Pharmaceutical compositions containing heteroaryloxynaphthalene compounds, methods for producing the same, and uses

Abstract

This application relates to a pharmaceutical composition containing compound (A), a method for producing the same, and its use. The method for producing the pharmaceutical composition is simple and suitable for industrial production, and tablets produced with the pharmaceutical composition have excellent uniformity of active ingredient content and dissolution properties, are stable in nature, and are suitable for long-term storage. [Formula 1] JPEG2026531697000044.jpg55170

Description

Technical Field

[0001] The present invention belongs to the field of medicaments, and specifically relates to a pharmaceutical composition comprising a heteroaryloxynaphthalene compound, a preparation method and use thereof provided by the invention.

Background Art

[0002] Fibroblast growth factor receptors (FGFR) are important molecular classification targets for tumors, and are abnormally activated in various tumors, particularly in several refractory tumors and tumor types with specific characteristics in China. Currently, most of the clinical research on FGFR-targeted inhibitors is in the early stage. The clinically studied FGFR inhibitors are mainly multi-targeted, and have low inhibitory activity against FGFR, so they often enhance the antagonistic effect against human kinase insert domain containing receptor (KDR), which causes serious side effects, and greatly limits the application of the anti-tumor effect of FGFR-targeted inhibitors and the maximization of clinical therapeutic effect. However, since both FGFR and KDR have the ability of compensatory activation, it has been indicated that they mediate drug resistance through mutual compensation. In fact, studies have reported that FGFR activation is a drug resistance mechanism of KDR inhibitors. In addition, the effect of KDR family on enhancing immunosuppression and promoting tumors has also been gradually revealed in recent years. Therefore, the development of FGFR and KDR co-targeted inhibitors has important potential for clinical application.

[0003] In recent years, tumor therapy has not only focused on tumor cells themselves, but has also attracted significant attention for the role of the indivisible tumor microenvironment as a whole in promoting tumor progression and mediating drug resistance. Tumor-associated macrophages (TAMs) are important microenvironmental stromal cells that directly inhibit the toxic effects of effector T cells, synergistically promote the tumor immunosuppressant microenvironment, and promote angiogenesis within tumors, thereby promoting tumor cell proliferation and metastasis in multiple stages and mediating tumor drug resistance. Colony-stimulating factor 1 receptor (CSF-1R) is expressed in macrophages and is crucial for maintaining the differentiation and proliferation survival of TAMs into the M2 polarized phenotype. Based on this, simultaneous targeting of FGFR / KDR / CSF-1R can not only antagonize tumor cells themselves but also modulate the tumor microenvironment, antagonizing tumors in multiple stages, reconstructing the immunosuppressive microenvironment, and mitigating the development of acquired drug resistance.

[0004] The compound of formula (I) is a novel FGFR / CSF1R / KDR-targeted small molecule inhibitor developed based on the above mechanism, and preclinical pharmacological studies have shown it to have good therapeutic effects in various tumor models. [ka]

[0005] PCT Patent Document WO2017 / 140269A1 discloses the structure of a compound of formula (I), a method for producing the same, and the use of a pharmaceutical product for the prevention and / or treatment of diseases related to FGFR.

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

[0007] None of the above-mentioned patent documents have examined the formulation and manufacture of the compound of formula (I) or its pharmaceutically acceptable salts. Given the enormous potential applications of the compound of formula (I) as an FGFR / CSF1R / KDR target inhibitor in tumor therapy, there is a need to provide pharmaceutical compositions containing the compound of formula (I) or its pharmaceutically acceptable salts that have excellent drug discovery potential. [Overview of the project] [Problems that the invention aims to solve]

[0008] 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 is easy to manufacture and suitable for industrial production.

[0009] 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 drug discovery potential.

[0010] Another object of the present invention is to provide a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, which can be used in the manufacture of an oral solid dosage form having excellent dissolution properties and uniformity of active ingredient content.

[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 has excellent stability and is suitable for long-term storage. [Means for solving the problem]

[0012] To achieve the objectives of the above invention, the inventors of this application, through initial research, found that compound (A), which is the dihydrochloride salt of the compound of formula (I), is suitable as an active ingredient in a pharmaceutical composition because it is easily dried, highly soluble, has stable quality, is thermodynamically stable, and is easy to use in drug discovery. Furthermore, the inventors conducted screening experiments on other components in the pharmaceutical composition and, as a result, found a specific formulation of a pharmaceutical composition that can satisfy one or more of the above requirements, thereby completing the present invention. [ka]

[0013] A first aspect of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition contains, by weight percentage of the pharmaceutical composition, A compound (A) having the structure represented by the following formula (A) in a concentration of 0.1% to 10%, [ka] 70% to 95% filler, 0-15% disintegrant, 0-3% flow accelerator, Contains 0.5-5% lubricant.

[0014] The pharmaceutical composition of the present invention contains compound (A) as an active ingredient.

[0015] In some embodiments of the present invention, compound (A) is in crystalline form.

[0016] In some embodiments of the present invention, the crystalline form of compound (A) is crystal form I, and crystal form I has characteristic peaks at 2θ 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 a powder X-ray diffraction pattern obtained using Cu-Kα radiation, or The aforementioned crystal form I has characteristic peaks at 2θ 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 The aforementioned crystal form I has characteristic peaks at 2θ 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 The aforementioned crystal form I has characteristic peaks at 2θ in the powder X-ray diffraction pattern obtained using Cu-Kα radiation, 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°, or The aforementioned crystal form I exhibits the following powder X-ray diffraction patterns obtained using Cu-Kα radiation: 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°, and 19.3±0.2°. It has characteristic peaks at 2θ of 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°, or Said crystalline form I has characteristic peaks at 2θ 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°, 30.1±0.2°, 32.0±0.2°, 33.0±0.2° in a powder X-ray diffraction pattern obtained using Cu-Kα radiation, or Said crystalline form I basically has the powder X-ray diffraction analysis data shown in Table 2 or Table 3 below.

[0017] For related contents such as the preparation and measurement of said compound (A) and crystalline form I thereof, reference may be made to patent application CN202310263447.7 or PCT / CN2023 / 082140, the entire contents of which are incorporated herein by reference.

[0018] In some embodiments of the present invention, the percentage by weight of said compound (A) in the pharmaceutical composition is 1% to 10%, preferably 2% to 8%, more preferably 2% to 7%, still more preferably 2% to 6%, even more preferably 2% to 5%, and still even more preferably 2% to 4%.

[0019] The pharmaceutical composition of the present invention comprises one or more fillers. As used herein, the term "filler" refers to an inert substance for imparting the necessary volume, fluidity and compression properties in the production of solid dosage forms. In an embodiment of the present invention, the filler is selected from one or more selected from the group consisting 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 selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, starch, pregelatinized starch and dextrin, more preferably one or more selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, lactose and pregelatinized starch, still more preferably one of microcrystalline cellulose or silicified microcrystalline cellulose, or a combination of one of microcrystalline cellulose and silicified microcrystalline cellulose with one of mannitol and lactose (e.g., 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 or silicified microcrystalline cellulose, one of mannitol or lactose and pregelatinized starch (e.g., a combination of microcrystalline cellulose, mannitol and pregelatinized starch, a combination of microcrystalline cellulose, lactose and pregelatinized starch, a combination of silicified microcrystalline cellulose, mannitol and pregelatinized starch, a combination of silicified microcrystalline cellulose, lactose and pregelatinized starch), and even more preferably a combination of microcrystalline cellulose, mannitol and pregelatinized starch.

[0020] In some embodiments of the present invention, the weight percentage of the filler in the pharmaceutical composition is 75% to 95%, preferably 80% to 95%, more preferably 85% to 95%, and still more preferably 85% to 92%.

[0021] 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 mannitol or lactose is 15-50%, preferably 20-45%, more preferably 20-40%, and even more preferably 20-30%, and the weight percentage of microcrystalline cellulose or silicified microcrystalline cellulose is 40-75%, preferably The weight ratio of mannitol or lactose to microcrystalline cellulose or silicified microcrystalline cellulose is 50-75%, more preferably 60-75%, and still more preferably 65-75%.

[0022] In some embodiments of the present invention, 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, the weight percentage of mannitol or lactose is 15-45%, preferably 20-45%, more preferably 20-41%, and even more preferably 20-30%, and the weight percentage of microcrystalline cellulose or silicified microcrystalline cellulose is 35-70%, preferably 40-65%, and the mannitol or lactose is mixed with microcrystalline cellulose or silicified microcrystalline cellulose. The weight ratio with crystalline cellulose is 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 weight percentage of pregelatinized starch is 5 to 25%, preferably 5 to 15%, more preferably 8 to 12%, even more preferably 10 to 11%, and even more preferably 10.5%.

[0023] The pharmaceutical compositions of the present invention may contain one or more disintegrants. As used herein, “disintegrant” means a substance used in a solid dosage form to facilitate the disintegration of a solid into smaller particles that are easily dispersed or dissolved. In embodiments of the present invention, the disintegrant is selected from sodium carboxymethyl starch, sodium carboxymethylcellulose, sodium croscarmellose, dried starch, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, crospovidone, effervescent disintegrant, potassium polaritrin, or sodium alginate, preferably sodium carboxymethyl starch, sodium carboxymethylcellulose, sodium croscarmellose, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, or crospovidone, more preferably sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, or crospovidone, and even more preferably crospovidone.

[0024] In some embodiments of the present invention, the weight percentage of the disintegrant in the pharmaceutical composition is 0 to 10%, preferably 1% to 6%, more preferably 2% to 6%, more preferably 2% to 5%, more preferably 2% to 4%, even more preferably 3% to 5%, even more preferably 3.5% to 4.5%, and even more preferably 3% to 4%.

[0025] The pharmaceutical composition of the present invention comprises one or more flow promoters. In this specification, "flow promoter" refers to a reagent for promoting solid fluidity in a solid dosage form. In embodiments of the present invention, the flow promoter is selected from talc powder, silica, or colloidal silica, preferably silica or colloidal silica, and more preferably colloidal silica.

[0026] In some embodiments of the present invention, the weight percentage of the flow promoter in the pharmaceutical composition is 0.5 to 3.0%, preferably 0.5 to 2.5%, more preferably 0.5 to 2%, and even more preferably 1 to 2%.

[0027] The pharmaceutical composition of the present invention comprises one or more lubricants. As used herein, "lubricant" refers to a substance for reducing friction between particles of the pharmaceutical composition and between particles and die holes. In embodiments of the present invention, the lubricant is selected from calcium stearate, magnesium stearate, zinc stearate, talc powder, sodium stearyl fumarate, stearic acid, glyceryl behenate, palmitic acid, glyceryl stearate palmitate, magnesium lauryl sulfate, hydrogenated vegetable oil, sodium dodecyl sulfate, magnesium dodecyl sulfate, polyethylene glycol, fine silica gel, or aluminum hydroxide, preferably glyceryl behenate, magnesium stearate, or sodium stearyl fumarate, and more preferably glyceryl behenate or sodium stearyl fumarate.

[0028] In some embodiments of the present invention, the weight percentage of the lubricant in the pharmaceutical composition is 0.5% to 4%, preferably 1% to 4%, more preferably 1% to 3%, and even more preferably 0.8% to 3%.

[0029] 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 flow promoter 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%.

[0030] 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 3% to 4%, the weight percentage of the flow promoter in the pharmaceutical composition is 1% to 2%, and the weight percentage of the lubricant in the pharmaceutical composition is 1% to 3%.

[0031] 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 flow promoter 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%. The filler is one of microcrystalline cellulose or silicified microcrystalline cellulose, or a combination of one of microcrystalline cellulose and silicified microcrystalline cellulose with one of mannitol and lactose (for example, 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 or silicified microcrystalline cellulose, one of mannitol or lactose and pregelatinized starch (for example, a combination of microcrystalline cellulose, mannitol and pregelatinized starch, a combination of microcrystalline cellulose, lactose and pregelatinized starch, a combination of silicified microcrystalline cellulose, mannitol and pregelatinized starch, silicified microcrystalline cellulose, lactose and alpha The disintegrant is selected from a combination of carboxymethyl starch, sodium carboxymethylcellulose, sodium croscarmellose, dried starch, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, crospovidone, foaming disintegrant, potassium polaritrin, or sodium alginate, the flow promoter is selected from talc powder, silica, or colloidal silica, and the lubricant is selected from calcium stearate, magnesium stearate, zinc stearate, talc powder, sodium stearyl fumarate, stearic acid, glyceryl behenate, palmitic acid, glyceryl stearate palmitate, magnesium lauryl sulfate, hydrogenated vegetable oil, sodium dodecyl sulfate, magnesium dodecyl sulfate, polyethylene glycol, fine silica gel, or aluminum hydroxide. 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 mannitol or lactose is 15-50%, preferably 20-45%, more preferably 20-40%, and even more preferably 20-30%, the weight percentage of microcrystalline cellulose or silicified microcrystalline cellulose is 40-75%, preferably 50-75%, more preferably 60-75%, and even more preferably 65-75%, and 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, even more preferably 1:3.6-1:1.5, even more preferably 1:3.6-1:2.8, even more preferably 1:3.6-1:3, or 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, the weight percentage of mannitol or lactose is 15-45%, preferably 20-45%, more preferably 20-41%, and even more preferably 20-30%, and the weight percentage of microcrystalline cellulose or silicified microcrystalline cellulose is 35-70%, preferably 40-65%, and the mannitol or lactose and microcrystalline cellulose or silicified microcrystalline cellulose The weight ratio is 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 weight percentage of the pregelatinized starch is 5 to 25%, preferably 5 to 15%, more preferably 8 to 12%, even more preferably 10 to 11%, and even more preferably 10.5%.

[0032] 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 flow promoter 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%. The filler is one of microcrystalline cellulose or silicified microcrystalline cellulose, or a combination of one of microcrystalline cellulose and silicified microcrystalline cellulose with one of mannitol and lactose (for example, 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 or silicified microcrystalline cellulose, one of mannitol or lactose and pregelatinized starch (for example, a combination of microcrystalline cellulose, mannitol and pregelatinized starch, microcrystalline cellulose The disintegrant is selected from a combination of crystalline cellulose, lactose and pregelatinized starch, a combination of silicified microcrystalline cellulose, mannitol and pregelatinized starch, or a combination of silicified microcrystalline cellulose, lactose and pregelatinized starch; the disintegrant is selected from sodium carboxymethyl starch, sodium carboxymethylcellulose, sodium croscarmellose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone or crospovidone; the flow promoter is selected from talc powder, silica or colloidal silica; and the lubricant is selected from magnesium stearate, sodium stearyl fumarate or glyceryl behenate. 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 mannitol or lactose is 15-50%, preferably 20-45%, more preferably 20-40%, and even more preferably 20-30%, the weight percentage of microcrystalline cellulose or silicified microcrystalline cellulose is 40-75%, preferably 50-75%, more preferably 60-75%, and even more preferably 65-75%, and 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, even more preferably 1:3.6-1:1.5, even more preferably 1:3.6-1:2.8, even more preferably 1:3.6-1:3, or 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, the weight percentage of mannitol or lactose is 15-45%, preferably 20-45%, more preferably 20-41%, and even more preferably 20-30%, and the weight percentage of microcrystalline cellulose or silicified microcrystalline cellulose is 35-70%, preferably 40-65%, and the mannitol or lactose and microcrystalline cellulose or silicified microcrystalline cellulose The weight ratio is 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 weight percentage of the pregelatinized starch is 5 to 25%, preferably 5 to 15%, more preferably 8 to 12%, even more preferably 10 to 11%, and even more preferably 10.5%.

[0033] 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 3% to 4%, the weight percentage of the flow promoter in the pharmaceutical composition is 1% to 2%, and the weight percentage of the lubricant in the pharmaceutical composition is 1% to 3%, and the filler is a combination of microcrystalline cellulose, mannitol and pregelatinized starch. The following are selected from the above, the weight percentage of mannitol being 20-45%, the weight percentage of microcrystalline cellulose being 40-65%, the weight ratio of mannitol to microcrystalline cellulose being 1:3.5-1:1, the weight percentage of pregelatinized starch being 5-25%, the disintegrant being crospovidone, the flow promoter being selected from colloidal silica, and the lubricant being selected from glyceryl behenate and sodium stearyl fumarate.

[0034] 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 3% to 4%, the weight percentage of the flow promoter in the pharmaceutical composition is 1% to 2%, and the weight percentage of the lubricant in the pharmaceutical composition is 1% to 3%, and the filler is a combination of microcrystalline cellulose, mannitol, and pregelatinized starch. The following are selected from the above, the weight percentage of mannitol being 20-45%, the weight percentage of microcrystalline cellulose being 40-65%, the weight ratio of mannitol to microcrystalline cellulose being 1:3.3-1:2.8, the weight percentage of pregelatinized starch being 5-15%, the disintegrant being crospovidone, the flow promoter being selected from colloidal silica, and the lubricant being selected from glyceryl behenate and sodium stearyl fumarate.

[0035] In some embodiments of the present invention, the pharmaceutical composition may further contain an acidic pH adjuster to adjust the pH of the composition's microenvironment and improve the stability of the composition. The acidic pH adjuster is selected from oxalic acid, maleic acid, fumaric acid, or glutaric acid, and its weight percentage in the pharmaceutical composition is 0-3%.

[0036] The sum of the weight percentages of all components in the pharmaceutical composition of the present invention is 100%.

[0037] A second aspect of the present invention provides an oral solid preparation manufactured with the above-described pharmaceutical composition. The term "oral solid preparation" as used herein refers to a solid pharmaceutical preparation used for oral administration, preferably a capsule or tablet, more preferably a tablet, and even more preferably a film-coated tablet.

[0038] In some embodiments of the present invention, the oral solid dosage form is a film-coated tablet. The coating material used in 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 one or more of a light-shielding agent (e.g., titanium dioxide), a plasticizer (e.g., polyethylene glycols, glycerin, propylene glycol, diethyl phthalate, diethyl o-phthalate, triacetin, triethyl citrate, caprylic / capric monodiglyceride, etc.), a lubricant (e.g., talc powder), or a coloring agent (e.g., lemon yellow aluminum lake, allura red aluminum lake, brilliant blue aluminum lake). The coating material is available through commercial channels, and a suitable premix of coating material may be selected from Opadry® 03B28796 or Opadry® 321A610052.

[0039] In some embodiments of the present invention, the weight increase due to the film coating is 1% to 5% of the tablet core (i.e., the pharmaceutical composition of the present invention), preferably 2% to 4%, for example, 2%, 2.6%, 3%, 3.7%, or 4%.

[0040] A third aspect of the present invention provides a method for producing the above-mentioned pharmaceutical composition, the method being: The steps include: pre-mixing compound (A) with other additives other than a lubricant, then mixing the resulting pre-mixture with a lubricant to obtain a pharmaceutical composition containing compound (A); The method further optionally includes the step of filling a pharmaceutical composition containing the obtained compound (A) into capsules or pressing it into tablets.

[0041] In some embodiments of the present invention, the premixing can be carried out in multiple steps. Furthermore, the premixing may further include a depolymerization step, for example, premixing one or more materials with a flow accelerator and then depolymerizing one or more times.

[0042] In some embodiments of the present invention, the manufacturing method further comprises the step of adding an acidic pH adjusting agent, the acidic pH adjusting agent being selected from oxalic acid, maleic acid, fumaric acid, or glutaric acid.

[0043] A fourth aspect of the present invention provides the use of the above-mentioned pharmaceutical composition or oral solid dosage form in the manufacture of a pharmaceutical for the prevention and / or treatment of a disease related to the activity or expression of FGFR, KDR and / or CSF-1R. Preferably, the disease is a tumor. More preferably, the tumor is selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, bladder cancer, urinary tract transition cell carcinoma, esophageal cancer, gastric cancer (esophagogastric junction adenocarcinoma), 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.

[0044] A fifth aspect of the present invention provides the above-mentioned pharmaceutical composition or oral solid preparation for preventing and / or treating diseases related to the activity or expression of FGFR, KDR, and / or CSF-1R. Preferably, the disease is a tumor. More preferably, the tumor is selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, bladder cancer, urinary tract transition cell carcinoma, esophageal cancer, gastric cancer (esophagogastric junction adenocarcinoma), 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.

[0045] A sixth aspect of the present invention provides a method for preventing and / or treating a disease related to the activity or expression of FGFR, KDR, and / or CSF-1R, comprising the step of administering an effective dose of the pharmaceutical composition or oral solid preparation to a subject in need of prevention and / or treatment of the disease. Preferably, the disease is a tumor. More preferably, the tumor is selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, bladder cancer, urinary tract transition cell carcinoma, esophageal cancer, gastric cancer (esophagogastric junction adenocarcinoma), 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.

[0046] The term “subject” as used herein is interchangeable with “patient” and includes, but is not limited to, all members of the animal kingdom, including non-human mammals (e.g., mice, rats, cats, monkeys, dogs, horses, pigs, etc.) and humans.

[0047] As used herein, “effective dose” means the amount of compound of formula (A) that is sufficient to achieve the expected therapeutic effect in the body of a “subject” or “patient” when administered as a single or multiple doses.

[0048] Within the scope of this application, various options of any feature can be combined with various options of other features to constitute many different embodiments. This application is intended to include all possible embodiments consisting of various options of all technical features. Within the scope of the invention, it should be understood that each of the above technical features of the invention and each of the technical features specifically described below (e.g., Examples) can be combined with each other to constitute new or preferred technical means. [Effects of the Invention]

[0049] The pharmaceutical composition of the present invention achieves the following beneficial effects.

[0050] (1) The pharmaceutical composition of the present invention contains compound (A) as an active ingredient. Compared to the free base compound (I), compound (A) in salt-forming form has advantages such as being easy to dry, highly soluble, stable in quality, thermodynamically stable, and easy to use in drug discovery, making it more suitable as an active ingredient in a pharmaceutical composition.

[0051] (2) The pharmaceutical composition of the present invention has excellent dissolution properties of the active ingredient.

[0052] (3) The pharmaceutical composition of the present invention has uniformity in the content of the active ingredient that meets the requirements.

[0053] (4) The pharmaceutical composition of the present invention is advantageous in providing an oral solid dosage form that is stable in properties and suitable for long-term storage.

[0054] (5) The method for producing the pharmaceutical composition of the present invention is simple and convenient for industrial production. [Modes for carrying out the invention]

[0055] The present invention will be further described below with reference to specific examples. It should be understood that these examples are merely illustrative and do not limit the scope of the present invention. Experimental methods in the following examples where specific conditions are not explicitly stated will be carried out according to general conditions or conditions suggested by the manufacturer.

[0056] The analytical detection conditions for the following examples are as follows:

[0057] 1. Powder X-ray diffraction (X-ray powder diffractometer, XRPD) Equipment: BRUKER D8 Advance powder X-ray diffractometer (Germany) The conditions are as follows: Cu-Kα radiation (λ=1.5418Å), tube voltage 40kV, tube current 40mA, 2θ scanning range 3~40°, scanning step size 0.02°(2θ), scanning speed 10s / step, and sample disk is a zero-background sample disk. Method: Place the sample on a zero-background single-crystal silicon sample disc, lightly press it down with a spatula to flatten it, and then measure it.

[0058] 2. Chloride Detection equipment: DIONEX ICS-900 ion chromatograph Column: Dionex Ion Pac AS11-HC anion column (Specifications: 4 x 250 mm) Measurement method: Precisely weigh 10 μL each of the control solution and the test solution, inject them separately into an ion chromatograph, record the chromatograms, and calculate the chloride ion content by peak area based on the external standard method.

[0059] 3. Dynamic Moisture Adsorption / Desorption Analysis (DVS) Equipment: DVS Intrinsic plus (SMS, UK) Method: Place the samples in a sample basket from which the weight has been removed, weigh the samples automatically, and analyze the samples according to the parameters in the table below.

[0060] [Table 1A]

[0061] 4. Thermogravimetric Analysis (TGA) Detection Conditions Equipment: Discovery TGA 55 The conditions are as follows: the temperature range is room temperature to 350°C, the heating rate is 10°C / min, the purge gas is nitrogen gas, the flow rate in the balance chamber is 40 mL / min, and the flow rate in the sample chamber is 25 mL / min. Sample: 1-5 mg

[0062] 5. Content measurement conditions Equipment: High-performance liquid chromatography (Waters e2689 2495) Chromatography column: Waters Symmetry C18, 250 × 4.6 mm, 5 μm Mobile phase: 10 mmol / L ammonium acetate solution - acetonitrile (40:60) Injection volume: 10 μl

[0063] 6. Elution measurement conditions Equipment: High-performance liquid chromatography (Waters e2689 2495) Chromatography column: Waters XBridge C18, 250 × 4.6 mm, 5 μm Mobile phase: 10 mmol / L ammonium acetate solution - acetonitrile (60:40) Injection volume: 20 μl Dissolution method: Paddle method Rotation speed: 50 revolutions / minute Elution medium: 1000 ml of potassium dihydrogen phosphate-sodium hydroxide buffer at pH 6.0 Medium temperature: 37±0.5℃

[0064] Manufacturing Example 1: Manufacturing of Compound (A) [ka]

[0065] Compound (I) (0.52 g, prepared according to Production Example 10 of WO2017140269A1) and methanol (25 mL) were added to a reaction flask and stirred until the system was uniformly dispersed. Then, while stirring, a methanol hydrochloric acid solution (1.2 mL, 2 mol / L) was added dropwise, and stirring was continued for 5 hours after the addition was complete. The mixture was filtered and vacuum-dried (vacuum-dried at 30°C for 12 hours until the weight was constant, and then vacuum-dried at 45°C until the solvent residue was passed) to obtain a solid (0.53 g). Nuclear magnetic resonance detection confirmed salt formation.

[0066] The chloride ion content was measured by ion chromatography, and the stoichiometric ratio of the hydrochloride salt was calculated (shown in Table 1 below), leading to the estimation that the base / acid ratio of the hydrochloride salt was 1:2.

[0067] [Table 1]

[0068] Powder X-ray diffraction was performed on the obtained solid sample, and as can be seen from the results, it showed excellent crystallinity and was named crystal form I. Its diffraction peak data is shown in Table 2.

[0069] [Table 2]

[0070] Manufacturing Example 2: Production of crystalline form I of compound (A) Compound (I) (1.0432 g, prepared according to Production Example 10 of WO2017140269A1) and purified water (3 mL) were added to a reaction flask and stirred until the system was uniformly dispersed. Hydrochloric acid aqueous solution (2 N) was added dropwise and stirred until completely dissolved. A sample of crystalline form I obtained in Production Example 1 (0.01 g) was added as a seed crystal, and the mixture was stirred for 20-24 hours to crystallize. After crystallization, the mixture was filtered by suction. After vacuum drying at 30°C for 12 hours, it was vacuum dried at 45°C until it passed the solvent residue test to obtain a solid (1.112 g). Detection revealed that crystalline form I of compound (A) with excellent crystallinity was obtained. XRPD characteristic data of the obtained sample are shown in Table 3. A TGA-DSC test was performed on the sample, and as can be seen from the results, the sample does not contain crystal water or crystal solvent.

[0071] [Table 3]

[0072] Production Example 3: Production of other salts of compound (I) To each flask containing 5 mL of a tetrahydrofuran / methanol (1:1 volume ratio, the same applies below) solution of a 0.02 mol / mL acid (phosphoric acid, maleic acid, tartaric acid, fumaric acid), 10 mL of a tetrahydrofuran / methanol (1:1) solution of compound (I) was sequentially added. The mixture was then stirred and mixed uniformly, and the reaction was carried out at 40°C for 1 hour. The reaction solution was evaporated and dried at 50°C for 3-4 hours to obtain solids. The phosphate, maleate, tartrate, and fumarate salts of compound (I) were obtained by detection using nuclear magnetic resonance and ion chromatography, respectively.

[0073] Furthermore, XRPD detection revealed that the resulting solids all exhibited excellent crystallinity.

[0074] Test Example 1: Solubility experiment of compound (I) and its salt First, solubility tests were performed in water for compound (I), the sample obtained in production example 2 (compound (A)), and the sample obtained in production example 3. Next, solubility tests were performed in Na2HPO4-citrate buffer (pH 4.6) for compound (I) and the sample obtained in production example 2 (compound (A)). The experimental results are shown in Tables 4 and 5, respectively.

[0075] [Table 4]

[0076] [Table 5]

[0077] As can be seen from the results, both compound (A) obtained in Production Example 2 and the samples of the different salts obtained in Production Example 3 exhibited high solubility in water, significantly superior to that of the free base, meeting the general requirements for the solubility of the active pharmaceutical ingredient (API) in orally administered formulations. Compound (A) in particular showed excellent solubility, meeting the general requirements for the solubility of the API in various pharmaceutical formulations (e.g., oral solid dosage forms, injections, oral solutions, etc.). Compound (A) also exhibited better solubility than compound (I) in buffer solutions.

[0078] Experiment Example 2: Water adsorption and desorption experiments of different salt forms of compound (I) The water adsorption and desorption of samples obtained in Production Example 2 and Production Example 3 at relative humidity levels of 40-80% were observed using a dynamic water adsorption analyzer (DVS) at a temperature of 25°C to measure the hygroscopic properties of different salt types. The experimental results are shown in Table 6.

[0079] [Table 6]

[0080] As the results show, compound (A) has slight hygroscopic properties, and its weight increase due to moisture absorption is relatively low.

[0081] Test Example 3: Solid Stability Test of Compound (A) The physical and chemical stability of the sample obtained in Production Example 2 was observed after 7 days of storage under 40°C / 75%RH (open) and 60°C (sealed) conditions, and the physical stability after 10 days of storage under room temperature / 92.5%RH (open) conditions. The experimental results are shown in Table 7 below.

[0082] [Table 7]

[0083] As can be seen from the results, when compound (A) was left for 7 days under conditions of 40°C / 75%RH and 60°C, its purity did not change and its crystal form did not change. Even when left for 10 days under conditions of 92.5%RH, its crystal form did not change. The above results demonstrate that compound (A) has excellent chemical and physical stability.

[0084] Test Example 4: Polishing Stability Test of Compound (A) Samples obtained in Production Example 2 were mechanically polished in a mortar for 2 minutes and 5 minutes respectively, and powder X-ray diffraction tests were performed. As can be seen from the results, the crystal form of crystal form I does not change after polishing.

[0085] Furthermore, appropriate amounts of organic solvents (methanol, ethanol, acetone, acetonitrile, and ethyl acetate) were added dropwise to the samples obtained in Production Example 2, and mechanical polishing was performed. Powder X-ray diffraction tests were then conducted, and as can be seen from the results, no crystal form transition occurred in any of the crystal forms I after polishing.

[0086] The active ingredient compound (A) used in the following examples is always in crystalline form I.

[0087] Table 8 shows the limit requirements for the observed parameters of tablets containing compound (A) produced in the following examples.

[0088] [Table 8]

[0089] Example 1: Preparation of tablets (51 mg / tablet) containing compound (A) The tablet formulation for Example 1 is shown in Table 9 below.

[0090] [Table 9]

[0091] Regarding the manufacturing method (1) Weighing: Weigh the raw materials accurately according to the prescribed amounts in Table 9. (2) Pre-mixing: Colloidal silica and mannitol were mixed and sieved through a 40-mesh sieve, dividing into two parts: the first part accounted for approximately 6% of the total weight, and the second part accounted for 94%. After adding pregelatinized starch, compound (A), crospovidone, and a mixture of part 1 colloidal silica and mannitol to a container of appropriate volume and mixing, add about 1 / 2 of the container's volume of microcrystalline cellulose and mix. Add the remaining microcrystalline cellulose and the mixture of colloidal silica and mannitol from part 2 to the above container and mix. (3) Total mixing: Add glyceryl behenate in equal amounts and mix. (4) Tableting: The mixture obtained in (3) is compressed into tablets, with a theoretical tablet weight of 51 mg / tablet, a difference in tablet weight of ±7.5%, and a hardness of 4-10 kg.

[0092] The dissolution properties (in a phosphate buffer solution at pH 6.0), content, content uniformity, and process feasibility were observed for the manufactured tablets, and the results are shown in Table 10 below.

[0093] [Table 10]

[0094] As can be seen from the results, tablets containing compound (A) as the active ingredient were manufactured using the formulation of this embodiment, the tableting process was smooth, the dissolution and uniformity of content of the manufactured tablet samples both met the requirements, the manufacturing process was simple and highly feasible.

[0095] Example 2: Production of tablets (100 mg / tablet) containing compound (A) The tablet formulation for Example 2 is shown in Table 11 below.

[0096] [Table 11]

[0097] Regarding the manufacturing method (1) Pretreatment of the active pharmaceutical ingredient: Compound (A) is passed through a 100-mesh sieve, and the sieved portion is removed. (2) Weighing: Weigh the raw materials accurately according to the prescribed amounts in Table 11. (3) Pre-mixing: Preliminary Mixing I: Mix mannitol, compound (A), colloidal silica, and crospovidone in a suitable container. Depolymerization I: The mixture obtained in premixing I is depolymerized by removing the pregelatinized starch and placing it in a sizing machine or by sieving it. Pre-mixing II: Take the mixture obtained in depolymerization I, put it in a container, and mix it. Pre-mixing III: Add the microcrystalline cellulose and the pre-mixing obtained in Pre-mixing II to another container of appropriate volume and mix. Depolymerization II: The mixture obtained in Pre-mixing III is taken and placed in a sizing machine or sieved to depolymerize it. Pre-mixing IV: Add the mixture obtained in depolymerization II to the container and mix. (4) Total mixture: Mix sodium stearyl fumarate with approximately equal amounts of pre-mix IV, sift through a 24-mesh sieve, and add to a container containing the pre-mix IV mixture, then mix. (5) Tableting: The mixture obtained in (4) is compressed into tablets, with a theoretical tablet weight of 0.1 g / tablet, a difference in tablet weight of ±7.5%, and a hardness of 3 to 12 kg.

[0098] The dissolution properties (in a phosphate buffer solution at pH 6.0), content, content uniformity, and process feasibility were observed for the manufactured tablets, and the results are shown in Table 12 below.

[0099] [Table 12]

[0100] As can be seen from the results, tablets containing compound (A) as the active ingredient, manufactured using the formulation of this embodiment, exhibit excellent dissolution properties, pass the test for uniformity of content, and demonstrate a high feasibility of the manufacturing process.

[0101] Examples 3-7: Production of tablets containing compound (A) (observation of filler dosage) (1) Observation of the weight ratio of mannitol to microcrystalline cellulose Tablets for Examples 3-5 were manufactured by referring to the formulation and manufacturing method of Example 2, with only the weight ratio of mannitol to microcrystalline cellulose being changed. The dosages and ratios of mannitol and microcrystalline cellulose in Examples 3-5 are shown in Table 13 below.

[0102] [Table 13]

[0103] The dissolution properties (in a phosphate buffer solution at pH 6.0), content, content uniformity, and process feasibility were observed for the tablets produced in Examples 3 to 5, and the results are shown in Table 14 below.

[0104] [Table 14]

[0105] As the results show, tablets manufactured using different ratios of mannitol and microcrystalline cellulose as fillers all exhibited excellent dissolution of the active ingredient and were highly processable. However, tablets manufactured with a mannitol-to-microcrystalline cellulose ratio of 2:1 failed to achieve uniformity in the active ingredient content.

[0106] (2) Observation of the dosage of pregelatinized starch Referring to the formulation and manufacturing method of Example 2, the dosage of pregelatinized starch was changed, and the dosage of microcrystalline cellulose was adjusted to ensure that the dosage of filler and the total tablet weight remained unchanged, and tablets of Examples 6 and 7 were manufactured. The dosages of pregelatinized starch in Examples 6 and 7 are shown in Table 15 below.

[0107] [Table 15]

[0108] The dissolution properties (in a phosphate buffer solution at pH 6.0), content, content uniformity, and process feasibility were observed for the tablets produced in Examples 6 and 7, and the results are shown in Table 16 below.

[0109] [Table 16]

[0110] As the results show, tablets manufactured with the screened pregelatinized starch dosages all exhibited excellent dissolution and uniformity of active ingredient content, indicating high process feasibility.

[0111] Examples 8-10: Production of tablets containing compound (A) (observation of disintegrant dosage) Referring to the formulation and manufacturing method of Example 2, only the dosage of the disintegrant was changed (and the total tablet weight changed accordingly) to produce the tablets of Examples 8-10. The dosages of the disintegrant in Examples 8-10 are shown in Table 17 below.

[0112] [Table 17]

[0113] The dissolution properties (in a phosphate buffer solution at pH 6.0) of the tablets produced in Examples 8-10 were measured, and the results are shown in Table 18 below.

[0114] [Table 18]

[0115] As can be seen from the results, the tablets of Example 8, which did not contain a disintegrant, also showed acceptable dissolution of the active ingredient, and as shown in Examples 9-10, the dissolution of the active ingredient was further improved by adding a disintegrant.

[0116] Examples 11-14: Manufacturing of tablets containing compound (A) (observation of the dosage of the flow promoter) Referring to the formulation and manufacturing method of Example 2, only the dosage of the flow accelerator was changed (and the total tablet weight changed accordingly) to produce the tablets of Examples 11 and 12.

[0117] Referring to the formulation and manufacturing method of Example 1, the ratio of mannitol to microcrystalline cellulose was adjusted to 1:1, and the amount of the flow promoter was changed to produce the tablets of Examples 13-14.

[0118] The dosages of the flow promoter in Examples 11-14 are shown in Table 19 below.

[0119] [Table 19]

[0120] The content and uniformity of the content were measured for the tablets (n=6) produced in Examples 11-14, and the results are shown in Table 20 below.

[0121] [Table 20]

[0122] As the results show, all tablets manufactured with the tested dosages of the fluidity enhancer demonstrated satisfactory uniformity of content.

[0123] Examples 15-16: Preparation of tablets containing compound (A) (observation of lubricant dosage) Referring to the formulation and manufacturing method of Example 2, only the amount of lubricant was changed (and the total tablet weight changed accordingly) to produce the tablets of Examples 15-16. The amounts of lubricant in Examples 15-16 are shown in Table 21 below.

[0124] [Table 21]

[0125] Dissolution properties (in a phosphate buffer solution at pH 6.0) and process feasibility were measured for the tablets produced in Examples 15-16, and the results are shown in Table 22 below.

[0126] [Table 22]

[0127] As the results show, tablets manufactured with the tested lubricant dosages all exhibited excellent dissolution properties, indicating the feasibility of the manufacturing process.

[0128] Examples 17-19: Production of film-coated tablets containing compound (A) (observation of weight increase due to coating) Tablets containing compound (A) were prepared with reference to the formulation and manufacturing method of Example 2, and coated with film coating premix (gastricly soluble)-Opadry® 321A610052. Film-coated tablets of Examples 17-19 were produced, with a solid content of 30% in the coating solution and a controlled weight increase range of 2.0% to 4.0% of the tablet core weight. The percentage weight increase due to coating in Examples 17-19 is shown in Table 23 below.

[0129] [Table 23]

[0130] The film-coated tablets produced in Examples 17-19 were subjected to dissolution measurements (in a phosphate buffer solution at pH 6.0), and their appearance was observed. The results are shown in Table 24 below.

[0131] [Table 24]

[0132] As the results show, the film-coated tablets obtained after coating still exhibited excellent dissolution of the active ingredient and had a good appearance.

[0133] Examples 20-21: Other manufacturing examples of tablets containing compound (A) Referring to the manufacturing method of Example 1, tablets for Examples 20-21 were manufactured according to the formulations in Table 25 below.

[0134] [Table 25]

[0135] The dissolution properties (in a phosphate buffer solution at pH 6.0), content, content uniformity, and process feasibility were observed for the tablets produced in Examples 20-21, and the results are shown in Table 26 below.

[0136] [Table 26]

[0137] Examples 22-24: Preparation of tablets containing compound (A) (observation of different lubricants) Referring to the manufacturing method of Example 2, tablets for Examples 22-24 were manufactured according to the formulations in Table 27 below.

[0138] [Table 27]

[0139] The tablets produced in Example 2 and Examples 22-24 were observed for stability at 60°C for one month, and the results are shown in Table 28 below.

[0140] [Table 28]

[0141] As the results show, under conditions of being left at 60°C for one month, the total impurities in tablets manufactured using stearic acid as a lubricant increased slightly, while the total impurities in tablets manufactured using magnesium stearate and sodium stearyl fumarate as lubricants did not differ significantly compared to day 0. The total impurities in tablets manufactured using all three lubricants, when left at 60°C for one month, all met the specified limits.

[0142] Examples 25-28: Preparation of tablets containing compound (A) (observation of different fillers) Referring to the manufacturing method of Example 2, tablets of Examples 25 to 28 were manufactured according to the formulations in Table 29 below.

[0143] [Table 29]

[0144] The dissolution properties (in a phosphate buffer solution at pH 6.0), content, content uniformity, and process feasibility were observed for the tablets produced in Examples 25-28, and the results are shown in Table 30 below.

[0145] [Table 30]

[0146] As can be seen from the results, tablets manufactured using microcrystalline cellulose as a single filler (Example 25), or tablets manufactured 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), lactose, and pregelatinized starch (Examples 27-28), all showed excellent dissolution of the active ingredient and satisfactory uniformity of content.

[0147] Examples 29-30: Production of tablets containing compound (A) (observation of different disintegrants) Referring to the manufacturing method of Example 2, the tablets of Examples 29-30 were manufactured by replacing only the disintegrant crospovidone with the disintegrants listed in Table 31 below.

[0148] [Table 31]

[0149] The dissolution properties (in a phosphate buffer solution at pH 6.0) of the tablets produced in Examples 29-30 were observed, and the results are shown in Table 32 below.

[0150] [Table 32]

[0151] As the results show, even when using low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch as disintegrants, tablets with excellent dissolution of the active ingredient can be manufactured.

[0152] Example 31: Manufacturing of tablets containing compound (A) (observation of different flow enhancers) Referring to the formulation and manufacturing method of Example 2, the tablets of Example 31 were manufactured simply by replacing colloidal silica with silica. The dissolution (in a phosphate buffer solution at pH 6.0), content, content uniformity, and process feasibility were observed for the manufactured tablets, and the results are shown in Table 33 below.

[0153] [Table 33]

[0154] As the results show, tablets manufactured using silica as a flow enhancer also exhibited excellent dissolution and uniformity of active ingredient content, indicating a high feasibility of the process.

[0155] Example 32: Manufacture of coated tablets containing compound (A) Tablets containing compound (A), prepared according to the formulation and manufacturing method of Example 1, were coated with a film coating premix (gastricly soluble) - Opadry® 03B28796 to obtain coated tablets containing compound (A) with a solid content of 10% in the coating solution and a weight increase of 3.7%.

[0156] Example 33: Manufacture of coated tablets containing compound (A) Tablets containing compound (A), prepared with reference to the formulation and manufacturing method of Example 2, were coated with a film coating premix (gastricly soluble) - Opadry® 321A610052 to obtain coated tablets containing compound (A) with a solid content of 30% in the coating solution and a weight increase of 2.6%.

[0157] The manufactured tablets may have incisions on both sides to meet flexible requirements regarding product dosage. This facilitates the division of the resulting tablets, and the quality of the resulting half-tablet products meets the requirements, as shown in Table 34 below.

[0158] [Table 34]

[0159] Example 34: Preparation of capsules containing compound (A) Referring to steps (1) to (4) of the formulation and manufacturing method of Example 2, a pharmaceutical composition containing compound (A) was obtained and filled into capsules to obtain capsules containing compound (A).

[0160] Test Example 5: Long-Term Stability Test (1) The tablets produced in Example 32 were packaged in low-density polyethylene bottles (with desiccant) and left at 25°C ± 2°C / 60% ± 5% RH to observe their stability. The test results are shown in Table 35 below.

[0161] [Table 35]

[0162] (2) The tablets produced in Example 33 were packaged in a double aluminum blister package and left at 30°C ± 2°C / 65% ± 5% RH to observe their stability. The test results are shown in Table 36 below.

[0163] [Table 36]

[0164] As can be seen from the experimental results above, when the formulation of the present invention is left at 25°C±2°C / 60%±5%RH for 24 months or at 30°C±2°C / 65%±5%RH for 18 months, there is no significant change in the related substances, elution properties, and content. This indicates that the formulation is stable in quality and suitable for long-term storage.

[0165] The above description is merely a preferred embodiment of the present invention, and it should be noted that those skilled in the art can make several further improvements and modifications without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the present invention.

Claims

1. By weight percentage of the pharmaceutical composition, A compound (A) having the structure represented by the following formula (A) in a concentration of 0.1% to 10%, 【Chemistry 1】 70% to 95% filler, 0% to 15% disintegrant, 0% to 3% of a flow accelerator, A pharmaceutical composition comprising 0.5% to 5% of a lubricant.

2. The pharmaceutical composition according to claim 1, characterized in that the weight percentage of compound (A) in the pharmaceutical composition is 1% to 10%, preferably 2% to 8%, more preferably 2% to 7%, even more preferably 2% to 6%, even more preferably 2% to 5%, and even more preferably 2% to 4%.

3. The pharmaceutical composition according to any one of claims 1 to 2, characterized in that the weight percentage of the filler in the pharmaceutical composition is 75% to 95%, more preferably 80% to 95%, more preferably 85% to 95%, and more preferably 85% to 92%.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the weight percentage of the disintegrant in the pharmaceutical composition is 1% to 6%, preferably 2% to 6%, more preferably 2% to 5%, more preferably 2% to 4%, even more preferably 3% to 5%, even more preferably 3.5% to 4.5%, and even more preferably 3% to 4%.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that the weight percentage of the flow promoter in the pharmaceutical composition is 0.5 to 3.0%, preferably 0.5% to 2.5%, more preferably 0.5% to 2%, and even more preferably 1% to 2%.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that the weight percentage of the lubricant in the pharmaceutical composition is 0.5% to 4%, preferably 1% to 4%, more preferably 1% to 3%, and even more preferably 0.8% to 3%.

7. The filler is selected from one or more of the following: 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, it is one or more of the following: microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, lactose, pregelatinized starch, and dextrin. More preferably, it is microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, lactose, and alpha The pharmaceutical composition according to any one of claims 1 to 6, characterized in that it is one or more types of crystalline starch, more preferably one of microcrystalline cellulose or silicified microcrystalline cellulose, or a combination of one of microcrystalline cellulose and silicified microcrystalline cellulose and one of mannitol and lactose, or a combination of one of microcrystalline cellulose or silicified microcrystalline cellulose, one of mannitol or lactose and pregelatinized starch, and even more preferably a combination of microcrystalline cellulose, mannitol and pregelatinized starch.

8. 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 mannitol or lactose is 15 to 50%, preferably 20 to 45%, more preferably 20 to 40%, and even more preferably 20 to 30%, and the weight percentage of microcrystalline cellulose or silicified microcrystalline cellulose is 40 to 75%, preferably 50 to 75%, and more preferably 6 The pharmaceutical composition according to claim 7, characterized in that the amount is 0 to 75%, more preferably 65 to 75%, and the weight ratio of mannitol or lactose to microcrystalline cellulose or silicified microcrystalline cellulose is 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. 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, the weight percentage of mannitol or lactose is 15 to 45%, preferably 20 to 45%, more preferably 20 to 41%, and even more preferably 20 to 30%, the weight percentage of microcrystalline cellulose or silicified microcrystalline cellulose is 35 to 70%, preferably 40 to 65%, and the weight ratio of mannitol or lactose to microcrystalline cellulose or silicified microcrystalline cellulose is 1:5 to 1: The pharmaceutical composition according to claim 7, characterized in that the ratio is 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, and the weight percentage of pregelatinized starch is 5 to 25%, preferably 5 to 15%, more preferably 8 to 12%, even more preferably 10 to 11%, and even more preferably 10.5%.

10. The pharmaceutical composition according to any one of claims 1 to 9, characterized in that the disintegrant is selected from sodium carboxymethyl starch, sodium carboxymethylcellulose, sodium croscarmellose, dried starch, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, crospovidone, foaming disintegrant, potassium polaritrin, or sodium alginate, preferably sodium carboxymethyl starch, sodium carboxymethylcellulose, sodium croscarmellose, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, or crospovidone, more preferably sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, or crospovidone, and even more preferably crospovidone.

11. The pharmaceutical composition according to any one of claims 1 to 10, characterized in that the flow promoter is selected from talc powder, silica, or colloidal silica, preferably silica or colloidal silica, and more preferably colloidal silica.

12. The pharmaceutical composition according to any one of claims 1 to 11, characterized in that the lubricant is selected from calcium stearate, magnesium stearate, zinc stearate, talc powder, sodium stearyl fumarate, stearic acid, glyceryl behenate, palmitic acid, glyceryl stearate palmitate, magnesium lauryl sulfate, hydrogenated vegetable oil, sodium dodecyl sulfate, magnesium dodecyl sulfate, polyethylene glycol, fine silica gel, or aluminum hydroxide, preferably glyceryl behenate, magnesium stearate, or sodium stearyl fumarate, and more preferably glyceryl behenate or sodium stearyl fumarate.

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

14. The crystalline form of compound (A) is crystal form I, and crystal form I has characteristic peaks at 2θ 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 the powder X-ray diffraction pattern obtained using Cu-Kα radiation, or The aforementioned crystal form I has characteristic peaks at 2θ 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 The aforementioned crystal form I has characteristic peaks at 2θ 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 The aforementioned crystal form I has characteristic peaks at 2θ in the powder X-ray diffraction pattern obtained using Cu-Kα radiation, 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°, or The aforementioned crystal form I exhibits the following powder X-ray diffraction patterns obtained using Cu-Kα radiation: 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°, and 19.3±0.2°. It has characteristic peaks at 2θ of 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°, or The aforementioned crystal form I exhibits the following powder X-ray diffraction patterns obtained using Cu-Kα radiation: 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°, and 20.5±0.2°. The pharmaceutical composition according to claim 13, characterized by having characteristic peaks at 2θ of 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°.

15. An oral solid preparation manufactured with the pharmaceutical composition according to any one of claims 1 to 14, which is a capsule or a tablet, preferably a tablet, and more preferably a film-coated tablet.

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

17. A method for producing the pharmaceutical composition described in claim 1, A method for producing a pharmaceutical composition, comprising the steps of: pre-mixing compound (A) with other additives other than a lubricant; mixing the resulting pre-mixture with a lubricant to obtain a pharmaceutical composition containing compound (A); and optionally further, filling the obtained pharmaceutical composition containing compound (A) into capsules or pressing it into tablets.

18. Use of a pharmaceutical composition according to any one of claims 1 to 14 or an oral solid dosage form according to claim 15 or 16 in the manufacture of a pharmaceutical for preventing and / or treating diseases related to the activity or expression of FGFR, KDR and / or CSF-1R.

19. The use according to claim 18, characterized in that the disease is a tumor, and preferably the tumor is selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, bladder cancer, urinary tract transition cell carcinoma, esophageal cancer, gastric cancer (esophagogastric junction adenocarcinoma), 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.

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