A PHARMACEUTICAL COMPOSITION CONTAINING A HETEROARYLOXYNAPHTHALENE COMPOUND, A METHOD FOR ITS PRODUCTION AND ITS USE

Abstract

The invention relates to a pharmaceutical composition containing a compound (A), a preparation method therefor, and a use thereof. The preparation method for the pharmaceutical composition is simple and suitable for industrial large-scale production, and tablets prepared from the pharmaceutical composition have good active ingredient content uniformity and a good active ingredient dissolution rate, have stable properties, and are suitable for long-term storage.

Description

Pharmaceutical composition containing heteroaryloxynaphthalene compounds, preparation method and application thereof Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a pharmaceutical composition comprising a heteroaryloxynaphthalene compound, and a preparation method and application thereof. Background Art

[0002] Fibroblast growth factor receptors (FGFRs) are important molecular targets for tumor classification and are aberrantly activated in a variety of tumors, particularly some refractory tumors and those with Chinese characteristics. Currently, clinical research on FGFR-targeted inhibitors is largely in the early stages. FGFR inhibitors under investigation primarily target multiple targets, exhibit weak inhibitory activity against FGFRs, and often enhance antagonism against the human vascular endothelial growth factor receptor (VEGF) KDR (kinase insert domain containing receptor), resulting in serious adverse reactions. This significantly limits the application of FGFR-targeted anti-tumor inhibitors and the maximization of their clinical efficacy. However, FGFRs and KDRs exhibit compensatory activation, suggesting that mutual compensation mediates drug resistance. Indeed, studies have reported that FGFR activation is a mechanism of resistance to KDR inhibitors. Furthermore, the enhanced immunosuppression and tumor-promoting effects of the KDR family have been increasingly revealed in recent years. Therefore, the development of co-targeted FGFR and KDR inhibitors holds significant clinical potential.

[0003] It is important to note that in recent years, cancer treatment is not limited to the tumor cells themselves. The role of the tumor microenvironment, as a functional and integral entity, in driving tumor progression and mediating drug resistance has also attracted significant attention. Among them, tumor-associated macrophages (TAMs) are important stromal cells in the microenvironment. They not only directly inhibit the killing effects of effector T cells and synergistically promote the tumor's immunosuppressive microenvironment, but also promote tumor angiogenesis, promoting tumor cell growth and metastasis in multiple ways and mediating tumor drug resistance. Among them, the colony-stimulating factor 1 receptor (CSF-1R) is expressed on macrophages and is crucial for TAMs to differentiate, maintain, proliferate, and survive toward the M2 polarized phenotype. Based on this, simultaneous targeting of FGFR / KDR / CSF-1R can both antagonize tumor cells themselves and regulate the tumor microenvironment, facilitating a multi-step tumor antagonism, reshaping the host's immunosuppressive microenvironment, and mitigating the development of acquired drug resistance.

[0004] The compound of formula (I) is a new type of FGFR / CSF1R / KDR targeted small molecule inhibitor developed based on the above mechanism. Preclinical pharmacology trials have shown good therapeutic effects in various tumor models.

[0005] PCT patent document WO2017 / 140269A1 discloses the structure of the compound of formula (I), its preparation method, and its pharmaceutical use for preventing and / or treating diseases related to FGFR.

[0006] PCT patent document WO2021 / 170078A1 discloses the use of the compound of formula (I) as a CSF-1R inhibitor.

[0007] None of the aforementioned patent documents investigates the formulation and preparation of the compound of formula (I) and its pharmaceutically acceptable salts. Given the enormous potential for application of the compound of formula (I) as a targeted inhibitor of FGFR / CSF1R / KDR in tumor treatment, there is a need to provide a pharmaceutical composition comprising the compound of formula (I) or its pharmaceutically acceptable salts with excellent druggable properties.

[0008] Summary of the Invention

[0009] One object of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, which has a simple preparation method and is suitable for industrial production.

[0010] Another object of the present invention is to provide a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, which has good druggable properties.

[0011] Another object of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, which can be used to prepare a solid oral preparation having good dissolution and content uniformity of the active ingredient.

[0012] Another object of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, which has excellent stability and is suitable for long-term storage.

[0013] To achieve the above-mentioned objectives, the inventors of this application discovered through preliminary research that the dihydrochloride salt of the compound of formula (I), Compound (A), is suitable as an active ingredient in a pharmaceutical composition due to its easy drying, good solubility, stable quality, thermodynamic stability, and ease of drug formulation. Furthermore, the inventors conducted screening experiments on other components of the pharmaceutical composition and discovered a specific formulation for the pharmaceutical composition that meets one or more of the above-mentioned requirements, thereby completing the present invention.

[0014] The first aspect of the present invention provides a pharmaceutical composition comprising the following components in percentage by weight of the pharmaceutical composition:

[0015] 0.1% to 10% of a compound (A) having a structure represented by the following formula (A):

[0016] 70% to 95% filler;

[0017] 0-15% disintegrant;

[0018] 0-3% glidant; and

[0019] 0.5-5% lubricant.

[0020] The pharmaceutical composition of the present invention comprises compound (A) as an active ingredient.

[0021] In some embodiments of the present invention, the compound (A) is in crystalline form.

[0022] In some embodiments of the present invention, the crystalline form of compound (A) is Form I, which has characteristic peaks at 5.0±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, and 25.2±0.2° 2θ in an X-ray powder diffraction pattern obtained using Cu-Kα radiation, or

[0023] The crystalline form I has characteristic peaks at 5.0±0.2°, 10.4±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 23.4±0.2°, and 25.2±0.2° 2θ in an X-ray powder diffraction pattern obtained using Cu-Kα radiation, or

[0024] The crystalline form I has characteristic peaks at 5.0±0.2°, 10.4±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2°, and 25.2±0.2° 2θ in an X-ray powder diffraction pattern obtained using Cu-Kα radiation, or

[0025] The crystalline form I has characteristic peaks at 5.0±0.2°, 10.4±0.2°, 11.2±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 22.0±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2°, 25.2±0.2°, and 26.6±0.2° 2θ in an X-ray powder diffraction pattern obtained using Cu-Kα radiation, or

[0026] The crystalline form I has characteristic peaks at 5.0±0.2°, 10.0±0.2°, 10.4±0.2°, 11.2±0.2°, 13.5±0.2°, 14.1±0.2°, 15.7±0.2°, 17.4±0.2°, 18.0±0.2°, 19.3±0.2°, 20.1±0.2°, 20.5±0.2°, 21.4±0.2°, 22.0±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2°, 25.2±0.2°, 26.6±0.2°, 28.6±0.2°, and 30.1±0.2° 2θ in an X-ray powder diffraction pattern obtained using Cu-Kα radiation, or

[0027] The X-ray powder diffraction pattern of the crystalline form I obtained using Cu-Kα radiation showed that the crystalline form I had the following peaks: 5.0±0.2°, 10.0±0.2°, 10.4±0.2°, 11.2±0.2°, 13.5±0.2°, 14.1±0.2°, 15.7±0.2°, 17.4±0.2°, 18.0±0.2°, 19.3±0.2°, 20.1±0.2°, 2 There are characteristic peaks at 0.5±0.2°, 21.4±0.2°, 22.0±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2°, 25.2±0.2°, 26.6±0.2°, 28.6±0.2°, 30.1±0.2°, 32.0±0.2°, and 33.0±0.2° 2θ, or

[0028] The crystalline form I has X-ray powder diffraction analysis data substantially as shown in Table 2 or 3 below.

[0029] For the preparation and testing of the compound (A) and its crystalline form I, please refer to patent application CN202310263447.7 or PCT / CN2023 / 082140, the entire contents of which are incorporated herein by reference.

[0030] In some embodiments of the present invention, the weight percentage of compound (A) in the pharmaceutical composition is 1% to 10%, preferably 2% to 8%, more preferably 2% to 7%, further preferably 2% to 6%, further preferably 2% to 5%, and further preferably 2% to 4%.

[0031] The pharmaceutical composition of the present invention comprises one or more fillers. The "filler" described herein refers to an inert substance used to produce the desired volume, fluidity and compression characteristics in the preparation of solid dosage forms. In an embodiment of the present invention, the filler is selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose, xylitol, mannitol, sorbitol, starch, pregelatinized starch, dextrin, lactose, sucrose, glucose, fructose, maltose, calcium carbonate, calcium sulfate, and calcium hydrogen phosphate; preferably one or more of microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, starch, pregelatinized starch, and dextrin; more preferably one or more of microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, lactose, and pregelatinized starch; further preferably one of microcrystalline cellulose or silicified microcrystalline cellulose, or one of microcrystalline cellulose, silicified microcrystalline cellulose and dextrin. A combination of mannitol and one of lactose (such as the combination of microcrystalline cellulose and mannitol, the combination of microcrystalline cellulose and lactose, the combination of silicified microcrystalline cellulose and mannitol, the combination of silicified microcrystalline cellulose and lactose), or a combination of one of microcrystalline cellulose or silicified microcrystalline cellulose and one of mannitol or lactose and pregelatinized starch (such as the combination of microcrystalline cellulose and mannitol, pregelatinized starch; the combination of microcrystalline cellulose and lactose, pregelatinized starch; the combination of silicified microcrystalline cellulose and mannitol, pregelatinized starch; the combination of silicified microcrystalline cellulose and lactose, pregelatinized starch); more preferably, the combination of microcrystalline cellulose, mannitol and pregelatinized starch.

[0032] In some embodiments of the present invention, the filler accounts for 75% to 95% by weight of the pharmaceutical composition, preferably 80% to 95%, more preferably 85% to 95%, and even more preferably 85% to 92%.

[0033] In some embodiments of the present invention, when the filler is selected from a combination of one of microcrystalline cellulose or silicified microcrystalline cellulose and one of mannitol and lactose, the weight percentage of the mannitol or lactose is 15-50%, preferably 20-45%, more preferably 20%-40%, and further preferably 20%-30%; the weight percentage of microcrystalline cellulose or silicified microcrystalline cellulose is 40-75%, preferably 50-75%, more preferably 60-75%, and further preferably 65-75%; the weight ratio of mannitol or lactose to microcrystalline cellulose or silicified microcrystalline cellulose is 1:5-1:1, preferably 1:4-1:1, more preferably 1:4-1:1.5, further preferably 1:3.6-1:1.5, further preferably 1:3.6-1:2.8, and further preferably 1:3.6-1:3.

[0034] In some embodiments of the present invention, when the filler is selected from a combination of one of microcrystalline cellulose or silicified microcrystalline cellulose and one of mannitol or lactose and pregelatinized starch, the weight percentage of mannitol or lactose is 15-45%, preferably 20-45%, more preferably 20%-41%, further preferably 20%-30%, the weight percentage of microcrystalline cellulose or silicified microcrystalline cellulose is 35-70%, preferably 40%-65%, the weight percentage of mannitol or lactose and ... The weight ratio of cellulose is 1:5 to 1:1, preferably 1:4 to 1:1, more preferably 1:4 to 1:1.5, further preferably 1:3.6 to 1:1.5, further preferably 1:3.6 to 1:2.8, further preferably 1:3.3 to 1:2.8, further preferably 1:3.05; the weight percentage of the pregelatinized starch is 5 to 25%, preferably 5 to 15%, more preferably 8 to 12%, further preferably 10 to 11%, and further preferably 10.5%.

[0035] The pharmaceutical composition of the present invention may contain one or more disintegrants. The "disintegrant" described herein refers to a substance used in a solid dosage form to promote the breakage of a solid into smaller particles that are easier to disperse or dissolve. In an embodiment of the present invention, the disintegrant is selected from: sodium starch glycolate, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, dry starch, low-substituted hydroxypropyl cellulose, polyvinyl pyrrolidone, cross-linked polyvinylpyrrolidone, effervescent disintegrant, polacrilin potassium or sodium alginate; preferably sodium starch glycolate, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinyl pyrrolidone, or cross-linked polyvinylpyrrolidone; more preferably sodium starch glycolate, low-substituted hydroxypropyl cellulose or cross-linked polyvinylpyrrolidone; further preferably cross-linked polyvinylpyrrolidone.

[0036] In some embodiments of the present invention, the weight percentage of the disintegrant in the pharmaceutical composition is 0-10%, preferably 1%-6%, more preferably 2%-6%, more preferably 2%-5%, more preferably 2%-4%, further preferably 3%-5%, further preferably 3.5%-4.5%, further preferably 3%-4%.

[0037] The pharmaceutical compositions of the present invention include one or more glidants. As used herein, a "glidant" refers to an agent used in a solid dosage form to promote solid flowability. In an embodiment of the present invention, the glidant is selected from the group consisting of talc, silicon dioxide, or colloidal silicon dioxide; preferably silicon dioxide or colloidal silicon dioxide; and more preferably colloidal silicon dioxide.

[0038] In some embodiments of the present invention, the weight percentage of the glidant in the pharmaceutical composition is 0.5-3.0%, preferably 0.5%-2.5%, more preferably 0.5%-2%, and further preferably 1-2%.

[0039] The pharmaceutical composition of the present invention comprises one or more lubricants. As used herein, a "lubricant" refers to a substance used to reduce friction between particles of the pharmaceutical composition and between the particles and the die orifice. In an embodiment of the present invention, the lubricant is selected from the group consisting of calcium stearate, magnesium stearate, zinc stearate, talc, sodium stearyl fumarate, stearic acid, glyceryl behenate, palmitic acid, glyceryl palmitostearate, magnesium lauryl sulfate, hydrogenated vegetable oil, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol, micronized silica gel, or aluminum hydroxide; preferably, glyceryl behenate, magnesium stearate, or sodium stearyl fumarate; more preferably, glyceryl behenate or sodium stearyl fumarate.

[0040] In some embodiments of the present invention, the lubricant accounts for 0.5% to 4% by weight of the pharmaceutical composition, preferably 1% to 4%, more preferably 1% to 3%, and further preferably 0.8% to 3%.

[0041] In some embodiments of the present invention, the weight percentage of compound (A) in the pharmaceutical composition is 2% to 5%, the weight percentage of the filler in the pharmaceutical composition is 85% to 95%, the weight percentage of the disintegrant in the pharmaceutical composition is 2% to 6%, the weight percentage of the glidant in the pharmaceutical composition is 0.5% to 3.0%, and the weight percentage of the lubricant in the pharmaceutical composition is 0.8% to 3%.

[0042] In some embodiments of the present invention, compound (A) accounts for 2% to 4% by weight of the pharmaceutical composition, the filler accounts for 85% to 92% by weight of the pharmaceutical composition, the disintegrant accounts for 3% to 4% by weight of the pharmaceutical composition, the glidant accounts for 1% to 2% by weight of the pharmaceutical composition, and the lubricant accounts for 1% to 3% by weight of the pharmaceutical composition.

[0043] In some embodiments of the present invention, the weight percentage of compound (A) in the pharmaceutical composition is 2% to 5%, the weight percentage of the filler in the pharmaceutical composition is 85% to 95%, the weight percentage of the disintegrant in the pharmaceutical composition is 2% to 6%, the weight percentage of the glidant in the pharmaceutical composition is 0% to 3.0%, and the weight percentage of the lubricant in the pharmaceutical composition is 0.8% to 3%.

[0044] The filler is selected from one of microcrystalline cellulose and silicified microcrystalline cellulose, or a combination of one of microcrystalline cellulose and silicified microcrystalline cellulose with one of mannitol and lactose (such as a combination of microcrystalline cellulose and mannitol, a combination of microcrystalline cellulose and lactose, a combination of silicified microcrystalline cellulose and mannitol, a combination of silicified microcrystalline cellulose and lactose), or a combination of one of microcrystalline cellulose and one of mannitol or lactose and pregelatinized starch (such as a combination of microcrystalline cellulose and mannitol and pregelatinized starch; a combination of microcrystalline cellulose and lactose and pregelatinized starch; a combination of silicified microcrystalline cellulose and mannitol and pregelatinized starch; a combination of silicified microcrystalline cellulose and mannitol and pregelatinized starch; a combination of silicified microcrystalline cellulose and mannitol and pregelatinized starch). The disintegrant is selected from sodium starch glycolate, sodium carboxymethyl cellulose, croscarmellose sodium, dry starch, low-substituted hydroxypropyl cellulose, polyvinyl pyrrolidone, crospovidone, effervescent disintegrant, polacrilin potassium or sodium alginate; the glidant is selected from talc, silicon dioxide or colloidal silicon dioxide; the lubricant is selected from calcium stearate, magnesium stearate, zinc stearate, talc, sodium stearyl fumarate, stearic acid, glyceryl behenate, palmitic acid, glyceryl palmitostearate, magnesium lauryl sulfate, hydrogenated vegetable oil, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol, micropowdered silica or aluminum hydroxide;

[0045] When the filler is selected from a combination of one of microcrystalline cellulose or silicified microcrystalline cellulose and one of mannitol and lactose, the weight percentage of the mannitol or lactose is 15-50%, preferably 20-45%, more preferably 20%-40%, and further preferably 20%-30%; the weight percentage of the microcrystalline cellulose or silicified microcrystalline cellulose is 40-75%, preferably 50-75%, more preferably 60-75%, and further preferably 65-75%; the weight ratio of the mannitol or lactose to the microcrystalline cellulose or silicified microcrystalline cellulose is 1:5-1:1, preferably 1:4-1:1, more preferably 1:4-1:1.5, further preferably 1:3.6-1:1.5, further preferably 1:3.6-1:2.8, and further preferably 1:3.6-1:3; or

[0046] When the filler is selected from a combination of one of microcrystalline cellulose or silicified microcrystalline cellulose and one of mannitol or lactose and pregelatinized starch, the weight percentage of the mannitol or lactose is 15-45%, preferably 20-45%, more preferably 20%-41%, and further preferably 20%-30%, the weight percentage of the microcrystalline cellulose or silicified microcrystalline cellulose is 35-70%, preferably 40%-65%, and the weight ratio of the mannitol or lactose to the microcrystalline cellulose or silicified microcrystalline cellulose is The weight percentage of the pregelatinized starch is 1:5 to 1:1, preferably 1:4 to 1:1, more preferably 1:4 to 1:1.5, further preferably 1:3.6 to 1:1.5, further preferably 1:3.6 to 1:2.8, further preferably 1:3.3 to 1:2.8, further preferably 1:3.05; the weight percentage of the pregelatinized starch is 5 to 25%, preferably 5 to 15%, more preferably 8 to 12%, further preferably 10 to 11%, and further preferably 10.5%.

[0047] In some embodiments of the present invention, the weight percentage of compound (A) in the pharmaceutical composition is 2% to 4%, the weight percentage of the filler in the pharmaceutical composition is 85% to 92%, the weight percentage of the disintegrant in the pharmaceutical composition is 2% to 6%, the weight percentage of the glidant in the pharmaceutical composition is 0.5% to 3.0%, and the weight percentage of the lubricant in the pharmaceutical composition is 0.8% to 3%;

[0048] The filler is selected from one of microcrystalline cellulose and silicified microcrystalline cellulose, or a combination of microcrystalline cellulose, silicified microcrystalline cellulose and mannitol or lactose (such as a combination of microcrystalline cellulose and mannitol, a combination of microcrystalline cellulose and lactose, a combination of silicified microcrystalline cellulose and mannitol, a combination of silicified microcrystalline cellulose and lactose), or a combination of microcrystalline cellulose or silicified microcrystalline cellulose and mannitol or lactose and pregelatinized starch (such as microcrystalline cellulose and mannitol, pregelatinized starch). the disintegrant is selected from sodium starch glycolate, sodium carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, polyvinyl pyrrolidone or cross-linked polyvinylpyrrolidone; the glidant is selected from talc, silicon dioxide or colloidal silicon dioxide; the lubricant is selected from magnesium stearate, sodium stearyl fumarate or glyceryl behenate;

[0049] When the filler is selected from a combination of one of microcrystalline cellulose or silicified microcrystalline cellulose and one of mannitol and lactose, the weight percentage of the mannitol or lactose is 15-50%, preferably 20-45%, more preferably 20%-40%, and further preferably 20%-30%; the weight percentage of the microcrystalline cellulose or silicified microcrystalline cellulose is 40-75%, preferably 50-75%, more preferably 60-75%, and further preferably 65-75%; the weight ratio of the mannitol or lactose to the microcrystalline cellulose or silicified microcrystalline cellulose is 1:5-1:1, preferably 1:4-1:1, more preferably 1:4-1:1.5, further preferably 1:3.6-1:1.5, further preferably 1:3.6-1:2.8, and further preferably 1:3.6-1:3; or

[0050] When the filler is selected from a combination of one of microcrystalline cellulose or silicified microcrystalline cellulose and one of mannitol or lactose and pregelatinized starch, the weight percentage of the mannitol or lactose is 15-45%, preferably 20-45%, more preferably 20%-41%, and further preferably 20%-30%, the weight percentage of the microcrystalline cellulose or silicified microcrystalline cellulose is 35-70%, preferably 40%-65%, and the weight ratio of the mannitol or lactose to the microcrystalline cellulose or silicified microcrystalline cellulose is The weight percentage of the pregelatinized starch is 1:5 to 1:1, preferably 1:4 to 1:1, more preferably 1:4 to 1:1.5, further preferably 1:3.6 to 1:1.5, further preferably 1:3.6 to 1:2.8, further preferably 1:3.3 to 1:2.8, further preferably 1:3.05; the weight percentage of the pregelatinized starch is 5 to 25%, preferably 5 to 15%, more preferably 8 to 12%, further preferably 10 to 11%, and further preferably 10.5%.

[0051] In some embodiments of the present invention, compound (A) accounts for 2% to 4% by weight of the pharmaceutical composition, the filler accounts for 85% to 92% by weight of the pharmaceutical composition, the disintegrant accounts for 3% to 4% by weight of the pharmaceutical composition, the glidant accounts for 1% to 2% by weight of the pharmaceutical composition, and the lubricant accounts for 1% to 3% by weight of the pharmaceutical composition; wherein the filler is selected from a combination of microcrystalline cellulose, mannitol and pregelatinized starch, the weight percentage of the mannitol is 20% to 45%, the weight percentage of microcrystalline cellulose is 40% to 65%, the weight ratio of mannitol to microcrystalline cellulose is 1:3.5 to 1:1, and the weight percentage of the pregelatinized starch is 5% to 25%; the disintegrant is selected from cross-linked polyvinylpyrrolidone; the glidant is selected from colloidal silicon dioxide; and the lubricant is selected from glyceryl behenate and sodium stearyl fumarate.

[0052] In some embodiments of the present invention, compound (A) accounts for 2% to 4% by weight of the pharmaceutical composition, the filler accounts for 85% to 92% by weight of the pharmaceutical composition, the disintegrant accounts for 3% to 4% by weight of the pharmaceutical composition, the glidant accounts for 1% to 2% by weight of the pharmaceutical composition, and the lubricant accounts for 1% to 3% by weight of the pharmaceutical composition; wherein the filler is selected from a combination of microcrystalline cellulose, mannitol and pregelatinized starch, the weight percentage of the mannitol is 20% to 45%, the weight percentage of microcrystalline cellulose is 40% to 65%, the weight ratio of mannitol to microcrystalline cellulose is 1:3.3 to 1:2.8, and the weight percentage of the pregelatinized starch is 5% to 15%; the disintegrant is selected from cross-linked polyvinylpyrrolidone; the glidant is selected from colloidal silicon dioxide; and the lubricant is selected from glyceryl behenate and sodium stearyl fumarate.

[0053] In some embodiments of the present invention, the pharmaceutical composition may further include an acidic pH regulator to adjust the pH of the composition's microenvironment and enhance the composition's stability. The acidic pH regulator is selected from oxalic acid, maleic acid, fumaric acid, or glutaric acid, and its weight percentage in the pharmaceutical composition is 0-3%.

[0054] The total weight percentage of all components in the pharmaceutical composition of the present invention is 100%.

[0055] The second aspect of the present invention provides a solid oral preparation made from the above pharmaceutical composition. The "solid oral preparation" described herein refers to a pharmaceutical preparation in a solid state for oral administration, which is preferably a capsule or tablet, more preferably a tablet, and even more preferably a film-coated tablet.

[0056] In some embodiments of the present invention, the solid oral dosage form is a film-coated tablet. The coating material used for the film-coated tablet is a gastric soluble coating material, preferably comprising one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, or polyvinyl alcohol polyethylene glycol copolymer, and may further comprise a sunscreen (e.g., titanium dioxide), a plasticizer (e.g., polyethylene glycols, glycerol, propylene glycol, diethyl phthalate, diethyl phthalate, triacetin, triethyl citrate, caprylic and capric mono- and diglycerides, etc.), a lubricant (e.g., talc), or a colorant (e.g., lemon yellow aluminum lake, allura red aluminum lake, brilliant blue aluminum lake). The coating material can also be obtained commercially, and a suitable premix of the coating material can be selected from: Opadry 03B28796 or Opadry 321A610052.

[0057] In some embodiments of the present invention, the film coating weight gain is 1%-5% of the tablet core (ie, the pharmaceutical composition of the present invention), preferably 2%-4%, such as 2%, 2.6%, 3%, 3.7% or 4%.

[0058] A third aspect of the present invention provides a method for preparing the above-mentioned pharmaceutical composition, the method comprising:

[0059] Compound (A) is premixed with other excipients except lubricant, and the obtained premix is ​​then mixed with lubricant to obtain a pharmaceutical composition containing compound (A).

[0060] Optionally, the obtained pharmaceutical composition comprising compound (A) is filled into capsules or compressed into tablets.

[0061] In some embodiments of the present invention, the premixing can be performed in multiple steps. Furthermore, the premixing can also include a deaggregation step, for example, premixing one or more materials with a flow aid and then deaggregating them once or multiple times.

[0062] In some embodiments of the present invention, the preparation method further comprises the step of adding an acidic pH regulator, wherein the acidic pH regulator is selected from oxalic acid, maleic acid, fumaric acid or glutaric acid.

[0063] A fourth aspect of the present invention provides the use of the above-mentioned pharmaceutical composition or the above-mentioned solid oral dosage form in the preparation of a medicament for preventing and / or treating a disease associated with the activity or expression of FGFR, KDR and / or CSF-1R. Preferably, the disease is a tumor. Further preferably, the tumor is selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, bladder cancer, urinary tract transitional cell carcinoma, esophageal cancer, gastric cancer (including gastroesophageal junction cancer), pancreatic cancer, prostate cancer, colorectal cancer, myeloma, multiple myeloma, acute myeloid leukemia, liver cancer, melanoma, thyroid cancer, head and neck cancer, renal cell carcinoma, glioblastoma, squamous cell carcinoma, esophageal squamous cell carcinoma, lung squamous cell carcinoma, nasopharyngeal squamous cell carcinoma, testicular cancer, and bile duct cancer.

[0064] A fifth aspect of the present invention provides the above-mentioned pharmaceutical composition or the above-mentioned solid oral dosage form, which is used to prevent and / or treat a disease related to the activity or expression of FGFR, KDR and / or CSF-1R. Preferably, the disease is a tumor. Further preferably, the tumor is selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, bladder cancer, urinary tract transitional cell carcinoma, esophageal cancer, gastric cancer (including gastroesophageal junction cancer), pancreatic cancer, prostate cancer, colorectal cancer, myeloma, multiple myeloma, acute myeloid leukemia, liver cancer, melanoma, thyroid cancer, head and neck cancer, renal cell carcinoma, glioblastoma, squamous cell carcinoma, esophageal squamous cell carcinoma, lung squamous cell carcinoma, nasopharyngeal squamous cell carcinoma, testicular cancer and bile duct cancer.

[0065] A sixth aspect of the present invention provides a method for preventing and / or treating a disease associated with the activity or expression of FGFR, KDR, and / or CSF-1R, the method comprising administering an effective dose of the above-mentioned pharmaceutical composition or the above-mentioned solid oral dosage form to a subject in need thereof. Preferably, the disease is a tumor. Further preferably, the tumor is selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, bladder cancer, urinary tract transitional cell carcinoma, esophageal cancer, gastric cancer (including gastroesophageal junction cancer), pancreatic cancer, prostate cancer, colorectal cancer, myeloma, multiple myeloma, acute myeloid leukemia, liver cancer, melanoma, thyroid cancer, head and neck cancer, renal cell carcinoma, glioblastoma, squamous cell carcinoma, esophageal squamous cell carcinoma, lung squamous cell carcinoma, nasopharyngeal squamous cell carcinoma, testicular cancer, and bile duct cancer.

[0066] The term "subject" as used herein is interchangeable with "patient" and includes all members of the animal kingdom, including but not limited to non-human mammals (e.g., mice, rats, cats, monkeys, dogs, horses, pigs, etc.) and humans, preferably humans.

[0067] The "effective dose" described herein refers to the amount of the compound of formula (A) sufficient to achieve the desired therapeutic effect in a "subject" or "patient" when administered in single or multiple doses.

[0068] Within the scope of this application, the various options of any feature can be combined with the various options of other features to form many different embodiments. This application is intended to include all possible embodiments consisting of the various options of all technical features. It should be understood that within the scope of the present invention, the above-mentioned various technical features of the present invention and the various technical features described in detail below (such as in the examples) can be combined with each other to form new or preferred technical solutions.

[0069] The pharmaceutical composition of the present invention has the following beneficial effects:

[0070] (1) The pharmaceutical composition of the present invention comprises Compound (A) as an active ingredient. Compared with the free base Compound (I), the salt form of Compound (A) has the advantages of being easy to dry, having good solubility, stable quality, thermodynamic stability, and being easy to formulate into a drug, and is therefore more suitable as an active ingredient in the pharmaceutical composition;

[0071] (2) The pharmaceutical composition of the present invention has good dissolution of the active ingredient;

[0072] (3) The pharmaceutical composition of the present invention has a qualified content uniformity of the active ingredient;

[0073] (4) The pharmaceutical composition of the present invention is advantageous for providing a solid oral preparation that is stable in nature and suitable for long-term storage; and

[0074] (5) The preparation method of the pharmaceutical composition of the present invention is simple and convenient for industrial-scale production. DETAILED DESCRIPTION

[0075] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, were performed under conventional conditions or under conditions recommended by the manufacturer.

[0076] The analysis and detection conditions involved in the following examples are as follows:

[0077] 1. X-ray powder diffractometer (XRPD)

[0078] Instrument: BRUKER D8 Advance X-ray powder diffractometer, Germany.

[0079] Conditions: Cu-Kα radiation The tube voltage was 40 kV, the tube current was 40 mA, the 2θ scanning range was 3-40°, the scanning step was 0.02° (2θ), the scanning speed was 10 s / step, and the sample plate was a zero-background sample plate.

[0080] Method: Place the sample on a zero-background single crystal silicon sample plate and flatten it with a medicine spoon for measurement.

[0081] 2. Chloride

[0082] Detection instrument: Dionex ICS-900 ion chromatograph

[0083] Column: Dionex Ion Pac AS11-HC anion chromatography column (specifications: 4×250 mm)

[0084] Determination method: Accurately measure 10 μL of the reference solution and the test solution, inject them into the ion chromatograph respectively, record the chromatogram, and calculate the chloride ion content by the peak area according to the external standard method.

[0085] 3. Dynamic moisture adsorption and desorption analysis (DVS)

[0086] Instrument: DVS Intrinsic plus (SMS, UK).

[0087] Method: Place the sample in a peeled sample basket, the sample weight is automatically weighed, and the sample is analyzed according to the parameters in the table below.

[0088] 4. Thermogravimetric analysis (TGA) test conditions

[0089] Instrument: Discovery TGA 55.

[0090] Conditions: temperature range from room temperature to 350 °C, heating rate 10 °C / min, purge gas nitrogen, equilibrium chamber flow rate: 40 mL / min, sample chamber flow rate: 25 mL / min.

[0091] Sample: 1-5mg.

[0092] 5. Content determination conditions

[0093] Instrument: High Performance Liquid Chromatograph (Waters e26892495)

[0094] Column: Waters Symmetry C18, 250 × 4.6 mm, 5 μm

[0095] Mobile phase: 10 mmol / L ammonium acetate solution-acetonitrile (40:60)

[0096] Injection volume: 10 μl

[0097] 6. Dissolution test conditions

[0098] Instrument: High Performance Liquid Chromatograph (Waters e26892495)

[0099] Column: Waters XBridge C18, 250 × 4.6 mm, 5 μm

[0100] Mobile phase: 10 mmol / L ammonium acetate solution-acetonitrile (60:40)

[0101] Injection volume: 20 μl

[0102] Dissolution method: Paddle method

[0103] Speed: 50 rpm

[0104] Dissolution medium: 1000ml potassium dihydrogen phosphate-sodium hydroxide buffer solution at pH 6.0

[0105] Medium temperature: 37±0.5℃

[0106] Preparation Example 1: Preparation of Compound (A)

[0107] Compound (I) (0.52 g, prepared with reference to Preparation Example 10 of WO2017140269A1) and methanol (25 mL) were added to a reaction flask and stirred. Once the system was evenly dispersed, a methanolic hydrochloric acid solution (1.2 mL, 2 mol / L) was added dropwise with stirring. Stirring was continued for 5 h. The mixture was filtered and vacuum-dried (at 30°C for 12 h to constant weight, then at 45°C to a desired solvent residue) to obtain a solid (0.53 g). Nuclear magnetic resonance (NMR) analysis confirmed the formation of a salt.

[0108] The chloride ion content was determined by ion chromatography, and the stoichiometric ratio of the hydrochloride was calculated (see Table 1 below). It was inferred that the base / acid ratio of the hydrochloride was 1:2.

[0109] Table 1

[0110] The obtained solid sample was subjected to X-ray powder diffraction analysis, and the results showed that it exhibited good crystallinity and was named Form I. Its diffraction peak data are shown in Table 2.

[0111] Table 2 XRPD diffraction peak data of Form I sample obtained in Preparation Example 1

[0112] Preparation Example 2: Preparation of Form I of Compound (A)

[0113] Compound (I) (1.0432 g, prepared with reference to WO2017140269A1 Preparation Example 10) and purified water (3 mL) were added to the reaction flask, stirred to disperse the system evenly, and aqueous hydrochloric acid solution (2 N) was added dropwise, stirred until completely dissolved, and the Form I sample (0.01 g) obtained in Preparation Example 1 was added as a seed crystal. After stirring and crystallizing for 20 to 24 hours, the mixture was filtered. After vacuum drying at 30 ° C for 12 hours, the mixture was vacuum-dried at 45 ° C until the solvent residue was qualified to obtain a solid (1.112 g). After testing, it was confirmed that Form I of compound (A) was obtained, and its crystallinity was good. The XRPD characterization data of the obtained sample are shown in Table 3. The sample was taken for TGA-DSC test, and the results showed that the sample did not contain crystal water and crystallization solvent.

[0114] Table 3 XRPD diffraction peak data of Form I sample obtained in Preparation Example 2

[0115] Preparation Example 3: Preparation of other salts of compound (I)

[0116] To each vial containing 5 mL of a 0.02 mol / mL solution of an acid (phosphoric acid, maleic acid, tartaric acid, or fumaric acid) in tetrahydrofuran / methanol (1:1, volume ratio, the same applies hereafter) was added a 0.01 mol / mL solution of compound (I) in tetrahydrofuran / methanol (1:1) (10 mL), stirred, and reacted at 40°C for 1 h. The reaction solution was evaporated to dryness and dried at 50°C for 3-4 h to obtain a solid. Nuclear magnetic resonance (NMR) and ion chromatography revealed the phosphate, maleate, tartarate, and fumarate salts of compound (I), respectively.

[0117] Further XRPD detection showed that the obtained solids had good crystallinity.

[0118] Test Example 1: Solubility test of compound (I) and its salts

[0119] First, the solubility of Compound (I), the sample obtained in Preparation Example 2 (Compound (A)), and the sample obtained in Preparation Example 3 were tested in water. Then, the solubility of Compound (I) and the sample obtained in Preparation Example 2 (Compound (A)) were tested in NaHPO-citrate buffer (pH 4.6). The experimental results are shown in Tables 4 and 5, respectively.

[0120] Table 4 Solubility test results of compound (I) and its different salt forms in water (25°C, mg / mL)

[0121] Table 5 Solubility test results of compound (I) and compound (A) in buffer (25°C, mg / mL)

[0122] The results showed that Compound (A) obtained in Preparation Example 2 and various salts obtained in Preparation Example 3 exhibited good solubility in water, significantly superior to the free base, meeting the general solubility requirements for APIs in oral dosage forms. Compound (A) exhibited particularly excellent solubility, meeting the general solubility requirements for APIs in various pharmaceutical dosage forms (e.g., solid oral dosage forms, injections, oral liquids, etc.). Compound (A) also exhibited better solubility in buffer than Compound (I).

[0123] Test Example 2: Water adsorption and desorption experiments of different salt forms of compound (I)

[0124] The samples obtained in Preparation Examples 2 and 3 were tested for water adsorption and desorption at 40-80% relative humidity at 25°C using a dynamic water sorption instrument (DVS) to determine the hygroscopic properties of the various salt types. The experimental results are shown in Table 6.

[0125] Table 6 Hygroscopicity test results of different salt forms of compound (I) (DVS, 40-80%)

[0126] The results showed that compound (A) was slightly hygroscopic and its weight gain upon moisture absorption was relatively low.

[0127] Test Example 3: Solid Stability Test of Compound (A)

[0128] The physical and chemical stability of the sample obtained in Preparation Example 2 was investigated after being placed under 40°C / 75% RH (open) and 60°C (sealed) conditions for 7 days, as well as the physical stability after being placed under room temperature / 92.5% RH (open) conditions for 10 days. The experimental results are shown in Table 7 below.

[0129] Table 7 Solid stability test results of compound (A)

[0130] Note: / indicates not detected; the crystal form was tested using X-ray powder diffraction method.

[0131] The results showed that after 7 days of storage at 40°C / 75% RH and 60°C, the purity of compound (A) remained unchanged, and its crystalline form remained unchanged. After 10 days of storage at 92.5% RH, its crystalline form also remained unchanged. These results demonstrate that compound (A) possesses good chemical and physical stability.

[0132] Test Example 4: Grinding stability test of compound (A)

[0133] The samples obtained in Preparation Example 2 were mechanically ground using a mortar for 2 minutes and 5 minutes, respectively. X-ray powder diffraction test results showed that no crystal form transformation occurred in Form I after grinding.

[0134] Furthermore, the samples obtained in Preparation Example 2 were added with appropriate amounts of organic solvents (methanol, ethanol, acetone, acetonitrile, ethyl acetate) and then mechanically ground. X-ray powder diffraction test results showed that no crystal form I underwent crystal transformation after grinding.

[0135] The active ingredient compound (A) used in the following examples is all in crystalline form I.

[0136] The inspection item limit requirements of the tablets containing compound (A) prepared in the following examples are shown in Table 8:

[0137] Table 8 Limit requirements for inspection items of example tablets

[0138] Example 1: Preparation of tablets (51 mg / tablet) containing compound (A)

[0139] The tablet formulation of Example 1 is shown in Table 9 below:

[0140] Table 9 Prescription of Example 1

[0141] Preparation method:

[0142] ① Weighing: Accurately weigh the raw and auxiliary materials according to the prescription amount in Table 9;

[0143] ② Premix:

[0144] Mix the colloidal silicon dioxide and mannitol bags, pass through a 40-mesh sieve, and divide into two parts, the first part is about 6% of the total weight, and the second part is 94%;

[0145] Add pregelatinized starch, compound (A), crospovidone and the first portion of the mixture of colloidal silicon dioxide and mannitol into a container of appropriate volume and mix, then add about 1 / 2 of microcrystalline cellulose into the container and mix;

[0146] Add the remaining microcrystalline cellulose, the second portion of colloidal silicon dioxide and the mixture of mannitol into the above container and mix;

[0147] ③Total mixing: add glyceryl behenate in equal amounts and mix;

[0148] ④ Tableting: The mixture obtained in ③ was tableted, with a theoretical tablet weight of 51 mg / tablet; tablet weight variation ±7.5%; hardness 4-10 kg.

[0149] The dissolution rate (pH 6.0 phosphate buffer), content, content uniformity and process feasibility of the prepared tablets were investigated. The results are shown in Table 10 below:

[0150] Table 10 Test results of the tablets of Example 1

[0151] The results showed that the tablets containing compound (A) as the active ingredient were prepared using the prescription of this example. The tableting process was smooth, and the dissolution and content uniformity of the prepared tablet samples met the requirements; the preparation process was simple and highly feasible.

[0152] Example 2: Preparation of tablets containing compound (A) (100 mg / tablet)

[0153] The tablet formulation of Example 2 is shown in Table 11 below:

[0154] Table 11 Tablet formulation of Example 2

[0155] Preparation method:

[0156] ① Pretreatment of raw materials: Pass compound (A) through a 100-mesh sieve and take the undersize fraction.

[0157] ② Weighing: Accurately weigh the raw and auxiliary materials according to the prescription amount in Table 11;

[0158] ③ Premix:

[0159] Premix I: Add mannitol, compound (A), colloidal silicon dioxide, and crospovidone into a suitable container and mix;

[0160] Depolymerization I: Take the mixture obtained in premixing I and pregelatinized starch and add them to a granulator or sieve for depolymerization;

[0161] Premix II: Take the mixture obtained from depolymerization I and add it into the container for mixing;

[0162] Premix III: Add microcrystalline cellulose and the premix obtained from premix II into another container of appropriate volume and mix;

[0163] Deagglomeration II: Take the mixture obtained from premixing III and pass it through a granulator or sieve for deagglomeration;

[0164] Premix IV: Add the mixture obtained from depolymerization II into the container and mix;

[0165] ④Total mixing:

[0166] Sodium stearyl fumarate was mixed with approximately equal amounts of the premixed IV mixture, passed through a 24 mesh screen, and added to the container containing the premixed IV mixture and mixed.

[0167] ⑤ Tableting: The mixture obtained in ④ is tableted, with a theoretical tablet weight of 0.1 g / tablet; tablet weight variation ±7.5%; and a hardness of 3-12 kg.

[0168] The dissolution rate (pH 6.0 phosphate buffer), content, content uniformity and process feasibility of the prepared tablets were investigated. The results are shown in Table 12 below:

[0169] Table 12 Test results of the tablets of Example 2

[0170] The results showed that the tablets containing compound (A) as the active ingredient prepared by the prescription of this example had good dissolution and qualified content uniformity; the preparation process was highly feasible.

[0171] Example 3-7: Preparation of tablets containing compound (A) (investigation of filler dosage)

[0172] (1) Investigation of the weight ratio of mannitol to microcrystalline cellulose

[0173] Tablets of Examples 3-5 were prepared by referring to the formulation and preparation method of Example 2, except that the weight ratio of mannitol to microcrystalline cellulose was changed. The amounts and ratios of mannitol and microcrystalline cellulose used in Examples 3-5 are shown in Table 13 below.

[0174] Table 13 Amounts and ratios of mannitol and microcrystalline cellulose in Examples 3-5

[0175] The tablets prepared in Examples 3-5 were tested for dissolution (pH 6.0 phosphate buffer), content, content uniformity, and process feasibility. The results are shown in Table 14 below:

[0176] Table 14 Test results of tablets of Examples 3-5

[0177] The results showed that tablets prepared using different ratios of mannitol and microcrystalline cellulose as fillers all showed good dissolution of the active ingredient and high process feasibility, but the content uniformity of the active ingredient in the tablets prepared when the ratio of mannitol to microcrystalline cellulose was 2:1 was unqualified.

[0178] (2) Investigation of the dosage of pregelatinized starch

[0179] Referring to the formulation and preparation method of Example 2, the amount of pregelatinized starch was varied, and the amount of microcrystalline cellulose was adjusted to maintain the filler amount and total tablet weight unchanged, to prepare the tablets of Examples 6-7. The amount of pregelatinized starch used in Examples 6-7 is shown in Table 15 below.

[0180] Table 15 Amount of pregelatinized starch used in Examples 6-7

[0181] The tablets prepared in Examples 6-7 were tested for dissolution (pH 6.0 phosphate buffer), content, content uniformity, and process feasibility. The results are shown in Table 16 below:

[0182] Table 16 Test results of tablets of Examples 6-7

[0183] The results showed that at the selected dosage of pregelatinized starch, the prepared tablets showed good dissolution and content uniformity of the active ingredient, and the process feasibility was high.

[0184] Examples 8-10: Preparation of tablets containing compound (A) (investigation of the amount of disintegrant used)

[0185] Referring to the formulation and preparation method of Example 2, only the amount of disintegrant was changed (the total tablet weight was changed accordingly) to prepare the tablets of Examples 8-10. The amount of disintegrant used in Examples 8-10 is shown in Table 17 below.

[0186] Table 17 Amount of disintegrant used in Examples 8-10

[0187] The tablets prepared in Examples 8-10 were subjected to dissolution testing (pH 6.0 phosphate buffer), and the results are shown in Table 18 below:

[0188] Table 18 Dissolution test results of tablets of Examples 8-10

[0189] The results showed that the tablet of Example 8 without a disintegrant also exhibited acceptable dissolution of the active ingredient; the addition of a disintegrant further improved the dissolution of the active ingredient, as shown in Examples 9-10.

[0190] Examples 11-14: Preparation of tablets containing compound (A) (investigation of the amount of glidant)

[0191] Referring to the prescription and preparation method of Example 2, only the amount of the glidant was changed (the total tablet weight was changed accordingly) to prepare the tablets of Examples 11-12.

[0192] With reference to the prescription and preparation method of Example 1, the ratio of mannitol to microcrystalline cellulose was adjusted to 1:1 and the amount of the glidant was changed to prepare the tablets of Examples 13-14.

[0193] The amount of glidant used in Examples 11-14 is shown in Table 19 below.

[0194] Table 19 Amount of glidant used in Examples 11-14

[0195] The tablets prepared in Examples 11-14 (n=6) were tested for content and content uniformity. The results are shown in Table 20 below:

[0196] Table 20 Test results of tablets of Examples 11-14

[0197] The results showed that at the tested glidant dosages, the prepared tablets all exhibited qualified content uniformity.

[0198] Examples 15-16: Preparation of tablets containing compound (A) (investigation of lubricant dosage)

[0199] Referring to the formulation and preparation method of Example 2, only the amount of lubricant was changed (the total tablet weight was changed accordingly) to prepare the tablets of Examples 15-16. The amount of lubricant used in Examples 15-16 is shown in Table 21 below.

[0200] Table 21 Lubricant dosage in Examples 15-16

[0201] The tablets prepared in Examples 15-16 were subjected to dissolution (pH 6.0 phosphate buffer) and process feasibility tests. The results are shown in Table 22 below:

[0202] Table 22: Test results of tablets of Examples 15-16

[0203] The results showed that at the tested lubricant dosages, the prepared tablets exhibited good dissolution and the preparation process was highly feasible.

[0204] Examples 17-19: Preparation of film-coated tablets containing compound (A) (investigation of coating weight gain)

[0205] Tablets containing compound (A) were prepared according to the formulation and preparation method of Example 2, and film-coated premix (gastric soluble)- 321A610052 was applied, with a coating liquid solid content of 30%, and the weight gain was controlled within a range of 2.0% to 4.0% of the tablet core weight to prepare the film-coated tablets of Examples 17-19. The coating weight gain percentages of Examples 17-19 are shown in Table 23 below.

[0206] Table 23 Coating Weight Gain in Examples 17-19

[0207] The film-coated tablets prepared in Examples 17-19 were subjected to a dissolution test (pH 6.0 phosphate buffer) and their appearance was observed. The results are shown in Table 24 below:

[0208] Table 24 Dissolution results and appearance of film-coated tablets of Examples 17-19

[0209] The results showed that the film-coated tablets obtained after coating still showed good dissolution of the active ingredient and had a good appearance.

[0210] Examples 20-21: Other preparation examples of tablets containing compound (A)

[0211] Referring to the preparation method of Example 1, the tablets of Examples 20-21 were prepared according to the prescription in Table 25 below.

[0212] Table 25 Tablet formulations for Examples 20-21

[0213] The tablets prepared in Examples 20-21 were tested for dissolution (pH 6.0 phosphate buffer), content, content uniformity, and process feasibility. The results are shown in Table 26 below:

[0214] Table 26 Test results of tablets of Examples 20-21

[0215] Examples 22-24: Preparation of tablets containing compound (A) (investigation of different lubricants)

[0216] Referring to the preparation method of Example 2, tablets of Examples 22-24 were prepared according to the prescription shown in Table 27 below.

[0217] Table 27 Tablet formulations for Examples 22-24

[0218] The tablets prepared in Examples 2 and 22-24 were subjected to a stability test at 60°C for one month. The results are shown in Table 28 below:

[0219] Table 28 Tablet stability test results of Examples 2 and 22-24

[0220] The results showed that after one month at 60°C, tablets prepared with stearic acid as a lubricant showed a slight increase in total impurities, while tablets prepared with magnesium stearate and sodium stearyl fumarate as lubricants showed no significant difference in total impurities compared to day 0. Tablets prepared with all three lubricants met the requirements for total impurities after one month at 60°C.

[0221] Examples 25-28: Preparation of tablets containing compound (A) (investigation of different fillers)

[0222] Referring to the preparation method of Example 2, tablets of Examples 25-28 were prepared according to the prescription in Table 29 below.

[0223] Table 29 Tablet formulations for Examples 25-28

[0224] The tablets prepared in Examples 25-28 were tested for dissolution (pH 6.0 phosphate buffer), content, content uniformity, and process feasibility. The results are shown in Table 30 below:

[0225] Table 30 Tablet test results of Examples 25-28

[0226] The results showed that the tablets prepared by using microcrystalline cellulose as a single filler (Example 25) or using a combination of microcrystalline cellulose and other fillers, such as a combination of microcrystalline cellulose and mannitol (Example 26) or a combination of microcrystalline cellulose (or silicified microcrystalline cellulose) with lactose and pregelatinized starch (Examples 27-28) as fillers, all showed good dissolution of the active ingredient and acceptable content uniformity.

[0227] Examples 29-30: Preparation of tablets containing compound (A) (investigation of different disintegrants)

[0228] The tablets of Examples 29-30 were prepared by referring to the preparation method of Example 2, except that the disintegrant crospovidone was replaced with the disintegrants listed in Table 31 below.

[0229] Table 31 Disintegrants used in Examples 29-30

[0230] The tablets prepared in Examples 29-30 were subjected to a dissolution test (pH 6.0 phosphate buffer). The results are shown in Table 32 below:

[0231] Table 32 Dissolution test results of tablets of Examples 29-30

[0232] The results showed that tablets with good dissolution of the active ingredient could also be prepared by using low-substituted hydroxypropyl cellulose and sodium starch glycolate as disintegrants.

[0233] Example 31: Preparation of tablets containing compound (A) (investigation of different glidants)

[0234] Tablets of Example 31 were prepared by referring to the formulation and preparation method of Example 2, except that the colloidal silicon dioxide was replaced with silicon dioxide. The tablets were tested for dissolution (pH 6.0 phosphate buffer), content, content uniformity, and process feasibility. The results are shown in Table 33 below:

[0235] Table 33 Test results of the tablets of Example 31

[0236] The results showed that tablets prepared using silicon dioxide as a glidant also exhibited good dissolution rate and content uniformity of the active ingredient, and the process feasibility was high.

[0237] Example 32: Preparation of coated tablets containing compound (A)

[0238] Film coating premix for tablets (gastric soluble type) containing compound (A) prepared according to the prescription and preparation method of Example 1 03B28796 coating, the coating liquid solid content is 10%, weight gain: 3.7%, to obtain coated tablets containing compound (A).

[0239] Example 33: Preparation of coated tablets containing compound (A)

[0240] Film coating premix for tablets (gastric soluble type) containing compound (A) prepared according to the prescription and preparation method of Example 2 321A610052 coating, the coating liquid solid content is 30%, weight gain: 2.6%, to obtain coated tablets containing compound (A).

[0241] The prepared tablets can be scored on both sides to meet the flexible dosage requirements. The tablets obtained are easy to split, and the quality of the half-tablets obtained after splitting meets the requirements, see Table 34 below:

[0242] Table 34 Half-slice detection results obtained after segmentation

[0243] Example 34: Preparation of capsules containing compound (A)

[0244] A pharmaceutical composition comprising compound (A) was obtained by referring to the prescription and steps ① to ④ of the preparation method of Example 2, and the pharmaceutical composition was filled into capsules to obtain capsules comprising compound (A).

[0245] Test Example 5: Long-term stability test

[0246] (1) The tablets prepared in Example 32 were packaged in low-density polyethylene bottles (containing a desiccant) and placed at 25°C ± 2°C / 60% ± 5% RH to investigate their stability. The test results are shown in Table 35 below:

[0247] Table 35 Stability test results of the tablets of Example 32 at 25°C ± 2°C / 60% ± 5% RH

[0248] (2) The tablets prepared in Example 33 were packaged in double aluminum blisters and placed at 30°C ± 2°C / 65% ± 5% RH to investigate their stability. The test results are shown in Table 36 below:

[0249] Table 36 Stability test results of the tablets of Example 33 at 30°C ± 2°C / 65% ± 5% RH

[0250] The above experimental results show that the preparation of the present invention does not show significant changes in the relevant substances, solubility and content when placed at 25°C±2°C / 60%±5% RH for 24 months or at 30°C±2°C / 65%±5% RH for 18 months, indicating that the preparation has stable quality and is suitable for long-term storage.

[0251] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be considered to be within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition containing the following components, as a percentage of the weight of the pharmaceutical composition: 0.1-10 wt.% of a compound (A) having a structure of formula (A) below 70-95 wt.% filler, 0-15 wt.% disintegrant, 0-3 wt.% glidant, and 0.5-5 wt.% lubricant.

2. The pharmaceutical composition according to claim 1, wherein said compound (A) constitutes 1-10 wt.%, preferably 2-8 wt.%, more preferably 2-7 wt.%, even more preferably 2-6 wt.%, even more preferably 2-5 wt.% and even more preferably 2-4 wt.% of the weight of the pharmaceutical composition.

3. The pharmaceutical composition according to any one of claims 1, 2, wherein said filler constitutes 75-95% by weight, even more preferably 80-95% by weight, even more preferably 85-95% by weight and even more preferably 85-92% by weight of the pharmaceutical composition.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein said disintegrant constitutes 1-6 wt.%, preferably 2-6 wt.%, more preferably 2-5 wt.%, more preferably 2-4 wt.%, even more preferably 3-5 wt.%, even more preferably 3.5-4.5 wt.% and even more preferably 3-4 wt.% of the weight of the pharmaceutical composition.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein said glidant constitutes 0.5 to 3.0 wt.%, preferably 0.5 to 2.5 wt.%, more preferably 0.5 to 2 wt.% and even more preferably 1 to 2 wt.% of the weight of the pharmaceutical composition.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein said lubricant constitutes 0.5-4 wt.%, preferably 1-4 wt.%, more preferably 1-3 wt.% and even more preferably 0.8-3 wt.% of the weight of the pharmaceutical composition.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the filler is selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose, xylitol, mannitol, sorbitol, starch, pregelatinized starch, dextrin, lactose, sucrose, glucose, fructose, maltose, calcium carbonate, calcium sulfate and dicalcium phosphate; preferably, the filler is one or more of microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, lactose, pregelatinized starch and dextrin; more preferably, the filler is one or more of microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, lactose and pregelatinized starch;even more preferably, the filler is one of microcrystalline cellulose or silicified microcrystalline cellulose, a combination of one of microcrystalline cellulose or silicified microcrystalline cellulose and one of mannitol or lactose, or a combination of one of microcrystalline cellulose or silicified microcrystalline cellulose, one of mannitol or lactose and pregelatinized starch; even more preferably, the filler is a combination of microcrystalline cellulose, mannitol and pregelatinized starch.

8. The pharmaceutical composition according to claim 7, wherein when the filler is selected from a combination of one of microcrystalline cellulose or silicified microcrystalline cellulose and one of mannitol or lactose, mannitol or lactose has a weight fraction of 15-50 wt.%, preferably 20-45 wt.%, more preferably 20-40 wt.% and even more preferably 20-30 wt.%; microcrystalline cellulose or silicified microcrystalline cellulose has a weight fraction of 40-75 wt.%, preferably 50-75 wt.%, more preferably 60-75 wt.% and even more preferably 65-75 wt.%; mannitol or lactose and microcrystalline cellulose or silicified microcrystalline cellulose are in a weight ratio of 1:5 to 1:1, preferably 1:4 to 1:1, more preferably 1:4 to 1:1.5, even more preferably 1:3.6 to 1:1.5, even more preferably 1:3.6 to 1:2.8 and even more preferably 1:3.6 to 1:

3.

9. The pharmaceutical composition of claim 7, wherein when the filler is selected from a combination of one of microcrystalline cellulose or silicified microcrystalline cellulose, one of mannitol or lactose and pregelatinized starch, mannitol or lactose has a weight fraction of 15-45 wt.%, preferably 20-45 wt.%, more preferably 20-41 wt.% and more preferably 20-30 wt.%; microcrystalline cellulose or silicified microcrystalline cellulose has a weight fraction of 35-70%, preferably 40-65%; mannitol or lactose and microcrystalline cellulose or silicified microcrystalline cellulose are in a weight ratio of 1:5 to 1:1, preferably 1:4 to 1:1, more preferably 1:4 to 1:1.5, even more preferably 1:3.6 to 1:1.5, even more preferably 1:3.6 to 1:2.8, even more preferably 1:3.3 to 1:2.8 and even more preferably 1:3.05; the pregelatinized starch has a weight fraction of 5-25 wt.%, preferably 5-15 wt.%, more preferably 8-12 wt.%, even more preferably 10-11 wt.% and even more preferably 10.5 wt.%.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the disintegrant is selected from: sodium carboxymethyl starch, sodium carboxymethyl cellulose, sodium croscarmellose, dry starch, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, crospovidone, an effervescent disintegrant, potassium polacrilin and sodium alginate; preferably, the disintegrant is sodium carboxymethyl starch, sodium carboxymethyl cellulose, sodium croscarmellose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone or crospovidone; more preferably, the disintegrant is sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose or crospovidone; more preferably, the disintegrant is crospovidone.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the glidant is selected from: talc, silicon dioxide and colloidal silicon dioxide; preferably, the glidant is silicon dioxide or colloidal silicon dioxide; more preferably, the glidant is colloidal silicon dioxide.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the lubricant is selected from: calcium stearate, magnesium stearate, zinc stearate, talc, sodium stearyl fumarate, stearic acid, glyceryl behenate, palmitic acid, glyceryl palmitostearate, magnesium lauryl sulfate, hydrogenated vegetable oil, sodium dodecyl sulfate, magnesium dodecyl sulfate, polyethylene glycol, colloidal silicon dioxide and aluminum hydroxide; preferably, the lubricant is glyceryl behenate, magnesium stearate or sodium stearyl fumarate; more preferably, the lubricant is glyceryl behenate or sodium stearyl fumarate.

13. A pharmaceutical composition according to any one of claims 1-12, wherein the compound (A) is in crystalline form.

14. The pharmaceutical composition of claim 13, wherein the crystalline form of compound (A) is crystalline form I, wherein crystalline form I has characteristic peaks at 20 values ​​of 5.0±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2° and 25.2±0.2° in an X-ray powder diffraction pattern obtained using Cu-Kα radiation, or crystalline form I has characteristic peaks at 29 values ​​of 5.0±0.2°, 10.4±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 23.4±0.2° and 25.2±0.2° in the powder X-ray diffraction pattern obtained using Cu-Kα radiation, or crystalline form I has characteristic peaks at 29 values ​​of 5.0±0.2°, 10.4±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2° and 25.2±0.2° in the powder X-ray diffraction pattern obtained using Cu-Kα radiation, or crystalline form I has characteristic peaks at 2θ values ​​of 5.0±0.2°, 10.4±0.2°, 11.2±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 22.0±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2°, 25.2±0.2° and 26.6±0.2° in the powder X-ray diffraction pattern obtained using Cu-Kα radiation, or crystalline form I has characteristic peaks at 2θ values ​​of 5.0±0.2°, 10.0±0.2°, 10.4±0.2°, 11.2±0.2°, 13.5±0.2°, 14.1±0.2°, 15.7±0.2°, 17.4±0.2°, 18.0±0.2°, 19.3±0.2°, 20.1±0.2°, 20.5±0.2°, 21.4±0.2°, 22.0±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2°, 25.2±0.2°, 26.6±0.2°, 28.6±0.2° and 30.1±0.2° in the powder X-ray diffraction pattern obtained using Cu-Kα radiation, or crystalline form I has characteristic peaks at values ​​of 29 5.0±0.2°, 10.0±0.2°, 10.4±0.2°, 11.2±0.2°, 13.5±0.2°, 14.1±0.2°, 15.7±0.2°, 17.4±0.2°, 18.0±0.2°, 19.3±0.2°, 20.1±0.2°, 20.5±0.2°, 21.4±0.2°, 22.0±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2°, 25.2±0.2°,26.6±0.2°, 28.6±0.2°, 30.1±0.2°, 32.0±0.2° and 33.0±0.2° in the powder X-ray diffraction pattern obtained using Cu-Kα radiation.

15. A solid oral dosage form obtained from the pharmaceutical composition according to any one of claims 1 to 14, wherein the solid oral dosage form is a capsule or a tablet, preferably a tablet and more preferably a film-coated tablet.

16. A solid oral dosage form according to claim 15, wherein the solid oral dosage form is a film-coated tablet, wherein the increase in mass due to the film coating is 1-5 wt.%, preferably 2-4 wt.%, for example 2 wt.%, 2.6 wt.%, 3 wt.%, 3.7 wt.% or 4 wt.% of the mass of the tablet core.

17. A method for producing a pharmaceutical composition according to claim 1, comprising: pre-mixing compound (A) with another excipient other than a lubricant, and mixing the resulting premix with a lubricant to produce a pharmaceutical composition containing compound (A); optionally and additionally, filling the resulting pharmaceutical composition containing compound (A) into a capsule or pressing the resulting pharmaceutical composition containing compound (A) into a tablet.

18. Use of a pharmaceutical composition according to any one of claims 1-14 or a solid oral dosage form according to claim 15 or 16 for the preparation of a medicament for the prevention and / or treatment of a disease associated with the activity or expression of FGFR, KDR and / or CSF-1R.

19. The use according to claim 18, wherein said disease is a tumor; preferably, said tumor is selected from the group consisting of: breast cancer, lung cancer, non-small cell lung cancer, bladder cancer, transitional cell carcinoma of the urinary tract, esophageal cancer, gastric cancer (including cancer of the esophagogastric junction), pancreatic cancer, prostate cancer, colorectal cancer, myeloma, multiple myeloma, acute myeloid leukemia, liver cancer, melanoma, thyroid cancer, head and neck cancer, renal cell carcinoma, glioblastoma, squamous cell carcinoma, squamous cell carcinoma of the esophagus, squamous cell carcinoma of the lung, nasopharyngeal squamous cell carcinoma, testicular cancer and cholangiocarcinoma.

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