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

Abstract

The present invention discloses 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.

Description

Technical Field

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

[0002] The compound involved in the present invention is a substituted indole-5-phenol derivative, which is a compound independently developed by the applicant for regulating protein kinase and treating protein kinase-mediated diseases, mainly as a multi-target broad-spectrum anticancer drug. For the related compounds involved in the present invention, see compound patents: ZL 201380069244.9 and ZL 201480026101.4, and their relevant contents can be cited in this patent application.

[0003] In order to increase the efficiency of new drug discovery and research, the applicant has been committed to finding new methods for drug design and drug screening, molecular design, synthesis and anti-cancer activity research of inhibitors. Design and synthesize small molecule anti-tumor drugs based on new pharmacological mechanisms for tumor-specific target proteins. The applicant has analyzed the crystal structures of multiple protein kinases or protein kinase-complexes, and applied computer-aided design and fragment-based drug design methods to design new kinase small molecule inhibitors. Then determine the disease target and target of action for treatment; after model determination, lead compound discovery, lead compound identification, lead compound optimization, etc., finally obtain excellent compounds-candidate drugs. Subsequently, its development work was carried out, including further confirmation of drug targets, amplification synthesis of compounds, 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. Summary of the invention

[0005] In view of this, the present invention provides a first pharmaceutical composition comprising a substituted indole-5-phenol derivative, the first pharmaceutical composition comprising

[0006] (a) a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; and

[0007]

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

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

[0010] Further, the first pharmaceutical composition further comprises one or more antioxidants, such as 1, 2, 3, 4 or 5 antioxidants. Further, 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. Further, the antioxidant is sodium metabisulfite. Further, 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.

[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 premixes.

[0013] Further, 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. Further, the microcrystalline cellulose is microcrystalline cellulose PH101. Further, 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. Further, the surfactant is sodium lauryl sulfate. Further, the glidant is colloidal silicon dioxide. Further, the lubricant is magnesium stearate and / or glyceryl tribehenate.

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

[0015] Further, 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] Further, the solvent is selected from one or more of the following: water, methanol, acetone, ethanol, isopropanol, acetonitrile, ethyl acetate, propylene glycol and dichloromethane. Further, the solvent is selected from one or more of the following: water, methanol, ethanol, acetone and dichloromethane. Further, the solvent is water, methanol, ethanol, acetone and / or dichloromethane. Further, the mass ratio of the acetone to the methanol is 1:1 to 3:1, for example, about 2:1. Further, the solvent is about 70% acetone and methanol and about 30% water. Further, the solvent is about 40% acetone and methanol and about 60% dichloromethane.

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

[0019] Further, the spray drying conditions are: set the inlet air temperature to 70°C to 90°C, the outlet air 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. Further, the vacuum drying conditions are: after the vacuum degree is stabilized at ≤-0.1MPa, dry at 55°C to 65°C for 12h to 48h. Further, the double cone drying conditions are: after the vacuum degree is stabilized at ≤-0.1MPa, dry at 55°C to 65°C for 4h to 24h.

[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 speed to 5rpm to 20rpm, and the screw speed to 20rpm to 80rpm, performing hot melt extrusion, and optionally cooling and crushing to obtain the first pharmaceutical composition.

[0021] Further, 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, vitamin E-TPGS.

[0022] Furthermore, 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 discharging 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 at 45°C to 65°C using a rotary evaporator, crushing the dried mixture, and passing it through a 18-mesh to 80-mesh sieve to obtain the first pharmaceutical composition.

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

[0025] Further, the mass ratio of the solvent to the first pharmaceutical composition is 85:15 to 97:3. Further, 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

[0027] (b) mixing the first drug mixture with a suitable filler, disintegrant and lubricant, and further compressing, filling capsules or packaging into granules to obtain tablets, capsules or granules of the second drug composition.

[0028] Further, 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 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.

[0029] 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.

[0030] 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 the 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 and tableting the second pharmaceutical mixture to obtain tablets of the second pharmaceutical composition; (e) optionally, dividing and filling the second pharmaceutical mixture into capsules to obtain capsules of the second pharmaceutical composition; (f) optionally, dividing and bagging the second pharmaceutical mixture to obtain granules of the second pharmaceutical composition.

[0031] Further, the first mixing has a rotation speed of 10 rpm to 20 rpm and a mixing time of 10 min to 15 min. Further, the second mixing has a rotation speed of 10 rpm to 20 rpm and a mixing time of 2 min to 10 min.

[0032] Further, in step (a), the disintegrant is cross-linked polyvinylpyrrolidone and pregelatinized starch. Further, in step (c), the disintegrant is cross-linked polyvinylpyrrolidone.

[0033] Further, the mass ratio between the cross-linked polyvinylpyrrolidone added in step (a) and the cross-linked polyvinylpyrrolidone added in step (c) is about 1.

[0034] Further, the mass ratio between the lubricant added in step (a) and the lubricant added in step (c) is about 2.

[0035] Furthermore, the conditions of the dry granulation 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.

[0036] Furthermore, 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.

[0037] According to one aspect of the present invention, the present invention provides a use of the above-mentioned first pharmaceutical composition or the above-mentioned second pharmaceutical composition in the preparation of a drug for regulating protein kinase and / or treating protein kinase-mediated diseases, disorders and / or pathologies.

[0038] 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.

[0039] 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.

[0040] Further, the vascular disorder is myocardial infarction, stroke or ischemia. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the description of the embodiments will be briefly introduced below. 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.

[0042] Figure 1 Schematic diagram of the dissolution curves of API+PVP physical mixture and API+PVP solid dispersion.

[0043] Figure 2 Schematic diagram of the dissolution curve during the tablet experiment phase.

[0044] Figure 3 Schematic diagram of the dissolution profile of tablet formulations used for filler screening.

[0045] Figure 4 Schematic diagram of the dissolution curves of tablet formulations in different dissolution media for screening filler types and addition methods (1).

[0046] Figure 5 Schematic diagram of the dissolution curves of tablet formulations in different dissolution media for screening filler types and addition methods (2).

[0047] Figure 6 Schematic diagram of the dissolution curve of the tablet formulation used to investigate the dosage and addition method of the disintegrant P.Starch.

[0048] Figure 7 Schematic diagram of the dissolution curve of the tablet formulation used to investigate the dosage and addition method of the disintegrant cross-linked polyvinylpyrrolidone. DETAILED DESCRIPTION

[0049] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0050] 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.

[0051] Unless otherwise indicated, all technical and scientific terms and abbreviations used herein have the meanings commonly understood by those of ordinary skill in the field of the invention or the field in which the terms are used. Although any methods, conditions, substances or materials similar to or equivalent to those disclosed herein may be used in the practice of the present invention, preferred methods, conditions, substances or materials are described herein.

[0052] In the present invention, the term "comprising" is synonymous with "including". As used herein, the terms "comprising", "including", "having", "containing" or any other variation thereof are intended to cover a non-exclusive inclusion. For example, a composition, medicinal material, component, step, method, article or device comprising the listed elements is not necessarily limited to only those elements, but may include other elements not explicitly listed or elements inherent to such composition, medicinal material, component, step, method, article or device.

[0053] The auxiliary materials involved in the present invention are only enumerated, and 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 conditions, and all can achieve the effects of the present invention and are within the protection scope of the present invention.

[0054] As described in the background technology section, 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. In order to solve the above problem, the present invention provides a first pharmaceutical composition comprising a substituted indole-5-phenol derivative. The first pharmaceutical composition comprises

[0055] (a) a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; and

[0056]

[0057] (b) one or more, such as 1, 2, 3, 4 or 5, polymer materials.

[0058] In a preferred embodiment, the polymer material is selected from one or more of the following: hydroxypropyl methylcellulose acetate succinate, hydroxyalkyl cellulose, povidone, copolyvidone, polypropylene resin, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and polyethylene glycol. In a preferred embodiment, the hydroxypropyl methylcellulose acetate succinate is hydroxypropyl methylcellulose acetate succinate AS-MMP and / or hydroxypropyl methylcellulose acetate succinate AS-MF. In a preferred embodiment, the hydroxyalkyl cellulose is hydroxypropyl cellulose, hydroxypropyl methylcellulose 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 hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E3, hydroxypropyl methylcellulose E5 and / or hydroxypropyl methylcellulose 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, hydroxypropyl methylcellulose E3, hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose acetate succinate AS-MMP, hydroxypropyl cellulose EXF, copovidone S630, polyethylene glycol 4000, polyethylene caprolactam-polyvinyl acetate-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.

[0059] 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 portion or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper preferred values ​​and lower preferred values, it 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.

[0060] In a preferred embodiment, the first pharmaceutical composition further comprises one or more antioxidants, such as 1, 2, 3, 4 or 5 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%, such as about 0.2%, based on the weight of the first pharmaceutical composition.

[0061] In the present invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 0.2" includes ±5% of 0.2, i.e., from 0.19 to 0.21.

[0062] In a preferred embodiment, the first pharmaceutical composition is in the form of a solid dispersion.

[0063] 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 premixes.

[0064] 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.

[0065] 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%, such as about 3%, based on the weight of the second pharmaceutical composition. In a preferred embodiment, the antioxidant is present in an amount of 0.01% to 1%, such as about 0.1%, based on the weight of the second pharmaceutical composition.

[0066] In the present invention, "about" refers to a value within the range of ±5% of a specific value. For example, "about 58.5" includes ±5% of 58.5, i.e., from 55.575 to 61.425; "about 15" includes ±5% of 15.

[0067] ±5%, i.e., from 14.25 to 15.75; "about 1" includes ±5% of 1, i.e., from 0.95 to 1.05;

[0068] “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.

[0069] 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.

[0070] 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.

[0071] 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 about 70% acetone and methanol and about 30% water. In a preferred embodiment, the solvent is about 40% acetone and methanol and about 60% dichloromethane.

[0072] 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.

[0073] The saturated solubility of the compounds of the present invention in different solvents / mediums is shown in Table 1 (detection method: place an appropriate excess of API in an appropriate amount of solvent, shake at room temperature for 24 hours, and analyze and detect the sample solution after treatment). Among them, methanol and acetone are the best choices.

[0074] Table 1 Saturated solubility of the compounds of the present invention in different solvents / mediums

[0075] Solvent or medium name Solubility (mg / mL) Solubility Methanol 8.36 Slightly soluble Ethanol 5.17 Slightly soluble Isopropyl alcohol 2.34 Slightly soluble acetone 5.99 Slightly soluble Acetonitrile 1.22 Slightly soluble Ethyl acetate 4.98 Slightly soluble Propylene glycol 2.22 Slightly soluble

[0076] The composition of solvents capable of simultaneously dissolving the compound of the present invention and the carrier material is shown in Table 2. The solubility test method of API in different solvent combinations is as follows: 20 mg of the compound of the present invention is weighed and added to 4 mL of different solvents or solvent combinations, respectively, and gently shaken to observe the dissolution phenomenon. If the dissolution is complete, a small amount of API is added to the above solution, and the shaking is continued to observe the dissolution phenomenon. The results show that the solubility of API in the solvent combinations listed in Table 2 is greater than 5 mg / ml.

[0077] The support materials listed in Table 2 are all soluble in the selected solvent or solvent combination.

[0078] Table 2 Solvent composition capable of simultaneously dissolving the compound of the present invention and the carrier

[0079]

[0080] 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.

[0081] In a preferred embodiment, the spray drying conditions are: setting the inlet air temperature to 70°C to 90°C, the outlet air 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. In a preferred embodiment, the vacuum drying conditions are: after the vacuum degree is stabilized 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 is stabilized at ≤-0.1MPa, drying at 55°C to 65°C for 4h to 24h.

[0082] 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 speed to 5rpm to 20rpm, and the screw speed to 20rpm to 80rpm, performing hot melt extrusion, and optionally cooling and crushing to obtain the first pharmaceutical composition.

[0083] The compound (API) of the present invention has a melting point of 195-198° C., and is a high melting point compound. It is necessary to select a carrier material with a suitable glass transition temperature for the development of a hot melt extrusion process.

[0084] In order to reduce the temperature required for hot melt extrusion and improve the molten 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, triacetin, Tween 80, vitamin E-TPGS.

[0085] In a preferred embodiment, the hot melt extrusion 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 discharge section.

[0086] 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 at 45°C to 65°C using a rotary evaporator, taking out the spin-dried mixture from the rotary evaporator, grinding it with a mortar, and passing it through a 18-mesh to 80-mesh sieve to obtain the first pharmaceutical composition.

[0087] 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 about 70% acetone and methanol and about 30% water. In a preferred embodiment, the solvent is about 40% acetone and methanol and about 60% dichloromethane.

[0088] 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.

[0089] 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.

[0090] 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, one or more solvents, and optionally one or more antioxidants, 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 particles; (d) mixing the sieved particles with an appropriate amount of filler, disintegrant, glidant and / or 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 and filling capsules with the second drug mixture to obtain capsules of the second drug composition; (g) optionally, dividing and bagging the second drug mixture to obtain granules of the second drug composition.

[0091] 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.

[0092] 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 the 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 and tableting the second pharmaceutical mixture to obtain tablets of the second pharmaceutical composition; (e) optionally, dividing and filling the second pharmaceutical mixture into capsules to obtain capsules of the second pharmaceutical composition; (f) optionally, dividing and bagging the second pharmaceutical mixture to obtain granules of the second pharmaceutical composition.

[0093] 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.

[0094] 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.

[0095] In a preferred embodiment, the mass ratio between the cross-linked polyvinylpyrrolidone added in step (a) and the cross-linked polyvinylpyrrolidone added in step (c) is about 1.

[0096] In a preferred embodiment, the mass ratio between the lubricant added in step (a) and the lubricant added in step (c) is about 2.

[0097] 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.

[0098] 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.

[0099] According to one aspect of the present invention, the present invention provides a use of the above-mentioned first pharmaceutical composition or the above-mentioned second pharmaceutical composition in the preparation of a drug for regulating protein kinase and / or treating protein kinase-mediated diseases, disorders and / or pathologies.

[0100] 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.

[0101] 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.

[0102] In a preferred embodiment, the vascular disorder is myocardial infarction, stroke or ischemia.

[0103] 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.

[0104] 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.

[0105] In the present invention, the term "subject" is a mammal. The mammal may 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.

[0106] 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., weeks to months) or longer time periods (months to years).

[0107] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out according to conventional conditions or conditions recommended by the manufacturer.

[0108] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0109] The above features mentioned in the present invention or the features mentioned in the embodiments can be combined in any way. All the features disclosed in this patent specification can be used in combination with any combination form, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features.

[0110] Example

[0111] 1. Example of using polyvidone to prepare solid dispersion

[0112] 1.1 Prescription composition

[0113] Table 3 Summary of examples of formulas for preparing solid dispersions using polyvidone

[0114]

[0115] 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.

[0116] 1.2 Preparation method

[0117] 1.2.1 Preparation method of Example 1

[0118] Weigh API and PVP K90 into a rotary evaporator, add an appropriate amount of acetone: ethanol = 4:1 (w / w) mixed solvent to ensure that API and PVP K90 are completely dissolved, and use a rotary evaporator to remove the solvent at 55°C. Take the dried mixture out of the rotary evaporator, crush it, and pass it through a 24-mesh sieve to obtain the product.

[0119] 1.2.2 Preparation method of Example 2

[0120] Weigh API and PVP K30 into a rotary evaporator, add an appropriate amount of acetone: ethanol = 4:1 (w / w) mixed solvent to ensure that API and PVP K30 are completely dissolved, and use a rotary evaporator to remove the solvent at 55°C. Take the dried mixture out of the rotary evaporator, crush it, and pass it through a 40-mesh sieve to obtain the product.

[0121] 1.2.3 Preparation methods of Examples 3 to 6

[0122] 1) Material preparation: weigh API, excipients and solvents according to the prescribed amount.

[0123] 2) Preparation of drug solution: prepare a mixed solvent according to acetone:methanol=2:1, add API to the mixed solvent, stir magnetically until the solution is clear, then add PVP K30, continue stirring until dissolved, and obtain a clear solution.

[0124] 3) Spray drying:

[0125] a. Start and set the fan power to 80% to 90%, the nitrogen flow valve to 30 to 40 mm, and balance the system.

[0126] b. After the system is balanced, set the inlet air temperature to 85℃ (70~85℃) 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℃.

[0127] c. Spray the drug solution to prepare a solid dispersion.

[0128] 4) Vacuum drying: Collect the samples, transfer them to a vacuum drying oven, and vacuum dry them at 60°C for 24 to 48 hours.

[0129] 1.2.4 Preparation methods of Examples 7 to 8

[0130] Weigh API and PVP K30 into a rotary evaporator, add an appropriate amount of acetone:methanol = 2:1 (w / w) mixed solvent to ensure that API and PVP K30 are completely dissolved, and use a rotary evaporator to remove the solvent at 55°C. Take the dried mixture out of the rotary evaporator, crush it, and pass it through a 24-mesh sieve to obtain the product.

[0131] 1.3 Solubility test

[0132] Weigh the powder of Examples 1 to 7 equivalent to 50 mg of API weight into a 10 mL vial, add 5 mL of medium with different pH values, so that the theoretical concentration of API in the sample solution is about 10 mg / mL, shake on a shaker for 24 hours, and measure the solubility. During the shaking process, observe the dissolution of the powder in the solution. If the solution is clear, add a certain amount of sample powder. The results are shown in Table 4.

[0133] Table 4 Solubility of solid dispersions prepared using polyvidone in different media

[0134]

[0135] The results showed that the solid dispersion prepared with povidone can solubilize API when the drug-excipient ratio is between 1:0.5 and 1:10. The preferred drug-excipient ratio is 1:1 to 1:6, and the more preferred ratio is 1:3 to 1:6. 1.4 Comparison of dissolution curves of API+PVP physical mixture and API+PVP solid dispersion

[0136] API:PVP K30=1:6 physical mixture preparation method: 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.

[0137] The dissolution method was: paddle method, 75 RPM, 37°C ± 0.5°C, 900 mL of 0.1 mol / L HCl medium. The dissolution results are shown in Table 5 and Figure 1 shown.

[0138] Table 5 Dissolution results

[0139]

[0140] The results showed that in 0.1 mol / L HCl medium, the physical mixture of API and povidone K30 was not completely dissolved, but after forming a solid dispersion, complete dissolution could be achieved in a short time.

[0141] 1.5XRPD spectrum

[0142] It can be seen from the XRPD spectrum that Examples 2 to 8 all formed amorphous substances.

[0143] 2. Example of using Hydroxypropyl Methylcellulose to prepare solid dispersion

[0144] 2.1 Prescription composition

[0145] Table 6 Summary of examples of formulas for preparing solid dispersions using hydroxypropyl methylcellulose

[0146]

[0147]

[0148] 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.

[0149] 2.2 Preparation method

[0150] 2.2.1 Preparation methods of Examples 9 to 12

[0151] Weigh API and HPMC E5 into a rotary evaporator, add an appropriate amount of a mixed solvent of acetone:methanol = 2:1 (w / w) + dichloromethane (ratio 4:6 (w / w)), ensure that API and HPMC E5 are completely dissolved, and remove the solvent using a rotary evaporator at 55°C. Take the dried mixture out of the rotary evaporator, crush it and pass it through a 24-mesh sieve for later use.

[0152] 2.2.2 Preparation method of Example 13

[0153] 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.

[0154] Spray drying: Set the blower frequency to 75% to 85%, the nitrogen flow rate to 590 to 710 L / h, the air inlet temperature to 90 to 125°C, and the spray speed to 3 to 5 g / min for spray drying.

[0155] Drying: After spray drying, collect the samples and dry them in a vacuum drying oven at 60°C for 24 hours (until the residual solvent is qualified), then take out the materials.

[0156] 2.3 Solubility test

[0157] Weigh the powder of Examples 9 to 13 equivalent to 50 mg of API weight into a 10 mL vial, add the corresponding volume of medium with different pH values ​​so that the theoretical concentration of API in the solution is about 10 mg / mL (the theoretical concentration of API in the sample solution of Example 13 is about 5 mg / ml), shake on a shaker for 24 hours, and take samples at 4 hours and 24 hours to measure the solubility. Observe the dissolution of the powder in the solution during the shaking process. If the solution is clear, add a certain amount of sample powder. The results are shown in Table 7.

[0158] Table 7 Solubility of solid dispersions prepared using HPMC in different media

[0159]

[0160]

[0161] The results showed that the solid dispersions prepared using HPMC E5 and HPMC E15 can solubilize API when the drug-excipient ratio is between 1:1 and 1:6. Preferably, the solubilization effect is best when the drug-excipient ratio is between 1:4 and 1:6.

[0162] 2.4 XRPD spectrum

[0163] XRPD spectra showed that Examples 9 to 13 all formed amorphous substances.

[0164] 3. Example of using hydroxypropyl cellulose to prepare solid dispersion

[0165] 3.1 Prescription composition

[0166] HPC EXF was selected as the carrier material for the preparation of solid dispersion, as shown in Table 8.

[0167] Table 8 Summary of examples of formulas for preparing solid dispersions using hydroxypropyl cellulose

[0168]

[0169] 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.

[0170] 3.2 Preparation process

[0171] Weigh API and HPC EXF into a rotary evaporator, add an appropriate amount of acetone:methanol = 2:1 (w / w) mixed solvent, stir to completely dissolve API and HPC EXF, and use a rotary evaporator to remove the solvent at 45-55°C. Take the dried mixture out of the rotary evaporator, crush it, and pass it through a 24-mesh sieve.

[0172] 3.3 Solubility test

[0173] Weigh the powder of Examples 14 to 16 equivalent to 50 mg of API weight into a 10 ml vial, add the corresponding volume of medium with different pH values ​​so that the theoretical concentration of API in the sample solution is about 10 mg / ml, shake in a shaker for 24 hours, and take samples at 4 hours and 24 hours to measure the solubility. During the shaking process, observe the dissolution of the powder in the solution. If the solution is clear, add a certain amount of sample powder. The results are shown in Table 9.

[0174] Table 9 Solubility of solid dispersions prepared using HPC in different media

[0175]

[0176] The results showed that the solid dispersions prepared using HPC EXF could solubilize API when the drug-excipient ratio was between 1:1 and 1:6.

[0177] 3.4 XRPD spectrum

[0178] XRPD patterns showed that Examples 14 to 16 all formed amorphous substances.

[0179] 4. Example of using copolyvidone to prepare solid dispersion

[0180] 4.1 Prescription composition

[0181] Table 10 Summary of examples of formulas for preparing solid dispersions using copolyvidone S630

[0182]

[0183] 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.

[0184] 4.2 Preparation process

[0185] 4.2.1 Preparation methods of Examples 17 to 18

[0186] Weigh API and copovidone S630 into a rotary evaporator, add an appropriate amount of acetone to ensure that API and copovidone S630 are completely dissolved, and use a rotary evaporator to remove the solvent at 45°C to 55°C. Take the dried mixture out of the rotary evaporator, crush it, and pass it through a 24-mesh sieve.

[0187] 4.2.2 Preparation method of Example 19

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

[0189] 2) Preparation of drug solution: Add API and copolyvidone S630 into a mixed solvent of acetone:methanol=2:1, stir until completely dissolved to obtain a clear solution.

[0190] 3) Spray drying:

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

[0192] b. After the system is balanced, set the inlet air temperature to 85℃ (70~85℃) 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℃.

[0193] 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.

[0194] 4.2.3 Preparation methods of Examples 20 to 21

[0195] Weigh API and copolyvidone S630 into a rotary evaporator, add an appropriate amount of acetone:methanol = 2:1 (w / w) mixed solvent to ensure that API and copolyvidone S630 are completely dissolved, and use a rotary evaporator to remove the solvent at 55°C. Take the dried mixture out of the rotary evaporator, crush it, and pass it through a 24-mesh sieve.

[0196] 4.3 Solubility test

[0197] Weigh the powder of Examples 17 to 21 equivalent to 50 mg of API weight into a 10 ml vial, add the corresponding volume of medium with different pH values ​​so that the theoretical concentration of API in the sample solution is about 10 mg / ml, shake in a shaker for 24 hours, and take samples at 4 hours and 24 hours to measure the solubility. During the shaking process, observe the dissolution of the powder in the solution. If the solution is clear, add a certain amount of sample powder. The results are shown in Table 11.

[0198] Table 11 Solubility of solid dispersions prepared using copolyvidone S630 in different media

[0199]

[0200]

[0201] The results show that the solid dispersion prepared using copovidone S630 can solubilize the API when the drug-excipient ratio is between 1:1 and 1:6. Preferably, the drug-excipient ratio is 1:3 to 1:6.

[0202] 4.4 XRPD spectrum

[0203] It can be seen from the XRPD spectrum that Examples 17 to 21 all formed amorphous substances.

[0204] 5. Example of preparing solid dispersion using HPMC AS

[0205] 5.1 Prescription composition

[0206] Table 12 Summary of examples of solid dispersions prepared using HPMC AS

[0207]

[0208] 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.

[0209] 5.2 Preparation process

[0210] 5.2.1 Preparation methods of Example 22 and Example 24

[0211] Weigh API and HPMC AS into a rotary evaporator, add an appropriate amount of acetone:methanol = 2:1 (w / w) mixed solvent to ensure that API and HPMC AS are completely dissolved, and use a rotary evaporator to remove the solvent at 55°C. Take the dried mixture out of the rotary evaporator, crush it, and pass it through a 24-mesh sieve.

[0212] 5.2.2 Preparation method of Example 23

[0213] 1) Material preparation: weigh API, excipients and solvents according to the prescribed amount.

[0214] 2) Preparation of drug solution: Prepare a mixed solvent according to acetone:methanol=2:1, add API to the mixed solvent, stir magnetically until the solution is clear, then add HPMC AS, continue stirring until dissolved, and obtain a clear solution.

[0215] 3) Spray drying:

[0216] a. Start and set the fan power to 80% to 90%, the nitrogen flow valve to 30 to 40 mm, and balance the system.

[0217] b. After the system is balanced, set the inlet air temperature to 85℃ (70~85℃) 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℃.

[0218] c. Spray the drug solution to prepare a solid dispersion.

[0219] 4) Vacuum drying: Collect the samples, transfer them to a vacuum drying oven, and vacuum dry them at 60°C for 24 to 48 hours.

[0220] 5.3 Solubility determination

[0221] The powder of Examples 22 to 24 equivalent to 50 mg of API was weighed into a 10 ml vial, and the corresponding volume of medium with different pH values ​​was added so that the theoretical concentration of API in the sample solution was about 10 mg / ml. The solution was shaken on a shaker for 24 h, and samples were taken at 4 h and 24 h to determine the solubility. The results are shown in Table 13.

[0222] Table 13 Solubility of solid dispersions prepared using HPMC AS in different media

[0223]

[0224] The results showed that the solid dispersions prepared using HPMC AS could solubilize API when the drug-excipient ratio was between 1:1 and 1:6.

[0225] 5.4 XRPD spectrum

[0226] It can be seen from the XRPD spectrum that Examples 22 to 24 all formed amorphous substances.

[0227] 6. Preparation of solid dispersion using polyethylene glycol (solid, molecular weight greater than 1000)

[0228] 6.1 Prescription composition

[0229] Table 14 Summary of examples of formulas for preparing solid dispersions using polyethylene glycol

[0230]

[0231]

[0232] 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.

[0233] 6.2 Preparation process

[0234] Weigh the API and carrier material into a rotary evaporator, add an appropriate amount of acetone:methanol = 2:1 (w / w) mixed solvent to ensure that the API and carrier material are completely dissolved, and use a rotary evaporator to remove the solvent at 45°C. Take the dried mixture out of the rotary evaporator, crush it, and pass it through a 24-mesh sieve for later use.

[0235] 6.3 Solubility determination

[0236] Weigh the powder of Examples 25 to 28 equivalent to 50 mg of API weight into a 10 ml vial, add the corresponding volume of medium with different pH values ​​so that the theoretical concentration of API in the sample solution is about 10 mg / ml, shake in a shaker for 24 hours, and take samples at 4 hours and 24 hours to measure the solubility. During the shaking process, observe the dissolution of the powder in the solution. If the solution is clear, add a certain amount of sample powder. The results are shown in Table 15.

[0237] Table 15 Solubility of solid dispersions prepared using polyethylene glycol in different media

[0238]

[0239] 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.

[0240] 6.4 XRPD spectrum

[0241] It can be seen from the XRPD spectrum that Examples 25 to 28 all formed amorphous substances.

[0242] 7. Use polypropylene resin E100 ( E100) Preparation of solid dispersion

[0243] 7.1 Prescription composition

[0244] Table 16 Use Summary of solid dispersion formulations prepared by E100

[0245]

[0246] 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.

[0247] 7.2 Preparation process

[0248] 1) Material preparation: weigh API, excipients and solvents according to the prescribed amount.

[0249] 2) Preparation of drug solution: Prepare a mixed solvent of acetone:methanol=2:1, add API to the mixed solvent, stir magnetically until the solution is clear, and then add E100, continue stirring until dissolved to obtain a clear solution.

[0250] 3) Spray drying:

[0251] a. Start and set the fan power to 80% to 90%, the nitrogen flow valve to 30 to 40 mm, and balance the system.

[0252] b. After the system is balanced, set the inlet air temperature to 85℃ (70~85℃) 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℃.

[0253] c. Spray the drug solution to prepare a solid dispersion.

[0254] 4) Vacuum drying: Collect the samples, transfer them to a vacuum drying oven, and vacuum dry them at 60°C for 24 h.

[0255] 7.3 Solubility test

[0256] Weigh the powder of Examples 29-30 equivalent to 50 mg of API weight into a 10 ml vial, add the corresponding volume of medium with different pH values ​​so that the theoretical concentration of API in the sample solution is about 10 mg / ml, shake on a shaker for 24 hours, and take samples at 4 hours and 24 hours to measure the solubility. Observe the dissolution of the powder in the solution during the shaking process. If the solution is clear, add a certain amount of sample powder. The results are shown in Table 17

[0257] Table 17 Use Solubility of solid dispersions prepared by E100 in different media

[0258]

[0259] The results showed that the solid dispersions prepared in Examples 29 and 30 could solubilize API.

[0260] 7.4 XRPD spectrum

[0261] It can be seen from the XRPD spectrum that Examples 29 to 30 formed amorphous substances.

[0262] 8. Example of preparing solid dispersion using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus)

[0263] 8.1 Prescription composition

[0264] Table 18 Summary of solid dispersion formulations prepared using Soluplus

[0265]

[0266] 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.

[0267] 8.2 Preparation process

[0268] 8.2.1 Preparation methods of Examples 31 and 33

[0269] Weigh API and Soluplus into a rotary evaporator, add an appropriate amount of acetone:methanol = 2:1 (w / w) mixed solvent to ensure that API and Soluplus are completely dissolved, and use a rotary evaporator to remove the solvent at 45℃~55℃. Take the dried mixture out of the rotary evaporator, disperse it, and pass it through a 30-mesh sieve for later use.

[0270] 8.2.2 Preparation method of Example 32

[0271] 1) Material preparation: weigh API, excipients and solvents according to the prescribed amount.

[0272] 2) Preparation of drug solution: Prepare a mixed solvent according to acetone:methanol=2:1, add API to the mixed solvent, stir magnetically until the solution is clear, then add Soluplus, continue stirring until dissolved, and obtain a clear solution.

[0273] 3) Spray drying:

[0274] a. Start and set the fan power to 80% to 90%, the nitrogen flow valve to 30 to 40 mm, and balance the system.

[0275] b. After the system is balanced, set the inlet air temperature to 85℃ (70~85℃) 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℃.

[0276] 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.

[0277] 8.3 Solubility test

[0278] Weigh the powder of Examples 31 to 33 equivalent to 50 mg of API weight into a 10 ml vial, add the corresponding volume of medium with different pH values ​​so that the theoretical concentration of API in the sample solution is about 10 mg / ml, shake on a shaker for 24 hours, and take samples at 4 hours and 24 hours to measure the solubility. During the shaking process, observe the dissolution of the powder in the solution. If the solution is clear, add a certain amount of sample powder. The results are shown in Table 19.

[0279] Table 19 Solubility of solid dispersions prepared using Soluplus in different media

[0280]

[0281] The results showed that the solid dispersion prepared using Soluplus could solubilize API when the drug-excipient ratio was between 1:2 and 1:6.

[0282] 8.4 XRPD spectrum

[0283] It can be seen from the XRPD spectrum that Examples 31 to 33 all formed amorphous substances.

[0284] 9. Hot melt extrusion prescription and process

[0285] The examples of solid dispersions prepared by hot melt extrusion process have a batch size of 20 g / batch.

[0286] 9.1 Example of preparing solid dispersion using povidone by hot melt extrusion

[0287] 9.1.1 Prescription composition

[0288] Table 20 Prescription Summary

[0289]

[0290] 9.1.2 Preparation process

[0291] The API and excipients were sieved through a 40-mesh sieve twice and mixed thoroughly in a ziplock bag. The temperature of each section of the hot melt extruder screw (as shown in Table 21) was adjusted to a feed rate of 5-20 rpm and a screw speed of 20-80 rpm for hot melt extrusion. The extruded material was cooled and then crushed. The crushed material could be directly filled into capsules or mixed with other excipients for tableting.

[0292] Table 21 Hot melt extruder process parameters

[0293]

[0294] 9.1.33 Test results

[0295] The results showed that using polyvidone as a carrier material (specific models are PVP K-12 and PVP K-17), an amorphous solid dispersion can be prepared by hot melt extrusion when the drug-excipient ratio is in the range of 1:1 to 1:10.

[0296] The XRPD results show that when the drug-excipient ratio is 1:1 to 1:6, both the API and the carrier material polyvidone (PVP K-12 and PVPK-17) form amorphous substances.

[0297] 9.2 Example of preparing solid dispersion using copolyvidone by hot melt extrusion

[0298] 9.2.1 Prescription composition

[0299] Table 22 Prescription Summary

[0300]

[0301] 9.2.2 Preparation process:

[0302] API and excipients are mixed evenly. The temperature of each section of the hot melt extruder screw is (as shown in Table 23), and the feed rate is adjusted to 5-20rpm and the screw speed is 20-80rpm for hot melt extrusion. The extruded material is cooled and then crushed. The crushed material can be directly filled into capsules or mixed with other excipients and then tableted.

[0303] Table 23 Hot melt extruder process parameters

[0304]

[0305] 9.2.3 Test results

[0306] Copolyvidone S630 can be used to prepare an amorphous solid dispersion by hot melt extrusion within a drug-excipient ratio range 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.

[0307] 9.3 Example of preparing solid dispersion using hypromellose by hot melt extrusion

[0308] 9.3.1 Prescription composition

[0309] Table 24 Summary of HPMC Carrier Material Prescriptions

[0310]

[0311]

[0312] 9.3.2 Preparation process

[0313] API and excipients are mixed evenly. The temperature of each section of the hot melt extruder screw is set (as shown in Table 25), and the feed rate is adjusted to 5-20 rpm and the screw speed to 20-80 rpm for hot melt extrusion. The extruded material is cooled and then crushed. The crushed material can be directly filled into capsules or mixed with other excipients for tableting.

[0314] Table 25 Hot melt extruder process parameters

[0315]

[0316] 9.3.3 Test results

[0317] 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.

[0318] 9.4 Example of preparing solid dispersion using hydroxypropyl cellulose by hot melt extrusion

[0319] 9.4.1 Prescription composition

[0320] Table 26 Prescription Summary

[0321]

[0322] 9.4.2 Preparation process

[0323] The API and excipients were screened through a 40-mesh sieve twice and mixed thoroughly in a ziplock bag. The temperature of each section of the hot melt extruder screw (as shown in Table 27) was adjusted to a feed rate of 5-20 rpm and a screw speed of 20-80 rpm for hot melt extrusion. The extruded material was cooled and then crushed. The crushed material could be directly filled into capsules or mixed with other excipients for tableting.

[0324] Table 27 Hot Melt Extruder Process Parameters

[0325]

[0326] 9.4.3 Test results

[0327] 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.

[0328] 9.5 Example of preparing solid dispersion by hot melt extrusion using hydroxypropyl methylcellulose acetate succinate as carrier material

[0329] 9.5.1 Prescription composition

[0330] Table 28 Prescription Summary

[0331]

[0332] 9.5.2 Preparation process

[0333] API and excipients are mixed evenly. The temperature of each section of the hot melt extruder screw is (as shown in Table 29), and the feed rate is adjusted to 5-20rpm and the screw speed is 20-80rpm for hot melt extrusion. The extruded material is cooled and then crushed. The crushed material can be directly filled into capsules or mixed with other excipients and then tableted.

[0334] Table 29 Hot Melt Extruder Process Parameters

[0335]

[0336] 9.5.3 Test results

[0337] 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.

[0338] 10. Example of the Second Pharmaceutical Composition

[0339] The first composition obtained by spray drying is usually a loose powder with high static electricity and poor fluidity. It is usually necessary to add one or more of the appropriate fillers, disintegrants, lubricants and glidants to improve the fluidity of the solid dispersion powder, increase the dissolution rate, and prepare a dosage form that is convenient for oral administration, such as tablets, capsules or granules. Commonly used oral solid preparation excipients (including but not limited to) are shown in Table 30.

[0340] Table 30 Common Tablet Excipients

[0341] Serial number Excipient name Function of auxiliary materials 1 Lactose (monohydrate or anhydrous) Fillers 2 starch Fillers 3 Calcium hydrogen phosphate (anhydrous or dihydrate) Fillers 4 Calcium sulfate dihydrate Fillers 5 MCC PH101 Fillers 6 Cross-linked carboxymethyl cellulose sodium (CC-Na) Disintegrants 7 Cross-linked polyvinylpyrrolidone (PVPP XL-10) Disintegrants 8 Cross-linked polyvinylpyrrolidone (PVPP CL) Disintegrants 9 Pregelatinized starch (P.Starch) Disintegrants 10 Sodium Carboxymethyl Starch (CMS-Na) Disintegrants 11 Sodium dodecyl sulfate (SDS) Surfactants 12 <![CDATA[Colloidal silica (SiO 2 )]]> Glidants and anti-adhesive agents 13 Magnesium Stearate (Mg.S) Lubricants and anti-sticking agents 14 Compritol 888 Lubricants

[0342] The specific embodiments are as follows:

[0343] 10.1 Tablet Example

[0344] 10.1.1 Tablet Examples 59 and 60

[0345] The prescription composition is shown in Table 31.

[0346] Table 31 Summary of Example Prescriptions

[0347]

[0348]

[0349] Preparation process of Example 59 and Example 60

[0350] (1) Preparation of solid dispersion

[0351] 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, which is then weighed according to the required amount for tablets.

[0352] Preparation: Weigh povidone, sodium metabisulfite and API in order according to the feed amount.

[0353] Preparation of drug solution: Prepare a mixed solvent of acetone:methanol = 2:1, add the weighed API into the stirring tank, and stir until the solution is clear. Add the weighed povidone into the above solution, stir until the solution is clear, and prepare a drug solution with a solid content of 10%, and set aside.

[0354] Spray drying: set the air inlet temperature to 85°C, the air outlet temperature to 50°C, 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.

[0355] 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).

[0356] (2) Tablet preparation

[0357] Material preparation: Weigh each material in turn according to the input quantity.

[0358] Premixing: Add the solid dispersion and internal auxiliary materials lactose, microcrystalline cellulose, pregelatinized starch, and colloidal silicon dioxide (internal addition) into a mortar and grind and mix well.

[0359] 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.

[0360] Total mixing: According to the weight of the granules after the drying process, convert and weigh the magnesium stearate (external addition). The granules after the drying process and the magnesium stearate (external addition) are fully mixed in a PE bag.

[0361] Tablet pressing: Use Φ8mm round punch die and use single punch tablet press to press into tablets.

[0362] 10.1.2 Tablet Examples with Different Drug Loadings

[0363] The prescription composition is shown in Table 32.

[0364] Table 32 Summary of prescriptions for 30 mg tablets

[0365]

[0366]

[0367] Preparation process:

[0368] (1) Preparation of solid dispersion:

[0369] Preparation: Weigh povidone, sodium metabisulfite and API in order according to the feed amount.

[0370] Preparation of drug solution: Prepare a mixed solvent of acetone / methanol (w / w, 2:1), add the weighed API to a stirring 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 it to a stirring tank.) Add the weighed povidone to a stirring tank, stir until the solution is clear, and prepare a drug solution with a solid content of 10% for use.

[0371] Spray drying: Set the air inlet temperature to 85°C (80-90°C), the air outlet temperature to 50°C (45-55°C), the atomizing gas flow rate to 6.0kg / h (3.0kg / h-12.0kg / h), spray the drug solution, and start preparing the API solid dispersion.

[0372] Vacuum drying: API solid dispersion is placed in a vacuum drying oven, set at 60°C, vacuum degree ≤-0.1MPa, and dried for 24 to 48 hours.

[0373] (2) Tablet pressing

[0374] Material preparation: Weigh each material in turn according to the feed amount.

[0375] Premixing: Add API solid dispersion, lactose, microcrystalline cellulose, pregelatinized starch, crospovidone (added internally), colloidal silicon dioxide and magnesium stearate (added internally) into a mixing hopper. Set the speed to 15 rpm, mix for 12 minutes, and collect the material.

[0376] Dry granulation: the first-stage granulation screen is 2.0 mm, the second-stage granulation screen is 0.8 mm. Set the roller unit to 6.0 (3.4-14.8) rpm, the roller spacing to 1.5 (1.0-4.0) mm, the hydraulic pressure to 19 (18-50) bar, the second-stage granulator to 70.0 (24.9-108.4) rpm, and start the equipment for granulation.

[0377] Total mixing: Add the dry granules and cross-linked polyvinylpyrrolidone (external) into the mixing hopper, set the mixing speed to 15 rpm, and mix for 5 minutes. After the mixing is completed, add magnesium stearate (external), set the mixing speed to 15 rpm, and mix for 2 minutes.

[0378] Tablet pressing: Examples 61-62: 8 mm round punch was used for pressing; Example 63: 9 mm round punch was used for pressing; Examples 64-65: 15.8*8.2 mm punch was used for pressing using a rotary tablet press.

[0379] Coating: prepare 12% concentration of coating solution; preheat the coating pan and plain tablets (if necessary, add lining sheets), set the main engine speed to 12.0 (6.0-20.0) rpm, air inlet temperature to 60℃ (55-65℃), air inlet volume to 1000 (500-1500) rpm, exhaust volume to 1200 (800-2900) rpm, peristaltic pump spray rate to 30 (10-100) ml / min, atomization pressure to 0.2 (0.1-0.5)

[0380] MPa, start spraying, control the tablet bed temperature at 37.0-45.0°C, control the coating weight gain at about 3% (2-4%), and dry and cool.

[0381] The dissolution results of each batch of the experiment are shown in Table 33, and the dissolution curves are shown in Figure 2 shown.

[0382] Table 33 Tablet experimental stage dissolution results

[0383]

[0384] 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.

[0385] 10.1.3 Example of Tablet Filler Screening

[0386] 10.1.3.1 Example of Filler Dosage Screening

[0387] The tablet examples in this section take the tablet prescription with a drug content of 6% and a specification of 30 mg as an example, but the examples in this section are not restrictive in any way and do not represent the final drug content and specifications of the preparations. They are merely used as examples for explanation.

[0388] 10.1.3.1.1 Prescription composition

[0389] Table 34 Summary of tablet formulations for filler dosage screening

[0390]

[0391] 10.1.3.1.2 Preparation process

[0392] (1) Preparation of solid dispersion

[0393] Preparation: Weigh povidone, sodium metabisulfite and API in order according to the feed amount.

[0394] Preparation of drug solution: Prepare a mixed solvent of acetone:methanol = 2:1, add the weighed API into the stirring tank, and stir until the solution is clear. Add the weighed povidone into the above solution, stir until the solution is clear, and prepare a drug solution with a solid content of 10%, and set aside.

[0395] Spray drying: set the air inlet temperature to 85°C, the air outlet temperature to 50°C, 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.

[0396] 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).

[0397] (2) Tablet preparation

[0398] Material preparation: Weigh each material in turn according to the input quantity.

[0399] 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.

[0400] Dry granulation: set the hydraulic pressure to 20 bar (18-230 bar), the roller unit to 8 rpm (3.4-14.8 rpm), the roller spacing to 1.5 mm, the first granulation speed to 40 rpm, the second granulation speed to 50 rpm (24.9-108.4 rpm) for granulation.

[0401] Total mixing: According to the weight of the granules after the dry process, calculate the amount of the additional excipients and weigh them. Mix the granules after the dry process and the additional excipients (except magnesium stearate) in a hopper mixer, set the mixing speed to 15 rpm, and mix for 5 minutes. Add magnesium stearate (external), set the mixing speed to 15 rpm, and mix for 2 minutes.

[0402] Tablet pressing: Use a 15.8*8.2mm punch and use a single punch tablet press to press into tablets.

[0403] The tablet preparation processes of Examples 66 to 73 are all feasible.

[0404] 10.1.3.1.3 Test results

[0405] The dissolution data of Examples 64 to 73 are shown in Tables 35 and Figure 3 shown.

[0406] Table 35 Summary of dissolution data for tablet formulations used for filler screening

[0407]

[0408] The dissolution methods of the above embodiments are: paddle method 75 rpm, 0.1 mol / L HCl+0.1% Tween 80.

[0409] 10.1.3.2 Example of Filler Type Screening

[0410] 10.1.3.2.1 Prescription composition

[0411] Mannitol, anhydrous calcium hydrogen phosphate, etc. were selected as fillers for tablet preparation. The results are shown in Table 36 and Table 37.

[0412] Table 36: Prescription list for screening of filler types and dosages (1)

[0413]

[0414] Table 37 Prescription list for screening of filler types and dosages (2)

[0415]

[0416]

[0417] 10.1.3.2.2 Preparation process

[0418] The preparation process of Examples 74 to 84 is the same as the preparation process of Examples 66 to 73.

[0419] 10.1.3.2.3 Test results

[0420] The dissolution results are shown in Tables 38, 39 and Figure 4 and Figure 5 shown.

[0421] Table 38 Summary of dissolution data of tablet formulations for screening of filler types and addition methods (1)

[0422]

[0423] Table 39 Summary of dissolution data of tablet formulations for screening of filler types and addition methods (2)

[0424]

[0425] The dissolution methods of the above embodiments are: paddle method 75 rpm, 0.1 mol / L HCl+0.1% Tween 80.

[0426] 10.1.4 Example of Tablet Disintegrant Screening

[0427] 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.

[0428] 10.1.4.1 Tablet Examples Using Pregelatinized Starch as the Main Disintegrant

[0429] 10.1.4.1.1 Prescription composition

[0430] Table 40 Disintegrant P.Starch dosage and addition method

[0431]

[0432] 10.1.4.1.2 Preparation process

[0433] The preparation process of Examples 85 to 91 is the same as the preparation process of Examples 66 to 73.

[0434] 10.1.4.1.3 Test results

[0435] The dissolution results are shown in Table 41 and Figure 6 shown.

[0436] Table 41 Summary of dissolution data of tablet formulations used to investigate the dosage and addition method of disintegrant P.Starch

[0437]

[0438]

[0439] The dissolution methods of the above embodiments are: paddle method 75 rpm, 0.1 mol / L HCl+0.1% Tween 80.

[0440] It can be seen from Table 41 that in the 0.1 mol / L HCl-0.1% Tween 80 medium, the dissolution becomes faster as the amount of P.Starch increases.

[0441] 10.1.4.2 Tablet Examples Using Crospovidone as Disintegrant

[0442] 10.1.4.2.1 Prescription composition

[0443] Table 42 The dosage and addition method of disintegrant cross-linked polyvinylpyrrolidone

[0444]

[0445] 10.1.4.2.2 Preparation process

[0446] The preparation process of Examples 85 to 91 is the same as the preparation process of Examples 66 to 73.

[0447] 10.1.4.2.3 Test results

[0448] The dissolution results are shown in Table 43 and Figure 7 shown.

[0449] Table 43 Summary of dissolution data of tablet formulations used for investigation of dosage and addition method of disintegrant crospovidone

[0450]

[0451]

[0452] The dissolution methods of the above embodiments are: paddle method 75 rpm, 0.1 mol / L HCl+0.1% Tween 80.

[0453] It can be seen from Table 43 that in the 0.1 mol / L HCl-0.1% Tween 80 medium, the dissolution becomes faster as the amount of cross-linked polyvinylpyrrolidone increases.

[0454] 10.1.5 Example of Antioxidant Screening for Tablet Formulations

[0455] The compound (API) in the present invention is easily oxidized. When preparing the formulation, a certain amount of antioxidant can be added to slow down the oxidation reaction. There are two ways to add the antioxidant, one is to add it to the first pharmaceutical composition, that is, the solid dispersion; the other is to add it to the excipients of the second pharmaceutical composition except the first pharmaceutical composition.

[0456] 10.1.5.1 Examples of Solid Dispersions Containing Antioxidants

[0457] 10.1.5.1.1 The prescription is shown in Table 44.

[0458] Table 44 Prescription Summary

[0459]

[0460] 10.1.5.1.2 Preparation process:

[0461] Preparation of drug solution: prepare a mixed solvent of acetone: methanol = 2:1 (w / w), dissolve API, povidone and antioxidant in the mixed solvent of acetone: methanol = 2:1 (w / w), and stir until the solution is clear.

[0462] Spray drying: set the air inlet temperature to 85°C, the air outlet temperature to 50°C, 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.

[0463] Vacuum drying: Set the temperature of the vacuum drying oven to 60°C, the vacuum degree ≤-0.1MPa, and dry for 12 to 48 hours (until the residual solvent test is qualified).

[0464] 10.1.5.1.3 Test results

[0465] The prepared Examples 98 to 100 were placed under 40°C / 75% RH conditions, and samples were taken at 10 days and 30 days to detect related substances, with a focus on the impurity level of oxidized impurities. The experimental results showed that the oxidized impurities of Example 98 increased significantly from 0.20% at 0 days to 0.33% at 10 days and 0.41% at 30 days. The oxidized impurities of Example 99 increased from 0.12% at 0 days to 0.15% at 10 days and 0.20% at 30 days. Compared with the sample of Example 98 without adding antioxidants, the increase was significantly reduced, and the level at 0 days was lower than that of Example 98, indicating that the addition of antioxidants BHA and BHT (ratio of 1:1, total amount accounting for 0.02% (percentage of the total amount of solid dispersion)) in SDD played a significant antioxidant role in the sample. The oxidative impurities of 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.

[0466] Therefore, adding antioxidants such as BHA, BHT and sodium metabisulfite (used alone or in combination) to the solid dispersion formulation can significantly inhibit the growth of oxidative impurities, and the antioxidant addition amount of 0.01% to 0.5% (in proportion to the total amount of the solid dispersion) can exert an antioxidant effect. Other antioxidants such as Vitamin E, Vitamin E Acetate, L-ascorbyl palmitate (L-AP), etc. can also provide similar antioxidant effects.

[0467] 10.1.5.2 Examples of Tablets Containing Antioxidants

[0468] 10.1.5.2.1 Tablets containing antioxidants Example Formulation Composition

[0469] Table 45 Tablets containing antioxidants Example prescription list

[0470]

[0471]

[0472] 10.1.5.2.2 Preparation process

[0473] The preparation process of Example 101 and Example 102 is the same as the preparation process of Example 65.

[0474] 10.1.5.2.3 Investigating the changes in oxidative impurities in tablets

[0475] The samples were placed under 40°C / 75%RH conditions and packaged in HDPE bottles and sealed. The changes in oxidative impurities were summarized as shown in Table 46 by measuring the related substances of the samples at different time points:

[0476] Table 46 Changes of oxidative impurities in tablets over time

[0477]

[0478] 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%, a significant antioxidant effect was exhibited.

[0479] 10.2 Capsule Example

[0480] 10.2.1 Prescription

[0481] Table 47 Example prescription list

[0482]

[0483]

[0484] Preparation process:

[0485] (1) Preparation of solid dispersion

[0486] Mix API and excipients evenly. Set the hot melt extrusion temperature to 160-175°C, adjust the feed rate to 5-20rpm, and the screw speed to 20-80rpm for hot melt extrusion. After the extruded material is cooled, it is crushed and passed through a 40-mesh sieve for later use.

[0487] (2) Preparation of the Second Pharmaceutical Composition

[0488] Preparation: Weigh the internal auxiliary materials lactose, microcrystalline cellulose and cross-linked carboxymethyl cellulose sodium according to the prescribed amount. Weigh sodium metabisulfite and dissolve it in purified water to prepare a 2% (w / w) sodium metabisulfite aqueous solution.

[0489] Preparation of sodium metabisulfite-containing internal 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°C, the fluidized bed material temperature to 35-55°C, and adjust the inlet air volume to 15-80m 3 / h, spray speed 5-50g / min and atomization pressure 0.05-1.0bar, fluidized bed one-step granulation is carried out, and drying is 10-30min after spraying is completed.

[0490] 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 auxiliary materials, add them to the above mixture, set the mixing speed to 15 rpm, and mix for 2 to 3 minutes.

[0491] Capsule filling: Take the total mixture and fill it into hard gelatin capsules using a capsule filling machine. The capsule size is 00.

[0492] 10.3 Granule Examples

[0493] 10.3.1 Prescription composition

[0494] Table 48 Prescription composition

[0495]

[0496] 10.3.2 Preparation process:

[0497] Preparation of drug solution: dissolve the API and carrier excipients in a mixed solvent of acetone:methanol = 2:1, stir until completely dissolved to obtain a drug solution with a solid content of 5%, which is set aside.

[0498] 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°C, the fluidized bed material temperature to 35-55°C, and adjust the inlet air volume to 15-80m 3 / h, spray speed 5-50g / min and atomization pressure 0.05-1.0bar, fluidized bed one-step granulation is carried out, and after spraying, it is dried for 10-30min and discharged.

[0499] 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.

[0500] Granule packaging: The total mixture is packaged into aluminum foil bags and sealed to obtain granules of the second pharmaceutical composition.

[0501] 10.4 Example of preparing a second pharmaceutical composition using a fluidized bed one-step granulation method Example of preparing a second pharmaceutical composition using a fluidized bed granulation method (top spray granulation method)

[0502] 10.4.1 Examples 105-106 (taking a batch size of 1000 g as an example) Formulation

[0503] Table 49 Summary of prescription composition

[0504]

[0505]

[0506] 10.4.2 Preparation process:

[0507] (1) Fluidized bed one-step granulation:

[0508] Preparation of drug solution: dissolve 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.

[0509] 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, spray speed 5-50g / min and atomization pressure 0.05-1.0bar, fluidized bed one-step granulation is carried out, and after spraying, it is dried for 10-30min and discharged.

[0510] Dry granulation: The granules obtained by fluidized bed granulation are sieved and mixed with colloidal silicon dioxide and magnesium stearate (added internally) in a hopper mixer. The mixed granules are dry granulated using a dry granulator. The dry granulation parameters are as follows: set the hydraulic pressure to 20 bar (18-230 bar), the roller unit to 8 rpm (3.4-14.8 rpm), the roller spacing to 1.5 mm, the first granulation speed to 40 rpm, and the second granulation speed to 50 rpm (24.9-108.4 rpm) for granulation.

[0511] Total mixing: According to the weight of the granules after the dry process, calculate the amount of the additional excipients and weigh them. Mix the granules after the dry process and the additional excipients (except magnesium stearate) in a hopper mixer, set the mixing speed to 15 rpm, and mix for 5 minutes. Add magnesium stearate (external), set the mixing speed to 15 rpm, and mix for 2 minutes.

[0512] 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.

[0513] 11. Animal PK experiment

[0514] 11.1 Comparison of bioavailability of solid dispersion and API in dogs

[0515] According to the solubility of the above solid dispersion prescription examples, 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 experiments. The solid dispersions were filled into hard capsules and orally administered to beagle dogs (male, fasting, 3 / group) at a dose of 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. The blood samples will be placed in anticoagulation tubes, gently inverted several times, and then placed on wet ice for centrifugation. Within 30 minutes after collection, the samples will be centrifuged at a speed of about 2000 x g (force) at 4 ° C for 10 minutes to obtain plasma. The plasma samples obtained by centrifugation will be immediately separated into 2 portions (~75 μL each) and transferred to cryogenic bottles. Samples will be kept on wet ice throughout processing and stored in a freezer at -75 ± 15°C prior to analysis. The concentration of test article in plasma samples will be analyzed using LC-MS / MS method.

[0516] Table 50 Summary of canine PK data for SDD formulations

[0517]

[0518] 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 API: at a dose of 5 mg / kg, the AUC of animals given SDD increased by 2- to 3-fold, and the C max It increased by 1 to 2 times, proving that the formation of solid dispersion can significantly improve the oral absorption and exposure of the active substance.

[0519] 11.2 Tablet PK Study in Dogs

[0520] The tablet formulations of Example 59, Example 60 and Example 65 were selected for canine PK experiments.

[0521] Example 59 and Example 60 were orally administered to beagles (male, fasting, 3 / group) at a dose of about 5 mg / kg, and Example 65 was orally administered to beagles (half male and half female, fasting, 8) at a dose of 50 mg / animal (close to 5 mg / kg), and 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. The blood sample will be placed in an anticoagulation tube, gently inverted several times, and then placed on wet ice for centrifugation. Within 30 minutes after collection, the sample will be centrifuged at a speed of about 2000 x g (force) at 4 ° C for 10 minutes to obtain plasma. The plasma sample obtained by centrifugation will be immediately separated into 2 portions (~75 μL each) and transferred to a cryogenic bottle. The sample will be kept on wet ice throughout the processing and stored in a refrigerator at -75 ± 15 ° C before analysis. The concentration of the test article in the plasma samples was analyzed using LC-MS / MS method.

[0522] Table 51 Summary of canine PK data for tablets

[0523]

[0524] AUC and C max The data showed that there was a significant difference in the exposure of the active substance after oral tablet formulation and API: at a dose of 5 mg / kg or 50 mg / animal, the AUC of the tablet increased by 2 to 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.

[0525] 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 used to help understand the method of the present invention and its core idea. At the same time, changes or deformations made by those skilled in the art based on the ideas of the present invention, the specific implementation methods and application scope of the present invention, all belong to the scope of protection of the present invention. In summary, the content 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 polymer materials, wherein the polymer material is povidone and / or copovidone; Wherein, the mass ratio between the compound of formula (I) and the polymer material is 1:2 to 1:6; Wherein, the first pharmaceutical composition is in the form of a solid dispersion.

2. The first pharmaceutical composition according to claim 1, characterized in that The povidone is povidone K25, povidone K30, povidone K-12 and / or povidone K-17.

3. The first pharmaceutical composition according to claim 1, characterized in that The copolyvidone is copolyvidone S630.

4. The first pharmaceutical composition according to claim 1, characterized in that The mass ratio between the compound of formula (I) and the polymer material is 1:2.5 to 1:

6.

5. The first pharmaceutical composition according to claim 4, characterized in that: The mass ratio between the compound of formula (I) and the polymer material is 1:3 to 1:

6.

6. The first pharmaceutical composition according to any one of claims 1 to 5, characterized in that The first pharmaceutical composition further comprises one or more antioxidants.

7. The first pharmaceutical composition according to claim 6, characterized in that The plurality of antioxidants is 1, 2, 3, 4 or 5 antioxidants.

8. The first pharmaceutical composition according to claim 6, characterized in that 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.

9. The first pharmaceutical composition according to claim 8, characterized in that The antioxidant is sodium pyrosulfite.

10. The first pharmaceutical composition according to claim 6, characterized in that: The antioxidant is present in an amount of 0.01% to 3% by weight of the first pharmaceutical composition.

11. The first pharmaceutical composition according to claim 10, characterized in that: The antioxidant is present in an amount of about 0.2% by weight of the first pharmaceutical composition.

12. A second pharmaceutical composition comprising the first pharmaceutical composition according to any one of claims 1 to 11, wherein the second pharmaceutical composition further comprises (1) one or more fillers; (2) one or more disintegrants; (3) optionally one or more surfactants; (4) optionally one or more glidants; (5) optionally one or more lubricants; and (6) optionally one or more film coating premixes; in, The plurality of types is 1, 2, 3, 4 or 5 types.

13. The second pharmaceutical composition according to claim 12, characterized in that: The filler is selected from one or more of the following: lactose, starch, calcium hydrogen phosphate, calcium sulfate dihydrate, mannitol, sorbitol and microcrystalline cellulose.

14. The second pharmaceutical composition according to claim 13, characterized in that: The lactose is lactose monohydrate or anhydrous lactose.

15. The second pharmaceutical composition according to claim 13, characterized in that The calcium hydrogen phosphate is anhydrous calcium hydrogen phosphate or dihydrate calcium hydrogen phosphate.

16. The second pharmaceutical composition according to claim 13, characterized in that: The microcrystalline cellulose is microcrystalline cellulose PH101.

17. The second pharmaceutical composition according to claim 12, characterized in that: The disintegrant is selected from one or more of the following: cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, pregelatinized starch and sodium carboxymethyl starch.

18. The second pharmaceutical composition according to claim 17, characterized in that The cross-linked polyvinylpyrrolidone is cross-linked polyvinylpyrrolidone XL-10 or cross-linked polyvinylpyrrolidone CL.

19. The second pharmaceutical composition according to claim 12, characterized in that: The surfactant is sodium lauryl sulfate.

20. The second pharmaceutical composition according to claim 12, characterized in that: The glidant is colloidal silicon dioxide.

21. The second pharmaceutical composition according to claim 12, characterized in that: The lubricant is magnesium stearate and / or glyceryl tribehenate.

22. The second pharmaceutical composition according to claim 12, characterized in that: The filler is present in an amount of 30% to 70% by weight of the second pharmaceutical composition.

23. The second pharmaceutical composition according to claim 22, characterized in that The filler is present in an amount of 55% to 65% by weight of the second pharmaceutical composition.

24. The second pharmaceutical composition according to claim 23, characterized in that The filler is present in an amount of about 58.5% by weight of the second pharmaceutical composition.

25. The second pharmaceutical composition according to claim 12, characterized in that The disintegrant is present in an amount of 6% to 20% by weight of the second pharmaceutical composition.

26. The second pharmaceutical composition according to claim 25, characterized in that The disintegrant is present in an amount of 10% to 20% by weight of the second pharmaceutical composition.

27. The second pharmaceutical composition according to claim 26, characterized in that The disintegrant is present in an amount of about 15% by weight of the second pharmaceutical composition.

28. The second pharmaceutical composition according to claim 12, characterized in that The surfactant is present in an amount of 1% to 6% by weight of the second pharmaceutical composition.

29. The second pharmaceutical composition according to claim 28, characterized in that The glidant is present in an amount of 0.5% to 3% by weight of the second pharmaceutical composition.

30. The second pharmaceutical composition according to claim 29, characterized in that The glidant is present in an amount of about 1% by weight of the second pharmaceutical composition.

31. The second pharmaceutical composition according to claim 12, characterized in that The lubricant is present in an amount of 0.5% to 3% by weight of the second pharmaceutical composition.

32. The second pharmaceutical composition according to claim 31, characterized in that The lubricant is present in an amount of about 1.5% by weight of the second pharmaceutical composition.

33. The second pharmaceutical composition according to claim 12, characterized in that The film coating premix is ​​present in an amount of 0.5% to 5% by weight of the second pharmaceutical composition.

34. The second pharmaceutical composition according to claim 33, characterized in that The film coating premix is ​​present in an amount of about 3% by weight of the second pharmaceutical composition.

35. The second pharmaceutical composition according to claim 12, characterized in that The antioxidant is present in an amount of 0.01% to 1% by weight of the second pharmaceutical composition.

36. The second pharmaceutical composition according to claim 35, characterized in that The antioxidant is present in an amount of about 0.1% by weight of the second pharmaceutical composition.

37. The second pharmaceutical composition according to claim 12, characterized in that The second pharmaceutical composition is in the form of an oral preparation.

38. The second pharmaceutical composition according to claim 37, characterized in that The second pharmaceutical composition is in the form of a solid oral preparation.

39. The second pharmaceutical composition according to claim 38, characterized in that The solid oral preparation is in the form of tablets or capsules.

40. A method for preparing the first pharmaceutical composition according to any one of claims 1 to 11, 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 two polymer materials, one or more solvents, and optionally one or more 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; Wherein, the plurality is 1, 2, 3, 4 or 5 kinds.

41. The method according to claim 40, characterized in that The solvent is selected from one or more of the following: water, methanol, acetone, ethanol, isopropanol, acetonitrile, ethyl acetate, propylene glycol and dichloromethane.

42. The method according to claim 41, characterized in that The solvent is selected from one or more of the following: water, methanol, ethanol, acetone and dichloromethane.

43. The method according to claim 41, characterized in that The solvent is water, methanol, ethanol, acetone and / or dichloromethane.

44. The method according to claim 43, characterized in that The mass ratio of the acetone to the methanol is 1:1 to 3:

1.

45. The method according to claim 44, characterized in that The mass ratio of the acetone to the methanol is about 2:

1.

46. ​​The method according to claim 43, characterized in that The solvent is about 70% acetone and methanol and about 30% water.

47. The method according to claim 43, characterized in that The solvent was about 40% acetone and methanol and about 60% dichloromethane.

48. The method according to claim 40, characterized in that The mass ratio of the solvent to the first pharmaceutical composition is 85:15 to 97:

3.

49. The method according to claim 48, characterized in that The mass ratio of the solvent to the first pharmaceutical composition is 90:10 to 94:

6.

50. The method according to claim 40, characterized in that 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.

51. The method according to claim 40, characterized in that The vacuum drying conditions are as follows: after the vacuum degree is stabilized at ≤-0.1 MPa, drying is performed at 55° C. to 65° C. for 12 h to 48 h.

52. The method according to claim 40, characterized in that The double cone drying conditions are as follows: 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.

53. A method for preparing the first pharmaceutical composition according to any one of claims 1 to 11, 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 two polymer materials and optionally one or more 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; Wherein, the plurality is 1, 2, 3, 4 or 5 kinds.

54. The method according to claim 53, characterized in that 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.

55. The method according to claim 53, characterized in that 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.

56. A method for preparing the first pharmaceutical composition according to any one of claims 1 to 11, 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 two polymer materials and one or more 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; Wherein, the plurality is 1, 2, 3, 4 or 5 kinds.

57. The method according to claim 56, characterized in that The solvent is selected from one or more of the following: water, methanol, acetone, ethanol, isopropanol, acetonitrile, ethyl acetate, propylene glycol and dichloromethane.

58. The method according to claim 57, characterized in that The solvent is selected from one or more of the following: water, methanol, ethanol, acetone and dichloromethane.

59. The method according to claim 58, characterized in that The solvent is water, ethanol, acetone and / or dichloromethane.

60. The method according to claim 58, characterized in that The mass ratio of the acetone to the methanol is 1:1 to 3:

1.

61. The method according to claim 60, characterized in that The mass ratio of the acetone to the methanol is about 2:

1.

62. The method of claim 58, wherein: The solvent is about 70% acetone and methanol and about 30% water.

63. The method according to claim 58, characterized in that The solvent was about 40% acetone and methanol and about 60% dichloromethane.

64. The method according to claim 56, characterized in that The mass ratio of the solvent to the first pharmaceutical composition is 85:15 to 97:

3.

65. The method according to claim 64, characterized in that The mass ratio of the solvent to the first pharmaceutical composition is 90:10 to 94:

6.

66. A method for preparing the second pharmaceutical composition of any one of claims 12 to 39, 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 11 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.

67. The method according to claim 66, characterized in that The dosage form of the second pharmaceutical composition is tablet, capsule or granule.

68. The method according to claim 66, 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 two polymer materials, one or more solvents, and optionally one or more 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.

69. The method according to claim 68, characterized in that The plurality of types is 1, 2, 3, 4 or 5 types.

70. The method of claim 68, wherein: The conditions for the one-step granulation in the fluidized bed include an air inlet temperature of 45°C to 75°C, a material temperature of 35°C to 55°C, an 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.

71. A method for preparing the second pharmaceutical composition of any one of claims 12 to 39, 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.

72. The method according to claim 71, characterized in that The rotation speed of the first mixing is 10 rpm to 20 rpm, and the mixing time is 10 min to 15 min.

73. The method according to claim 71, characterized in that The second mixing has a rotation speed of 10 rpm to 20 rpm and a mixing time of 2 min to 10 min.

74. The method according to claim 71, characterized in that In step (a), the disintegrants are cross-linked polyvinylpyrrolidone and pregelatinized starch.

75. The method according to claim 71, characterized in that In step (c), the disintegrant is cross-linked polyvinylpyrrolidone.

76. The method according to claim 71, characterized in that The mass ratio between the crospovidone added in step (a) and the crospovidone added in step (c) is about 1.

77. The method according to claim 71, characterized in that The mass ratio between the lubricant added in step (a) and the lubricant added in step (c) is about 2.

78. The method according to claim 71, characterized in that The conditions of the dry granulation are as follows: hydraulic pressure is 18 bar to 50 bar, roller speed is 3.4 rpm to 14.8 rpm, roller spacing is 1 mm to 4 mm, secondary granulation speed is 24.9 rpm to 108.4 rpm, and primary granulation speed is 10 rpm to 90 rpm.

79. The method according to claim 71, characterized in that 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.

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