Pharmaceutical composition containing substituted indol-5-ol derivative and use thereof

Abstract

Disclosed is a first pharmaceutical composition comprising a substituted indol-5-ol derivative, characterized in that the first pharmaceutical composition comprises (a) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) one or more polymer materials, for example, one, two, three, four or five types of polymer materials.

Description

A pharmaceutical composition comprising substituted indole-5-phenol derivatives and its application Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a pharmaceutical composition containing a substituted indole-5-phenol derivative and application thereof. Background Art

[0002] The compound involved in this invention is a substituted indole-5-phenol derivative independently developed by the applicant for use in regulating protein kinases and treating protein kinase-mediated diseases. It is primarily used as a multi-target, broad-spectrum anticancer drug. For related compounds involved in this invention, see compound patents ZL 201380069244.9 and ZL 201480026101.4, the relevant contents of which are incorporated into this patent application.

[0003] To increase the efficiency of new drug discovery and research, the applicant has been committed to identifying novel methods for drug design and screening, as well as molecular design, synthesis, and anticancer activity studies of inhibitors. Small molecule anti-tumor drugs based on novel pharmacological mechanisms have been designed and synthesized for tumor-specific target proteins. The applicant has resolved the crystal structures of multiple protein kinases or protein kinase complexes and applied computer-aided design and fragment-based drug design methods to design novel small molecule kinase inhibitors. This approach then identifies the disease targets and targets of action. Through model validation, lead compound discovery, lead compound identification, and lead compound optimization, excellent compounds—drug candidates—are ultimately obtained. Subsequent development work includes further confirmation of the drug target, scale-up synthesis of the compound, process optimization, drug evaluation, and formulation development.

[0004] At present, there is no report in the prior art on a pharmaceutical composition comprising a substituted indole-5-phenol derivative and its application as claimed in the present invention.

[0005] Summary of the Invention

[0006] In view of this, the present invention provides a first pharmaceutical composition comprising a substituted indole-5-ol derivative, the first pharmaceutical composition comprising

[0007] (a) a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; and

[0008] (b) one or more, such as 1, 2, 3, 4 or 5, polymer materials.

[0009] Furthermore, the polymer material is selected from one or more of the following: hypromellose acetate succinate, hydroxyalkyl cellulose, povidone, copovidone, polypropylene resin, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and polyethylene glycol. Furthermore, the hypromellose acetate succinate is hypromellose acetate succinate AS-MMP and / or hypromellose acetate succinate AS-MF. Furthermore, the hydroxyalkyl cellulose is hydroxypropyl cellulose, hypromellose, and / or hydroxyethyl cellulose. Furthermore, the hydroxypropyl cellulose is hydroxypropyl cellulose EXF, hydroxypropyl cellulose HXF, and / or hydroxypropyl cellulose LXF. Furthermore, the hypromellose is hypromellose E3, hypromellose E5, and / or hypromellose E15. Furthermore, the povidone is povidone K25, povidone K30, povidone K-12, and / or povidone K-17. Furthermore, the copovidone is copovidone S630. Furthermore, the polypropylene resin is polypropylene resin E100. Furthermore, the polyethylene glycol is polyethylene glycol 4000 and / or polyethylene glycol 6000. Furthermore, the polymer material is povidone K30, hypromellose E3, hypromellose E15, hypromellose acetate succinate AS-MMP, hydroxypropyl cellulose EXF, copovidone S630, polyethylene glycol 4000, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or polypropylene resin E100. Furthermore, the mass ratio between the compound of formula (I) and the polymer material is 1:1 to 1:10. Furthermore, the mass ratio between the compound of formula (I) and the polymer material is 1:1 to 1:6. Furthermore, the mass ratio between the compound of formula (I) and the polymer material is 1:3 to 1:6.

[0010] Furthermore, the first pharmaceutical composition further comprises one or more, such as one, two, three, four, or five, antioxidants. Furthermore, the antioxidant is selected from one or more of the following: butylated hydroxyanisole, butylated hydroxytoluene, sodium metabisulfite, vitamin E, vitamin E acetate, and L-ascorbyl palmitate. Furthermore, the antioxidant is sodium metabisulfite. Furthermore, the antioxidant is present in an amount of 0.01% to 3%, for example, about 0.2%, by weight of the first pharmaceutical composition.

[0011] Furthermore, the first pharmaceutical composition is in the form of a solid dispersion.

[0012] According to one aspect of the present invention, the present invention provides a second pharmaceutical composition comprising the above-mentioned first pharmaceutical composition, wherein the second pharmaceutical composition further comprises (1) one or more fillers such as 1, 2, 3, 4 or 5 fillers; (2) one or more disintegrants such as 1, 2, 3, 4 or 5 disintegrants; (3) optionally one or more surfactants such as 1, 2, 3, 4 or 5 surfactants; (4) optionally one or more glidants such as 1, 2, 3, 4 or 5 glidants; (5) optionally one or more lubricants such as 1, 2, 3, 4 or 5 lubricants; and (6) optionally one or more film coating premixes such as 1, 2, 3, 4 or 5 film coating premixes.

[0013] Furthermore, the filler is selected from one or more of the following: lactose (e.g., lactose monohydrate or anhydrous lactose), starch, calcium hydrogen phosphate (e.g., calcium hydrogen phosphate anhydrous or calcium hydrogen phosphate dihydrate), calcium sulfate dihydrate, mannitol, sorbitol, and microcrystalline cellulose. Furthermore, the microcrystalline cellulose is microcrystalline cellulose PH101. Furthermore, the disintegrant is selected from one or more of the following: cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone (e.g., cross-linked polyvinylpyrrolidone XL-10, cross-linked polyvinylpyrrolidone CL), pregelatinized starch, and sodium carboxymethyl starch. Furthermore, the surfactant is sodium lauryl sulfate. Furthermore, the glidant is colloidal silicon dioxide. Furthermore, the lubricant is magnesium stearate and / or glyceryl tribehenate.

[0014] Furthermore, the filler is present in an amount of 30% to 70% by weight of the second pharmaceutical composition. Furthermore, the filler is present in an amount of 55% to 65% by weight of the second pharmaceutical composition, for example, about 58.5%. Furthermore, the disintegrant is present in an amount of 6% to 20% by weight of the second pharmaceutical composition. Furthermore, the disintegrant is present in an amount of 10% to 20% by weight of the second pharmaceutical composition, for example, about 15%. Furthermore, the surfactant is present in an amount of 1% to 6% by weight of the second pharmaceutical composition. Furthermore, the glidant is present in an amount of 0.5% to 3% by weight of the second pharmaceutical composition, for example, about 1%. Furthermore, the lubricant is present in an amount of 0.5% to 3% by weight of the second pharmaceutical composition, for example, about 1.5%. Furthermore, the film coating premix is ​​present in an amount of 0.5% to 5% by weight of the second pharmaceutical composition, for example, about 3%. Furthermore, the antioxidant is present in an amount of 0.01% to 1% by weight of the second pharmaceutical composition, for example, about 0.1%.

[0015] Furthermore, the second pharmaceutical composition is in the form of an oral preparation. Further, the second pharmaceutical composition is in the form of a solid oral preparation, such as a tablet or capsule.

[0016] According to one aspect of the present invention, the present invention provides a method for preparing the above-mentioned first pharmaceutical composition, which comprises the following steps: (a) mixing and dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more polymer materials, such as 1, 2, 3, 4 or 5, one or more solvents, such as 1, 2, 3, 4 or 5, and optionally one or more antioxidants, such as 1, 2, 3, 4 or 5, to form a mixed solution; (b) spray drying the mixed solution to obtain a mixed powder; and (c) vacuum drying or double cone drying the mixed powder to obtain the first pharmaceutical composition.

[0017] Furthermore, the solvent is selected from one or more of the following: water, methanol, acetone, ethanol, isopropanol, acetonitrile, ethyl acetate, propylene glycol, and dichloromethane. Furthermore, the solvent is selected from one or more of the following: water, methanol, ethanol, acetone, and dichloromethane. Furthermore, the solvent is water, methanol, ethanol, acetone, and / or dichloromethane. Furthermore, the mass ratio of the acetone to the methanol is 1:1 to 3:1, for example, about 2:1. Furthermore, the solvent is about 70% acetone and methanol and about 30% water. Furthermore, the solvent is about 40% acetone and methanol and about 60% dichloromethane.

[0018] Furthermore, the mass ratio of the solvent to the first pharmaceutical composition is 85:15 to 97:3. Furthermore, the mass ratio of the solvent to the first pharmaceutical composition is 90:10 to 94:6.

[0019] Furthermore, the spray drying conditions are as follows: an inlet air temperature of 70°C to 90°C, an outlet air temperature of 45°C to 55°C, a pump power of 20% to 45%, a condenser temperature of -15°C to -5°C, and an atomizing gas flow rate of 3kg / h to 12kg / h. Furthermore, the vacuum drying conditions are as follows: after the vacuum degree stabilizes at ≤-0.1MPa, drying at 55°C to 65°C for 12 to 48 hours. Furthermore, the double-cone drying conditions are as follows: after the vacuum degree stabilizes at ≤-0.1MPa, drying at 55°C to 65°C for 4 to 24 hours.

[0020] According to one aspect of the present invention, the present invention provides a method for preparing the above-mentioned first pharmaceutical composition, which comprises the following steps: (a) screening and mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more polymer materials, such as 1, 2, 3, 4 or 5, and optionally one or more plasticizers, such as 1, 2, 3, 4 or 5, to obtain a mixture; and (b) setting the temperature of each section of the screw of a hot melt extruder, adjusting the feed rate to 5 rpm to 20 rpm and the screw speed to 20 rpm to 80 rpm, performing hot melt extrusion, and optionally cooling and crushing to obtain the first pharmaceutical composition.

[0021] Furthermore, the plasticizer is selected from one or more of the following: dibutyl sebacate, diethyl phthalate, Pluronic F-68, Pluronic F-127, glyceryl monostearate, polyethylene glycol, sodium lauryl sulfate, sodium octylbutyl sulfonate, triethyl citrate, glyceryl triacetate, Tween 80, and vitamin E-TPGS.

[0022] Furthermore, the temperature is 20℃~40℃ in the initial section, 110℃~130℃ in the transmission section, 160℃~180℃ in the mixing section, 160℃~180℃ in the meshing section, and 150℃~170℃ in the transmission and discharge section.

[0023] According to one aspect of the present invention, the present invention provides a method for preparing the above-mentioned first pharmaceutical composition, which comprises the following steps: (a) mixing and dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more polymer materials, such as 1, 2, 3, 4 or 5, and one or more solvents, such as 1, 2, 3, 4 or 5, to form a mixed solution; and (b) removing the solvent using a rotary evaporator at 45°C to 65°C, pulverizing the dried mixture, and passing it through an 18-mesh to 80-mesh sieve to obtain the first pharmaceutical composition.

[0024] Furthermore, the solvent is selected from one or more of the following: water, methanol, acetone, ethanol, isopropanol, acetonitrile, ethyl acetate, propylene glycol, and dichloromethane. Furthermore, the solvent is selected from one or more of the following: water, methanol, ethanol, acetone, and dichloromethane. Furthermore, the solvent is water, ethanol, acetone, and / or dichloromethane. Furthermore, the mass ratio of the acetone to the methanol is 1:1 to 3:1, for example, about 2:1. Furthermore, the solvent is about 70% acetone and methanol and about 30% water. Furthermore, the solvent is about 40% acetone and methanol and about 60% dichloromethane.

[0025] Furthermore, the mass ratio of the solvent to the first pharmaceutical composition is 85:15 to 97:3. Furthermore, the mass ratio of the solvent to the first pharmaceutical composition is 90:10 to 94:6.

[0026] According to one aspect of the present invention, the present invention provides a method for preparing the above-mentioned second pharmaceutical composition, which comprises the following steps: (a) preparing a mixed solution containing a compound of the present invention (i.e., a compound of formula (I), referred to as API) and one or more polymer materials (optionally, one or more such as 1, 2, 3, 4 or 5 antioxidants), spraying the mixed solution into an appropriate amount of filler and / or disintegrant, drying and sieving to obtain a first drug mixture; and (b) mixing the first drug mixture with suitable fillers, disintegrants and lubricants, etc., further tableting, filling capsules or packaging into granules to obtain tablets, capsules or granules of the second pharmaceutical composition, respectively.

[0027] Furthermore, the method comprises the following steps: (a) mixing and dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more polymer materials, such as 1, 2, 3, 4 or 5, one or more solvents, such as 1, 2, 3, 4 or 5, and optionally one or more antioxidants, such as 1, 2, 3, 4 or 5, to form a mixed solution; (b) adding the filler and the disintegrant into a fluidized bed and preheating; (c) spraying the mixed solution of the first pharmaceutical composition into the fluidized bed, drying, and sieving the obtained particles; (d) mixing the sieved particles with an appropriate amount of filler, disintegrant, glidant and / or lubricant to obtain a second pharmaceutical mixture; and (e) optionally, dividing and tableting the second pharmaceutical mixture to obtain tablets of the second pharmaceutical composition; (f) optionally, dividing and filling the second pharmaceutical mixture into capsules to obtain capsules of the second pharmaceutical composition; (g) optionally, dividing and bagging the second pharmaceutical mixture to obtain granules of the second pharmaceutical composition.

[0028] Furthermore, the one-step granulation conditions include a fluidized bed air inlet temperature of 45°C to 75°C, a fluidized bed material temperature of 35°C to 55°C, a fluidized bed air inlet volume of 15m 3 / h~80m 3 / h, the fluidized bed spray rate is 5g / min~50g / min and the fluidized bed atomization pressure is 0.05bar~1.0bar.

[0029] According to one aspect of the present invention, the present invention provides a method for preparing the above-mentioned second pharmaceutical composition, characterized in that the method comprises the following steps: (a) mixing the first pharmaceutical composition with an appropriate amount of filler, disintegrant, glidant and lubricant for a first time to obtain a first pharmaceutical mixture; (b) dry granulating the first pharmaceutical mixture to obtain granules; (c) mixing the granules with an appropriate amount of disintegrant and lubricant for a second time to obtain a second pharmaceutical mixture; and (d) optionally, dividing the second pharmaceutical mixture and tableting to obtain tablets of the second pharmaceutical composition; (e) optionally, dividing the second pharmaceutical mixture and filling capsules to obtain capsules of the second pharmaceutical composition; (f) optionally, dividing the second pharmaceutical mixture and bagging to obtain granules of the second pharmaceutical composition.

[0030] Furthermore, the first mixing is performed at a rotation speed of 10 rpm to 20 rpm, and the mixing time is 10 min to 15 min. Furthermore, the second mixing is performed at a rotation speed of 10 rpm to 20 rpm, and the mixing time is 2 min to 10 min.

[0031] Furthermore, in step (a), the disintegrant is cross-linked polyvinylpyrrolidone and pregelatinized starch. Furthermore, in step (c), the disintegrant is cross-linked polyvinylpyrrolidone.

[0032] Furthermore, the mass ratio of the cross-linked polyvinylpyrrolidone added in step (a) to the cross-linked polyvinylpyrrolidone added in step (c) is about 1.

[0033] Further, the mass ratio between the lubricant added in step (a) and the lubricant added in step (c) is about 2.

[0034] Furthermore, the dry granulation conditions are as follows: hydraulic pressure of 18 bar to 50 bar, roller speed of 3.4 rpm to 14.8 rpm, roller spacing of 1 mm to 4 mm, secondary granulation speed of 24.9 rpm to 108.4 rpm, and primary granulation speed of 10 rpm to 90 rpm.

[0035] Furthermore, the specification of the first-level granulation screen of the dry granulation is 2.0 mm, and the specification of the second-level granulation screen is 0.8 mm.

[0036] According to one aspect of the present invention, the present invention provides a use of the first pharmaceutical composition or the second pharmaceutical composition in the preparation of a medicament for regulating protein kinase and / or treating protein kinase-mediated diseases, disorders and / or pathologies.

[0037] Further, the disease, disorder and / or pathology is cancer, a vascular disorder, an anoxic disorder, osteoporosis or a disease affecting cell motility, adhesion and cell cycle progression.

[0038] Furthermore, the cancer is leukemia, lung cancer, liver cancer, endometrial cancer, gastric cancer, rectal cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer or breast cancer.

[0039] Furthermore, the vascular disorder is myocardial infarction, stroke or ischemia. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without exceeding the scope of protection required by the present invention.

[0041] Figure 1 is a schematic diagram of the dissolution curves of the API+PVP physical mixture and the API+PVP solid dispersion.

[0042] FIG2 is a schematic diagram of the dissolution curve of the tablet experiment stage.

[0043] FIG3 is a schematic diagram of the dissolution curve of the tablet formulation used for filler screening.

[0044] Figure 4 is a schematic diagram of the dissolution curves of tablet formulations in different dissolution media for screening filler types and addition methods (1).

[0045] Figure 5 is a schematic diagram of the dissolution curves of tablet formulations in different dissolution media for screening filler types and addition methods (2).

[0046] FIG6 is a schematic diagram of the dissolution curve of the tablet formulation used to investigate the dosage and addition method of the disintegrant P.Starch.

[0047] FIG7 is a schematic diagram of the dissolution curve of the tablet formulation used to investigate the dosage and addition method of the disintegrant crospovidone. DETAILED DESCRIPTION

[0048] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work shall fall within the scope of protection of the present invention.

[0049] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0050] Unless otherwise indicated, all technical and scientific terms and abbreviations used herein have the meanings commonly understood by those skilled in the art in the field of the present invention or the field in which the terms are used. Although any methods, conditions, substances or materials similar or equivalent to those disclosed herein can be used in the practice of the present invention, preferred methods, conditions, substances or materials are described herein.

[0051] In the present invention, the term "comprising" is synonymous with "including." As used herein, the terms "comprise," "include," "have," "contain," or any other variations thereof, are intended to cover a non-exclusive inclusion. For example, a composition, medicinal material, component, step, method, article, or apparatus that comprises the listed elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, medicinal material, component, step, method, article, or apparatus.

[0052] The auxiliary materials involved in the present invention are only enumerated. The auxiliary materials actually used in the present invention are not limited to the auxiliary materials listed in the present invention. The use of auxiliary materials can be adjusted according to the actual application situation, and the effects of the present invention can be achieved and are within the scope of protection of the present invention.

[0053] As described in the background technology section, there is no report in the prior art on a pharmaceutical composition comprising a substituted indole-5-ol derivative and its application as claimed in the present invention. In order to solve the above problem, the present invention provides a first pharmaceutical composition comprising a substituted indole-5-ol derivative. The first pharmaceutical composition comprises

[0054] (a) a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; and

[0055] (b) one or more, such as 1, 2, 3, 4 or 5, polymer materials.

[0056] In a preferred embodiment, the polymer material is selected from one or more of the following: hypromellose acetate succinate, hydroxyalkyl cellulose, povidone, copovidone, polypropylene resin, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and polyethylene glycol. In a preferred embodiment, the hypromellose acetate succinate is hypromellose acetate succinate AS-MMP and / or hypromellose acetate succinate AS-MF. In a preferred embodiment, the hydroxyalkyl cellulose is hydroxypropyl cellulose, hypromellose, and / or hydroxyethyl cellulose. In a preferred embodiment, the hydroxypropyl cellulose is hydroxypropyl cellulose EXF, hydroxypropyl cellulose HXF, and / or hydroxypropyl cellulose LXF. In a preferred embodiment, the hypromellose is hypromellose E3, hypromellose E5, and / or hypromellose E15. In a preferred embodiment, the povidone is povidone K25, povidone K30, povidone K-12, and / or povidone K-17. In a preferred embodiment, the copovidone is copovidone S630. In a preferred embodiment, the polypropylene resin is polypropylene resin E100. In a preferred embodiment, the polyethylene glycol is polyethylene glycol 4000 and / or polyethylene glycol 6000. In a preferred embodiment, the polymer material is povidone K30, hypromellose E3, hypromellose E15, hypromellose acetate succinate AS-MMP, hydroxypropyl cellulose EXF, copovidone S630, polyethylene glycol 4000, polyethylene glycol graft copolymer, or polypropylene resin E100. In a preferred embodiment, the mass ratio between the compound of formula (I) and the polymer material is 1:1 to 1:10. In a preferred embodiment, the mass ratio between the compound of formula (I) and the polymer material is 1:1 to 1:6. In a preferred embodiment, the mass ratio between the compound of formula (I) and the polymer material is 1:3 to 1:6.

[0057] In the present invention, when mass ratio, mass proportion, volume proportion, power, flow rate, time, pressure, speed, pressure, air volume, rotation speed, spacing, concentration, wavelength, temperature, flow rate, weight part or other value or parameter is expressed as a range, a preferred range, or a range limited by a series of upper preferred values ​​and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any range upper limit or preferred value with any range lower limit or preferred value, regardless of whether the range is disclosed separately. For example, when a range such as "1:1 to 1:10" is disclosed, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within the range, i.e., at least 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, and 1:10.

[0058] In a preferred embodiment, the first pharmaceutical composition further comprises one or more, such as one, two, three, four, or five, antioxidants. In a preferred embodiment, the antioxidant is selected from one or more of the following: butylated hydroxyanisole, butylated hydroxytoluene, sodium metabisulfite, vitamin E, vitamin E acetate, and L-ascorbyl palmitate. In a preferred embodiment, the antioxidant is sodium metabisulfite. In a preferred embodiment, the antioxidant is present in an amount of 0.01% to 3%, for example, about 0.2%, by weight of the first pharmaceutical composition.

[0059] In the present invention, "about" refers to a value within the range of ±5% of a specific value. For example, "about 0.2" includes ±5% of 0.2, that is, from 0.19 to 0.21.

[0060] In a preferred embodiment, the first pharmaceutical composition is in the form of a solid dispersion.

[0061] According to one aspect of the present invention, the present invention provides a second pharmaceutical composition comprising the above-mentioned first pharmaceutical composition, wherein the second pharmaceutical composition further comprises (1) one or more fillers such as 1, 2, 3, 4 or 5 fillers; (2) one or more disintegrants such as 1, 2, 3, 4 or 5 disintegrants; (3) optionally one or more surfactants such as 1, 2, 3, 4 or 5 surfactants; (4) optionally one or more glidants such as 1, 2, 3, 4 or 5 glidants; (5) optionally one or more lubricants such as 1, 2, 3, 4 or 5 lubricants; and (6) optionally one or more film coating premixes such as 1, 2, 3, 4 or 5 film coating premixes.

[0062] In a preferred embodiment, the filler is selected from one or more of the following: lactose (e.g., lactose monohydrate or anhydrous lactose), starch, calcium hydrogen phosphate (e.g., calcium hydrogen phosphate anhydrous or calcium hydrogen phosphate dihydrate), calcium sulfate dihydrate, mannitol, sorbitol, and microcrystalline cellulose. In a preferred embodiment, the microcrystalline cellulose is microcrystalline cellulose PH101. In a preferred embodiment, the disintegrant is selected from one or more of the following: cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone (e.g., cross-linked polyvinylpyrrolidone XL-10, cross-linked polyvinylpyrrolidone CL), pregelatinized starch, and sodium carboxymethyl starch. In a preferred embodiment, the surfactant is sodium lauryl sulfate. In a preferred embodiment, the glidant is colloidal silicon dioxide. In a preferred embodiment, the lubricant is magnesium stearate and / or glyceryl tribehenate.

[0063] In a preferred embodiment, the filler is present in an amount of 30% to 70% by weight of the second pharmaceutical composition. In a preferred embodiment, the filler is present in an amount of 55% to 65% by weight of the second pharmaceutical composition, for example, about 58.5%. In a preferred embodiment, the disintegrant is present in an amount of 6% to 20% by weight of the second pharmaceutical composition. In a preferred embodiment, the disintegrant is present in an amount of 10% to 20% by weight of the second pharmaceutical composition, for example, about 15%. In a preferred embodiment, the surfactant is present in an amount of 1% to 6% by weight of the second pharmaceutical composition. In a preferred embodiment, the glidant is present in an amount of 0.5% to 3% by weight of the second pharmaceutical composition, for example, about 1%. In a preferred embodiment, the lubricant is present in an amount of 0.5% to 3% by weight of the second pharmaceutical composition, for example, about 1.5%. In a preferred embodiment, the film coating premix is ​​present in an amount of 0.5% to 5% by weight of the second pharmaceutical composition, such as about 3%. In a preferred embodiment, the antioxidant is present in an amount of 0.01% to 1% by weight of the second pharmaceutical composition, such as about 0.1%.

[0064] In the present invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 58.5" includes ±5% of 58.5, that is, from 55.575 to 61.425; "about 15" includes ±5% of 15, that is, from 14.25 to 15.75; "about 1" includes ±5% of 1, that is, from 0.95 to 1.05; "about 1.5" includes ±5% of 1.5, that is, from 1.425 to 1.575; "about 3" includes ±5% of 3, that is, from 2.85 to 3.15; "about 0.1" includes ±5% of 0.1, that is, from 0.095 to 0.105.

[0065] In a preferred embodiment, the second pharmaceutical composition is in the form of an oral preparation. In a preferred embodiment, the second pharmaceutical composition is in the form of a solid oral preparation, such as a tablet.

[0066] According to one aspect of the present invention, the present invention provides a method for preparing the above-mentioned first pharmaceutical composition, which comprises the following steps: (a) mixing and dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more polymer materials, such as 1, 2, 3, 4 or 5, one or more solvents, such as 1, 2, 3, 4 or 5, and optionally one or more antioxidants, such as 1, 2, 3, 4 or 5, to form a mixed solution; (b) spray drying the mixed solution to obtain a mixed powder; and (c) vacuum drying or double cone drying the mixed powder to obtain the first pharmaceutical composition.

[0067] In a preferred embodiment, the solvent is selected from one or more of the following: water, methanol, acetone, ethanol, isopropanol, acetonitrile, ethyl acetate, propylene glycol, and dichloromethane. In a preferred embodiment, the solvent is selected from one or more of the following: water, methanol, ethanol, acetone, and dichloromethane. In a preferred embodiment, the solvent is water, methanol, ethanol, acetone, and / or dichloromethane. In a preferred embodiment, the mass ratio of the acetone to the methanol is 1:1 to 3:1, for example, about 2:1. In a preferred embodiment, the solvent is approximately 70% acetone and methanol and approximately 30% water. In a preferred embodiment, the solvent is approximately 40% acetone and methanol and approximately 60% dichloromethane.

[0068] In the present invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 2:1" includes ±5% of 2:1, i.e., from 1.9:1 to 2.1:1; "about 70" includes ±5% of 70, i.e., from 66.5 to 73.5; "about 30" includes ±5% of 30, i.e., from 28.5 to 31.5; "about 40" includes ±5% of 40, i.e., from 38 to 42; "about 60" includes ±5% of 60, i.e., from 57 to 63.

[0069] The saturated solubility of the compounds of the present invention in various solvents / media is shown in Table 1 (Test method: place an appropriate excess of API in an appropriate amount of solvent, shake at room temperature for 24 hours, and then treat the sample solution for analysis and testing). Methanol and acetone are the best choices.

[0070] Table 1 Saturated solubility of the compounds of the present invention in different solvents / mediums

[0071] Table 2 lists solvent compositions capable of simultaneously dissolving the compounds of the present invention and the carrier materials. The solubility of the API in various solvent combinations was tested as follows: 20 mg of the compound of the present invention was weighed and added to 4 mL of various solvents or solvent combinations. The solution was gently shaken and observed for dissolution. If dissolution was complete, a small amount of the API was added to the solution, further shaken, and observed for dissolution. The results showed that the API solubility in the solvent combinations listed in Table 2 was greater than 5 mg / mL. All the carrier materials listed in Table 2 were soluble in the selected solvents or solvent combinations.

[0072] Table 2 Solvent composition capable of simultaneously dissolving the compound of the present invention and the carrier

[0073] In a preferred embodiment, the mass ratio of the solvent to the first pharmaceutical composition is 85:15 to 97:3. In a preferred embodiment, the mass ratio of the solvent to the first pharmaceutical composition is 90:10 to 94:6.

[0074] In a preferred embodiment, the spray drying conditions are: an inlet air temperature of 70°C to 90°C, an outlet air temperature of 45°C to 55°C, a pump power of 20% to 45%, a condenser temperature of -15°C to -5°C, and an atomizing gas flow rate of 3kg / h to 12kg / h. In a preferred embodiment, the vacuum drying conditions are: after the vacuum degree stabilizes at ≤-0.1MPa, drying at 55°C to 65°C for 12h to 48h. In a preferred embodiment, the double-cone drying conditions are: after the vacuum degree stabilizes at ≤-0.1MPa, drying at 55°C to 65°C for 4h to 24h.

[0075] According to one aspect of the present invention, the present invention provides a method for preparing the above-mentioned first pharmaceutical composition, which comprises the following steps: (a) screening and mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more polymer materials, such as 1, 2, 3, 4 or 5, and optionally one or more plasticizers, such as 1, 2, 3, 4 or 5, to obtain a mixture; and (b) setting the temperature of each section of the screw of a hot melt extruder, adjusting the feed rate to 5 rpm to 20 rpm and the screw speed to 20 rpm to 80 rpm, performing hot melt extrusion, and optionally cooling and crushing to obtain the first pharmaceutical composition.

[0076] The compound (API) of the present invention has a melting point of 195-198° C., and is a high-melting-point compound. Therefore, it is necessary to select a carrier material with a suitable glass transition temperature for the development of a hot-melt extrusion process.

[0077] In order to reduce the temperature required for hot melt extrusion and improve melt fluidity, in a preferred embodiment, the plasticizer is selected from one or more of the following: dibutyl sebacate, diethyl phthalate, Pluronic F-68, Pluronic F-127, glyceryl monostearate, polyethylene glycol, sodium lauryl sulfate, sodium octyl butyl sulfonate, triethyl citrate, glyceryl triacetate, Tween 80, and vitamin E-TPGS.

[0078] In a preferred embodiment, the hot melt extrusion temperature is an initial section temperature of 20°C to 40°C, a transmission section temperature of 110°C to 130°C, a mixing section temperature of 160°C to 180°C, a meshing section temperature of 160°C to 180°C, and a transmission discharge section temperature of 150°C to 170°C.

[0079] According to one aspect of the present invention, the present invention provides a method for preparing the above-mentioned first pharmaceutical composition, which comprises the following steps: (a) mixing and dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more polymer materials, such as 1, 2, 3, 4 or 5, and one or more solvents, such as 1, 2, 3, 4 or 5, to form a mixed solution; and (b) removing the solvent using a rotary evaporator at 45°C to 65°C, taking the dried mixture out of the rotary evaporator, grinding it using a mortar, and passing it through an 18-mesh to 80-mesh sieve to obtain the first pharmaceutical composition.

[0080] In a preferred embodiment, the solvent is selected from one or more of the following: water, methanol, acetone, ethanol, isopropanol, acetonitrile, ethyl acetate, propylene glycol, and dichloromethane. In a preferred embodiment, the solvent is selected from one or more of the following: water, methanol, ethanol, acetone, and dichloromethane. In a preferred embodiment, the solvent is water, ethanol, acetone, and / or dichloromethane. In a preferred embodiment, the mass ratio of the acetone to the methanol is 1:1 to 3:1, for example, about 2:1. In a preferred embodiment, the solvent is approximately 70% acetone and methanol and approximately 30% water. In a preferred embodiment, the solvent is approximately 40% acetone and methanol and approximately 60% dichloromethane.

[0081] In a preferred embodiment, the mass ratio of the solvent to the first pharmaceutical composition is 85:15 to 97:3. In a preferred embodiment, the mass ratio of the solvent to the first pharmaceutical composition is 90:10 to 94:6.

[0082] According to one aspect of the present invention, the present invention provides a method for preparing the above-mentioned second pharmaceutical composition, which comprises the following steps: (a) preparing a mixed solution containing a compound of the present invention (API) and one or more polymer materials (optionally, one or more such as 1, 2, 3, 4 or 5 antioxidants), spraying the mixed solution into an appropriate amount of filler and / or disintegrant, drying and sieving to obtain a first drug mixture; and (b) mixing the first drug mixture with suitable fillers, disintegrants and lubricants, etc., further tableting, filling capsules or packaging into granules to obtain tablets, capsules or granules of the second pharmaceutical composition, respectively.

[0083] In a preferred embodiment, the method comprises the following steps: (a) mixing and dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more polymer materials, such as 1, 2, 3, 4 or 5, one or more solvents, such as 1, 2, 3, 4 or 5, and optionally one or more antioxidants, such as 1, 2, 3, 4 or 5, to form a mixed solution; (b) adding the filler and the disintegrant to a fluidized bed and preheating; (c) spraying the mixed solution of the first pharmaceutical composition into the fluidized bed and drying for 10 to 30 minutes; in, sieving the obtained granules; (d) mixing the sieved granules with an appropriate amount of filler, disintegrant, glidant and / or lubricant to obtain a second drug mixture; and (e) optionally, dividing the second drug mixture and tableting to obtain tablets of the second drug composition; (f) optionally, dividing the second drug mixture and filling capsules to obtain capsules of the second drug composition; (g) optionally, dividing the second drug mixture and bagging to obtain granules of the second drug composition.

[0084] In a preferred embodiment, the one-step granulation conditions include a fluidized bed air inlet temperature of 45°C to 75°C, a fluidized bed material temperature of 35°C to 55°C, a fluidized bed air inlet volume of 15m 3 / h~80m 3 / h, the fluidized bed spray rate is 5g / min~50g / min and the fluidized bed atomization pressure is 0.05bar~1.0bar.

[0085] According to one aspect of the present invention, the present invention provides a method for preparing the above-mentioned second pharmaceutical composition, which comprises the following steps: (a) mixing the first pharmaceutical composition with an appropriate amount of filler, disintegrant, glidant and lubricant for a first time to obtain a first pharmaceutical mixture; (b) dry granulating the first pharmaceutical mixture to obtain granules; (c) mixing the granules with an appropriate amount of disintegrant and lubricant for a second time to obtain a second pharmaceutical mixture; and (d) optionally, dividing the second pharmaceutical mixture and tableting to obtain tablets of the second pharmaceutical composition; (e) optionally, dividing the second pharmaceutical mixture and filling capsules to obtain capsules of the second pharmaceutical composition; (f) optionally, dividing the second pharmaceutical mixture and bagging to obtain granules of the second pharmaceutical composition.

[0086] In a preferred embodiment, the first mixing speed is 10 rpm to 20 rpm, and the mixing time is 10 min to 15 min. In a preferred embodiment, the second mixing speed is 10 rpm to 20 rpm, and the mixing time is 2 min to 10 min.

[0087] In a preferred embodiment, in step (a), the disintegrant is cross-linked polyvinylpyrrolidone and pregelatinized starch. In a preferred embodiment, in step (c), the disintegrant is cross-linked polyvinylpyrrolidone.

[0088] In a preferred embodiment, the mass ratio between the crospovidone added in step (a) and the crospovidone added in step (c) is about 1.

[0089] In a preferred embodiment, the mass ratio between the lubricant added in step (a) and the lubricant added in step (c) is about 2.

[0090] In a preferred embodiment, the dry granulation conditions are: hydraulic pressure of 18 bar to 50 bar, roller speed of 3.4 rpm to 14.8 rpm, roller spacing of 1 mm to 4 mm, secondary granulation speed of 24.9 rpm to 108.4 rpm, and primary granulation speed of 10 rpm to 90 rpm.

[0091] In a preferred embodiment, the specification of the primary granulation screen of the dry granulation is 2.0 mm, and the specification of the secondary granulation screen is 0.8 mm.

[0092] According to one aspect of the present invention, the present invention provides a use of the first pharmaceutical composition or the second pharmaceutical composition in the preparation of a medicament for regulating protein kinase and / or treating protein kinase-mediated diseases, disorders and / or pathologies.

[0093] In a preferred embodiment, the disease, disorder and / or pathology is cancer, a vascular disorder, an anoxic disorder, osteoporosis or a disease affecting cell motility, adhesion and cell cycle progression.

[0094] In a preferred embodiment, the cancer is leukemia, lung cancer, liver cancer, endometrial cancer, gastric cancer, rectal cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer or breast cancer.

[0095] In a preferred embodiment, the vascular disorder is myocardial infarction, stroke or ischemia.

[0096] According to one aspect of the present invention, the present invention provides the above-mentioned first pharmaceutical composition or the above-mentioned second pharmaceutical composition for regulating protein kinase and / or treating protein kinase-mediated diseases, disorders and / or pathologies.

[0097] According to one aspect of the present invention, the present invention provides a method for regulating protein kinase and / or treating protein kinase-mediated diseases, disorders and / or pathologies, comprising administering an effective amount of the above-mentioned first pharmaceutical composition or the above-mentioned second pharmaceutical composition to the subject.

[0098] In the present invention, the term "subject" refers to a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects representing models for regulating protein kinases and / or treating protein kinase-mediated diseases, disorders, and / or pathologies. Preferably, the subject is a human.

[0099] The "effective amount" of the pharmaceutical composition or preparation used in the present invention can obtain the desired treatment and / or prevention effect. The amount effective for this purpose will depend on, for example, the pharmaceutical composition, the mode of administration, the stage and severity of the disease to be treated, the individual's body weight and overall health, and the judgment of the prescribing physician. The dosage can be given once a week, or once every two days or every day, or even several times a day. The dosage unit can be given in a short period of time (e.g., several weeks to several months) or a longer period of time (several months to several years).

[0100] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or conditions recommended by the manufacturer.

[0101] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0102] The above-mentioned features of the present invention or the features described in the embodiments may be combined in any combination. All features disclosed in this patent specification may be used in any combination, and each feature disclosed in the specification may be replaced by any alternative feature that can provide the same, equal, or similar purpose. Therefore, unless otherwise specified, the features disclosed are only general examples of equal or similar features.

[0103] Example

[0104] 1. Example of using povidone to prepare solid dispersion

[0105] 1.1 Prescription composition

[0106] Table 3 Summary of Examples of Prescriptions for Preparing Solid Dispersions Using Povidone Note: The batch size of the examples listed in Table 3 is 10 g / batch, and the amount of solvent used is calculated based on the solid content.

[0107] 1.2 Preparation method

[0108] 1.2.1 Preparation method of Example 1

[0109] Weigh the API and PVP K90 into a rotary evaporator. Add an appropriate amount of a 4:1 (w / w) acetone:ethanol mixture to ensure complete dissolution of the API and PVP K90. Remove the solvent using a rotary evaporator at 55°C. Remove the dried mixture from the rotary evaporator, pulverize it, and pass it through a 24-mesh sieve.

[0110] 1.2.2 Preparation method of Example 2

[0111] Weigh the API and PVP K30 into a rotary evaporator. Add an appropriate amount of a 4:1 (w / w) acetone:ethanol mixture to ensure complete dissolution of the API and PVP K30. Remove the solvent using a rotary evaporator at 55°C. Remove the dried mixture from the rotary evaporator, pulverize it, and pass it through a 40-mesh sieve.

[0112] 1.2.3 Preparation methods of Examples 3 to 6

[0113] 1) Prepare materials: weigh API, excipients and solvents according to the prescribed amount.

[0114] 2) Solution Preparation: Prepare a mixed solvent of acetone:methanol = 2:1, add the API to the mixed solvent, and stir magnetically until the solution becomes clear. Then add PVP K30 and continue stirring until dissolved to obtain a clear solution.

[0115] 3) Spray drying:

[0116] a. Start and set the fan power to 80% to 90% and the nitrogen flow valve to 30 to 40 mm to balance the system.

[0117] b. After the system is balanced, set the inlet air temperature to 85°C (70-85°C) for preheating. After the measured temperature reaches the set temperature, spray the mixed solvent of acetone and methanol, adjust the pump power to 20%-45%, and balance the system to an outlet air temperature of 45-55°C.

[0118] c. Spray the drug solution to prepare a solid dispersion.

[0119] 4) Vacuum drying: Collect the sample, transfer it to a vacuum drying oven, and vacuum dry it at 60°C for 24 to 48 hours.

[0120] 1.2.4 Preparation methods of Examples 7 to 8

[0121] Weigh the API and PVP K30 into a rotary evaporator. Add an appropriate amount of a 2:1 (w / w) mixture of acetone and methanol to ensure complete dissolution of the API and PVP K30. Remove the solvent using a rotary evaporator at 55°C. Remove the dried mixture from the rotary evaporator, pulverize it, and pass it through a 24-mesh sieve.

[0122] 1.3 Solubility test

[0123] The powder from Examples 1-7, equivalent to 50 mg of API, was weighed into a 10 mL vial. 5 mL of medium at varying pH values ​​was added to achieve a theoretical API concentration of approximately 10 mg / mL. The solution was shaken on a shaker for 24 hours, and the solubility was measured. The powder was observed for dissolution during the shaking process. If the solution became clear, additional sample powder was added. The results are shown in Table 4.

[0124] Table 4 Solubility of solid dispersions prepared using povidone in different media

[0125] The results showed that the solid dispersion prepared with povidone could solubilize the API when the drug-excipient ratio was between 1:0.5 and 1:10. The preferred drug-excipient ratio was 1:1 to 1:6, and the more preferred ratio was 1:3 to 1:6. 1.4 Comparison of the dissolution curves of the API + PVP physical mixture and the API + PVP solid dispersion

[0126] Preparation method of physical mixture of API:PVP K30=1:6: weigh one part of the compound of the present invention and six parts of povidone K30 and mix them evenly to obtain a physical mixture of the two.

[0127] The dissolution method was paddle method, 75 RPM, 37°C ± 0.5°C, and 900 mL of 0.1 mol / L HCl. The dissolution results are shown in Table 5 and Figure 1.

[0128] Table 5 Dissolution results

[0129] The results showed that in 0.1 mol / L HCl medium, the physical mixture of API and povidone K30 did not dissolve completely, while the solid dispersion could achieve complete dissolution in a short time.

[0130] 1.5 XRPD patterns

[0131] It can be seen from the XRPD patterns that Examples 2 to 8 all formed amorphous substances.

[0132] 2. Example of using Hydroxypropyl Methylcellulose to prepare solid dispersion

[0133] 2.1 Prescription composition

[0134] Table 6 Summary of Examples of Formulas for Preparing Solid Dispersions Using Hydroxypropyl Methylcellulose Note: The batch size of the examples listed in Table 6 is 10 g / batch, and the amount of solvent used is calculated based on the solid content.

[0135] 2.2 Preparation method

[0136] 2.2.1 Preparation methods of Examples 9 to 12

[0137] Weigh the API and HPMC E5 into a rotary evaporator. Add an appropriate amount of a mixed solvent of acetone:methanol (2:1 (w / w)) + dichloromethane (4:6 (w / w)) to ensure complete dissolution of the API and HPMC E5. Remove the solvent using a rotary evaporator at 55°C. Remove the dried mixture from the rotary evaporator, pulverize it, and pass it through a 24-mesh sieve for later use.

[0138] 2.2.2 Preparation method of Example 13

[0139] Dissolution: Weigh the prescribed amount of raw materials and excipients, add hydroxypropyl cellulose E15 to a mixed solvent of (acetone: methanol 2:1): water = 7:3, stir to dissolve, add API after the solution is clear, and stir until the API is completely dissolved to obtain a yellowish clear solution.

[0140] Spray drying: Set the fan frequency to 75% to 85%, the nitrogen flow rate to 590 to 710 L / h, the inlet air temperature to 90 to 125°C, and the spray speed to 3 to 5 g / min for spray drying.

[0141] Drying: After spray drying, collect the sample and dry it in a vacuum drying oven at 60°C for 24 hours (until the residual solvent meets the requirements), then take out the material.

[0142] 2.3 Solubility test

[0143] The powders from Examples 9-13, equivalent to 50 mg of API, were weighed into 10 mL vials. Appropriate volumes of media with varying pH values ​​were added to achieve a theoretical API concentration of approximately 10 mg / mL (the theoretical API concentration in the sample solution of Example 13 was approximately 5 mg / mL). The solution was shaken for 24 hours, and samples were taken at 4 and 24 hours for solubility determination. The powder dissolution in the solution was observed during the shaking process. If the solution became clear, additional sample powder was added. The results are shown in Table 7.

[0144] Table 7 Solubility of solid dispersions prepared using HPMC in different media

[0145] The results showed that solid dispersions prepared using HPMC E5 and HPMC E15 were able to solubilize the API when the drug-excipient ratio was between 1:1 and 1:6. Preferably, the solubilization effect was best when the drug-excipient ratio was between 1:4 and 1:6.

[0146] 2.4 XRPD patterns

[0147] XRPD patterns showed that Examples 9 to 13 all formed amorphous substances.

[0148] 3. Example of preparing solid dispersion using hydroxypropyl cellulose

[0149] 3.1 Prescription composition

[0150] HPC EXF was selected as the carrier material for the preparation of solid dispersions, as shown in Table 8.

[0151] Table 8 Summary of Examples of Formulas for Preparing Solid Dispersions Using Hydroxypropyl Cellulose Note: The batch size of the examples listed in Table 8 is 10 g / batch, and the amount of solvent used is calculated based on the solid content.

[0152] 3.2 Preparation process

[0153] Weigh the API and HPC EXF into a rotary evaporator. Add an appropriate amount of a 2:1 (w / w) mixture of acetone and methanol. Stir to completely dissolve the API and HPC EXF. Remove the solvent using a rotary evaporator at 45-55°C. Remove the dried mixture from the rotary evaporator, pulverize, and pass through a 24-mesh sieve.

[0154] 3.3 Solubility test

[0155] The powders from Examples 14-16, equivalent to 50 mg of the API, were weighed into 10 ml vials. Appropriate volumes of media with varying pH values ​​were added to achieve a theoretical concentration of approximately 10 mg / ml of the API in the sample solution. The solution was shaken for 24 hours, and samples were taken at 4 and 24 hours for solubility determination. The solution was observed for dissolution of the powder during the shaking process. If the solution became clear, additional sample powder was added. The results are shown in Table 9.

[0156] Table 9 Solubility of solid dispersions prepared using HPC in different media

[0157] The results showed that the solid dispersions prepared using HPC EXF could solubilize the API when the drug-excipient ratio was between 1:1 and 1:6.

[0158] 3.4 XRPD patterns

[0159] XRPD patterns showed that Examples 14 to 16 all formed amorphous substances.

[0160] 4. Example of using copolyvidone to prepare solid dispersion

[0161] 4.1 Prescription composition

[0162] Table 10 Summary of examples of formulas for preparing solid dispersions using copolyvidone S630 Note: The batch size of the examples listed in Table 10 is 10 g / batch, and the amount of solvent used is calculated based on the solid content.

[0163] 4.2 Preparation process

[0164] 4.2.1 Preparation Methods of Examples 17 to 18

[0165] Weigh the API and copovidone S630 into a rotary evaporator. Add an appropriate amount of acetone to ensure complete dissolution of the API and copovidone S630. Remove the solvent using a rotary evaporator at 45°C to 55°C. Remove the dried mixture from the rotary evaporator, pulverize, and pass through a 24-mesh sieve.

[0166] 4.2.2 Preparation method of Example 19

[0167] 1) Prepare materials: weigh API, excipients and solvents according to the prescribed amount.

[0168] 2) Solution preparation: Add the API and copolyvidone S630 to a mixed solvent of acetone:methanol = 2:1 and stir until completely dissolved to obtain a clear solution.

[0169] 3) Spray drying:

[0170] a. Start and set the fan power to 80% to 90% and the nitrogen flow valve to 30 to 40 mm to balance the system.

[0171] b. After the system is balanced, set the inlet air temperature to 85°C (70-85°C) for preheating. After the measured temperature reaches the set temperature, spray the mixed solvent of acetone and methanol, adjust the pump power to 20%-45%, and balance the system to an outlet air temperature of 45-55°C.

[0172] c. Spray the drug solution to prepare a solid dispersion. 4) Vacuum drying: Collect the sample, transfer it to a vacuum drying oven, and vacuum dry it at 60°C for 24 to 48 hours.

[0173] 4.2.3 Preparation methods of Examples 20 to 21

[0174] Weigh the API and copovidone S630 into a rotary evaporator. Add an appropriate amount of a 2:1 (w / w) mixture of acetone and methanol to ensure complete dissolution of the API and copovidone S630. Remove the solvent using a rotary evaporator at 55°C. Remove the dried mixture from the rotary evaporator, pulverize, and pass through a 24-mesh sieve.

[0175] 4.3 Solubility test

[0176] The powder from Examples 17-21, equivalent to 50 mg of the API, was weighed into a 10 ml vial. Appropriate volumes of media at varying pH values ​​were added to achieve a theoretical concentration of approximately 10 mg / ml of the API in the sample solution. The solution was shaken on a shaker for 24 hours, and samples were taken at 4 and 24 hours for solubility determination. The solution was observed for dissolution of the powder. If the solution became clear, additional sample powder was added. The results are shown in Table 11.

[0177] Table 11 Solubility of solid dispersions prepared using copolyvidone S630 in different media

[0178] The results showed that solid dispersions prepared using copovidone S630 were able to solubilize the API when the drug-to-excipient ratio was between 1:1 and 1:6. Preferably, the drug-to-excipient ratio was between 1:3 and 1:6.

[0179] 4.4 XRPD patterns

[0180] From the XRPD patterns, it can be seen that Examples 17 to 21 all formed amorphous substances.

[0181] 5. Example of using HPMC AS to prepare solid dispersion

[0182] 5.1 Prescription Composition

[0183] Table 12 Summary of examples of solid dispersions prepared using HPMC AS Note: The batch size of the examples listed in Table 12 is 10 g / batch, and the amount of solvent used is calculated based on the solid content.

[0184] 5.2 Preparation process

[0185] 5.2.1 Preparation Methods of Examples 22 and 24

[0186] Weigh the API and HPMC AS into a rotary evaporator. Add an appropriate amount of a 2:1 (w / w) mixture of acetone and methanol to ensure complete dissolution. Remove the solvent using a rotary evaporator at 55°C. Remove the dried mixture from the rotary evaporator, pulverize, and pass through a 24-mesh sieve.

[0187] 5.2.2 Preparation method of Example 23

[0188] 1) Prepare materials: weigh API, excipients and solvents according to the prescribed amount.

[0189] 2) Solution Preparation: Prepare a mixed solvent of acetone:methanol = 2:1, add the API to the mixed solvent, and stir magnetically until the solution becomes clear. Then add HPMC AS and continue stirring until dissolved to obtain a clear solution.

[0190] 3) Spray drying:

[0191] a. Start and set the fan power to 80% to 90% and the nitrogen flow valve to 30 to 40 mm to balance the system.

[0192] b. After the system is balanced, set the inlet air temperature to 85°C (70-85°C) for preheating. After the measured temperature reaches the set temperature, spray the mixed solvent of acetone and methanol, adjust the pump power to 20%-45%, and balance the system to an outlet air temperature of 45-55°C.

[0193] c. Spray the drug solution to prepare a solid dispersion.

[0194] 4) Vacuum drying: Collect the sample, transfer it to a vacuum drying oven, and vacuum dry it at 60°C for 24 to 48 hours.

[0195] 5.3 Solubility determination

[0196] The powders of Examples 22 to 24, equivalent to 50 mg of the API, were weighed into 10 ml vials. Appropriate volumes of media with different pH values ​​were added so that the theoretical concentration of the API in the sample solution was approximately 10 mg / ml. The solution was shaken on a shaker for 24 h. Samples were taken at 4 h and 24 h to determine the solubility. The results are shown in Table 13.

[0197] Table 13 Solubility of solid dispersions prepared using HPMC AS in different media

[0198] The results showed that the solid dispersions prepared using HPMC AS could solubilize the API when the drug-excipient ratio was between 1:1 and 1:6.

[0199] 5.4 XRPD patterns

[0200] From the XRPD patterns, it can be seen that Examples 22 to 24 all formed amorphous substances.

[0201] 6. Use polyethylene glycol (solid, molecular weight greater than 1000) to prepare solid dispersion

[0202] 6.1 Prescription Composition

[0203] Table 14 Summary of Examples of Formulas for Preparing Solid Dispersions Using Polyethylene Glycol Note: The batch size of the examples listed in Table 14 is 10 g / batch, and the amount of solvent used is calculated based on the solid content.

[0204] 6.2 Preparation process

[0205] Weigh the API and carrier material into a rotary evaporator. Add an appropriate amount of a 2:1 (w / w) mixture of acetone and methanol to ensure complete dissolution. Remove the solvent using a rotary evaporator at 45°C. Remove the dried mixture from the rotary evaporator, pulverize it, and pass it through a 24-mesh sieve for later use.

[0206] 6.3 Solubility determination

[0207] The powder from Examples 25-28, equivalent to 50 mg of the API, was weighed into a 10 ml vial. Appropriate volumes of media at varying pH values ​​were added to achieve a theoretical concentration of approximately 10 mg / ml of the API in the sample solution. The solution was shaken on a shaker for 24 hours, and samples were taken at 4 and 24 hours for solubility determination. The solution was observed for dissolution of the powder. If the solution became clear, additional sample powder was added. The results are shown in Table 15.

[0208] Table 15 Solubility of solid dispersions prepared using polyethylene glycol in different media

[0209] The results showed that the solid dispersions prepared using polyethylene glycol could be solubilized when the drug-excipient ratio was between 1:1 and 1:6.

[0210] 6.4 XRPD patterns

[0211] From the XRPD patterns, it can be seen that Examples 25 to 28 all formed amorphous substances.

[0212] 7. Use polypropylene resin E100 Preparation of solid dispersions

[0213] 7.1 Prescription Composition

[0214] Table 16 Use Summary of prepared solid dispersion formulations Note: The batch size of the examples listed in Table 16 is 10 g / batch, and the amount of solvent used is calculated based on the solid content.

[0215] 7.2 Preparation process

[0216] 1) Prepare materials: weigh API, excipients and solvents according to the prescribed amount.

[0217] 2) Preparation of drug solution: Prepare a mixed solvent of acetone and methanol in a ratio of 2:1, add the API to the mixed solvent, stir magnetically until the solution is clear, and then add Continue stirring until dissolved to obtain a clear solution.

[0218] 3) Spray drying:

[0219] a. Start and set the fan power to 80% to 90% and the nitrogen flow valve to 30 to 40 mm to balance the system.

[0220] b. After the system is balanced, set the inlet air temperature to 85°C (70-85°C) for preheating. After the measured temperature reaches the set temperature, spray the mixed solvent of acetone and methanol, adjust the pump power to 20%-45%, and balance the system to an outlet air temperature of 45-55°C.

[0221] c. Spray the drug solution to prepare a solid dispersion.

[0222] 4) Vacuum drying: Collect the sample, transfer it to a vacuum drying oven, and vacuum dry it at 60°C for 24 h.

[0223] 7.3 Solubility test

[0224] Weigh 50 mg of the powder from Examples 29-30 into a 10 ml vial. Add the corresponding volume of medium at different pH values ​​to achieve a theoretical concentration of approximately 10 mg / ml of API in the sample solution. Shake the solution on a shaker for 24 hours. Samples were taken at 4 and 24 hours to determine solubility. The dissolution of the powder in the solution was observed during the shaking process. If the solution was clear, add an additional amount of sample powder. The results are shown in Table 17.

[0225] Table 17 Use Solubility of prepared solid dispersions in different media

[0226] The results showed that the solid dispersions prepared in Examples 29 and 30 could solubilize API.

[0227] 7.4 XRPD patterns

[0228] From the XRPD patterns, it was found that Examples 29 to 30 formed amorphous substances.

[0229] 8. Example of preparing solid dispersion using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus)

[0230] 8.1 Prescription Composition

[0231] Table 18 Summary of solid dispersion formulations prepared using Soluplus Note: The batch size of the examples listed in Table 18 is 10 g / batch, and the amount of solvent used is calculated based on the solid content.

[0232] 8.2 Preparation process

[0233] 8.2.1 Preparation Methods of Examples 31 and 33

[0234] Weigh the API and Soluplus into a rotary evaporator. Add an appropriate amount of a 2:1 (w / w) mixture of acetone and methanol to ensure complete dissolution. Remove the solvent using a rotary evaporator at 45°C to 55°C. Remove the dried mixture from the rotary evaporator, disperse it, and pass it through a 30-mesh sieve for later use.

[0235] 8.2.2 Preparation method of Example 32

[0236] 1) Prepare materials: weigh API, excipients and solvents according to the prescribed amount.

[0237] 2) Solution Preparation: Prepare a mixed solvent of acetone:methanol = 2:1, add the API to the mixed solvent, and stir magnetically until the solution becomes clear. Then add Soluplus and continue stirring until dissolved to obtain a clear solution.

[0238] 3) Spray drying:

[0239] a. Start and set the fan power to 80% to 90% and the nitrogen flow valve to 30 to 40 mm to balance the system.

[0240] b. After the system is balanced, set the inlet air temperature to 85°C (70-85°C) for preheating. After the measured temperature reaches the set temperature, spray the mixed solvent of acetone and methanol, adjust the pump power to 20%-45%, and balance the system to an outlet air temperature of 45-55°C.

[0241] c. Spray the drug solution to prepare a solid dispersion. 4) Vacuum drying: Collect the sample, transfer it to a vacuum drying oven, and vacuum dry it at 60°C for 24 to 48 hours.

[0242] 8.3 Solubility test

[0243] The powder from Examples 31-33, equivalent to 50 mg of the API, was weighed into a 10 ml vial. Appropriate volumes of media at varying pH values ​​were added to achieve a theoretical concentration of approximately 10 mg / ml of the API in the sample solution. The solution was shaken on a shaker for 24 hours, and samples were taken at 4 and 24 hours for solubility determination. The solution was observed for dissolution of the powder. If the solution became clear, additional sample powder was added. The results are shown in Table 19.

[0244] Table 19 Solubility of solid dispersions prepared using Soluplus in different media

[0245] The results showed that the solid dispersion prepared using Soluplus could solubilize the API when the drug-excipient ratio was between 1:2 and 1:6.

[0246] 8.4 XRPD patterns

[0247] From the XRPD patterns, it can be seen that Examples 31 to 33 all formed amorphous substances.

[0248] 9. Hot melt extrusion prescription and process

[0249] The solid dispersions were prepared using a hot melt extrusion process, and the batch size was 20 g / batch.

[0250] 9.1 Example of preparing solid dispersion using povidone by hot melt extrusion

[0251] 9.1.1 Prescription composition

[0252] Table 20 Prescription Summary

[0253] 9.1.2 Preparation process

[0254] Pass the API and excipients through a 40-mesh sieve twice and mix thoroughly in a ziplock bag. Hot-melt extrusion is performed using the screw section temperatures (as shown in Table 21), with a feed rate of 5-20 rpm and a screw speed of 20-80 rpm. The extruded material is cooled and then pulverized. The pulverized material can be directly filled into capsules or blended with other excipients for tableting.

[0255] Table 21 Hot melt extruder process parameters

[0256] 9.1.33 Test Results

[0257] The results showed that using polyvidone as a carrier material (specific models are PVP K-12 and PVP K-17) and a drug-excipient ratio in the range of 1:1 to 1:10, an amorphous solid dispersion can be prepared by hot melt extrusion.

[0258] The XRPD results show that when the drug-excipient ratio is 1:1 to 1:6, both the API and the carrier material povidone (PVP K-12 and PVP K-17) form amorphous substances.

[0259] 9.2 Example of preparing solid dispersion using copolyvidone by hot melt extrusion

[0260] 9.2.1 Prescription composition

[0261] Table 22 Prescription Summary

[0262] 9.2.2 Preparation process:

[0263] Mix the API and excipients uniformly. Adjust the screw section temperatures of the hot melt extruder to 5-20 rpm and the screw speed to 20-80 rpm for hot melt extrusion. Cool the extruded material and then pulverize it. The pulverized material can be directly filled into capsules or mixed with other excipients for tableting.

[0264] Table 23 Hot melt extruder process parameters

[0265] 9.2.3 Test results

[0266] Copolyvidone S630 can be used to prepare an amorphous solid dispersion by hot melt extrusion within a drug-excipient ratio of 1:1 to 1:10. If necessary, a certain proportion of a plasticizer such as triethyl citrate can be added for hot melt extrusion.

[0267] 9.3 Example of Preparation of Solid Dispersion Using Hydroxypropyl Methylcellulose by Hot Melt Extrusion

[0268] 9.3.1 Prescription composition

[0269] Table 24 Summary of HPMC carrier material prescriptions

[0270] 9.3.2 Preparation process

[0271] Mix the API and excipients uniformly. Adjust the screw section temperatures of the hot melt extruder to 5-20 rpm and the screw speed to 20-80 rpm for hot melt extrusion. Cool the extruded material and then pulverize it. The pulverized material can be directly filled into capsules or mixed with other excipients for tableting.

[0272] Table 25 Hot melt extruder process parameters

[0273] 9.3.3 Test results

[0274] HPMC E3 and HPMC E5 can be used to prepare amorphous solid dispersions by hot melt extrusion within a drug-excipient ratio range of 1:1 to 1:10.

[0275] 9.4 Example of preparing solid dispersion using hydroxypropyl cellulose by hot melt extrusion

[0276] 9.4.1 Prescription composition

[0277] Table 26 Prescription Summary

[0278] 9.4.2 Preparation process

[0279] Pass the API and excipients through a 40-mesh sieve twice and mix thoroughly in a ziplock bag. Hot-melt extrusion is performed using the screw section temperatures (as shown in Table 27), with a feed rate of 5-20 rpm and a screw speed of 20-80 rpm. The extruded material is cooled and then pulverized. The pulverized material can be directly filled into capsules or blended with other excipients for tableting.

[0280] Table 27 Hot Melt Extruder Process Parameters

[0281] 9.4.3 Test results

[0282] XRPD results showed that when the ratio of API to HPC EXF was 1:1, amorphous material was not completely formed; when the drug-excipient ratio was 1:2 to 1:6, the extrudate obtained was amorphous.

[0283] 9.5 Example of preparing solid dispersion using Hydroxypropyl Methylcellulose Acetate Succinate as a carrier material by hot melt extrusion

[0284] 9.5.1 Prescription Composition

[0285] Table 28 Prescription Summary

[0286] 9.5.2 Preparation process

[0287] Mix the API and excipients uniformly. Adjust the screw section temperatures of the hot melt extruder to 5-20 rpm and the screw speed to 20-80 rpm for hot melt extrusion. Cool the extruded material and then pulverize it. The pulverized material can be directly filled into capsules or mixed with other excipients for tableting.

[0288] Table 29 Hot melt extruder process parameters

[0289] 9.5.3 Test results

[0290] HPMC AS can be used to prepare an amorphous solid dispersion by hot melt extrusion within a drug-excipient ratio of 1:1 to 1:6 or a wider range such as 1:1 to 1:10.

[0291] 10. Example of the Second Pharmaceutical Composition

[0292] The first composition obtained by spray drying is typically a loose powder with high static charge and poor fluidity. It is usually necessary to add one or more excipients such as fillers, disintegrants, lubricants, and glidants to improve the fluidity and dissolution rate of the solid dispersion powder, thereby preparing a dosage form suitable for oral administration, such as tablets, capsules, or granules. Commonly used excipients for oral solid dosage forms (including but not limited to) are shown in Table 30.

[0293] Table 30 Commonly used tablet excipients

[0294] The specific embodiments are as follows:

[0295] 10.1 Tablet Examples

[0296] 10.1.1 Tablet Examples 59 and 60

[0297] The prescription composition is shown in Table 31.

[0298] Table 31 Summary of Example Prescriptions

[0299] Preparation process of Example 59 and Example 60

[0300] (1) Preparation of solid dispersion

[0301] Taking into account the yield of the solid dispersion prepared by the spray drying method, the batch size of the solid dispersion is 50 g / batch, and then weighed according to the required amount of tablets.

[0302] Preparation: Weigh povidone, sodium metabisulfite and API in order according to the input amount.

[0303] Solution Preparation: Prepare a 2:1 acetone:methanol mixture. Add the weighed API to a mixing tank and stir until the solution is clear. Add the weighed povidone to the above solution and stir until the solution is clear. Prepare a 10% solids solution for later use.

[0304] Spray drying: set the air inlet temperature to 85°C, the air outlet temperature to 50°C, and the atomizing gas flow rate to 5.5 kg / h (3.0 kg / h to 12.0 kg / h), spray the drug solution to prepare a solid dispersion.

[0305] Vacuum drying: Set the vacuum drying oven temperature to 60°C, vacuum degree ≤-0.1MPa, and dry for 12 to 48 hours (until the residual solvent test is qualified).

[0306] (2) Tablet preparation

[0307] Material preparation: Weigh each material in sequence according to the input quantity.

[0308] Premixing: Add the solid dispersion and internal excipients lactose, microcrystalline cellulose, pregelatinized starch, and colloidal silicon dioxide (added internally) into a mortar and grind to mix.

[0309] Dry granulation: (large tablet method) Use a single punch tablet press to prepare green tablets, crush the green tablets and pass them through a 24 mesh sieve for later use.

[0310] Total mixing: Based on the weight of the granules after drying, convert and weigh the magnesium stearate (external addition). Thoroughly mix the granules after drying and the magnesium stearate (external addition) in a PE bag.

[0311] Tablet pressing: Use Φ8mm round punch and single punch tablet press to press into tablets.

[0312] 10.1.2 Examples of Tablets with Different Drug Loadings

[0313] The prescription composition is shown in Table 32.

[0314] Table 32 Summary of 30mg tablet prescriptions

[0315] Preparation process:

[0316] (1) Preparation of solid dispersion:

[0317] Preparation: Weigh povidone, sodium metabisulfite and API in order according to the input amount.

[0318] Solution Preparation: Prepare a mixed solvent of acetone / methanol (w / w, 2:1). Add the weighed API to a mixing tank and stir until the solution is clear. (Example 65: Dissolve the weighed sodium metabisulfite in 3 times the amount of purified water and add to the mixing tank.) Add the weighed povidone to the mixing tank and stir until the solution is clear. Prepare a 10% solids solution and set aside.

[0319] Spray drying: Set the air inlet temperature to 85°C (80-90°C), the air outlet temperature to 50°C (45-55°C), and the atomizing gas flow rate to 6.0 kg / h (3.0 kg / h-12.0 kg / h). Spray the drug solution to start preparing the API solid dispersion.

[0320] Vacuum drying: Place the API solid dispersion in a vacuum drying oven, set at 60°C, vacuum degree ≤-0.1MPa, and dry for 24 to 48 hours.

[0321] (2) Tablet pressing

[0322] Material preparation: Weigh each material in sequence according to the input quantity.

[0323] Premixing: Add the API solid dispersion, lactose, microcrystalline cellulose, pregelatinized starch, crospovidone (added internally), colloidal silicon dioxide, and magnesium stearate (added internally) to a mixing hopper. Set the speed to 15 rpm and mix for 12 minutes. Collect the material.

[0324] Dry granulation: The first granulation screen is 2.0 mm, and the second granulation screen is 0.8 mm. Set the roller unit to 6.0 (3.4-14.8) rpm, the roller gap to 1.5 (1.0-4.0) mm, the hydraulic pressure to 19 (18-50) bar, and the second granulator to 70.0 (24.9-108.4) rpm, and start granulation.

[0325] Total mixing: Add the dry granules and crospovidone (external) to the mixing hopper, set the mixing speed to 15 rpm, and mix for 5 minutes. After mixing, add magnesium stearate (external) and set the mixing speed to 15 rpm and mix for 2 minutes.

[0326] Tablet pressing: Examples 61-62: 8 mm round punches were used for tablet pressing; Example 63: 9 mm round punches were used for tablet pressing; Examples 64-65: 15.8*8.2 mm punches were used for tablet pressing using a rotary tablet press.

[0327] Coating: Prepare a coating solution with a concentration of 12%; after preheating the coating pot and plain tablets (lining sheets can be added if necessary), set the main engine speed to 12.0 (6.0-20.0) rpm, the inlet air temperature to 60°C (55-65°C), the inlet air volume to 1000 (500-1500) rpm, the exhaust air volume to 1200 (800-2900) rpm, the peristaltic pump spray rate to 30 (10-100) ml / min, the atomization pressure to 0.2 (0.1-0.5) MPa, start spraying, control the tablet bed temperature to 37.0-45.0°C, control the coating weight gain to about 3% (2-4%), and dry and cool.

[0328] The dissolution results of each batch of the experiment are shown in Table 33, and the dissolution curves are shown in Figure 2.

[0329] Table 33 Tablet dissolution results during experimental phase

[0330] Among them, the dissolution method of Examples 61 to 62: paddle method 75 rpm, 0.1 mol / L HCl + 0.1% SDS; the dissolution method of Examples 63 to 65: paddle method 75 rpm, 0.1 mol / L HCl + 0.1% Tween 80.

[0331] 10.1.3 Examples of Tablet Filler Screening

[0332] 10.1.3.1 Example of Filler Dosage Screening

[0333] The tablet examples in this section are based on a tablet prescription with a drug content of 6% and a specification of 30 mg. However, the examples in this section are not restrictive and do not represent the final drug content and specifications of the preparation. They are merely used as examples for illustration.

[0334] 10.1.3.1.1 Prescription Composition

[0335] Table 34 Summary of tablet formulations for filler dosage screening

[0336] 10.1.3.1.2 Preparation Process

[0337] (1) Preparation of solid dispersion

[0338] Preparation: Weigh povidone, sodium metabisulfite and API in order according to the input amount.

[0339] Solution Preparation: Prepare a 2:1 acetone:methanol mixture. Add the weighed API to a mixing tank and stir until the solution is clear. Add the weighed povidone to the above solution and stir until the solution is clear. Prepare a 10% solids solution for later use.

[0340] Spray drying: set the air inlet temperature to 85°C, the air outlet temperature to 50°C, and the atomizing gas flow rate to 5.5 kg / h (3.0 kg / h to 12.0 kg / h), spray the drug solution to prepare a solid dispersion.

[0341] Vacuum drying: Set the vacuum drying oven temperature to 60°C, vacuum degree ≤-0.1MPa, and dry for 12 to 48 hours (until the residual solvent test is qualified).

[0342] (2) Tablet preparation

[0343] Material preparation: Weigh each material in sequence according to the input quantity.

[0344] Premixing: Add the solid dispersion and internal auxiliary materials into the mixing hopper, set the speed to 15 rpm, mix for 8 minutes, and collect the materials.

[0345] Dry granulation: granulation was performed at a hydraulic pressure of 20 bar (18-230 bar), a roller unit of 8 rpm (3.4-14.8 rpm), a roller spacing of 1.5 mm, a first-stage granulation speed of 40 rpm, and a second-stage granulation speed of 50 rpm (24.9-108.4 rpm).

[0346] Total Mixing: Calculate the amount of additional excipients based on the weight of the dry granules and weigh them. Mix the dry granules and additional excipients (except magnesium stearate) in a hopper mixer at 15 rpm for 5 minutes. Add magnesium stearate (external), set the mixing speed to 15 rpm, and mix for 2 minutes.

[0347] Tablet compression: Use a 15.8*8.2mm die and use a single punch tablet press to press into tablets.

[0348] The tablet preparation processes of Examples 66 to 73 are all feasible.

[0349] 10.1.3.1.3 Test Results

[0350] The dissolution data of Examples 64 to 73 are shown in Table 35 and Figure 3 .

[0351] Table 35 Summary of dissolution data for tablet formulations used for filler screening

[0352] The dissolution method of each of the above embodiments is: paddle method at 75 rpm, 0.1 mol / L HCl + 0.1% Tween 80.

[0353] 10.1.3.2 Example of Filler Type Screening

[0354] 10.1.3.2.1 Prescription Composition

[0355] Mannitol, anhydrous calcium hydrogen phosphate, etc. were selected as fillers for tablet preparation. The results are shown in Table 36 and Table 37.

[0356] Table 36: Prescription list for screening of filler types and dosages (1)

[0357] Table 37 Prescription list for screening of filler types and dosages (2)

[0358] 10.1.3.2.2 Preparation Process

[0359] The preparation process of Examples 74 to 84 is the same as that of Examples 66 to 73.

[0360] 10.1.3.2.3 Test Results

[0361] The dissolution results are shown in Table 38, Table 39 and Figures 4 and 5.

[0362] Table 38 Summary of dissolution data for tablet formulations used for screening of filler types and addition methods (1)

[0363] Table 39 Summary of dissolution data of tablet formulations for screening of filler types and addition methods (2)

[0364] The dissolution method of each of the above embodiments is: paddle method at 75 rpm, 0.1 mol / L HCl + 0.1% Tween 80.

[0365] 10.1.4 Example of Tablet Disintegrant Screening

[0366] Four disintegrants, cross-linked polyvinylpyrrolidone (PVPP), pregelatinized starch (P.Starch), cross-linked sodium carboxymethyl cellulose (CC-Na) and sodium carboxymethyl starch (CMS-Na), and their addition methods were investigated.

[0367] 10.1.4.1 Tablet Examples Using Pregelatinized Starch as the Primary Disintegrant

[0368] 10.1.4.1.1 Prescription Composition

[0369] Table 40 Disintegrant P.Starch dosage and addition method

[0370] 10.1.4.1.2 Preparation Process

[0371] The preparation process of Examples 85 to 91 is the same as that of Examples 66 to 73.

[0372] 10.1.4.1.3 Test Results

[0373] The dissolution results are shown in Table 41 and Figure 6.

[0374] Table 41 Summary of dissolution data for tablet formulations investigated using dosage and addition method of disintegrant P.Starch

[0375] The dissolution method of each of the above embodiments is: paddle method at 75 rpm, 0.1 mol / L HCl + 0.1% Tween 80.

[0376] As can be seen from Table 41, in the 0.1 mol / L HCl-0.1% Tween 80 medium, the dissolution becomes faster as the amount of P.Starch increases.

[0377] 10.1.4.2 Tablet Examples Using Crospovidone as a Disintegrant

[0378] 10.1.4.2.1 Prescription Composition

[0379] Table 42: Dosage and addition method of disintegrant cross-linked polyvinylpyrrolidone

[0380] 10.1.4.2.2 Preparation Process

[0381] The preparation process of Examples 85 to 91 is the same as that of Examples 66 to 73.

[0382] 10.1.4.2.3 Test Results

[0383] The dissolution results are shown in Table 43 and Figure 7.

[0384] Table 43 Summary of dissolution data for tablet formulations used to investigate the dosage and addition method of the disintegrant crospovidone

[0385] The dissolution method of each of the above embodiments is: paddle method at 75 rpm, 0.1 mol / L HCl + 0.1% Tween 80.

[0386] As can be seen from Table 43, in the 0.1 mol / L HCl-0.1% Tween 80 medium, the dissolution becomes faster as the amount of cross-linked polyvinylpyrrolidone increases.

[0387] 10.1.5 Example of Antioxidant Screening for Tablet Formulations

[0388] The compound (API) in this invention is susceptible to oxidation. During formulation preparation, a certain amount of antioxidant may be added to slow the oxidation reaction. There are two ways to add the antioxidant: one is to add it to the first pharmaceutical composition, i.e., the solid dispersion; the other is to add it to the excipients of the second pharmaceutical composition, excluding the first pharmaceutical composition.

[0389] 10.1.5.1 Examples of Solid Dispersions Containing Antioxidants

[0390] 10.1.5.1.1 The prescription is shown in Table 44.

[0391] Table 44 Prescription Summary

[0392] 10.1.5.1.2 Preparation process:

[0393] Preparation of drug solution: Prepare a mixed solvent of acetone:methanol = 2:1 (w / w), dissolve the API, povidone and antioxidant in the mixed solvent of acetone:methanol = 2:1 (w / w), and stir until the solution is clear.

[0394] Spray drying: set the air inlet temperature to 85°C, the air outlet temperature to 50°C, and the atomizing gas flow rate to 5.5 kg / h (3.0 kg / h to 12.0 kg / h), spray the drug solution to prepare a solid dispersion.

[0395] Vacuum drying: Set the vacuum drying oven temperature to 60°C, vacuum degree ≤-0.1MPa, and dry for 12 to 48 hours (until the residual solvent test is qualified).

[0396] 10.1.5.1.3 Test Results

[0397] The prepared Examples 98-100 were placed under 40°C / 75% RH conditions, and samples were taken at 10 and 30 days for testing of related substances, with a focus on the levels of oxidative impurities. The experimental results showed that the oxidative impurities in Example 98 increased significantly from 0.20% at 0 day to 0.33% at 10 days and 0.41% at 30 days. The oxidative impurities in Example 99 increased from 0.12% at 0 day to 0.15% at 10 days and 0.20% at 30 days. Compared with the sample of Example 98 without the addition of antioxidants, the increase was significantly reduced, and the level at 0 day was lower than that of Example 98, indicating that the addition of the antioxidants BHA and BHT (in a 1:1 ratio, with a total amount of 0.02% (as a percentage of the total solid dispersion)) to the SDD exerted a significant antioxidant effect on the sample. The oxidative impurities in Example 100 (API:PVP K30=1:4, 0.4% (percentage of the total solid dispersion) of the antioxidant sodium metabisulfite) were all 0.01% at 0 days, 10 days, and 30 days, indicating that the antioxidant sodium metabisulfite exerted a significant antioxidant effect on the SDD sample.

[0398] Therefore, adding antioxidants such as BHA, BHT, and sodium metabisulfite (alone or in combination) to solid dispersion formulations can significantly inhibit the growth of oxidative impurities. Antioxidant levels of 0.01% to 0.5% (of the total solid dispersion) are sufficient to exert antioxidant effects. Other antioxidants, such as Vitamin E, Vitamin E Acetate, and L-ascorbyl palmitate (L-AP), can also provide similar antioxidant effects.

[0399] 10.1.5.2 Examples of Tablets Containing Antioxidants

[0400] 10.1.5.2.1 Example of Tablets Containing Antioxidants

[0401] Table 45 Tablet Example Prescription List Containing Antioxidants

[0402] 10.1.5.2.2 Preparation Process

[0403] The preparation process of Example 101 and Example 102 is the same as the preparation process of Example 65.

[0404] 10.1.5.2.3 Investigating the Changes in Oxidized Impurities in Tablets

[0405] The samples were placed at 40°C / 75% RH and sealed in HDPE bottles. The changes in oxidative impurities were summarized in Table 46 by measuring the related substances in the samples at different time points.

[0406] Table 46 Changes of oxidative impurities in tablets over time

[0407] Example 65, Example 101 and Example 102 were prepared into tablets using the same batch of API. When the amount of the antioxidant sodium metabisulfite added to the prescription exceeded 0.0096%, significant antioxidant effects were exhibited.

[0408] 10.2 Capsule Example

[0409] 10.2.1 Prescription

[0410] Table 47 Example prescription list

[0411] Preparation process:

[0412] (1) Preparation of solid dispersion

[0413] Mix the API and excipients evenly. Set the hot melt extrusion temperature to 160-175°C, adjust the feed rate to 5-20 rpm, and the screw speed to 20-80 rpm for hot melt extrusion. Cool the extruded material, pulverize it, and pass it through a 40-mesh sieve for later use.

[0414] (2) Preparation of the Second Pharmaceutical Composition

[0415] Prepare materials: Weigh the internal excipients lactose, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose according to the prescribed amount. Weigh sodium metabisulfite and dissolve it in purified water to prepare a 2% (w / w) sodium metabisulfite aqueous solution.

[0416] Preparation of sodium metabisulfite-containing granules by fluidized bed one-step granulation method: Add the prescribed amount of lactose, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and sodium lauryl sulfate into the fluidized bed, set the fluidized bed inlet air temperature to 45-75℃, the fluidized bed material temperature to 35-55℃, and adjust the inlet air volume to 15-80m 3 / h, the spraying speed is 5-50g / min and the atomizing pressure is 0.05-1.0bar, and the fluidized bed is granulated in one step. After the spraying is completed, it is dried for 10-30min.

[0417] Total mixing: convert the added particles containing sodium metabisulfite according to the weight of the solid dispersion and weigh them. Add the solid dispersion and the added particles containing sodium metabisulfite into the hopper mixer, set the mixing speed to 15 rpm, and mix for 5 to 8 minutes; calculate and weigh the additional excipients, add them to the above mixture, set the mixing speed to 15 rpm, and mix for 2 to 3 minutes.

[0418] Capsule filling: Take the total mixture and use a capsule filling machine to fill gelatin hard capsules. The capsule size is 00.

[0419] 10.3 Granule Examples

[0420] 10.3.1 Prescription Composition

[0421] Table 48 Prescription composition

[0422] 10.3.2 Preparation process:

[0423] Preparation of drug solution: dissolve the API and carrier excipients in a mixed solvent of acetone:methanol = 2:1, stir until completely dissolved, and obtain a drug solution with a solid content of 5%, which is set aside.

[0424] Fluidized bed granulation: Add lactose, microcrystalline cellulose, sodium carboxymethyl starch and sodium lauryl sulfate to the fluidized bed, set the fluidized bed inlet air temperature to 45-75℃, the fluidized bed material temperature to 35-55℃, and adjust the inlet air volume to 15-80m 3 / h, the spraying speed is 5-50g / min and the atomizing pressure is 0.05-1.0bar, and the fluidized bed is granulated in one step. After the spraying is completed, it is dried for 10-30min and discharged.

[0425] Total mixing: sieve the granules obtained by fluidized bed granulation and mix them with magnesium stearate in a hopper mixer for 2 to 3 minutes to obtain a total mixture.

[0426] Granule packaging: The total mixture is packaged into aluminum foil bags and sealed to obtain granules of the second pharmaceutical composition.

[0427] 10.4 Example of Preparing a Second Pharmaceutical Composition Using Fluidized Bed One-Step Granulation Example of Preparing a Second Pharmaceutical Composition Using Fluidized Bed Granulation (Top Spray Granulation)

[0428] 10.4.1 Formulation Composition of Examples 105-106 (Taking a 1000g Batch as an Example)

[0429] Table 49 Summary of prescription composition

[0430] 10.4.2 Preparation process:

[0431] (1) Fluidized bed one-step granulation:

[0432] Prepare the drug solution: dissolve the API and carrier excipients in a mixed solvent of acetone:methanol = 2:1. Dissolve sodium metabisulfite in 3 times the amount of purified water, add to the above solution, mix well, and obtain a drug solution with a solid content of 10%, which is set aside.

[0433] Fluidized bed granulation: Add fillers lactose, microcrystalline cellulose, and pregelatinized starch into the fluidized bed, set the fluidized bed inlet air temperature to 45-75°C, the fluidized bed material temperature to 35-55°C, and adjust the inlet air volume to 15-80m 3 / h, the spraying speed is 5-50g / min and the atomizing pressure is 0.05-1.0bar, and the fluidized bed is granulated in one step. After the spraying is completed, it is dried for 10-30min and discharged.

[0434] Dry Granulation: Granulates obtained from fluidized bed granulation were screened and mixed with colloidal silicon dioxide and magnesium stearate (added internally) in a hopper mixer. The mixed granules were dry granulated using a dry granulator. The dry granulation parameters were as follows: hydraulic pressure 20 bar (18-230 bar), roller unit 8 rpm (3.4-14.8 rpm), roller gap 1.5 mm, primary granulation speed 40 rpm, secondary granulation speed 50 rpm (24.9-108.4 rpm).

[0435] Total Mixing: Calculate the amount of additional excipients based on the weight of the dry granules and weigh them. Mix the dry granules and additional excipients (except magnesium stearate) in a hopper mixer at 15 rpm for 5 minutes. Add magnesium stearate (external), set the mixing speed to 15 rpm, and mix for 2 minutes.

[0436] Capsule filling: The total mixture is filled into gelatin hard capsules or hydroxypropylmethylcellulose hard capsules to obtain capsules, thereby obtaining capsules of the second pharmaceutical composition.

[0437] 11. Animal PK experiments

[0438] 11.1 Comparison of Bioavailability of Solid Dispersion and API in Dogs

[0439] Based on the solubility of the solid dispersion formulation examples above, the API (dosage form: 10 mg / mL, suspension, API suspended in 0.5% CMC-Na solution) and solid dispersions prepared using PVP K30 (drug-to-excipient ratios of 1:3 and 1:4, respectively) were selected for canine PK studies. The solid dispersions were filled into hard capsules and administered orally to male beagle dogs (fasting, 3 dogs / group) at a dose of 5 mg / kg. 0.3 mL of whole blood was collected at 0, 10, 15, 30 minutes, 1, 2, 3, 4, 6, 8, 12, and 24 hours after dosing. Blood samples were placed in anticoagulant tubes, gently inverted several times, and then placed on wet ice for centrifugation. Within 30 minutes of collection, the samples were centrifuged at approximately 2000 x g for 10 minutes at 4°C to obtain plasma. The resulting plasma samples were immediately separated into two aliquots (~75 μL each) and transferred to cryogenic vials. Samples will be kept on wet ice throughout processing and stored in a freezer at -75 ± 15°C until analysis. The concentration of the test article in plasma samples will be analyzed using LC-MS / MS.

[0440] Table 50 Summary of dog PK data for SDD formulations

[0441] The AUC and Cmax data showed that there were significant differences in the exposure of the active substance after oral administration of the solid dispersion and the API: at a dose of 5 mg / kg, the AUC of animals given the SDD increased 2- to 3-fold, and the C max The increase was 1 to 2 times, proving that the formation of solid dispersions can significantly improve the oral absorption and exposure of active substances.

[0442] 11.2 Tablet PK Study in Dogs

[0443] The tablet formulations of Example 59, Example 60 and Example 65 were selected for dog PK experiments.

[0444] Examples 59 and 60 were orally administered to beagle dogs (male, fasting, 3 animals / group) at a dose of approximately 5 mg / kg. Example 65 was orally administered to beagle dogs (half male and half female, fasting, 8 animals) at a dose of 50 mg / animal (approximately 5 mg / kg). 0.3 mL of whole blood was collected at 0 min, 10 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration. Blood samples were placed in anticoagulant tubes, gently inverted several times, and then placed on wet ice in preparation for centrifugation. Within 30 minutes of collection, the samples were centrifuged at approximately 2000 x g (force) at 4°C for 10 minutes to obtain plasma. The plasma samples obtained by centrifugation were immediately separated into two aliquots (~75 μL each) and transferred to cryogenic vials. The samples were kept on wet ice throughout the processing and stored in a freezer at -75±15°C until analysis. The concentration of the test article in the plasma samples was analyzed using LC-MS / MS.

[0445] Table 51 Summary of dog PK data for tablets

[0446] AUC and C max The data showed that there was a significant difference in the exposure of the active substance after oral administration of the tablet formulation and the API: at a dose of 5 mg / kg or 50 mg / animal, the AUC of the tablet increased by 2-3 times, and the C max The increase was 1.5 to 2.5 times, proving that the tablet formulation prepared using solid dispersion can significantly improve the oral absorption and exposure of the active substance.

[0447] The embodiments of the present invention are described in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only intended to help understand the method of the present invention and its core concept. At the same time, changes or modifications made by those skilled in the art based on the concept of the present invention, the specific implementation methods of the present invention, and the scope of application are all within the scope of protection of the present invention. In summary, the contents of this specification should not be understood as limiting the present invention.

Claims

1. A first pharmaceutical composition comprising a substituted indole-5-phenol derivative, characterized in that: The first pharmaceutical composition comprises (a) a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; and (b) one or more, such as 1, 2, 3, 4 or 5, polymer materials.

2. The first pharmaceutical composition according to claim 1, characterized in that The polymer material is selected from one or more of the following: hydroxypropyl methylcellulose acetate succinate, hydroxyalkyl cellulose, povidone, copovidone, polypropylene resin, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and polyethylene glycol; Preferably, the hydroxypropyl methylcellulose acetate succinate is hydroxypropyl methylcellulose acetate succinate AS-MMP and / or hydroxypropyl methylcellulose acetate succinate AS-MF; Preferably, the hydroxyalkyl cellulose is hydroxypropyl cellulose, hydroxypropyl methyl cellulose and / or hydroxyethyl cellulose; Preferably, the hydroxypropyl cellulose is hydroxypropyl cellulose EXF, hydroxypropyl cellulose HXF and / or hydroxypropyl cellulose LXF; Preferably, the hypromellose is hypromellose E3, hypromellose E5 and / or hypromellose E15; Preferably, the povidone is povidone K25, povidone K30, povidone K-12 and / or povidone K-17; Preferably, the copovidone is copovidone S630; Preferably, the polypropylene resin is polypropylene resin E100; Preferably, the polyethylene glycol is polyethylene glycol 4000 and / or polyethylene glycol 6000; Preferably, the polymer material is povidone K30, hypromellose E3, hypromellose E15, hypromellose acetate succinate AS-MMP, hydroxypropyl cellulose EXF, copolyvidone S630, polyethylene glycol 4000, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or polypropylene resin E100; More preferably, the mass ratio between the compound of formula (I) and the polymer material is 1:1 to 1:10; More preferably, the mass ratio between the compound of formula (I) and the polymer material is 1:1 to 1:6; More preferably, the mass ratio between the compound of formula (I) and the polymer material is 1:3 to 1:

6.

3. The first pharmaceutical composition according to claim 1 or 2, characterized in that: The first pharmaceutical composition further comprises one or more, such as 1, 2, 3, 4 or 5 antioxidants; Preferably, the antioxidant is selected from one or more of the following: butylated hydroxyanisole, butylated hydroxytoluene, sodium metabisulfite, vitamin E, vitamin E acetate and L-ascorbyl palmitate; More preferably, the antioxidant is sodium metabisulfite; Also preferably, the antioxidant is present in an amount of 0.01% to 3%, such as about 0.2%, based on the weight of the first pharmaceutical composition; Particularly preferably, the first pharmaceutical composition is in the form of a solid dispersion.

4. A second pharmaceutical composition comprising the first pharmaceutical composition according to any one of claims 1 to 3, wherein the second pharmaceutical composition further comprises (1) one or more fillers, such as 1, 2, 3, 4 or 5 fillers; (2) one or more disintegrants, such as 1, 2, 3, 4 or 5 disintegrants; (3) one or more, such as 1, 2, 3, 4 or 5, surfactants; (4) one or more optional glidants, such as 1, 2, 3, 4 or 5 glidants; (5) optionally one or more, such as 1, 2, 3, 4 or 5 lubricants; and (6) one or more, such as 1, 2, 3, 4 or 5, film coating premixes; Preferably, the filler is selected from one or more of the following: lactose (e.g., lactose monohydrate or anhydrous lactose), starch, calcium hydrogen phosphate (e.g., anhydrous calcium hydrogen phosphate or dihydrate calcium hydrogen phosphate), calcium sulfate dihydrate, mannitol, sorbitol and microcrystalline cellulose; Preferably, the microcrystalline cellulose is microcrystalline cellulose PH101; Preferably, the disintegrant is selected from one or more of the following: cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone (e.g., cross-linked polyvinylpyrrolidone XL-10, cross-linked polyvinylpyrrolidone CL), pregelatinized starch and sodium carboxymethyl starch; Preferably, the surfactant is sodium dodecyl sulfate; Preferably, the glidant is colloidal silicon dioxide; Preferably, the lubricant is magnesium stearate and / or glyceryl tribehenate; More preferably, the filler is present in an amount of 30% to 70% by weight of the second pharmaceutical composition; More preferably, the filler is present in an amount of 55% to 65%, such as about 58.5%, based on the weight of the second pharmaceutical composition; More preferably, the disintegrant is present in an amount of 6% to 20% by weight of the second pharmaceutical composition; More preferably, the disintegrant is present in an amount of 10% to 20%, such as about 15%, based on the weight of the second pharmaceutical composition; More preferably, the surfactant is present in an amount of 1% to 6% by weight of the second pharmaceutical composition; More preferably, the glidant is present in an amount of 0.5% to 3%, for example about 1%, based on the weight of the second pharmaceutical composition; More preferably, the lubricant is present in an amount of 0.5% to 3%, such as about 1.5%, based on the weight of the second pharmaceutical composition; More preferably, the film coating premix is ​​present in an amount of 0.5% to 5%, for example about 3%, based on the weight of the second pharmaceutical composition; More preferably, the antioxidant is present in an amount of 0.01% to 1%, such as about 0.1%, by weight of the second pharmaceutical composition; Also preferably, the second pharmaceutical composition is in the form of an oral preparation; Also preferably, the second pharmaceutical composition is in the form of a solid oral preparation, such as a tablet or capsule.

5. A method for preparing the first pharmaceutical composition according to any one of claims 1 to 3, characterized in that: The method comprises the following steps: (a) mixing and dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more, such as 1, 2, 3, 4 or 5, polymer materials, one or more, such as 1, 2, 3, 4 or 5, solvents, and optionally one or more, such as 1, 2, 3, 4 or 5, antioxidants to form a mixed solution; (b) spray drying the mixed solution to obtain a mixed powder; and (c) vacuum drying or double cone drying the mixed powder to obtain the first pharmaceutical composition; Preferably, the solvent is selected from one or more of the following: water, methanol, acetone, ethanol, isopropanol, acetonitrile, ethyl acetate, propylene glycol and dichloromethane; Also preferably, the solvent is selected from one or more of the following: water, methanol, ethanol, acetone and dichloromethane; Also preferably, the solvent is water, methanol, ethanol, acetone and / or dichloromethane; Preferably, the mass ratio of the acetone to the methanol is 1:1 to 3:1, for example, about 2:1; Also preferably, the solvent is about 70% acetone and methanol and about 30% water; Also preferably, the solvent is about 40% acetone and methanol and about 60% dichloromethane; Preferably, the mass ratio of the solvent to the first pharmaceutical composition is 85:15 to 97:3; Preferably, the mass ratio of the solvent to the first pharmaceutical composition is 90:10 to 94:6; More preferably, the spray drying conditions are: setting the air inlet temperature to 70°C to 90°C, the air outlet temperature to 45°C to 55°C, the pump power to 20% to 45%, the condenser temperature to -15°C to -5°C, and the atomizing gas flow rate to 3kg / h to 12kg / h; More preferably, the vacuum drying conditions are: drying at 55°C to 65°C for 12h to 48h after the vacuum degree is stabilized at ≤-0.1MPa; More preferably, the double cone drying condition is: after the vacuum degree is stabilized at ≤-0.1 MPa, drying is performed at 55° C. to 65° C. for 4 h to 24 h.

6. A method for preparing the first pharmaceutical composition according to any one of claims 1 to 3, characterized in that: The method comprises the following steps: (a) screening and mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more, such as 1, 2, 3, 4 or 5 polymer materials, and optionally one or more, such as 1, 2, 3, 4 or 5 plasticizers to obtain a mixture; and (b) setting the temperature of each section of the hot melt extruder screw, adjusting the feed rate to 5 rpm to 20 rpm, the screw speed to 20 rpm to 80 rpm, performing hot melt extrusion, and optionally cooling and pulverizing to obtain a first pharmaceutical composition; Preferably, the plasticizer is selected from one or more of the following: dibutyl sebacate, diethyl phthalate, Pluronic F-68, Pluronic F-127, glyceryl monostearate, polyethylene glycol, sodium lauryl sulfate, sodium octyl butyl sulfonate, triethyl citrate, triacetin, Tween 80, vitamin E-TPGS; Preferably, the temperature is 20°C to 40°C in the initial section, 110°C to 130°C in the transmission section, 160°C to 180°C in the mixing section, 160°C to 180°C in the meshing section, and 150°C to 170°C in the transmission and discharge section.

7. A method for preparing the first pharmaceutical composition according to any one of claims 1 to 3, characterized in that: The method comprises the following steps: (a) mixing and dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more polymer materials, such as 1, 2, 3, 4 or 5 polymer materials, and one or more solvents, such as 1, 2, 3, 4 or 5 solvents, to form a mixed solution; and (b) removing the solvent using a rotary evaporator at 45° C. to 65° C., crushing the dried mixture, and passing it through a 18-mesh to 80-mesh sieve to obtain the first pharmaceutical composition; Preferably, the solvent is selected from one or more of the following: water, methanol, acetone, ethanol, isopropanol, acetonitrile, ethyl acetate, propylene glycol and dichloromethane; Also preferably, the solvent is selected from one or more of the following: water, methanol, ethanol, acetone and dichloromethane; Also preferably, the solvent is water, ethanol, acetone and / or dichloromethane; Preferably, the mass ratio of the acetone to the methanol is 1:1 to 3:1, for example, about 2:1; Also preferably, the solvent is about 70% acetone and methanol and about 30% water; Also preferably, the solvent is about 40% acetone and methanol and about 60% dichloromethane; Preferably, the mass ratio of the solvent to the first pharmaceutical composition is 85:15 to 97:3; Also preferably, the mass ratio of the solvent to the first pharmaceutical composition is 90:10 to 94:

6.

8. A method for preparing the second pharmaceutical composition according to claim 4, characterized in that: The method comprises the following steps: spraying the mixed solution of the first pharmaceutical composition according to any one of claims 1 to 3 into an appropriate amount of filler and / or disintegrant, drying and sieving to obtain a first pharmaceutical mixture; and mixing the first pharmaceutical mixture with a suitable filler, disintegrant and lubricant to prepare a second pharmaceutical composition; Preferably, the dosage form of the second pharmaceutical composition is tablets, capsules or granules; Preferably, the method comprises the following steps: (a) mixing and dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more, such as 1, 2, 3, 4 or 5, polymer materials, one or more, such as 1, 2, 3, 4 or 5, solvents, and optionally one or more, such as 1, 2, 3, 4 or 5, antioxidants to form a mixed solution; (b) adding the filler and the disintegrant into a fluidized bed and preheating; (c) spraying the mixed solution of the first pharmaceutical composition into the fluidized bed, drying for 10 to 30 minutes, and sieving the obtained particles; (d) mixing the sieved granules with an appropriate amount of a filler, a disintegrant, a glidant and / or a lubricant to obtain a second drug mixture; and (e) Optionally, dividing and tableting the second drug mixture to obtain tablets of the second drug composition; (f) Optionally, dividing the second drug mixture and filling capsules to obtain capsules of the second drug composition; (g) Optionally, the second drug mixture is divided and bagged to obtain granules of the second drug composition; Preferably, the one-step granulation conditions include a fluidized bed air inlet temperature of 45°C to 75°C, a fluidized bed material temperature of 35°C to 55°C, a fluidized bed air inlet volume of 15m 3 / h~80m 3 / h, the fluidized bed spray rate is 5g / min~50g / min and the fluidized bed atomization pressure is 0.05bar~1.0bar.

9. A method for preparing the second pharmaceutical composition according to claim 4, characterized in that: The method comprises the following steps: (a) mixing the first pharmaceutical composition with appropriate amounts of a filler, a disintegrant, a glidant and a lubricant for a first time to obtain a first pharmaceutical mixture; (b) dry granulating the first drug mixture to obtain granules; (c) mixing the granules with an appropriate amount of a disintegrant and a lubricant for a second time to obtain a second drug mixture; and (d) Optionally, dividing and tableting the second drug mixture to obtain tablets of the second drug composition; (e) Optionally, dividing the second drug mixture and filling capsules to obtain capsules of the second drug composition; (f) Optionally, the second drug mixture is divided and bagged to obtain granules of the second drug composition; Preferably, the first mixing speed is 10 rpm to 20 rpm, and the mixing time is 10 min to 15 min; Preferably, the second mixing speed is 10 rpm to 20 rpm, and the mixing time is 2 min to 10 min; More preferably, in step (a), the disintegrant is cross-linked polyvinylpyrrolidone and pregelatinized starch; More preferably, in step (c), the disintegrant is cross-linked polyvinylpyrrolidone; More preferably, the mass ratio between the cross-linked polyvinylpyrrolidone added in step (a) and the cross-linked polyvinylpyrrolidone added in step (c) is about 1; More preferably, the mass ratio between the lubricant added in step (a) and the lubricant added in step (c) is about 2; Preferably, the dry granulation conditions are: hydraulic pressure of 18 bar to 50 bar, roller speed of 3.4 rpm to 14.8 rpm, roller spacing of 1 mm to 4 mm, secondary granulation speed of 24.9 rpm to 108.4 rpm, primary granulation speed of 10 rpm to 90 rpm; Preferably, the specification of the primary granulation screen of the dry granulation is 2.0 mm, and the specification of the secondary granulation screen is 0.8 mm.

10. Use of the first pharmaceutical composition according to any one of claims 1 to 3 or the second pharmaceutical composition according to claim 4 in the preparation of a medicament for regulating protein kinases and / or treating protein kinase-mediated diseases, disorders and / or pathologies; Preferably, the disease, disorder and / or pathology is cancer, a vascular disorder, an anoxic disorder, osteoporosis or a disease affecting cell motility, adhesion and cell cycle progression; More preferably, the cancer is leukemia, lung cancer, liver cancer, endometrial cancer, gastric cancer, rectal cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer or breast cancer; More preferably, the vascular disorder is myocardial infarction, stroke or ischemia.

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