Solid dispersions of a fgfr inhibitor, formulations, methods of making and using the same

Abstract

The application discloses a solid dispersion of FGFR inhibitor, a preparation, a preparation method of the solid dispersion and application of the solid dispersion, and relates to the technical field of medicine, in particular to a solid dispersion of FGFR inhibitor, which comprises a carrier and an active ingredient, wherein the active ingredient is one or more of a compound as shown in formula (I) and / or a pharmaceutically acceptable salt of the compound, a crystal form of the compound and a solvate of the compound; and the carrier is one or a combination of polyvinylpyrrolidone / polyvinyl acetate copolymer, polyvinylpyrrolidone, HPMCAS, Soluplus, HPMC, PEG, HPMCP, polymethacrylate, polyvinyl alcohol and hydroxypropyl cellulose. The solid dispersion has good dissolution rate, and the solubility of the effective component is significantly improved; the preparation formed by using the solid dispersion can effectively improve the bioavailability of the FGFR inhibitor, has good dissolution rate and stability, and can improve the safety of the medicine.

Description

TECHNICAL FIELD

[0001] The present application relates to a solid dispersion of FGFR inhibitor, formulations, methods of preparation and uses thereof. BACKGROUND

[0002] Receptor tyrosine kinases play a key role in tumor development, invasion, metastasis, drug resistance and other aspects due to abnormal expression activation or gene mutation. It has become an important target for anti-tumor drug development. Among them, fibroblast growth factor receptors (FGFRs) are important members of the receptor tyrosine kinase family, mainly including FGFR1, FGFR2, FGFR3 and FGFR4 four subtypes. Its ligand is fibroblast growth factor (Fibroblast Growth Factors, FGFs). Due to gene amplification, mutation, fusion or ligand induction, FGFR members are continuously activated, inducing tumor cell proliferation, invasion, migration, promoting angiogenesis, and promoting tumor development. FGFRs are highly expressed and abnormally activated in many tumors, and are closely related to the poor prognosis of tumor patients, such as non-small cell lung cancer, breast cancer, gastric cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer, keratinocytoma, myeloma, rhabdomyosarcoma, etc. Studies have shown that FGFR1 amplification accounts for 20% of non-small cell lung cancer squamous cell carcinoma, and through in vitro proliferation and signal pathway studies of lung cancer cell lines with FGFR1 amplification, it has been shown that FGFR selective inhibitors can very effectively inhibit FGFR1 signal pathway activation and cell proliferation. In breast cancer, the amplification of the chromosome (8pll-12) region where FGFR1 is located accounts for about 10% of ER-positive patients, and its high expression of FGFR mRNA and poor prognosis of patients are related FGFR2 gene amplification or mutation leads to abnormal activation of FGFR2 signal pathway, mainly related to gastric cancer, triple-negative breast cancer, endometrial cancer, etc. The amplification rate of FGFR2 in gastric cancer tissue is 5%-10%. Analysis of 313 cases of gastric cancer tissue shows that FGFR2 amplification is significantly related to tumor size, local invasion, lymph node metastasis and distant metastasis, and gastric cancer with FGFR2 amplification is generally progressive, with poor prognosis and relatively low overall survival rate of patients. FGFR2 amplification accounts for 4% of refractory triple-negative breast cancer. Endometrial cancer is a common gynecological reproductive tract tumor, and FGFR2 mutation accounts for about 12% of endometrial cancer. FGFR3 mutation accounts for 50%-60% in non-invasive bladder cancer and 10%-15% in invasive bladder cancer. FGFR3 t(4;14)(p16.3;q32) gene rearrangement accounts for 15-20% in multiple myeloma. In addition, in liver cancer, various subtypes of FGFR and its ligand FGFs have abnormal expression and activation, such as FGFR2, FGFR3, FGFR4, FGF19, FGF2, FGF5, FGF8, FGF9, etc. Preclinical and clinical studies have shown the importance of abnormal activation of FGF / FGFR axis in liver cancer.It is not to be overlooked that abnormal activation of FGF / FGFR axis is closely related to drug resistance of EGFR inhibitors, neovascularization inhibitors and endocrine therapy. Therefore, the development of FGFR inhibitors has become a hot spot in the research of anti-tumor drugs.

[0003] In particular, it has been found that one or more of the compounds of formula I, pharmaceutically acceptable salts thereof, crystal forms thereof and solvates thereof are good FGFR inhibitors and have significant efficacy in the treatment of diseases including non-small cell lung cancer, breast cancer, gastric cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer, keratocystoma, myeloma, rhabdomyosarcoma, etc. caused by high expression and abnormal activation of FGFRs. Therefore, one or more of the compounds of formula I, pharmaceutically acceptable salts thereof, crystal forms thereof and solvates thereof will be used as drugs for treating the above-mentioned diseases.

[0004] The preferred route of administration is by oral administration. This route of administration provides the greatest comfort and convenience of administration. The bioavailability obtained after oral administration is a measure of the effectiveness of the oral dosage form of the drug. The bioavailability after oral administration depends on several factors, such as the solubility of the active substance in aqueous media, the dose strength, the dissolution of the dosage form, the absorption throughout the gastrointestinal tract and the first-pass effect. Therefore, it is necessary to develop solid pharmaceutical compositions comprising one or more of the compounds of formula I, pharmaceutically acceptable salts thereof, crystal forms thereof and solvates thereof for oral administration and their formulations to improve the drug dissolution, absorption and exposure characteristics of the drug after administration, etc. to improve the inter-patient variability and improve clinical efficacy. SUMMARY

[0005] The present application provides a solid dispersion of FGFR inhibitors comprising one or more of the compounds of formula (I), pharmaceutically acceptable salts thereof, crystal forms thereof and solvates thereof, formulations thereof, methods for preparing the same and uses thereof. Compared with crystalline API, the solid dispersion has obvious improvement in in-vitro solubility and bioavailability.

[0006] In a first aspect of the present application, a pharmaceutical composition comprising a solid dispersion is provided, the solid dispersion comprising (a) one or more of the compounds of formula (I), pharmaceutically acceptable salts thereof, crystal forms thereof and solvates thereof,

[0007]

[0008] and (b) a pharmaceutically acceptable matrix selected from the group consisting of polyvinylpyrrolidone / polyvinyl acetate copolymer, polyvinylpyrrolidone, HPMCAS, Soluplus, HPMC, PEG, HPMCP, polymethacrylate, polyvinyl alcohol and hydroxypropyl cellulose, or a combination thereof; preferably, the matrix is selected from the group consisting of polyvinylpyrrolidone / polyvinyl acetate copolymer, polyvinylpyrrolidone, polymethacrylate, or a combination thereof.

[0009] In another preferred embodiment, the content of the compound of formula (I) in the pharmaceutical composition is 0.001-99.999 wt%.

[0010] In another preferred embodiment, the pharmaceutically acceptable salt includes inorganic and organic salts; preferably, the pharmaceutically acceptable salt is a salt of the compound of the present application with an acid. Suitable acids to form salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and the like, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid and the like, and acidic amino acids such as aspartic acid, glutamic acid and the like.

[0011] In another preferred embodiment, the polyvinylpyrrolidone / polyvinyl acetate copolymer is PVP VA64.

[0012] In another preferred embodiment, the weight ratio of the compound of formula I, one or more of its pharmaceutically acceptable salts, its crystal forms and its solvates to the polyvinylpyrrolidone / polyvinyl acetate copolymer is 1:0.5 to 1:20 (preferably 1:2-8, more preferably 1:3-5), calculated on the mass of the free base of the compound of formula (I).

[0013] In another preferred embodiment, the polyvinylpyrrolidone is selected from the group consisting of PVP K30, PVP K12, PVP K15, PVP K17, PVP K25, PVP K60, PVP K90, or a combination thereof.

[0014] In another preferred embodiment, the weight ratio of the compound of formula I, one or more of its pharmaceutically acceptable salts, its crystal forms and its solvates to the polyvinylpyrrolidone is 1:0.5 to 1:20 (preferably 1:2-8, more preferably 1:3-5), calculated on the mass of the corresponding free base of the compound of formula (I).

[0015] In another preferred embodiment, the polymethacrylate is selected from the group consisting of: EPO, L100, S100, RL, RS and RD100, or a combination thereof.

[0016] In another preferred embodiment, the weight ratio of one or more of the compound of formula I, its pharmaceutically acceptable salts, its crystal forms and its solvates to the poly(meth)acrylate is 1:0.5 to 1:20 (preferably 1:2-8, more preferably 1:3-5), calculated on the mass of the free base of the compound of formula (I).

[0017] In a second aspect of the present application, there is provided a method for preparing the solid dispersion according to the first aspect of the present application, characterized in that the method is any one of the following method one, method two or method three:

[0018] The method one comprises the following steps: mixing (a) one or more of the compound of formula I, its pharmaceutically acceptable salts, its crystal forms and its solvates, (b) a pharmaceutically acceptable matrix, and (c) a solvent to form a solution or a suspension; and then removing the solvent by solvent evaporation to obtain the solid dispersion;

[0019] The method two comprises the following steps: mixing (a) one or more of the compound of formula I, its pharmaceutically acceptable salts, its crystal forms and its solvates, and (b) a pharmaceutically acceptable matrix, and then extruding after heating to obtain the solid dispersion;

[0020] The method three comprises the following steps: mixing (a) one or more of the compound of formula I, its pharmaceutically acceptable salts, its crystal forms and its solvates, (b) a pharmaceutically acceptable matrix, and (c) a solvent, and then performing spray drying to obtain the solid dispersion.

[0021] In another preferred embodiment, in the method one, the solvent is selected from the group consisting of water, C1-C6 alcohol solvent, C2-C6 ester solvent, C2-C6 ketone solvent, C1-C6 halogenated hydrocarbon solvent, C2-C6 nitrile solvent and C2-C6 ether solvent, or a combination thereof; preferably, the C1-C6 alcohol solvent is ethanol and / or methanol; the C2-C6 ester solvent is ethyl acetate; the C2-C6 ketone solvent is acetone; the C1-C6 halogenated hydrocarbon solvent is dichloromethane; the C2-C6 nitrile solvent is acetonitrile; the C2-C6 ether solvent is tetrahydrofuran; more preferably, the solvent is selected from the group consisting of acetone, ethanol, water, or a combination thereof;

[0022] And / or, in the method one, the mass to volume ratio of one or more of the compound of formula I, its pharmaceutically acceptable salts, its crystal forms and its solvates to the solvent is 0.1-60 mg / ml, preferably 5-30 mg / ml;

[0023] and / or, in the second method, the temperature of the extrusion is 150-250°C, preferably 160-220°C;

[0024] and / or, in the second method, the extrusion is followed by a step of comminution;

[0025] and / or, in the third method, the solvent is selected from the group consisting of water, a C1-C6alcohol solvent, a C2-C6ester solvent, a C2-C6ketone solvent, a C1-C6halogenated hydrocarbon solvent, a C2-C6nitrile solvent, and a C2-C6ether solvent, or a combination thereof; preferably, the C1-C6alcohol solvent is ethanol and / or methanol; the C2-C6ester solvent is ethyl acetate; the C2-C6ketone solvent is acetone; the C1-C6halogenated hydrocarbon solvent is dichloromethane; the C2-C6nitrile solvent is acetonitrile; the C2-C6ether solvent is tetrahydrofuran; more preferably, the solvent is a mixture of acetone, ethanol, and water; most preferably, the solvent is a mixture of acetone, ethanol, and water in a ratio of 2-4:6-8:1-3 (v:v:v);

[0026] and / or, in the third method, the mass-to-volume ratio of the one or more of the compound of Formula I, the pharmaceutically acceptable salt thereof, the crystalline form thereof, and the solvate thereof to the solvent is 0.1-30 mg / ml;

[0027] and / or, in the third method, the temperature of the spray drying apparatus is 40-200°C, preferably 50-150°C.

[0028] In a third aspect of the present application, a formulation is provided, which comprises the solid dispersion of the first aspect of the present application and a carrier selected from the group consisting of a filler, a disintegrant, a glidant, a lubricant, or a combination thereof.

[0029] In another preferred embodiment, the filler is selected from the group consisting of microcrystalline cellulose, lactose, pregelatinized starch, dibasic calcium phosphate, mannitol, calcium phosphate, or a combination thereof; preferably, the filler is selected from the group consisting of a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and mannitol, or a combination of microcrystalline cellulose and calcium phosphate; more preferably, the filler is microcrystalline cellulose or a combination of microcrystalline cellulose and lactose.

[0030] and / or, the amount of the filler is 0.2-8 parts by mass, preferably 0.2-2 parts by mass (e.g., 0.25 parts, 0.40 parts, 0.43 parts, 0.72 parts, 0.84 parts, 0.85 parts, 0.86 parts, or 0.90 parts) per 1 part by mass of the solid dispersion;

[0031] and / or, the disintegrant is selected from the group consisting of sodium croscarmellose, sodium low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, or a combination thereof; preferably, the disintegrant is sodium croscarmellose;

[0032] and / or, the disintegrant is present in an amount of 0.03 to 0.4 parts by mass, preferably 0.05 to 0.3 parts (e.g., 0.075 parts, 0.09 parts, 0.1 parts, 0.14 parts) per 1 part by mass of the solid dispersion;

[0033] and / or, the formulation further comprises a capsule shell;

[0034] and / or, the formulation further comprises a coating agent.

[0035] In another preferred embodiment, when the filler is a combination of microcrystalline cellulose and lactose, the mass ratio of the microcrystalline cellulose and lactose is 1 : (0.5 to 2) (e.g., 1 :0.5, 1 : 1, or 1 :2), preferably 1 : (1 to 2), and further preferably 1 : 1;

[0036] and / or, the microcrystalline cellulose is selected from the group consisting of microcrystalline cellulose Avicel® PH 102, silicified microcrystalline cellulose 90, silicified microcrystalline cellulose HD 90, microcrystalline cellulose PH 105, microcrystalline cellulose KG 802, microcrystalline cellulose Avicel® PH 101, or a combination thereof; preferably, the microcrystalline cellulose is Avicel® microcrystalline cellulose PH 102 and / or Avicel® microcrystalline cellulose KG 802;

[0037] and / or, the lactose is anhydrous lactose, lactose monohydrate;

[0038] and / or, the glidant is silicon dioxide;

[0039] and / or, when the formulation further comprises a glidant, the glidant is present in an amount of 0.006 to 0.2 parts by mass, preferably 0.01 to 0.06 parts (e.g., 0.01 parts, 0.02 parts, 0.03 parts, or 0.04 parts) per 1 part by mass of the solid dispersion;

[0040] and / or, the lubricant is magnesium stearate and / or sodium stearyl fumarate;

[0041] and / or, when the formulation further comprises a lubricant, the lubricant is present in an amount of 0.004 to 0.1 parts by mass, preferably 0.004 to 0.04 parts (e.g., 0.006 parts, 0.007 parts, 0.01 parts, or 0.02 parts) per 1 part by mass of the solid dispersion;

[0042] and / or, when the preparation further comprises a capsule shell, the capsule shell material is gelatin or hydroxypropyl methylcellulose;

[0043] and / or, when the preparation further comprises a coating agent, the coating agent is a gastro-soluble film coating premix, such as Opadry® II;

[0044] and / or, when the preparation further comprises a coating agent, the mass fraction of the coating agent is 0.01-0.2 parts based on 1 part of the mass of the solid dispersion; preferably, the mass fraction of the coating agent is 0.04-0.1 parts (e.g. 0.06 parts).

[0045] In another preferred embodiment, the preparation comprises:

[0046] a solid dispersion, wherein the weight ratio of the compound of formula (I) to the matrix is 1:3-5; and

[0047] a carrier, wherein the carrier is one or more selected from the group (1)-(6):

[0048] (1) 25-35 wt% microcrystalline cellulose, 10-20 wt% lactose and 4-6 wt% croscarmellose sodium (the remainder being the solid dispersion);

[0049] (2) 20-35 wt% microcrystalline cellulose, 5-20 wt% lactose, 4-6 wt% croscarmellose sodium, 0.1-5% silicon dioxide and 0.1-5% magnesium stearate (the remainder being the solid dispersion);

[0050] (3) 20-35 wt% microcrystalline cellulose, 5-20 wt% lactose, 4-6 wt% croscarmellose sodium, 0.1-5% silicon dioxide and 0.1-5% magnesium stearate (the remainder being the solid dispersion);

[0051] (4) 5-60 wt% microcrystalline cellulose, 4-6 wt% croscarmellose sodium and 0.1-5% magnesium stearate (the remainder being the solid dispersion);

[0052] (5) 5-60 wt% lactose, 4-6 wt% croscarmellose sodium, 0.1-5% silicon dioxide and 0.1-5% magnesium stearate (the remainder being the solid dispersion);

[0053] (6) a capsule shell.

[0054] In another preferred embodiment, the carrier is a combination of more than one of (1) - (6), for example, the solid dispersion is dispersed in a carrier of any one of (1) - (5), and then filled into a capsule shell; or the solid dispersion is dispersed in a combination of more than one of (1) - (5).

[0055] In a fourth aspect of the present application, there is provided a use of the formulation according to the first aspect of the present application in the preparation of a medicament for the treatment of a hyperproliferative disease.

[0056] In another preferred embodiment, the hyperproliferative disease is cancer; preferably, the cancer is selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer, keratocytoma, myeloma, rhabdomyosarcoma.

[0057] It should be understood that, within the scope of the present application, all the technical features described above and in the following (e.g. in the examples) of the present application can be combined with each other to form new or preferred technical solutions. Due to the limited space, they are not listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0058] Figure 1 Solubility profile of API crystal, API amorphous and solid dispersion in FaSSIF;

[0059] Figure 2 Polarized light microscope images of API crystal and solid dispersions (Example 10, Example 11 and Example 12);

[0060] Figure 3 XRPD overlay of API crystal and solid dispersions prepared with different carriers;

[0061] Figure 4 Solubility profile of API crystal and solid dispersions with different drug loading in SGF+FaSSIF;

[0062] Figure 5 Polarized light microscope images of solid dispersions with drug loading of 20% - 50% (Example 12, 13, 14 and 15);

[0063] Figure 6 XRPD overlay of API crystal and solid dispersions with drug loading of 20% - 50%. DETAILED DESCRIPTION

[0064] The present application provides a solid dispersion of FGFR inhibitor for one or more of the compounds of formula (I), pharmaceutically acceptable salts thereof, crystal forms thereof and solvates thereof, preparation thereof, preparation method thereof and application thereof. The solid dispersion effectively improves the solubility and dissolution of the drug, significantly improves the bioavailability of the FGFR inhibitor, has good stability, improves the safety of the drug, and solves the defects of low solubility and difficult preparation of the existing FGFR inhibitor.

[0065] The term

[0066] As used herein, PVP VA is a copolymer formed by polymerization of polyvinylpyrrolidone and polyvinyl acetate, and when PVP VA is identified by a number, it refers to the copolymer formed by polymerization of polyvinylpyrrolidone and polyvinyl acetate in a corresponding ratio (for example, PVP VA 64 refers to a copolymer formed by polymerization of polyvinylpyrrolidone and polyvinyl acetate in a ratio of 60:40).

[0067] As used herein, PVP in PVP K30 refers to polyvinylpyrrolidone, and K refers to the model number of PVP, which here refers to polyvinylpyrrolidone with a K value of 30.

[0068] As used herein, HPMCAS refers to hydroxypropyl methyl cellulose acetate succinate (such as HPMCAS LG and the like refer to hydroxypropyl methyl cellulose acetate succinate with different degrees of substitution, and here HPMCAS LG refers to hydroxypropyl methyl cellulose acetate succinate with a low degree of substitution (degree of substitution of acetyl groups), and the material state is granular.

[0069] As used herein, Soluplus refers to polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0070] As used herein, HPMC (such as HPMC E3LV and the like) refers to hydroxypropyl methyl cellulose, and here HPMC E3LV refers to hydroxypropyl methyl cellulose with a low viscosity, and the model number is E3.

[0071] As used herein, PEG refers to polyethylene glycol.

[0072] As used herein, HPMCP refers to hydroxypropyl methyl cellulose phthalate.

[0073] As used in the specification EPO refers to a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1). L100 refers to a copolymer of methyl methacrylate and ethyl acrylate (1:1). S100 refers to a copolymer of methyl methacrylate and methyl methacrylate (1:2). RL refers to a copolymer of ethyl acrylate, methyl methacrylate and chloro-trimethylammonium ethyl methacrylate (1:2:0.2). RS refers to a copolymer of ethyl acrylate, methyl methacrylate and chloro-trimethylammonium ethyl methacrylate (1:2:0.1). RD100 refers to RL and sodium hydroxymethyl cellulose (9:1) mixture. The above products are all from the Win Cre Industrial Group.

[0074] Solid dispersion containing the compound of formula (I)

[0075] The present application provides a solid dispersion comprising a carrier and an active ingredient, the active ingredient being one or more of a compound as shown in formula (I) and / or its pharmaceutically acceptable salt, its crystal form and its solvate, wherein the pharmaceutically acceptable salt includes inorganic and organic salts, and one preferred salt is a salt formed by the compound of the present application and an acid. Suitable acids for forming a salt include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, etc., and acidic amino acids such as aspartic acid, glutamic acid, etc.

[0076]

[0077] The carrier includes a component selected from the group consisting of a copolymer of polyvinylpyrrolidone / polyvinyl acetate (such as PVP VA64), polyvinylpyrrolidone (such as PVP K30), HPMCAS (such as HPMCAS LG), Soluplus, HPMC (such as HPMCE3LV), PEG, HPMCP, polymethacrylate (such as Eudragit® L30D-55), Eudragit® RLPO, Eudragit® RSPO, Eudragit® NE30D, Eudragit® EPO, polyvinyl alcohol and hydroxypropyl cellulose, or any combination of one or more thereof. EPO), polyvinyl alcohol and hydroxypropyl cellulose, or any combination of one or more thereof.

[0078] The compound of formula (I), its pharmaceutically acceptable salt and its solvate are usually in a crystalline form, and have extremely low solubility, with a solubility range of 0.0004-0.0198 mg / mL in an aqueous medium, at 37°C, for 24 hours, in an acidic to alkaline medium with a pH value of 1-10. Through research, the applicant unexpectedly found that by combining the compound of formula (I), its pharmaceutically acceptable salt and its solvate with a suitable carrier, the compound of formula (I), its pharmaceutically acceptable salt and its solvate can be highly dispersed in the carrier in an amorphous state, greatly improving the solubility and bioavailability of the compound of formula (I), its pharmaceutically acceptable salt and its solvate on the basis of maintaining a high drug loading amount, and the compound of formula (I), its pharmaceutically acceptable salt and its solvate in the solid dispersion of the present application will not be converted or degraded after the solid dispersion is accelerated for 2 months.

[0079] The carrier is preferably one or more of polyvinylpyrrolidone / copolymer of vinyl acetate (such as PVP VA64), polyvinylpyrrolidone (such as PVP K30), HPMCAS 716G, HPMCAS LG, HPMCAS 126G, HPMCAS MG, HPMCAS HG, HPMCAS 912G, Soluplus, HPMC E3LV, HPMC E5, HPMC K4M, PEG4000, PEG6000, HPMCP, polyvinyl acetate (such as EPO, polyvinyl alcohol and hydroxypropyl cellulose, more preferably one or more of polyvinylpyrrolidone / copolymer of vinyl acetate, polyvinylpyrrolidone and polymethacrylate.

[0080] In a preferred embodiment, the carrier is polyvinylpyrrolidone copolymerized with vinyl acetate (PVP-VA series, such as PVP VA64, i.e. a copolymer of polyvinylpyrrolidone and vinyl acetate polymerized at 60:40).

[0081] In another preferred embodiment, the carrier is polymethacrylate, including but not limited to EPO.

[0082] In another preferred embodiment, the carrier is polyvinylpyrrolidone (PVP), including but not limited to PVP K30.

[0083] In another preferred embodiment, the carrier can be a combination of one or more of the above.

[0084] The carrier can be used in an amount conventional in the art, for example, an appropriate amount selected according to the desired dosage form or administration amount. The mass ratio of the active ingredient to the carrier is preferably 1:(0.5-10) of one or a combination of the above carriers, and the combination ratio is further preferably 1:(1-7) (e.g. 1:1, 1:1.5, 3:7, 1:3, 1:4 or 1:6.7), and most preferably 1:(3-5). When the mass ratio of the active ingredient to the carrier is in the range of 1:(1-7), the solid dispersion has better effects in at least one of the equilibrium solubility, moldability and dissolution rate, for example, the dissolution rate is superior to that of the active ingredient alone. When the mass ratio of the active ingredient to the carrier is in the range of 1:(3-5), the solid dispersion has even better effects in at least one of the equilibrium solubility, moldability and dissolution rate.

[0085] In an embodiment of the present application, the solid dispersion is an amorphous solid dispersion.

[0086] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass: 1 part of the active ingredient prepared into a solid dispersion, and 4 parts of PVP K30, and the preferred preparation method of the solid dispersion is solvent evaporation method.

[0087] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass: 1 part of the active ingredient prepared into a solid dispersion, and 4 parts of PVP K30, and the preferred preparation method of the solid dispersion is solvent evaporation method.

[0088] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass: 1 part of the active ingredient prepared into a solid dispersion, and 4 parts of PVP VA64, and the preferred preparation method of the solid dispersion is solvent evaporation method.

[0089] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass: 1 part of the active ingredient prepared into a solid dispersion, and 4 parts of Soluplus, and the preferred preparation method of the solid dispersion is solvent evaporation method.

[0090] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass: 1 part of the active ingredient prepared into a solid dispersion, and 4 parts of HPMC E3 LV, and the preferred preparation method of the solid dispersion is solvent evaporation method.

[0091] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass: 1 part of the active ingredient prepared into a solid dispersion, and 4 parts of HPMC AS MG, and the preferred preparation method of the solid dispersion is solvent evaporation method.

[0092] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass: 1 part of the active ingredient prepared into a solid dispersion, and 4 parts of HPMC P, and the preferred preparation method of the solid dispersion is solvent evaporation method.

[0093] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass: 1 part of the active ingredient prepared into a solid dispersion, and 4 parts of EPO, and the preferred preparation method of the solid dispersion is solvent evaporation method.

[0094] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass: 1 part of the active ingredient prepared into a solid dispersion, and 4 parts of L100, and the preferred preparation method of the solid dispersion is solvent evaporation method.

[0095] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass fraction: 1 part of the active ingredient and 4 parts of PVP K30, and the preferred preparation method of the solid dispersion under this composition is spray drying. As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass fraction: 1 part of the active ingredient and 4 parts of PVP K30, and the preferred preparation method of the solid dispersion under this composition is spray drying.

[0096] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass fraction: 1 part of the active ingredient and 4 parts of PVP K30, and the preferred preparation method of the solid dispersion under this composition is spray drying.

[0097] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass fraction: 1 part of the active ingredient and 4 parts of PVP K30, and the preferred preparation method of the solid dispersion under this composition is spray drying.

[0098] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass fraction: 1 part of the active ingredient and 4 parts of PVP K30, and the preferred preparation method of the solid dispersion under this composition is spray drying.

[0099] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass fraction: 1 part of the active ingredient and 4 parts of PVP K30, and the preferred preparation method of the solid dispersion under this composition is spray drying.

[0100] As a preferred embodiment of the present application, the solid dispersion comprises the following components by mass fraction: 1 part of the active ingredient and 4 parts of PVP K30, and the preferred preparation method of the solid dispersion under this composition is spray drying.

[0101] Preparation of solid dispersion

[0102] The present application also provides a preparation method of the solid dispersion, comprising the following method I, method II or method III:

[0103] The method I comprises the following steps: mixing one or more of the compound as shown in formula I, its pharmaceutically acceptable salt, its crystal form and its solvate, and other components, with a solvent to form a solution or a suspension; removing the solvent by solvent evaporation to obtain the solid dispersion;

[0104] The method II comprises the following steps: mixing one or more of the compound as shown in formula I, its pharmaceutically acceptable salt, its crystal form and its solvate, and other components, and then extruding after heating to obtain the solid dispersion;

[0105] Method three comprises the following steps: mixing one or more of the compound of formula I, its pharmaceutically acceptable salt, its crystal form and its solvate, and other components with a solvent, and performing spray drying to obtain the solid dispersion.

[0106] In method one, the solvent can be a solvent used in the conventional solvent evaporation method in the art, preferably the solvent is one or more of water, an alcohol solvent, an ester solvent, a ketone solvent, a halogenated hydrocarbon solvent, a nitrile solvent and an ether solvent. The alcohol solvent can be ethanol and / or methanol; the ester solvent can be ethyl acetate; the ketone solvent can be acetone; the halogenated hydrocarbon solvent can be dichloromethane; the nitrile solvent can be acetonitrile; and the ether solvent can be tetrahydrofuran. Preferably, the solvent is tetrahydrofuran and / or acetone and / or ethanol and / or water.

[0107] In method one, the amount of the solvent can be conventional in the art, preferably the mass / volume ratio of the one or more of the compound of formula I, its pharmaceutically acceptable salt, its crystal form and its solvate to the solvent is 0.1-60 mg / ml, preferably 5-30 mg / ml.

[0108] In method two, the temperature of the extrusion can be conventional in the art, preferably the temperature of the extrusion is 150-250°C, more preferably the temperature of the extrusion is 160-220°C.

[0109] In method two, preferably, the extrusion operation is followed by a crushing step.

[0110] In method three, the solvent can be conventional in the art, preferably the solvent is one or more of water, an alcohol solvent, an ester solvent, a ketone solvent, a halogenated hydrocarbon solvent, a nitrile solvent and an ether solvent. The alcohol solvent can be ethanol and / or methanol; the ester solvent can be ethyl acetate; the ketone solvent can be acetone; the halogenated hydrocarbon solvent can be dichloromethane; the nitrile solvent can be acetonitrile; and the ether solvent can be tetrahydrofuran. Preferably, the solvent is tetrahydrofuran and / or acetone and / or ethanol and / or water. Preferably, the solvent is a combination of any one or more of acetone, ethanol and water, and most preferably the volume ratio of acetone, ethanol and water is most preferably 3:7:2.

[0111] In method three, the amount of the solvent can be conventional in the art, preferably the mass / volume ratio of the one or more of the compound of formula I, its pharmaceutically acceptable salt, its crystal form and its solvate to the solvent is 0.1-30 mg / ml.

[0112] In the third method, preferably, the spray-drying temperature can be set to 40°C to 200°C, preferably 50°C to 150°C.

[0113] Formulations comprising the solid dispersion

[0114] The present application also provides a formulation comprising the above-mentioned solid dispersion, which comprises: the solid dispersion, a filler, a disintegrant, a glidant, and a lubricant.

[0115] In the formulation, the filler can be of a kind conventional in the art, and preferably the filler is one or more of microcrystalline cellulose, lactose, pregelatinized starch, dibasic calcium phosphate, mannitol, and calcium phosphate; for example, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and mannitol, or a combination of microcrystalline cellulose and calcium phosphate; preferably, the filler is microcrystalline cellulose or a combination of microcrystalline cellulose and lactose.

[0116] When the filler is a combination of microcrystalline cellulose and lactose, preferably, the mass ratio of the microcrystalline cellulose to the lactose is 1:(0.5 to 2) (e.g., 1:0.5, 1:1, or 1:2), more preferably 1:(1 to 2), and most preferably 1:1.

[0117] When the filler contains microcrystalline cellulose, the microcrystalline cellulose can be of a kind conventional in the art, and preferably the microcrystalline cellulose is one or more of microcrystalline cellulose PH101, microcrystalline cellulose PH102, silicified microcrystalline cellulose 90, silicified microcrystalline cellulose HD90, microcrystalline cellulose PH105, microcrystalline cellulose KG802, and microcrystalline cellulose microcrystalline cellulose PH101, microcrystalline cellulose PH102, silicified microcrystalline cellulose 90, silicified microcrystalline cellulose HD90, microcrystalline cellulose PH105, microcrystalline cellulose KG802, and microcrystalline cellulose microcrystalline cellulose PH101, microcrystalline cellulose PH102, silicified microcrystalline cellulose 90, silicified microcrystalline cellulose HD90, microcrystalline cellulose PH105, microcrystalline cellulose KG802, and microcrystalline cellulose microcrystalline cellulose PH101, microcrystalline cellulose PH102, silicified microcrystalline cellulose 90, silicified microcrystalline cellulose HD90, microcrystalline cellulose PH105, microcrystalline cellulose KG802, and microcrystalline cellulose

[0118] When the filler contains lactose, the lactose can be of a kind conventional in the art, and preferably the lactose is anhydrous lactose and / or lactose monohydrate.

[0119] In the formulation, the amount of the filler can be of a kind conventional in the art, and preferably the amount of the filler is 0.2 to 8 parts by mass based on 1 part by mass of the solid dispersion; more preferably, the amount of the filler is 0.2 to 2 parts by mass, e.g., 0.25 parts, 0.40 parts, 0.43 parts, 0.72 parts, 0.84 parts, 0.85 parts, 0.86 parts, or 0.90 parts.

[0120] The disintegrant in the preparation can be conventional in the art, preferably the disintegrant is one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose sodium and carboxymethyl starch sodium; more preferably the disintegrant is croscarmellose sodium.

[0121] The disintegrant in the preparation can be conventional in the art, preferably the disintegrant is one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose sodium and carboxymethyl starch sodium; more preferably the disintegrant is croscarmellose sodium.

[0122] The preparation preferably further comprises a glidant. When the preparation further comprises a glidant, the glidant can be conventional in the art, preferably the glidant is silicon dioxide.

[0123] When the preparation further comprises a glidant, the amount of the glidant can be conventional in the art, preferably the amount of the glidant is 0.006-0.2 parts by mass based on 1 part by mass of the solid dispersion; more preferably the amount of the glidant is 0.01-0.06 parts by mass; for example 0.01 parts by mass, 0.02 parts by mass, 0.03 parts by mass or 0.04 parts by mass.

[0124] The preparation preferably further comprises a lubricant. When the preparation further comprises a lubricant, the lubricant can be conventional in the art, preferably the lubricant is magnesium stearate and / or sodium stearyl fumarate.

[0125] When the preparation further comprises a lubricant, the amount of the lubricant can be conventional in the art, preferably the amount of the lubricant is 0.004-0.1 parts by mass based on 1 part by mass of the solid dispersion; more preferably the amount of the lubricant is 0.004-0.04 parts by mass; for example 0.006 parts by mass, 0.007 parts by mass, 0.01 parts by mass or 0.02 parts by mass.

[0126] The preparation preferably further comprises a capsule shell. When the preparation is a capsule, the capsule shell material is gelatin or hydroxypropyl methyl cellulose.

[0127] The preparation preferably further comprises a coating agent. When the preparation further comprises a coating agent, the coating agent can be conventional in the art, preferably the coating agent is a gastro-soluble film coating premix, for example Opadry®. II.

[0128] When the preparation further comprises a coating agent, the amount of the coating agent can be conventional in the art, preferably, the amount of the coating agent is 0.01-0.2 parts by mass based on 1 part by mass of the solid dispersion; more preferably, the amount of the coating agent is 0.04-0.1 parts by mass, for example, 0.06 parts by mass.

[0129] The present application also provides the use of the above-mentioned preparation comprising the solid dispersion in the preparation of a medicament for treating a hyperproliferative disease.

[0130] Preferably, the hyperproliferative disease is cancer.

[0131] Preferably, the cancer is selected from non-small cell lung cancer, breast cancer, gastric cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer, keratocytoma, myeloma, rhabdomyosarcoma, etc.

[0132] On the basis of not violating the common knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain each preferred example of the present application.

[0133] The positive progress effect of the present application is that the solid dispersion provided by the present application can make the active ingredient highly dispersed in the carrier in an amorphous state, on the basis of maintaining a high drug loading, the solubility of the compound of formula (I), its pharmaceutically acceptable salt and its solvate in gastrointestinal fluid is also improved, the dissolution rate and bioavailability are improved. The preparation of the present application has good dissolution rate, low impurity content (total impurity content is less than 2%, maximum single impurity is less than 0.5%).

[0134] The present application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not used to limit the scope of the present application. The experimental methods in the following examples are not specified, which are usually carried out according to conventional conditions, or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0135] Example 1: Preparation of solid dispersion

[0136] The following solvent evaporation method was used to prepare the solid dispersion: 10 mg of crystalline form of hydrochloride salt of compound of formula (I) (hereinafter referred to as "API" or "drug substance") was accurately weighed into a 40 mL vial, 1 mL of solvent (tetrahydrofuran: water = 6:1, V:V) was added for dissolution, and then the solvent was quickly evaporated at 80°C to obtain the amorphous API.

[0137] In this example, the solid dispersion prepared from the crystalline form of hydrochloride salt of compound of formula (I) has a drug loading of 100%.

[0138] Drug solubility test was performed on API, API amorphous and solid dispersions (a certain amount of API, API amorphous of Example 1 and solid dispersions of Examples 2-9 were placed in 40 ml vials, respectively, 10 mL of FaSSIF solution at 37°C was added, and the samples were stirred at 500 rpm, and the solubility of the samples was detected at different time points), and the results are shown in Table 1 and Figure 1 .

[0139] Example 2: Preparation of solid dispersions

[0140] The following solvent evaporation method was used to prepare solid dispersions: 10 mg and 40 mg of crystalline form of hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") and polyvinylpyrrolidone copolymer with polyvinyl acetate (PVPVA64) were precisely weighed and placed in 40 mL vials, 1 mL of solvent (tetrahydrofuran: water = 6: 1, V: V) was added for dissolution, and then the solvent was quickly evaporated at 80°C to obtain a solid dispersion with a drug loading of 20%.

[0141] In this example, the mass ratio of crystalline form of hydrochloride salt of the compound of formula (I) and PVP VA64 was 1:4, i.e. the drug loading was 20%.

[0142] Drug solubility test was performed on API, API amorphous and solid dispersions (a certain amount of API, API amorphous of Example 1 and solid dispersions of Examples 2-9 were placed in 40 ml vials, respectively, 10 mL of FaSSIF solution at 37°C was added, and the samples were stirred at 500 rpm, and the solubility of the samples was detected at different time points), and the results are shown in Table 1 and Figure 1 .

[0143] Example 3: Preparation of solid dispersions

[0144] The following solvent evaporation method was used to prepare solid dispersions: 10 mg and 40 mg of crystalline form of hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") and polyvinylpyrrolidone K30 (PVP K30) were precisely weighed and placed in 40 mL vials, 1 mL of solvent (tetrahydrofuran: water = 6: 1, V: V) was added for dissolution, and then the solvent was quickly evaporated at 80°C to obtain a solid dispersion with a drug loading of 20%.

[0145] In this embodiment, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) and PVP K30 is 1:4, i.e. the drug loading is 20%. The drug dissolution test was performed on the API, API amorphous and solid dispersions (a certain amount of API, API amorphous of Example 1 and solid dispersions of Examples 2-9 were respectively placed in 40 ml vials, 10 mL of FaSSIF solution at 37°C was added, and the samples were stirred at 500 rpm, and the solubility of the samples was detected at different time points), and the results are shown in Table 1 and Figure 1 .

[0146] Example 4: Preparation of solid dispersions

[0147] The solid dispersions were prepared by the following solvent evaporation method: 10 mg and 40 mg of the crystalline form of the hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") were accurately weighed and placed in a 40 mL vial, 1 mL of solvent (tetrahydrofuran: water = 6:1, V:V) was added, and after dissolution, the solvent was quickly evaporated at 80°C to obtain a solid dispersion with a drug loading of 20%.

[0148] In this embodiment, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) and Soluplus is 1:4, i.e. the drug loading is 20%. The drug dissolution test was performed on the API, API amorphous and solid dispersions (a certain amount of API, API amorphous of Example 1 and solid dispersions of Examples 2-9 were respectively placed in 40 ml vials, 10 mL of FaSSIF solution at 37°C was added, and the samples were stirred at 500 rpm, and the solubility of the samples was detected at different time points), and the results are shown in Table 1 and Figure 1 .

[0149] Example 5: Preparation of solid dispersions

[0150] The solid dispersions were prepared by the following solvent evaporation method: 10 mg and 40 mg of the crystalline form of the hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") were accurately weighed and placed in a 40 mL vial, 1 mL of solvent (tetrahydrofuran: water = 6:1, V:V) was added, and after dissolution, the solvent was quickly evaporated at 80°C to obtain a solid dispersion with a drug loading of 20%.

[0151] In this embodiment, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) and HPMC E3LV is 1:4, i.e. the drug loading is 20%.

[0152] Drug solubility test was performed on API, API amorphous and solid dispersion (a certain amount of API, API amorphous of Example 1 and solid dispersion of Examples 2-9 were placed in 40 ml vials, respectively, 10 mL of FaSSIF solution at 37°C was added, and the samples were stirred at 500 rpm, and the solubility of the samples was detected at different time points), and the results are shown in Table 1 and Table 2. Figure 1 .

[0153] Example 6: Preparation of solid dispersion

[0154] The following solvent evaporation method was used to prepare the solid dispersion: 10 mg and 40 mg of crystalline form of hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") were precisely weighed and placed in a 40 mL vial, 1 mL of solvent (tetrahydrofuran: water = 6: 1, V: V) was added for dissolution, and then the sample was heated at 80°C to quickly evaporate the solvent, thereby obtaining a solid dispersion with a drug loading of 20%.

[0155] In this example, the mass ratio of the crystalline form of hydrochloride salt of the compound of formula (I) to HPMCAS MG was 1:4, i.e. the drug loading was 20%.

[0156] Drug solubility test was performed on API, API amorphous and solid dispersion (a certain amount of API, API amorphous of Example 1 and solid dispersion of Examples 2-9 were placed in 40 ml vials, respectively, 10 mL of FaSSIF solution at 37°C was added, and the samples were stirred at 500 rpm, and the solubility of the samples was detected at different time points), and the results are shown in Table 1 and Table 2. Figure 1 .

[0157] Example 7: Preparation of solid dispersion

[0158] The following solvent evaporation method was used to prepare the solid dispersion: 10 mg and 40 mg of crystalline form of hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") were precisely weighed and placed in a 40 mL vial, 1 mL of solvent (tetrahydrofuran: water = 6: 1, V: V) was added for dissolution, and then the sample was heated at 80°C to quickly evaporate the solvent, thereby obtaining a solid dispersion with a drug loading of 20%.

[0159] In this example, the mass ratio of the crystalline form of hydrochloride salt of the compound of formula (I) to HPMCAS MG was 1:4, i.e. the drug loading was 20%.

[0160] Drug solubility test was carried out on API, API amorphous and solid dispersions (a certain amount of API, API amorphous of Example 1 and solid dispersions of Examples 2-9 were respectively placed in 40 ml vials, 10 mL of FaSSIF solution at 37°C was added, stirring at 500 rpm, and the solubility of the samples was detected at different time points), and the results are shown in Table 1 and Figure 1 .

[0161] Example 8: Preparation of solid dispersions

[0162] The following solvent evaporation method was used to prepare solid dispersions: 10 mg and 40 mg of crystalline form of hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") were accurately weighed EPO was placed in a 40 mL vial, 1 mL of solvent (tetrahydrofuran: water = 6:1, V:V) was added for dissolution, and then heated at 80°C to quickly evaporate the solvent, thereby obtaining a solid dispersion with a drug loading of 20%.

[0163] In this example, the crystalline form of hydrochloride salt of the compound of formula (I) and The mass ratio of EPO was 1:4, i.e. the drug loading was 20%. Drug solubility test was carried out on API, API amorphous and solid dispersions (a certain amount of API, API amorphous of Example 1 and solid dispersions of Examples 2-9 were respectively placed in 40 ml vials, 10 mL of FaSSIF solution at 37°C was added, stirring at 500 rpm, and the solubility of the samples was detected at different time points), and the results are shown in Table 1 and Figure 1 .

[0164] Example 9: Preparation of solid dispersions

[0165] The following solvent evaporation method was used to prepare solid dispersions: 10 mg and 40 mg of crystalline form of hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") were accurately weighed L100 was placed in a 40 mL vial, 1 mL of solvent (tetrahydrofuran: water = 6:1, V:V) was added for dissolution, and then heated at 80°C to quickly evaporate the solvent, thereby obtaining a solid dispersion with a drug loading of 20%.

[0166] In this example, the crystalline form of hydrochloride salt of the compound of formula (I) and The mass ratio of L100 was 1:4, i.e. the drug loading was 20%.

[0167] Drug solubility test was performed on API, API amorphous and solid dispersion (a certain amount of API, API amorphous of Example 1 and solid dispersion of Examples 2-9 were respectively placed in 40ml vials, 10mL of FaSSIF solution at 37℃ was added, stirring at 500rpm, and the solubility of the samples was detected at different time points), the results are shown in Table 1 and Figure 1 .

[0168] Table 1 Solubility of solid dispersion with 20% drug loading prepared by solvent evaporation method in FaSSIF

[0169]

[0170] The results show that the solubility of the solid dispersion of the hydrochloride salt of the compound of formula I in the carrier such as polyvinylpyrrolidone / vinyl acetate copolymer, polyvinylpyrrolidone, polymethacrylate, etc. is significantly improved, while the solubility is limitedly improved when using some other carriers (such as HMPC), therefore, it is preferred to use polyvinylpyrrolidone / vinyl acetate copolymer, polyvinylpyrrolidone, polymethacrylate as the carrier to prepare the solid dispersion.

[0171] Example 10: Preparation of solid dispersion

[0172] The following spray drying method was used to prepare the solid dispersion: 2g and 8g of the crystalline form of the hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") were precisely weighed EPO was placed in a 100mL bottle, 80ml of solvent (tetrahydrofuran: water = 6:1, V:V) was added to the above 100ml bottle to prepare a clear solution containing API at a concentration of 25mg / ml, the relevant parameters of the spray drying equipment were set, the equipment was started, and the solid dispersion was prepared by spray drying, thereby obtaining a solid dispersion with a drug loading of 20%.

[0173] In this example, the crystalline form of the hydrochloride salt of the compound of formula (I) and The mass ratio of EPO was 1:4, i.e. the drug loading was 20%.

[0174] The drug solubility of API and solid dispersion was tested by two-step method (30 mg of the prepared solid dispersion and 6 mg of API were placed in a 40 ml vial, then 3 mL of SGF solution was added to prepare a solution with a target concentration of 2 mg / mL, under the condition of 37°C and 600 rpm, after stirring for 0.5 hr, 200 μL of the sample was taken to test the solubility of the sample in SGF, then 2 times of FaSSIF solution was added to the remaining sample, under the condition of 37°C and 600 rpm, after stirring for 0.5 hr, 1.5 hr and 3.5 hr, 200 μL of the sample was taken to test the solubility of the sample in SGF+FaSSIF solution), and the solubility results are shown in Table 2.

[0175] Another amount of the solid dispersion sample was taken and subjected to polarized light microscopy, XRPD and stability study, respectively. The polarized light microscopy results are shown in Figure 2 ; the XRPD superimposition is shown in Figure 3 (the sample name of Example 10 in the atlas: ASD_Eudragit EPO; API in the atlas represents the XRPD pattern of API); after being placed at 40°C / 75% RH for one week, the prepared solid dispersion had good stability.

[0176] Example 11: Preparation of solid dispersion

[0177] The solid dispersion was prepared by the following spray drying method: 2 g and 8 g of crystalline form of hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") were precisely weighed and placed in a 100 mL bottle, an appropriate amount of solvent (acetone: ethanol: water = 3:7:2, V:V) was added to the above 100 ml bottle to prepare a clear solution containing 25 mg / ml of API, the related parameters of the spray drying equipment were set, the equipment was started, and the solid dispersion was prepared by spray drying, thereby obtaining a solid dispersion with a drug loading of 20%.

[0178] In this example, the mass ratio of crystalline form of hydrochloride salt of the compound of formula (I) and PVP K30 was 1:4, i.e. the drug loading was 20%.

[0179] Drug solubility test was performed on API and solid dispersion (30 mg of the above prepared solid dispersion and 6 mg of API were placed in a 40 ml vial, then 3 mL of SGF solution was added to prepare a solution with a target concentration of 2 mg / mL, under the condition of 37°C and 600 rpm, after stirring for 0.5 hr, 200 μL of the sample was taken to test the solubility of the sample in SGF, then 2 times of FaSSIF solution was added to the remaining sample, under the condition of 37°C and 600 rpm, after continuous stirring for 0.5 hr, 1.5 hr and 3.5 hr, 200 μL of the sample was taken to test the solubility of the sample in SGF+FaSSIF solution), and the solubility results are shown in Table 2.

[0180] Another amount of the solid dispersion sample was taken and subjected to polarized light microscopy, XRPD and stability study, respectively. The polarized light microscopy results are shown in Figure 2 ; the XRPD superimposition is shown in Figure 3 (the sample name of Example 11 in the atlas: ASD_PVP K30; the sample atlas name of the sample dried for 48 hours: ASD_PVP K30_Dry 48h); after being placed at 40°C / 75% RH for one week, the prepared solid dispersion had good stability.

[0181] Example 12: Preparation of solid dispersion

[0182] The solid dispersion was prepared by the following spray drying method: 2 g and 8 g of the crystalline form of the hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") and a copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVPVA64) were precisely weighed and placed in a 100 mL bottle, an appropriate amount of solvent (acetone: ethanol: water = 3:7:2, V:V) was added to the above 100 ml bottle to prepare a clear solution containing 25 mg / ml of API, the relevant parameters of the spray drying equipment were set, the equipment was started, and the solid dispersion was prepared by spray drying to obtain a solid dispersion with a drug loading of 20%.

[0183] In this example, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) and the copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA64) was 1:4, i.e. the drug loading was 20%.

[0184] The drug solubility test was performed on the API and the solid dispersion (30 mg of the prepared solid dispersion and 6 mg of the API were placed in a 40 ml vial, 3 mL of SGF solution was then added to prepare a solution with a target concentration of 2 mg / mL, the solution was stirred at 37°C and 600 rpm for 0.5 hr, 200 μL of the sample was taken for testing the solubility of the sample in the SGF, then 2 times of FaSSIF solution was added to the remaining sample, the solution was continuously stirred at 37°C and 600 rpm for 0.5 hr, 1.5 hr and 3.5 hr, respectively, 200 μL of the sample was taken for testing the solubility of the sample in the SGF+FaSSIF solution), and the solubility results are shown in Table 2.

[0185] Another amount of the solid dispersion sample was taken and subjected to polarized light microscopy, XRPD and stability study, respectively. The polarized light microscopy results are shown in Figure 2 ; the XRPD superimposition is shown in Figure 3 (the sample name of Example 12 in the atlas: ASD_PVP VA64; the sample atlas name of the sample dried for 48 hours: ASD_PVP VA64_Dry 48h); after being placed at 40°C / 75% RH for one week, the prepared solid dispersion had good stability.

[0186] Table 2 Solubility of the solid dispersion prepared by the spray drying method in SGF+FaSSIF

[0187]

[0188] The results show that the prepared solid dispersion has good solubility, wherein the solubility in the postprandial gastric juice environment is increased by about 69 times relative to the API crystal, and the solubility in the fasting gastric juice environment is also increased by dozens of times. Therefore, the solid dispersion of the present application greatly improves the solubility of the API crystal.

[0189] Example 13: Preparation of the solid dispersion

[0190] The solid dispersion was prepared by the following spray drying method: 1 g and 4 g of the crystalline form of the hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") and a copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA64) were precisely weighed and placed in a 100 ml bottle, 40 ml of a solvent (acetone: ethanol: water = 3:7:2, V:V) was added to the above 100 ml bottle to prepare a clear solution containing 25 mg / ml of the API, the related parameters of the spray drying equipment were set, the equipment was started, and the solid dispersion was prepared by spray drying, thereby obtaining a solid dispersion with a drug loading of 20%.

[0191] In this embodiment, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) and the copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA64) is 1:4, i.e. the drug loading is 20%.

[0192] The drug solubility test was performed on the API and the solid dispersion (a certain amount of the solid dispersion was weighed, which was equivalent to 6 mg of API, and 6 mg of API was weighed as a control, and then 3 mL of SGF solution was added to prepare a solution with a target concentration of 2 mg / mL. After stirring at 37°C and 600 rpm for 0.5 hr, 200 μL of the sample was taken to test the solubility of the sample in SGF. Then, 2 times the amount of FaSSIF solution was added to the remaining sample, and after stirring at 37°C and 600 rpm for 0.5 hr, 1.5 hr and 3.5 hr, 200 μL of the sample was taken to test the solubility of the sample in SGF+FaSSIF solution), and the solubility results are shown in Table 3, and the solubility trend is shown in Figure 4 (Figure: Example 13 sample name in the spectrum: FR00895-6-ASD-PVP VA64-20%-0805; API crystal in the spectrum represents the dissolution trend of API).

[0193] Another amount of the solid dispersion sample was taken and subjected to polarizing microscope, XRPD and stability study. The polarizing microscope results are shown in Figure 5 ; the XRPD superimposition at 0 days is shown in Figure 6 (Figure: Example 13 sample name in the spectrum: FR00895-6-ASD-PVP VA64-20%-0805), and the prepared sample was placed at 25°C / 60RH, 40°C / 75%RH and 40°C for 2 weeks, 4 weeks and 2 months, respectively. The results showed that the prepared solid dispersion had good stability.

[0194] Example 14: Preparation of solid dispersion

[0195] The solid dispersion was prepared by the following spray drying method: 1 g of the crystalline form of the hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") and 2.33 g of the copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA64) were precisely weighed and placed in a 100 mL bottle. 40 ml of solvent (acetone: ethanol: water = 3:7:2, V:V) was added to the above 100 ml bottle to prepare a clear solution containing API at a concentration of 25 mg / ml. The relevant parameters of the spray drying equipment were set, the equipment was started, and the solid dispersion was prepared by spray drying, thereby obtaining a solid dispersion with a drug loading of 30%.

[0196] In this embodiment, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) and the copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA64) is 3:7, i.e. the drug loading is 30%.

[0197] The drug solubility test was performed on the API and the solid dispersion (a certain amount of the solid dispersion was weighed, which was equivalent to 6 mg of API, and was placed in a 40 ml vial, then 3 mL of SGF solution was added to prepare a solution with a target concentration of 2 mg / mL, after stirring at 37°C and 600 rpm for 0.5 hr, 200 μL of the sample was taken to test the solubility of the sample in SGF, then twice the amount of FaSSIF solution was added to the remaining sample, and after continuing to stir at 37°C and 600 rpm for 0.5 hr, 1.5 hr and 3.5 hr, 200 μL of the sample was taken to test the solubility of the sample in SGF+FaSSIF solution), and the solubility results are shown in Table 3, and the solubility trend is shown in Figure 4 (Figure: Example 14 sample name in the atlas: FR00895-6-ASD-PVP VA64-30%-0805).

[0198] Another certain amount of the solid dispersion sample was taken and subjected to polarizing microscope, XRPD and stability study. The polarizing microscope results are shown in Figure 5 ; the XRPD overlay at 0 days is shown in Figure 6 (Figure: Example 14 sample name in the atlas: FR00895-6-ASD-PVP VA64-30%-0805), and the results showed that the prepared solid dispersion had good stability after the prepared sample was placed at 25°C / 60 RH, 40°C / 75% RH and 40°C for 2 weeks, 4 weeks and 2 months, respectively.

[0199] Example 15: Preparation of the solid dispersion

[0200] The solid dispersion was prepared by the following spray drying method: 1 g and 1.5 g of the copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA64) and 1 g of the crystalline form of the hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") were precisely weighed and placed in a 100 ml bottle, 40 ml of solvent (acetone: ethanol: water = 3:7:2, V:V) was added to the above 100 ml bottle to prepare a clear solution containing 25 mg / ml of API, the relevant parameters of the spray drying equipment were set, the equipment was started, and the solid dispersion was prepared by spray drying, thereby obtaining a solid dispersion with a drug loading of 40%.

[0201] In this embodiment, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) and the copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA64) is 2:3, i.e. the drug loading is 40%.

[0202] The drug dissolution test was performed on the API and the solid dispersion (a certain amount of the solid dispersion was weighed, which was equivalent to 6 mg of API, and was placed in a 40 ml vial, then 3 mL of SGF solution was added to prepare a solution with a target concentration of 2 mg / mL, after stirring at 37°C and 600 rpm for 0.5 hr, 200 μL of the sample was taken to test the solubility of the sample in the SGF, then 2 times the amount of FaSSIF solution was added to the remaining sample, and after continuing to stir at 37°C and 600 rpm for 0.5 hr, 1.5 hr and 3.5 hr, 200 μL of the sample was taken to test the solubility of the sample in the SGF+FaSSIF solution), and the solubility results are shown in Table 3, and the solubility trend is shown in Figure 4 (Figure: Example 15 sample name in the atlas: FR00895-6-ASD-PVP VA64-40%-0805).

[0203] Another certain amount of the solid dispersion sample was taken and subjected to polarizing microscope, XRPD and stability study. The polarizing microscope results are shown in Figure 5 ; the XRPD superimposition at 0 days is shown in Figure 6 (Figure: Example 15 sample name in the atlas: FR00895-6-ASD-PVP VA64-40%-0805), and the results showed that the prepared solid dispersion had good stability after the prepared sample was placed at 25°C / 60 RH, 40°C / 75% RH and 40°C for 2 weeks, 4 weeks and 2 months, respectively.

[0204] Example 16: Preparation of the solid dispersion

[0205] The solid dispersion was prepared by the following spray drying method: 1 g of the crystalline form of the hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") and 1 g of a copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA64) were precisely weighed and placed in a 100 ml bottle, 40 ml of solvent (acetone: ethanol: water = 3:7:2, V:V) was added to the above 100 ml bottle to prepare a clear solution containing 25 mg / ml of API, the relevant parameters of the spray drying equipment were set, the equipment was started, and the solid dispersion was prepared by spray drying, thereby obtaining a solid dispersion with a drug loading of 50%.

[0206] In this example, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) and the copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA64) was 1:1, i.e. the drug loading was 50%.

[0207] Drug solubility test was performed on the API and the solid dispersion (a certain amount of the solid dispersion was weighed, which was equivalent to 6 mg of API and 6 mg of API, and was placed in a 40 ml vial, then 3 mL of SGF solution was added to prepare a solution with a target concentration of 2 mg / mL, after stirring at 37°C and 600 rpm for 0.5 hr, 200 μL of the sample was taken to test the solubility of the sample in the SGF, then twice the amount of FaSSIF solution was added to the remaining sample, and after stirring at 37°C and 600 rpm for 0.5 hr, 1.5 hr and 3.5 hr, 200 μL of the sample was taken to test the solubility of the sample in the SGF+FaSSIF solution), and the solubility results are shown in Table 3, and the solubility trend is shown in Figure 4 (Figure: Example 16 sample name in atlas: FR00895-6-ASD-PVP VA64-50%-0805).

[0208] Another certain amount of the solid dispersion sample was taken and subjected to polarizing microscope, XRPD and stability study. The polarizing microscope results are shown in Figure 5 ; the XRPD superimposition at 0 days is shown in Figure 6 (Figure: Example 16 sample name in atlas: FR00895-6-ASD-PVP VA64-50%-0805), and the prepared sample was placed at 25°C / 60 RH, 40°C / 75% RH and 40°C for 2 weeks, 4 weeks and 2 months, respectively, and the results showed that the prepared solid dispersion had good stability.

[0209] Table 3 Solubility of the solid dispersion prepared by spray drying in SGF+FaSSIF

[0210]

[0211]

[0212] The results showed that the prepared solid dispersion had good solubility, in which the solubility in the postprandial gastric juice environment was increased by about 42 times relative to the API crystal, and the solubility in the fasting gastric juice environment was also increased by several tens of times. Therefore, the solid dispersion of the present application greatly improved the solubility of the API crystal.

[0213] Example 17: Preparation of solid dispersion capsules

[0214] The crystalline form of hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "active pharmaceutical ingredient") 5 g and 20 g of a copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA64) were weighed in a beaker, 200 ml of a solvent (acetone: ethanol: water = 3:7:2, V:V) was added to the above beaker to prepare a clear solution containing 25 mg / ml of API, the relevant parameters of the spray drying equipment were set, the equipment was started, and the solid dispersion was prepared by spray drying. The sample was placed in a vacuum oven at 40°C and dried for about 20 hours to obtain a solid dispersion with a drug loading of 20%.

[0215] The solid dispersion with a drug loading of 20% (batch number: FR01146-9-20% ASD-0909) 125 mg was weighed and loaded into white opaque gelatin capsule shells of size 0 to prepare capsules of size 25 mg per capsule. The capsule batch number is: FR01146-9-20% ASD-Gelatin Capsule-0914.

[0216] Example 18: Preparation of solid dispersion tablets

[0217] According to the preparation method of Example 12, the solid dispersion, microcrystalline cellulose (Avicel® PH102), lactose and croscarmellose sodium were weighed (wherein the mass ratio of the solid dispersion, microcrystalline cellulose (Avicel® PH102), lactose and croscarmellose sodium in the total material is 50%, 30%, 15% and 3% respectively), and the solid dispersion, microcrystalline cellulose (Avicel® PH102), lactose and croscarmellose sodium were sieved and mixed uniformly, then granulated by a dry granulator. PH102), lactose and croscarmellose sodium in the total material is 50%, 30%, 15% and 3% respectively), and the solid dispersion, microcrystalline cellulose (Avicel® PH102), lactose and croscarmellose sodium were sieved and mixed uniformly, then granulated by a dry granulator. PH102), lactose and croscarmellose sodium in the total material is 50%, 30%, 15% and 3% respectively), and the solid dispersion, microcrystalline cellulose (Avicel® PH102), lactose and croscarmellose sodium were sieved and mixed uniformly, then granulated by a dry granulator.

[0218] Tablets were prepared on a experimental tablet press (ZP14) with a 10 mm round punch die, and the weight of the tablets was 400 mg. The parameters of the tablets were tested, among which the average hardness was 100 N, the average thickness was 5.87 mm, and the disintegration time was 5 minutes and 30 seconds.

[0219]

[0220] Test drug

[0221] API (hydrochloride salt of the compound of formula (I))

[0222]

[0223] ​Example 20 Solid Dispersion (ASD 1)

[0224]

[0225] Example 21 Solid Dispersion (ASD 2)

[0226]

[0227] 1. Study Outline

[0228] SD rats are the appropriate rodent species for PK evaluation of the test drug. The test article is administered orally (gavage) because the oral route is the intended route of administration in humans. The use of animals is reviewed and approved by the Institutional Animal Care and Use Committee (IACUC). PK sample collection: For intravenous treatment, blood samples are collected prior to injection, and at 0.083, 0.5, 1, 2, 4, 8, and 24 hours post-injection. For other dosing, blood samples are collected prior to dosing, and at 0.5, 1, 2, 4, 8, 12, and 24 hours post-dosing. PK sample analysis: All plasma samples collected are analyzed.

[0229] 2. Study Results

[0230] Table 8 Summary of Plasma Pharmacokinetic Parameters of Test Drug in Rats at Various Doses

[0231]

[0232] In all oral dosing, the absolute bioavailability of ASD 1 of Example 10 was 5.63% and the relative bioavailability was 840% at the same dose; the absolute bioavailability of ASD 2 of Example 12 was 7.74% and the relative bioavailability was 1155% at the same dose. The bioavailability of the solid dispersions of the examples was significantly improved in rats.

[0233] Example 22: Bioavailability Test of Solid Dispersion Capsules Prepared in Example 17 in Beagle Dogs

[0234] 1. Test Animals

[0235]

[0236] 2. Test Drug

[0237] API Formulation (Tablet of the Hydrochloride Salt of the Compound of Formula I)

[0238]

[0239] Example 23 Solid Dispersion Capsules Prepared

[0240]

[0241] 3. Study Outline

[0242] Beagle dogs are a suitable non-rodent species for PK evaluation of the test drug. The test article is administered orally (tablets / capsules) as the oral route is the intended route of administration in humans. The use of animals is reviewed and approved by the Institutional Animal Care and Use Committee (IACUC). PK sample collection: Blood samples are collected prior to dosing, and at 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose. PK sample analysis: All plasma samples collected are analyzed.

[0243] 4. Study Results

[0244] Table 9 Summary of Plasma Pharmacokinetic Parameters for Each Dose Group of Test Drug in Beagle Dogs

[0245]

[0246]

[0247] The relative bioavailability of the solid dispersion capsule ASD capsule prepared in Example 17 was 308% at the same dose as compared to all oral administration. The bioavailability of the solid dispersion of Example was significantly improved in beagle dogs.

[0248] All documents referred to in this disclosure are incorporated herein by reference as if each were individually incorporated by reference. In addition, it is to be understood that various alterations and modifications will become apparent to the skilled artisan after reviewing the above teachings of the present application and that the foregoing examples show some, but not all, of the various aspects of the application. Accordingly, it is to be understood that the application is to be limited only by the scope of the claims presented herein.

Claims

1. A pharmaceutical composition comprising a solid dispersion, said solid dispersion comprising one or more of a compound of formula (I), a pharmaceutically acceptable salt thereof, and a crystal form thereof. (I) (b) A pharmaceutically acceptable matrix selected from the group consisting of: copolymers of polyvinylpyrrolidone / polyvinyl acetate, polyvinylpyrrolidone, polymethacrylate, or combinations thereof; Furthermore, the weight ratio of one or more of the compound of formula I, its pharmaceutically acceptable salt, and its crystal form to the copolymer of polyvinylpyrrolidone / polyvinyl acetate is from 1:0.5 to 1:

20. The weight ratio of one or more of the compound of formula I, its pharmaceutically acceptable salt, and its crystal form to polyvinylpyrrolidone is from 1:0.5 to 1:

20. The weight ratio of one or more of the compound of formula I, its pharmaceutically acceptable salt, and its crystal form to polymethacrylate is from 1:0.5 to 1:

20.

2. The pharmaceutical composition according to claim 1, characterized in that, The copolymer of polyvinylpyrrolidone / polyvinyl acetate is PVP VA64.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The weight ratio of one or more of the compound of formula (I), its pharmaceutically acceptable salt, and its crystal form to the copolymer of polyvinylpyrrolidone / polyvinyl acetate is 1:2-8, calculated based on the free base mass of the compound of formula (I).

4. The pharmaceutical composition according to claim 1 or 2, characterized in that, The weight ratio of one or more of the compound of formula (I), its pharmaceutically acceptable salt, and its crystal form to the copolymer of polyvinylpyrrolidone / polyvinyl acetate is 1:3-5, calculated based on the free base mass of the compound of formula (I).

5. The pharmaceutical composition according to claim 1, characterized in that, The polyvinylpyrrolidone is selected from the group consisting of: PVPK30, PVP K12, PVP K15, PVP K17, PVP K25, PVP K60, PVP K90, or combinations thereof.

6. The pharmaceutical composition according to claim 1 or 5, characterized in that, The weight ratio of one or more of the compound of formula (I), its pharmaceutically acceptable salt, and its crystal form to polyvinylpyrrolidone is 1:2-8, calculated based on the mass of the free base corresponding to the compound of formula (I).

7. The pharmaceutical composition according to claim 1 or 5, characterized in that, The weight ratio of one or more of the compound of formula (I), its pharmaceutically acceptable salt, and its crystal form to polyvinylpyrrolidone is 1:3-5, calculated based on the mass of the free base corresponding to the compound of formula (I).

8. The pharmaceutical composition according to claim 1, characterized in that, The polymethacrylate mentioned is selected from the group consisting of Eudragit. ® EPO, Eudragit ® L100, Eudragit ® S100, Eudragit ® RL, Eudragit ® RS and Eudragit ® RD100, or a combination thereof.

9. The pharmaceutical composition according to claim 1 or 8, characterized in that, The weight ratio of one or more of the compound of formula (I), its pharmaceutically acceptable salt, and its crystal form to polymethacrylate is 1:2-8, calculated based on the free base mass of the compound of formula (I).

10. The pharmaceutical composition according to claim 1, characterized in that, The weight ratio of one or more of the compound of formula (I), its pharmaceutically acceptable salt, and its crystal form to polymethacrylate is 1:3-5, calculated based on the mass of free base corresponding to the compound of formula (I).

11. A method for preparing a pharmaceutical composition according to any one of claims 1-10, characterized in that, The method described is any one of the following methods: Method 1, Method 2, or Method 3: The method comprises the following steps: mixing one or more of (a) the compound of formula I, its pharmaceutically acceptable salt, and its crystal form with (b) a pharmaceutically acceptable matrix and (c) a solvent to form a solution or suspension; and then removing the solvent by solvent evaporation to obtain the solid dispersion; The second method comprises the following steps: mixing one or more of the following: (a) the compound of formula I, its pharmaceutically acceptable salt, and its crystal form with (b) a pharmaceutically acceptable matrix, heating and then extruding to obtain the solid dispersion; Method 3 comprises the following steps: mixing one or more of the following: (a) the compound of Formula I, its pharmaceutically acceptable salt, and its crystal form with (b) a pharmaceutically acceptable matrix and (c) a solvent, and then spray drying to obtain the solid dispersion.

12. The preparation method according to claim 11, characterized in that, In method one, the solvent is selected from the group consisting of water, C1-C6 alcohol solvents, C2-C6 ester solvents, C2-C6 ketone solvents, C1-C6 haloalkanes solvents, C2-C6 nitrile solvents, and C2-C6 ether solvents, or combinations thereof; and / or, in method one, one or more of the compound of formula I, its pharmaceutically acceptable salt, and its crystal form are present in a mass-to-volume ratio of 0.1 to 60 mg / ml to the solvent; And / or, in the second method, the extrusion temperature is 150–250°C; And / or, in the second method, the extrusion operation is further followed by a crushing step; And / or, in method three, the solvent is selected from the group consisting of: water, C1-C6 alcohol solvents, C2-C6 ester solvents, C2-C6 ketone solvents, C1-C6 haloalkanes solvents, C2-C6 nitrile solvents and C2-C6 ether solvents, or combinations thereof; And / or, in method three, one or more of the compound of formula I, its pharmaceutically acceptable salt, and its crystal form are in a mass-to-volume ratio of 0.1 to 30 mg / ml to the solvent; And / or, in method three, the spray drying equipment is set to a temperature of 40℃~200℃.

13. The preparation method according to claim 12, characterized in that, The C1-C6 alcohol solvent is ethanol and / or methanol; the C2-C6 ester solvent is ethyl acetate; the C2-C6 ketone solvent is acetone; the C1-C6 haloalkane solvent is dichloromethane; the C2-C6 nitrile solvent is acetonitrile; and the C2-C6 ether solvent is tetrahydrofuran. And / or, in method one, the mass-to-volume ratio of one or more of the compound of formula I, its pharmaceutically acceptable salt, and its crystal form to the solvent is 5 to 30 mg / ml; And / or, in the second method, the extrusion temperature is 160–220°C; And / or, in method three, the C1-C6 alcohol solvent is ethanol and / or methanol; the C2-C6 ester solvent is ethyl acetate; the C2-C6 ketone solvent is acetone; the C1-C6 haloalkane solvent is dichloromethane; the C2-C6 nitrile solvent is acetonitrile; and the C2-C6 ether solvent is tetrahydrofuran. And / or, in method three, the spray drying equipment is set to a temperature of 50℃~150℃.

14. The preparation method according to claim 12, characterized in that, The solvent is selected from the group consisting of acetone, ethanol, water, or combinations thereof.

15. A formulation, characterized in that, The formulation comprises: a pharmaceutical composition as described in any one of claims 1 to 10, and a carrier selected from the group consisting of fillers, disintegrants, gliding agents, lubricants, or combinations thereof.

16. The formulation of claim 15, characterized in that, The filler is selected from the group consisting of microcrystalline cellulose, lactose, pregelatinized starch, dicalcium phosphate, mannitol, calcium phosphate, or combinations thereof; And / or, based on 1 part by mass of the solid dispersion, the filler is 0.2 to 8 parts by mass; And / or, the disintegrant is selected from the group consisting of: croscarmellose sodium cellulose, low-substituted hydroxypropyl cellulose sodium cellulose, sodium carboxymethyl starch, or combinations thereof; And / or, based on 1 part by mass of the solid dispersion, the disintegrant is 0.03 to 0.4 parts by mass; And / or, the formulation further comprises a capsule shell; And / or, the formulation further comprises a coating agent.

17. The formulation of claim 16, characterized in that, The filler is selected from the group consisting of: a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and mannitol, or a combination of microcrystalline cellulose and calcium phosphate; And / or, based on 1 part by mass of the solid dispersion, the filler is 0.2 to 2 parts by mass; And / or, the disintegrant is croscarmellose sodium; And / or, based on 1 part by mass of the solid dispersion, the disintegrant is 0.05 to 0.3 parts by mass.

18. The formulation of claim 16, characterized in that, When the filler is a combination of microcrystalline cellulose and lactose, the mass ratio of the microcrystalline cellulose to lactose is 1:(0.5-2); And / or, the microcrystalline cellulose is selected from the group consisting of: microcrystalline cellulose Avicel ® PH102, Silicified Microcrystalline Cellulose 90, Silicified Microcrystalline Cellulose HD 90, Microcrystalline Cellulose PH105, Microcrystalline Cellulose KG802, Microcrystalline Cellulose Avicel ® PH101, or a combination thereof; And / or, the lactose is anhydrous lactose or lactose monohydrate; And / or, the flow aid is silicon dioxide; And / or, when the formulation further comprises a gliding agent, the gliding agent comprises 0.006 to 0.2 parts by mass, based on 1 part by mass of the solid dispersion; And / or, the lubricant is magnesium stearate and / or sodium stearate fumarate; And / or, when the formulation further comprises a lubricant, the lubricant comprises 0.004 to 0.1 parts by mass, based on 1 part by mass of the solid dispersion; And / or, when the formulation further comprises a capsule shell, the capsule shell is made of gelatin or hydroxypropyl methylcellulose; And / or, when the formulation further comprises a coating agent, the coating agent is a gastrointestinal film-coated premix; And / or, when the formulation further comprises a coating agent, the coating agent comprises 0.01 to 0.2 parts by mass, based on 1 part by mass of the solid dispersion.

19. The formulation of claim 16, characterized in that, When the filler is a combination of microcrystalline cellulose and lactose, the mass ratio of microcrystalline cellulose to lactose is 1:(1-2); And / or, the microcrystalline cellulose is microcrystalline cellulose PH102 and / or microcrystalline cellulose KG802; And / or, when the formulation further comprises a gliding agent, the gliding agent comprises 0.01 to 0.06 parts by mass, based on 1 part by mass of the solid dispersion; And / or, when the formulation further comprises a lubricant, the lubricant comprises 0.004 to 0.04 parts by mass, based on 1 part by mass of the solid dispersion; And / or, when the formulation further comprises a coating agent, the coating agent is Opadry. ® II; And / or, when the formulation further comprises a coating agent, the coating agent comprises 0.04 to 0.1 parts by mass, based on 1 part by mass of the solid dispersion.

20. The formulation of claim 17, characterized in that, The formulation includes: A solid dispersion in which the weight ratio of the compound of formula (I) to the matrix is ​​1:3-5; The carrier is selected from one or more of the following groups (1)-(6): (1) 25-35 wt% microcrystalline cellulose, 10-20 wt% lactose and 4-6 wt% croscarmellose sodium, with the balance being a solid dispersion; (2) 20-35 wt% microcrystalline cellulose, 5-20 wt% lactose, 4-6 wt% croscarmellose sodium, 0.1-5% silica and 0.1-5% magnesium stearate, with the balance being a solid dispersion; (3) 20-35 wt% microcrystalline cellulose, 5-20 wt% lactose, 4-6 wt% croscarmellose sodium, 0.1-5% silica and 0.1-5% magnesium stearate, with the balance being a solid dispersion; (4) 5-60 wt% microcrystalline cellulose, 4-6 wt% croscarmellose sodium cellulose and 0.1-5% magnesium stearate, with the balance being a solid dispersion; (5) 5-60 wt% lactose, 4-6 wt% croscarmellose sodium, 0.1-5% silica and 0.1-5% magnesium stearate, with the balance being a solid dispersion; (6) Capsule shell.

21. The use of the pharmaceutical composition according to any one of claims 1-10, or the formulation according to any one of claims 15-20, in the preparation of a medicament for treating cancer.

22. The application as described in claim 21, characterized in that, The cancers mentioned are selected from the following group: non-small cell lung cancer, breast cancer, gastric cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer, keratoblastoma, myeloma, and rhabdomyosarcoma.

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