0423] Dissolution results of dissolution method 2:

[0424] Example 11 Tablets (5% citric acid)

[0425] 11.1. Tablet Prescription:

[0426] 11.2. Preparation process: see 5.2 of Example 5

[0427] 11.3. For the in vitro dissolution test method, refer to dissolution method 1 and method 2 in 2.4 of Example 2.

[0428] Dissolution results of dissolution method 1:

[0429] Dissolution results of dissolution method 2:

[0430] Example 12 Tablets (5% Malic Acid)

[0431] 12.1. Tablet Prescription:

[0432] 12.2. Preparation process: see 5.2 of Example 5

[0433] 12.3. For the in vitro dissolution test method, refer to dissolution method 1 and method 2 in 2.4 of Example 2.

[0434] Dissolution results of dissolution method 1:

[0435] Dissolution results of dissolution method 2:

[0436] Example 13 Tablets (6% Soluplus)

[0437] 13.1. Tablet Prescription:

[0438] 13.2. Preparation process: see 5.2 of Example 5

[0439] 13.3. For the in vitro dissolution test method, refer to dissolution method 1 and method 2 in 2.4 of Example 2.

[0440] Dissolution results of dissolution method 1:

[0441] Dissolution results of dissolution method 2:

[0442] Example 14 Tablets (6% HPMC E3LV)

[0443] 14.1. Tablet Prescription:

[0444] 14.2. Preparation process: see 5.2 of Example 5

[0445] 14.3. For the in vitro dissolution test method, refer to dissolution method 1 and method 2 in 2.4 of Example 2.

[0446] Dissolution results of dissolution method 1:

[0447] Dissolution results of dissolution method 2:

[0448] Example 15 Tablet (6% PVPK30)

[0449] 15.1. Tablet Prescription:

[0450] 15.2. Preparation process: see 5.2 of Example 5

[0451] 15.3. For the in vitro dissolution test method, refer to dissolution method 1 and method 2 in 2.4 of Example 2.

[0452] Dissolution results of dissolution method 1:

[0453] Dissolution results of dissolution method 2:

[0454] Example 16 Tablet (0% PVPVA64)

[0455] 16.1. Tablet Prescription:

[0456] 16.2. Preparation process: see 5.2 of Example 5

[0457] 16.3. For the in vitro dissolution test method, refer to dissolution method 1 and method 2 in 2.4 of Example 2.

[0458] Dissolution results of dissolution method 1:

[0459] Dissolution results of dissolution method 2:

[0460] Example 17 Tablet (12% PVP VA64)

[0461] 17.1. Tablet Prescription:

[0462] 17.2. Preparation process: see 5.2 of Example 5

[0463] 17.3. For the in vitro dissolution test method, refer to Dissolution Method 1 and Method 2 in 2.4 of Example 2.

[0464] Dissolution results of dissolution method 1:

[0465] Dissolution results of dissolution method 2:

[0466] Example 18 Tablet (24% PVP VA64)

[0467] 18.1. Tablet Prescription:

[0468] 18.2. Preparation process: see 5.2 of Example 5

[0469] 18.3. For the in vitro dissolution test method, refer to Dissolution Method 1 and Method 2 in 2.4 of Example 2.

[0470] Dissolution results of dissolution method 1:

[0471] Dissolution results of dissolution method 2:

[0472] Example 19 Tablets

[0473] 19.1. Tablet Prescription:

[0474] 19.2. Preparation process: see 5.2 of Example 5

[0475] 19.3. In vitro dissolution test:

[0476] Dissolution results of dissolution method 3:

[0477] Example 20 Tablets

[0478] 20.1. Tablet Prescription:

[0479] 20.2. Preparation process:

[0480] 1) Premix

[0481] According to the prescription, the solid dispersion, SDS, and colloidal silicon dioxide were weighed and added to the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve. Then, mannitol, tartaric acid, and CCMC-Na were weighed according to the prescription, added to the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve.

[0482] 2) Dry granulation

[0483] Dry granulation was performed using a dry granulator.

[0484] 3) Dry whole grain

[0485] Use a 12-mesh screen of a granulator to perform dry granulation.

[0486] 4) Total Mixing

[0487] Calculation and weighing of the dosage of additional excipients: Calculate sodium starch glycolate and magnesium stearate according to the prescription and weigh the corresponding weights.

[0488] Total mixing: Add the dry granulated granules, sodium starch glycolate and magnesium stearate into the mixing hopper, set the mixing speed to 15 rpm, the mixing time to 5 min, and take samples to check the mixing uniformity.

[0489] 5) Tablet pressing

[0490] 75 mg tablets were compressed using 16.31 mm x 8.59 mm oval punches.

[0491] 20.3. In vitro dissolution test:

[0492] Example 21 Tablets

[0493] 21.1. Tablet Prescription:

[0494] 21.2. Preparation process:

[0495] 1) Premix

[0496] According to the prescription, the solid dispersion, Soluplus, and SDS were weighed and added into the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve. Then, according to the prescription, mannitol, tartaric acid, and CCMC-Na were weighed and added into the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve.

[0497] 2) Dry granulation

[0498] Dry granulation was performed using a dry granulator.

[0499] 3) Dry whole grain

[0500] Use a 12-mesh screen of a granulator to perform dry granulation.

[0501] 4) Total Mixing

[0502] Calculation and weighing of the dosage of additional excipients: Calculate sodium starch glycolate and magnesium stearate according to the prescription and weigh the corresponding weights.

[0503] Total mixing: Add the dry granulated granules, sodium starch glycolate and magnesium stearate into the mixing hopper, set the mixing speed to 15 rpm, the mixing time to 5 min, and take samples to check the mixing uniformity.

[0504] 5) Tablet pressing

[0505] 75 mg tablets were compressed using 16.31 mm x 8.59 mm oval punches.

[0506] 21.3. In vitro dissolution test:

[0507] Example 22 Tablets

[0508] 22.1. Tablet Prescription:

[0509] 22.2. Preparation process:

[0510] 1) Premix

[0511] According to the prescription, the solid dispersion, Soluplus, colloidal silicon dioxide, and SDS were weighed and added to the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve. Then, according to the prescription, mannitol and CCMC-Na were weighed and added to the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve.

[0512] 2) Dry granulation

[0513] Dry granulation was performed using a dry granulator.

[0514] 3) Dry whole grain

[0515] Use a 12-mesh screen of a granulator to perform dry granulation.

[0516] 4) Total Mixing

[0517] Calculation and weighing of the dosage of additional excipients: Calculate sodium starch glycolate and magnesium stearate according to the prescription and weigh the corresponding weights.

[0518] Total mixing: Add the dry granulated granules, sodium starch glycolate and magnesium stearate into the mixing hopper, set the mixing speed to 15 rpm, the mixing time to 5 min, and take samples to check the mixing uniformity.

[0519] 5) Tablet pressing

[0520] 75 mg tablets were compressed using 16.31 mm x 8.59 mm oval punches.

[0521] 22.3. In vitro dissolution test:

[0522] Example 23 Tablets

[0523] 23.1. Tablet Prescription:

[0524] 23.2. Preparation process:

[0525] 1) Premix

[0526] Weigh the solid dispersion and PVP K30 according to the recipe and add them into the mixing hopper.

[0527] 2) Dry granulation

[0528] Dry granulation was performed using a dry granulator.

[0529] 3) Dry whole grain

[0530] Use a 12-mesh screen of a granulator to perform dry granulation.

[0531] 4) Total Mixing

[0532] Calculation and weighing of the dosage of additional excipients: Calculate sodium starch glycolate and magnesium stearate according to the prescription and weigh the corresponding weights.

[0533] Total mixing: Add the dry granulated granules, sodium starch glycolate, and magnesium stearate into the mixing hopper, set the mixing speed to 15 rpm, the mixing time to 5 min, and take samples to check the mixing uniformity.

[0534] 5) Tablet pressing

[0535] 75 mg tablets were compressed using 16.31 mm x 8.59 mm oval punches.

[0536] 23.3. In vitro dissolution test:

[0537] Dissolution results of dissolution method 3:

[0538] Example 24 Tablets

[0539] 24.1. Tablet Prescription:

[0540] 24.2. Preparation process:

[0541] 1) Premix

[0542] According to the prescription, the solid dispersion, Soluplus, and colloidal silicon dioxide were weighed and added to the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve. Then, according to the prescription, mannitol and tartaric acid were weighed and added to the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve.

[0543] 2) Dry granulation

[0544] Dry granulation was performed using a dry granulator.

[0545] 3) Dry whole grain

[0546] Use a 12-mesh screen of a granulator to perform dry granulation.

[0547] 4) Total Mixing

[0548] Calculation and weighing of the dosage of additional excipients: Calculate sodium starch glycolate and magnesium stearate according to the prescription and weigh the corresponding weights.

[0549] Total mixing: Add the dry granulated granules, sodium starch glycolate and magnesium stearate into the mixing hopper, set the mixing speed to 15 rpm, the mixing time to 5 min, and take samples to check the mixing uniformity.

[0550] 5) Tablet pressing

[0551] 75 mg tablets were compressed using 16.31 mm x 8.59 mm oval punches.

[0552] 24.3. In vitro dissolution test:

[0553] Dissolution results of dissolution method 3:

[0554] Example 25 Tablets

[0555] 25.1. Tablet Prescription:

[0556] 25.2. Preparation process:

[0557] 1) Premix

[0558] According to the prescription, the solid dispersion, Soluplus, colloidal silicon dioxide, and SDS were weighed and added to the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve. Then, according to the prescription, mannitol, tartaric acid, and CCMC-Na were weighed and added to the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve.

[0559] 2) Dry granulation

[0560] Dry granulation was performed using a dry granulator.

[0561] 3) Dry whole grain

[0562] Use a 12-mesh screen of a granulator to perform dry granulation.

[0563] 4) Total Mixing

[0564] Calculation and weighing of the dosage of additional excipients: Calculate sodium starch glycolate and magnesium stearate according to the prescription and weigh the corresponding weights.

[0565] Total mixing: Add the dry granulated granules, sodium starch glycolate and magnesium stearate into the mixing hopper, set the mixing speed to 15 rpm, the mixing time to 5 min, and take samples to check the mixing uniformity.

[0566] 5) Tablet pressing

[0567] 75 mg tablets were compressed using a 16.31 mm × 8.59 mm oval die.

[0568] Example 26 Tablets

[0569] 26.1. Tablet Prescription:

[0570] Tablet prescription 1

[0571] Tablet prescription 2

[0572] 26.2. Preparation process:

[0573] 1) Premix

[0574] According to the prescription, the solid dispersion, copovidone VA64, colloidal silicon dioxide, and SDS were weighed and added to the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve. Then, mannitol, tartaric acid, and CCMC-Na were weighed according to the prescription, added to the mixing hopper, the mixing speed was set to 15 rpm, the mixing time was 10 min, and the mixture was passed through a 40-mesh sieve.

[0575] 2) Dry granulation

[0576] Dry granulation was performed using a dry granulator.

[0577] 3) Dry whole grain

[0578] Use a 12-mesh screen of a granulator to perform dry granulation.

[0579] 4) Total Mixing

[0580] Calculation and weighing of the dosage of additional excipients: Calculate sodium starch glycolate and magnesium stearate according to the prescription and weigh the corresponding weights.

[0581] Total mixing: Add the dry granulated granules, sodium starch glycolate and magnesium stearate into the mixing hopper, set the mixing speed to 15 rpm, the mixing time to 5 min, and take samples to check the mixing uniformity.

[0582] 5) Tablet pressing

[0583] 75 mg tablets were compressed using a 16.31 mm × 8.59 mm oval die.

[0584] Example 27 Tablet (CMS-Na 2%)

[0585] 27.1. Tablet Prescription:

[0586] 27.2. Preparation process: see 5.2 in Example 5

[0587] 27.3. For the in vitro dissolution test method, refer to the dissolution method 2 in 2.4.2 of Example 2.

[0588] Dissolution results of dissolution method 2:

[0589] Example 28 Tablet (CMS-Na 8%)

[0590] 28.1. Tablet Prescription:

[0591] 28.2. Preparation process: see 5.2 of Example 5

[0592] 28.3. For the in vitro dissolution test method, refer to the dissolution method 2 in 2.4 of Example 2.

[0593] Dissolution results of dissolution method 2:

[0594] Example 29 Tablets

[0595] 29.1. Tablet Prescription:

[0596] 29.2. Preparation process: see 5.2 of Example 5

[0597] 29.3. For the in vitro dissolution test method, refer to the dissolution method 2 in 2.4.2 of Example 2.

[0598] Dissolution results of dissolution method 2:

[0599] Example 30 Tablets

[0600] 30.1. Tablet Prescription:

[0601] 30.2. Preparation process: see 5.2 of Example 5

[0602] 30.3. In vivo PK test in Beagle dogs. Methods are as described in 2.3 of Example 2.

[0603] In vivo PK test (second time) results (parallel comparison with Examples 2 and 5):

[0604] Example 31 Screening of surfactant content

[0605] The comparison of the results of the in vivo PK experiments and in vitro dissolution experiments of the aforementioned embodiments can be seen in Figures 4, 5, 6, 7, 8, 9, 10, 11 and 12.

[0606] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A solid dispersion, characterized in that: The invention comprises the following components: compound 1 and a polymer carrier; Wherein, the polymer carrier is selected from one or more of HPMCAS, Soluplus and PVP-VA.

2. The solid dispersion according to claim 1, characterized in that It meets one or more of the following conditions: (1) The polymer carrier is HPMCAS, preferably one or two selected from HPMCAS-HF and HPMCAS-HG, more preferably HPMCAS-HG; or, the polymer carrier is Soluplus; or, the polymer carrier is PVP-VA, preferably PVP-VA64; (2) In the solid dispersion, the weight ratio of the compound 1 to the polymer carrier is about 1:1 to about 1:10; preferably about 1:2 to about 1:5, for example, 3:7, 1:3 or 1:4; more preferably about 1:3 to about 1:4; (3) In the solid dispersion, the weight percentage of the polymer carrier in the solid dispersion is at least about 50%, at least about 60%, at least about 67%, at least about 70%, at least about 75%, at least about 80% or at least about 90%; (4) In the solid dispersion, the weight percentage of Compound 1 in the solid dispersion is about 10% to about 50%, about 20% to about 40%, or about 25% to about 33%; (5) The solid dispersion further comprises an excipient, such as a surfactant, a glidant, or a plasticizer; (6) In the solid dispersion, the compound 1 is dispersed in the polymer carrier in an amorphous or nearly amorphous or substantially non-crystalline state; (7) The solid dispersion is obtained by spray drying, hot melt extrusion or solvent evaporation; (8) The solid dispersion consists of the compound 1 and the polymer carrier.

3. The solid dispersion according to claim 2, characterized in that The solid dispersion is composed of the following components in percentage by mass: Scheme 1.1: 25% compound 1 and 75% Soluplus; Scheme 1.2: 25% Compound 1 and 75% Plasdone TM S-630 ULTRA; Scheme 1.3: 20% compound 1 and 80% Soluplus; Scheme 1.4: 25% compound 1 and 75% HPMCAS-HG; Scheme 1.5: 30% of compound 1 and 70% of HPMCAS-HG.

4. A method for preparing a solid dispersion according to any one of claims 1 to 3, characterized in that: It includes the following steps: Just mix the components; Preferably, the preparation method of the solid dispersion comprises the following steps: dissolving the compound 1 and the polymer carrier in a solvent and mixing them uniformly, and evaporating the solvent to obtain a solid dispersion; wherein the preparation method preferably evaporates the solvent by spray drying; the solvent used in the preparation method is preferably an organic solvent, more preferably one selected from a halogenated alkane solvent and an alcohol solvent or a mixture of two, more preferably dichloromethane and ethanol.

5. A solid dispersion prepared by the preparation method as claimed in claim 4.

6. A pharmaceutical composition, characterized in that It comprises the solid dispersion according to any one of claims 1 to 5, and one or more pharmaceutically acceptable carriers; Preferably, the pharmaceutical composition satisfies one or both of the following conditions: (1) The excipient in the solid dispersion and the pharmaceutically acceptable carrier in the pharmaceutical composition are different from each other; (2) The pharmaceutical composition is a tablet, capsule, granule, powder, dry suspension or enteric-coated preparation; (3) In the pharmaceutical composition, the pharmaceutically acceptable carrier is selected from one or more of a solubilizing agent, an acidic pH adjusting agent, a disintegrant, a glidant, a filler, a lubricant and a surfactant.

7. The pharmaceutical composition according to claim 6, characterized in that It includes the following components in percentage by mass: 20%-70% of the solid dispersion according to any one of claims 1 to 5, 0%-30% cosolvent, 0%-20% acidic pH adjuster, 3%-30% disintegrant, 0%-10% glidant, 0%-50% fillers, 0%-1% lubricant, 0%-20% surfactant; Preferably, the pharmaceutical composition satisfies one or more of the following conditions: (1) When the mass percentage of the co-solvent is 0%, the mass percentage of the acidic pH regulator is not 0%; (2) In the pharmaceutical composition, the mass percentage of the solid dispersion is 40%, 50%, 64.5% or 66.4%; preferably 30%-60%, more preferably 40%-50%; (3) In the pharmaceutical composition, the mass percentage of the co-solvent is 0%-24%, for example, 0%, 5.8%, 6%, 7.5%, 12%, 14%, 17.5% or 24%; preferably 4%-14%, for example, 6%, 7.5% or 12%; (4) In the pharmaceutical composition, the mass percentage of the acidic pH regulator is 0%, 5%, 6.25%, 10%, 15%, 20% or 39.5%; preferably 0%-15%, for example 0%, 5%, 6.25% or 10%; more preferably 3%-12%, for example 5%, 6.25% or 10%; (5) In the pharmaceutical composition, the mass percentage of the disintegrant is 3%, 8%, 10%, 14%, 26.4% or 27.2%; preferably 3%-20%, more preferably 3%-15%, for example 3% or 10%; (6) In the pharmaceutical composition, the mass percentage of the glidant is 0% or 4%; preferably 1%-10%, for example 4%; (7) In the pharmaceutical composition, the mass percentage of the filler is 0%, 13.5%, 16.5%, 17.5%, 18.50%, 19.25%, 19.5%, 21.5%, 22.5%, 25.5%, 26.5%, 28.5%, 29.25%, 29.5%, 30.5%, 34.5%, 35.5%, 36.5%, 39.5% or 40.5%; preferably 10%-45%, more preferably 20%-40%, for example 28.5%, 29.25% or 34.5%; (8) In the pharmaceutical composition, the mass percentage of the lubricant is 0%, 0.4% or 0.5%, preferably 0% or 0.5%; (9) In the pharmaceutical composition, the mass percentage of the surfactant is 0%-12%, preferably 0%-10%, for example 0%, 1%, 5% or 10%; more preferably 0%-5%, for example 0%, 1% or 5%; (10) In the pharmaceutical composition, the mass ratio of the polymer carrier to the compound 1 is 2:1 to 4:1, for example, 2.3:1, 3:1 or 4:1; preferably 2:1 to 2.5:1, for example, 2.3:1; (11) In the pharmaceutical composition, the mass ratio of the acidic pH regulator to the compound 1 is preferably 1:1 to 1:3, for example, 1:1.2 or 1:2.4; (12) In the pharmaceutical composition, the cosolvent is selected from one or more of PEG, PVP, HPMCAS, HPMC, Eudragit and Soluplus, preferably selected from one or more of PVP, HPMC and Soluplus, more preferably PVP or Soluplus; the PEG is preferably selected from one or both of PEG4000 and PEG6000; the PVP is preferably selected from one or more of PVP K17, PVP K30, PVP K90 and PVP-VA64, more preferably PVP-VA64; the HPMC is preferably HPMC E3LV; the HPMCAS is preferably selected from one or more of HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LG, HPMCAS-MG and HPMCAS-HG, more preferably HPMCAS-HG; the Eudragit is selected from one or more of Eudragit L100-55 and Eudragit S100; (13) In the pharmaceutical composition, the acidic pH regulator is selected from one or both of an organic acid and an inorganic acid; the organic acid is selected from one or more of citric acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid, oxalic acid, aspartic acid, mandelic acid, glutaric acid and glutamic acid, preferably selected from one or more of fumaric acid, citric acid, tartaric acid and malic acid, more preferably tartaric acid; the inorganic acid is preferably selected from one or more of hydrochloric acid, phosphoric acid, nitric acid and sulfuric acid; (14) In the pharmaceutical composition, the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and sodium carboxymethyl cellulose, preferably one or both of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch, more preferably sodium carboxymethyl cellulose, or a mixture of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch; (15) In the pharmaceutical composition, the glidant is colloidal silicon dioxide; (16) In the pharmaceutical composition, the filler is selected from one or more of mannitol, lactose, compressible starch and microcrystalline cellulose, preferably mannitol; (17) In the pharmaceutical composition, the lubricant is magnesium stearate; (18) In the pharmaceutical composition described above, the surfactant is selected from one or two of sodium dodecyl sulfate, polyethylene glycol succinate of vitamin E, poloxamer 188 and poloxamer 407.

8. The pharmaceutical composition according to claim 7, characterized in that It meets one or more of the following conditions: (1) In the pharmaceutical composition, the PVP-VA64 is Plasdone TM S-630 or Plasdone TM S-630 ULTRA; (2) In the pharmaceutical composition, when the disintegrant is a mixture of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch, the mass ratio of the cross-linked sodium carboxymethyl cellulose to sodium carboxymethyl starch is 1:1 to 2:1, preferably 1.5:1; (3) In the pharmaceutical composition, the cosolvent is selected from one or more of PVP-VA64, Soluplus, HPMC E3LV and PVPk30, preferably PVP-VA64 or Soluplus; (4) The acidic pH regulator is selected from one or more of citric acid, fumaric acid, malic acid and tartaric acid, preferably tartaric acid; when the acidic pH regulator is tartaric acid, the mass percentage of the acidic pH regulator is preferably 3% to 7%, more preferably 4% to 6%, for example, 5%; when the acidic pH regulator is malic acid, the mass percentage of the acidic pH regulator is preferably 3% to 7%, more preferably 4% to 6%, for example, 5%; when the acidic pH regulator is fumaric acid, the mass percentage of the acidic pH regulator is preferably 8% to 12%, more preferably 9% to 11%, for example, 10%; when the acidic pH regulator is citric acid, the mass percentage of the acidic pH regulator is preferably 8% to 12%, more preferably 9% to 11%, for example, 10%; (5) The pharmaceutical composition is composed of the solid dispersion, the solubilizing agent, the acidic pH regulator, the disintegrant, the glidant, the filler, the lubricant and the surfactant.

9. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition comprises the following components in percentage by mass: Scheme 2.1: 19.35% of compound 1, 45.15% of HPMCAS-HG, 5.8% of PVPK90, 26.4% of CMS-Na, 0.4% of magnesium stearate and 2.9% of film coating premix (gastric soluble); Scheme 2.2: 15% compound 1, 35% HPMCAS-HG, 17.5% PVP-VA64, 4% colloidal silicon dioxide, 19.25% mannitol, 3% sodium carboxymethylcellulose and 6.25% tartaric acid; Scheme 2.3: 15% compound 1, 35% HPMCAS-HG, 7.5% Soluplus, 4% colloidal silicon dioxide, 29.25% mannitol, 3% sodium carboxymethylcellulose and 6.25% tartaric acid; Scheme 2.4: 15% compound 1, 35% HPMCAS-HG, 17.5% Soluplus, 4% colloidal silicon dioxide, 19.25% mannitol, 3% sodium carboxymethylcellulose and 6.25% tartaric acid; Scheme 2.5: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 34.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid and 0.5% magnesium stearate; Scheme 2.6: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 39.5% mannitol, 6% CCMC-Na, 4% CMS-Na and 0.5% magnesium stearate; Scheme 2.7: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 29.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 10% tartaric acid and 0.5% magnesium stearate; Scheme 2.8: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 19.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 20% tartaric acid and 0.5% magnesium stearate; Scheme 2.9: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silica, 6% CCMC-Na, 4% CMS-Na, 39.5% tartaric acid and 0.5% magnesium stearate; Scheme 2.10: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 34.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% fumaric acid and 0.5% magnesium stearate; Scheme 2.11: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 34.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% citric acid and 0.5% magnesium stearate; Scheme 2.12: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 34.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% malic acid and 0.5% magnesium stearate; Scheme 2.13: 12% compound 1, 28% HPMCAS-HG, 6% Soluplus, 4% colloidal silicon dioxide, 34.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid and 0.5% magnesium stearate; Scheme 2.14: 12% compound 1, 28% HPMCAS-HG, 6% HPMC E3LV, 4% colloidal silicon dioxide, 34.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid and 0.5% magnesium stearate; Scheme 2.15: 12% compound 1, 28% HPMCAS-HG, 6% PVP k30, 4% colloidal silica, 34.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid and 0.5% magnesium stearate; Scheme 2.16: 12% compound 1, 28% HPMCAS-HG, 4% colloidal silicon dioxide, 40.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% citric acid and 0.5% magnesium stearate; Scheme 2.17: 12% compound 1, 28% HPMCAS-HG, 12% PVP-VA64, 4% colloidal silicon dioxide, 28.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% citric acid and 0.5% magnesium stearate; Scheme 2.18: 12% compound 1, 28% HPMCAS-HG, 24% PVP-VA64, 4% colloidal silicon dioxide, 16.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% citric acid and 0.5% magnesium stearate; Scheme 2.19: 12% compound 1, 28% HPMCAS-HG, 14% Soluplus, 4% colloidal silicon dioxide, 26.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid and 0.5% magnesium stearate; Scheme 2.20: 12% compound 1, 28% HPMCAS-HG, 4% colloidal silicon dioxide, 35.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, 5% sodium lauryl sulfate and 0.5% magnesium stearate; Scheme 2.21: 12% compound 1, 28% HPMCAS-HG, 14% Soluplus, 25.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, 5% sodium lauryl sulfate and 0.5% magnesium stearate; Scheme 2.22: 12% compound 1, 28% HPMCAS-HG, 14% Soluplus, 4% colloidal silicon dioxide, 26.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% sodium lauryl sulfate, and 0.5% magnesium stearate; Scheme 2.23: 19.92% compound 1, 46.48% HPMCAS-HG, 6% PVPk30, 27.2% CMS-Na and 0.4% magnesium stearate; Scheme 2.24: 12% compound 1, 28% HPMCAS-HG, 14% Soluplus, 4% colloidal silicon dioxide, 26.5% mannitol, 10% CMS-Na, 5% tartaric acid and 0.5% magnesium stearate; Scheme 2.25: 12% compound 1, 28% HPMCAS-HG, 14% Soluplus, 4% colloidal silicon dioxide, 21.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, 5% sodium lauryl sulfate and 0.5% magnesium stearate; Scheme 2.26: 12% compound 1, 28% HPMCAS-HG, 14% PVP-VA64, 4% colloidal silicon dioxide, 21.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, 5% sodium lauryl sulfate and 0.5% magnesium stearate; Scheme 2.27: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silica, 29.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid, 5% sodium lauryl sulfate and 0.5% magnesium stearate; Scheme 2.28: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 36.5% mannitol, 6% CCMC-Na, 2% CMS-Na, 5% tartaric acid and 0.5% magnesium stearate; Scheme 2.29: 12% compound 1, 28% HPMCAS-HG, 6% PVP-VA64, 4% colloidal silicon dioxide, 30.5% mannitol, 6% CCMC-Na, 8% CMS-Na, 5% tartaric acid and 0.5% magnesium stearate; Scheme 2.30: 15% compound 1, 35% HPMCAS-HG, 4% colloidal silicon dioxide, 35.5% mannitol, 6% CCMC-Na, 4% CMS-Na and 0.5% magnesium stearate; Scheme 2.31: 12% compound 1, 28% HPMCAS-HG, 12% Soluplus, 4% colloidal silicon dioxide, 28.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 5% tartaric acid and 0.5% magnesium stearate; Scheme 2.32: 12% compound 1, 28% HPMCAS-HG, 12% PVP-VA64, 4% colloidal silicon dioxide, 22.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 10% tartaric acid, 0.5% magnesium stearate and 1% poloxamer 407; Scheme 2.33: 12% compound 1, 28% HPMCAS-HG, 12% PVP-VA64, 4% colloidal silicon dioxide, 18.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 10% tartaric acid, 0.5% magnesium stearate and 5% poloxamer 407; Scheme 2.34: 12% compound 1, 28% HPMCAS-HG, 12% PVP-VA64, 4% colloidal silicon dioxide, 13.5% mannitol, 6% CCMC-Na, 4% CMS-Na, 10% tartaric acid, 0.5% magnesium stearate and 10% poloxamer 407; The pharmaceutical composition preferably includes the components in mass percentages as shown in any one of the schemes 2.2 to 2.34, and more preferably includes the components in mass percentages as shown in any one of the schemes 2.3, 2.5 and 2.31; Preferably, in the schemes 2.1 to 2.34, the compound 1 and the HPMCAS-HG are in the form of solid dispersions as components; Preferably, the pharmaceutical composition is composed of the components in mass percentage as shown in any one of the schemes 2.1 to 2.34, preferably composed of the components in mass percentage as shown in any one of the schemes 2.2 to 2.34, and more preferably composed of the components in mass percentage as shown in any one of the schemes 2.3, 2.5 and 2.

31.

10. A method for preparing the pharmaceutical composition according to any one of claims 6 to 9, characterized in that: It includes the following steps: Just mix the components; Preferably, the preparation method of the pharmaceutical composition comprises a wet granulation method or a dry granulation method; More preferably, when the pharmaceutical composition is a tablet, the method for preparing the pharmaceutical composition comprises the following steps: (1) subjecting the solid dispersion and the co-solvent to wet granulation, wet granulation, drying and dry granulation to obtain granules; (2) mixing the granules and the remaining components uniformly and compressing the mixture to obtain tablets; When the pharmaceutical composition is a tablet, the preparation method of the pharmaceutical composition comprises the following steps: (1) subjecting the solid dispersion and the co-solvent to wet granulation, wet granulation, drying and dry granulation to obtain granules; (2) mixing the granules and the remaining components uniformly, compressing and coating to obtain tablets; When the pharmaceutical composition is a tablet, the preparation method of the pharmaceutical composition may include the following steps: (1) mixing the solid dispersion, the cosolvent, the glidant, the filler, the pH adjuster, the disintegrant and one or more of the surfactant evenly, and then performing dry granulation and dry granulation to obtain granules; (2) mixing the granules, the lubricant and the remaining components uniformly and tableting to obtain tablets; When the pharmaceutical composition is a tablet, the preparation method of the pharmaceutical composition comprises the following steps: (1) mixing the solid dispersion, the cosolvent, the glidant, the filler, the pH adjuster, the disintegrant and one or more of the surfactant evenly, and then performing dry granulation and dry granulation to obtain granules; (2) The granules are mixed with the lubricant and the remaining components, compressed and coated to obtain tablets.

11. Use of the solid dispersion according to any one of claims 1 to 3 and 5 in preparing a preparation of Compound 1; the preparation of Compound 1 is preferably a pharmaceutical composition according to any one of claims 6 to 9.

12. A use of one or more of the polymer carrier according to any one of claims 1 to 3 and 5, the cosolvent according to any one of claims 6 to 9, the acidic pH regulator according to any one of claims 6 to 9, the disintegrant according to any one of claims 6 to 9, and the surfactant according to any one of claims 6 to 9 for improving the solubility of Compound 1.

13. Use of the solid dispersion according to any one of claims 1 to 3 and 5, or the pharmaceutical composition according to any one of claims 6 to 9 in the preparation of a drug; the drug is preferably a drug for treating one or more of tumors, pulmonary fibrosis, autoimmune diseases and neurodegenerative diseases; the drug is more preferably a drug for treating one or more of Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke and neuromyelitis.

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