WO2024251252A1 - 一种fgfr4抑制剂组合物、其制备方法和在药学上的应用 - Google Patents

一种fgfr4抑制剂组合物、其制备方法和在药学上的应用 Download PDF

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Publication number
WO2024251252A1
WO2024251252A1 PCT/CN2024/098046 CN2024098046W WO2024251252A1 WO 2024251252 A1 WO2024251252 A1 WO 2024251252A1 CN 2024098046 W CN2024098046 W CN 2024098046W WO 2024251252 A1 WO2024251252 A1 WO 2024251252A1
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pharmaceutical composition
content
total weight
compound
formula
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English (en)
French (fr)
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高敏
张臻
喻红平
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Abbisko Therapeutics Co Ltd
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Abbisko Therapeutics Co Ltd
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Priority to AU2024285367A priority Critical patent/AU2024285367A1/en
Priority to EP24818780.9A priority patent/EP4725491A1/en
Priority to KR1020257039775A priority patent/KR20260004469A/ko
Priority to CN202480020098.9A priority patent/CN121038795A/zh
Publication of WO2024251252A1 publication Critical patent/WO2024251252A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention belongs to the field of drug development, and specifically relates to a FGFR4 inhibitor composition, a preparation method thereof and pharmaceutical application thereof.
  • Fibroblast growth factor is a family of 22 structurally related polypeptides with different biological activities.
  • the corresponding receptor of FGF belongs to a family of receptor tyrosine kinases RPTK.
  • RPTK receptor tyrosine kinases
  • Hepatocellular carcinoma is one of the leading causes of cancer-related deaths in China and one of the fastest growing cancers each year.
  • the current first-line treatment is Sorafenib, and there is no approved second-line drug, and targeted drugs with anti-tumor agents are still needed.
  • FGF19 is overexpressed in 5-10% of hepatocellular carcinoma patients, and FGFR4 is the dominant FGFR present in human hepatocytes, and its high expression in hepatocytes is considered to be associated with the aggressiveness of hepatocellular tumors. Therefore, FGFR4 plays a very important role in liver cancer.
  • the interaction between FGF19 and FGFR4 is also considered to be related to the aggressiveness of other cancer types (such as gastric cancer, prostate cancer, lung cancer, colorectal cancer, pancreatic cancer, and ovarian cancer).
  • FGFR4 inhibitors can effectively treat cancer diseases caused by abnormal FGFR4 signaling pathways and avoid related side effects such as hyperphosphatemia caused by FGFR1-3 inhibition.
  • Highly selective small molecule inhibitors of FGFR4 have great application prospects in the field of tumor targeted therapy.
  • FGFR4 inhibitors will be able to meet the needs of targeted drugs for liver cancer and other tumors at home and abroad, and bring the advantages of good safety and stronger specificity.
  • the Chinese name is: N-((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide (referred to as the compound of formula (I), or
  • the compound can significantly enhance the inhibitory effect on FGFR4 target and the selectivity for other FGFR1-3 kinase receptors, and can be used for the treatment of liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma, etc.
  • the purpose of the present invention is to provide a FGFR4 inhibitor composition to solve the problem of drug accessibility and meet the needs of drug clinical research and drug marketing.
  • the inventors screened suitable fillers and excipients to improve material fluidity, obtained a formulation that can be directly filled with powder or wet granulated, and optimized the filling process or wet granulation process, greatly improved the uniformity of the drug, and the dissolution characteristics of the preparation met clinical requirements.
  • the powder filling process or wet granulation process used in the present invention is simple, stable in quality, high in efficiency, and can be industrially produced, which solves the problem of drug accessibility and meets the needs of drug clinical research and marketing.
  • the first aspect of the present invention provides a pharmaceutical composition, which comprises a free base of a compound of formula (I) or an acid salt thereof as an active ingredient, a pharmaceutically acceptable filler, and other pharmaceutically acceptable carriers.
  • the pharmaceutically acceptable filler is one or more of calcium hydrogen phosphate, mannitol, lactose, microcrystalline cellulose or silicified microcrystalline cellulose.
  • the content of the active ingredient calculated as p-toluenesulfonate monohydrate of the compound of formula (I), is 0.1 to 60 wt % of the total weight of the pharmaceutical composition.
  • the content of the active ingredient calculated as p-toluenesulfonate monohydrate of the compound of formula (I), is 1.0 to 50 wt % of the total weight of the pharmaceutical composition.
  • the content of the active ingredient calculated as p-toluenesulfonate monohydrate of the compound of formula (I), is 5.0 to 40 wt % of the total weight of the pharmaceutical composition.
  • the other pharmaceutically acceptable carriers are one or more of glidants, lubricants, binders and disintegrants.
  • the glidant is colloidal silicon dioxide, and the content of the glidant is 0.1 to 5.0 wt % of the total weight of the pharmaceutical composition.
  • the content of the glidant is 0.5-4.0 wt % of the total weight of the pharmaceutical composition.
  • the content of the glidant is 0.8-2.0 wt % of the total weight of the pharmaceutical composition.
  • the lubricant is magnesium stearate and/or sodium stearyl fumarate, and the content of the lubricant is 0.1 to 5.0 wt % of the total weight of the pharmaceutical composition.
  • the content of the lubricant is 0.2-3.0 wt % of the total weight of the pharmaceutical composition.
  • the content of the lubricant is 0.3-1.5 wt % of the total weight of the pharmaceutical composition.
  • the content of the lubricant is 0.3-1.0 wt % of the total weight of the pharmaceutical composition.
  • the binder is hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, povidone and/or sodium carboxymethyl starch, and the content of the binder is 0.0 to 20.0 wt % of the total weight of the pharmaceutical composition.
  • the content of the binder is 0.0 to 10.0 wt % of the total weight of the pharmaceutical composition.
  • the content of the binder is 0.0 to 4.0 wt % of the total weight of the pharmaceutical composition.
  • the disintegrant is cross-linked sodium carboxymethyl cellulose and/or sodium starch glycolate, and the content of the disintegrant is 0.5 to 20.0 wt % of the total weight of the pharmaceutical composition.
  • the content of the disintegrant is 1.0 to 10.0 wt % of the total weight of the pharmaceutical composition.
  • the content of the disintegrant is 2.0 to 6.0 wt % of the total weight of the pharmaceutical composition.
  • the pharmaceutically acceptable filler is anhydrous calcium hydrogen phosphate.
  • the pharmaceutically acceptable filler is one or more of mannitol or microcrystalline cellulose.
  • the pharmaceutically acceptable filler is a mixture of mannitol and microcrystalline cellulose.
  • the mass ratio of mannitol to microcrystalline cellulose in the pharmaceutically acceptable filler is 1:(1 ⁇ 0.2), preferably 1:1.
  • the content of the pharmaceutically acceptable filler is 1.0 to 98.0 wt % of the total weight of the pharmaceutical composition.
  • the content of the pharmaceutically acceptable filler is 20.0 to 95.0 wt % of the total weight of the pharmaceutical composition.
  • the content of the pharmaceutically acceptable filler is 40.0 to 90.0 wt % of the total weight of the pharmaceutical composition.
  • the content of the pharmaceutically acceptable filler is 50.0 to 70 wt % of the total weight of the pharmaceutical composition.
  • the unit dosage form of the pharmaceutical composition comprises an active ingredient, a glidant, a lubricant, a binder and a disintegrant.
  • the content of the active ingredient is 5.0-40.0wt% of the total weight of the pharmaceutical composition, and/or
  • the content of the glidant is 0.8-2.0wt% of the total weight of the pharmaceutical composition, and/or
  • the content of the lubricant is 0.3-1.0 wt% of the total weight of the pharmaceutical composition, and/or
  • the content of the binder is 0.0-4.0wt% of the total weight of the pharmaceutical composition, and/or
  • the content of the disintegrant is 2.0-6.0 wt % of the total weight of the pharmaceutical composition.
  • the unit dosage form of the pharmaceutical composition comprises active ingredients, colloidal silicon dioxide, magnesium stearate, hydroxypropyl cellulose and cross-linked carboxymethyl cellulose sodium.
  • the content of the active ingredient is 5.0-40.0wt% of the total weight of the pharmaceutical composition, and/or
  • the content of the colloidal silicon dioxide is 0.8-2.0 wt% of the total weight of the pharmaceutical composition, and/or
  • the content of magnesium stearate is 0.3-1.0wt% of the total weight of the pharmaceutical composition, and/or
  • the content of hydroxypropyl cellulose is 0.0-4.0wt% of the total weight of the pharmaceutical composition, and/or
  • the content of the cross-linked sodium carboxymethyl cellulose is 2.0-6.0 wt % of the total weight of the pharmaceutical composition.
  • the unit dosage form of the pharmaceutical composition further comprises a filler, wherein the content of the filler is 40.0 to 90.0 wt % of the total weight of the pharmaceutical composition.
  • the unit dosage form of the pharmaceutical composition further comprises calcium hydrogen phosphate as a filler, wherein the content of the calcium hydrogen phosphate is 40.0 to 90.0 wt % of the total weight of the pharmaceutical composition.
  • the unit dosage form of the pharmaceutical composition further comprises mannitol and microcrystalline cellulose as fillers, wherein the content of the mannitol and microcrystalline cellulose is 40.0 to 90.0 wt % of the total weight of the pharmaceutical composition, and wherein the mass ratio of the mannitol to the microcrystalline cellulose is 1:1.
  • the content of the filler is adjusted so that the sum of the contents of the components in the pharmaceutical composition is 100wt%.
  • the sum of the contents of each component in the pharmaceutical composition is 100 wt%.
  • the active ingredient is an anhydrate, a hydrate or a solvate of the free base of the compound of formula (I) or its acid salt.
  • the active ingredient is a solvate of the free base of the compound of formula (I) or its acid salt
  • the solvent is selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides or sulfoxide organic solvents, or mixtures thereof, or aqueous solutions thereof.
  • the active ingredient is a solvate of the free base of the compound of formula (I) or its acid salt
  • the solvent is selected from methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether or 2-methoxyethyl ether, or a mixture thereof, or an aqueous solution thereof.
  • the active ingredient is an anhydrate or a hydrate of the free base or acid salt of the compound of formula (I).
  • the active ingredient is the anhydrous form of the free base of the compound of formula (I) or its acid salt.
  • the active ingredient is a hydrate of the free base of the compound of formula (I) or its acid salt, and each molecule of the hydrate contains 1 to 3 water molecules.
  • the active ingredient is a hydrate of the free base of the compound of formula (I) or its acid salt, and each molecule of the hydrate contains one water molecule.
  • the active ingredient is a hydrate of p-toluenesulfonate of the compound of formula (I), and each molecule of the hydrate contains 1 to 3 water molecules.
  • the active ingredient is a hydrate of p-toluenesulfonate of the compound of formula (I), and each molecule of the hydrate contains one water molecule.
  • the active ingredient is p-toluenesulfonate monohydrate of the compound of formula (I).
  • the X-ray powder diffraction pattern of the p-toluenesulfonate monohydrate of the compound of formula (I) includes 5 or more positions at 9.02 ⁇ 0.2°, 10.60 ⁇ 0.2°, 12.04 ⁇ 0.2°, 12.72 ⁇ 0.2°, 15.32 ⁇ 0.2°, 17.18 ⁇ 0.2°, 17.68 ⁇ 0.2°, 18.56 ⁇ 0.2°, 19.60 ⁇ 0.2°, 20.
  • the X-ray powder diffraction pattern of the p-toluenesulfonate monohydrate of the compound of formula (I) includes 5 or more peaks at diffraction angles (2 ⁇ ) of 17.68 ⁇ 0.2°, 22.9 ⁇ 0.2°, 19.6 ⁇ 0.2°, 17.18 ⁇ 0.2°, 9.02 ⁇ 0.2°, 24.9 ⁇ 0.2°, 12.72 ⁇ 0.2°, 21.22 ⁇ 0.2°, 18.56 ⁇ 0.2°, 10.6 ⁇ 0.2°, 23.82 ⁇ 0.2°, 24.12 ⁇ 0.2°, 24.6 ⁇ 0.2°, 25.58 ⁇ 0.2°, and 15.32 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the p-toluenesulfonate monohydrate of the compound of formula (I) has the 2 ⁇ characteristic peaks shown in Table A.
  • the active ingredient is the p-toluenesulfonate monohydrate of the compound of formula (I), and the particle size (D90) is 5 to 330 ⁇ m.
  • the active ingredient is p-toluenesulfonate monohydrate of the compound of formula (I), and the particle size (D90) is 10 to 200 ⁇ m.
  • the active ingredient is the p-toluenesulfonate monohydrate of the compound of formula (I), and the particle size (D90) is 20 to 150 ⁇ m.
  • the active ingredient is the p-toluenesulfonate monohydrate of the compound of formula (I), and the particle size (D50) is 2 to 200 ⁇ m.
  • the active ingredient is p-toluenesulfonate monohydrate of the compound of formula (I), and the particle size (D50) is 4 to 100 ⁇ m.
  • the active ingredient is the p-toluenesulfonate monohydrate of the compound of formula (I), and the particle size (D50) is 6 to 50 ⁇ m.
  • the active ingredient is the p-toluenesulfonate monohydrate of the compound of formula (I), and the particle size (D50) is 6 to 25 ⁇ m.
  • the content of the filler is adjusted so that the sum of the contents of the components in the pharmaceutical composition is 100wt%.
  • the total content of the active ingredient, pharmaceutically acceptable filler, glidant, lubricant, binder and disintegrant is 100 wt%.
  • the pharmaceutical composition is obtained by direct powder filling, dry granulation or wet granulation process.
  • the pharmaceutical composition is obtained by a wet granulation process.
  • the pharmaceutical composition is a capsule or a tablet.
  • the unit dosage form of the pharmaceutical composition contains 1 mg to 500 mg of active ingredient, calculated as the free base of the compound of formula (I).
  • the unit dosage form of the pharmaceutical composition contains 1 mg to 200 mg of active ingredient, calculated as the free base of the compound of formula (I).
  • the unit dosage form of the pharmaceutical composition contains 1 mg, 5 mg, 20 mg, 50 mg, 60 mg, 80 mg, 100 mg or 200 mg of the active ingredient, calculated as the free base of the compound of formula (I).
  • the second aspect of the present invention provides a method for preparing the pharmaceutical composition of the first aspect of the present invention, the preparation method comprising the following steps: mixing the free base of the active ingredient compound of formula (I) or its acid salt with a pharmaceutically acceptable filler to obtain the pharmaceutical composition,
  • the pharmaceutical composition prepared above is subjected to powder filling, dry granulation or wet granulation to obtain capsules or tablet compression to obtain tablets.
  • the preparation method is to mix the free base of the compound of formula (I) or its acid salt with a pharmaceutically acceptable filler to obtain the pharmaceutical composition, and then add other pharmaceutically acceptable carriers before or during the mixing.
  • the preparation method is to mix the free base of the compound of formula (I) or its acid salt with a pharmaceutically acceptable filler to obtain the pharmaceutical composition, and then add other pharmaceutically acceptable carriers after mixing.
  • the preparation method is to mix the free base of the compound of formula (I) or its acid salt with a pharmaceutically acceptable filler to obtain the pharmaceutical composition, and other pharmaceutically acceptable carriers are added before, during or during mixing.
  • the active ingredients of the pharmaceutical composition are individually pulverized and pre-treated before mixing.
  • the preparation method comprises: The capsules are obtained by filling.
  • the preparation method comprises compressing the pharmaceutical composition prepared above into tablets.
  • the other pharmaceutically acceptable carriers are one or more of glidants, lubricants, binders and disintegrants.
  • the preparation method is to mix p-toluenesulfonic acid monohydrate of the compound of formula (I), calcium hydrogen phosphate, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide and/or other pharmaceutically acceptable carriers to obtain the pharmaceutical composition.
  • the preparation method is to mix p-toluenesulfonic acid monohydrate of the compound of formula (I), calcium hydrogen phosphate, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide and/or other pharmaceutically acceptable carriers to obtain the pharmaceutical composition;
  • magnesium stearate and/or sodium stearyl fumarate are further mixed with the aforementioned pharmaceutical composition to obtain a pharmaceutical composition.
  • the preparation method is to mix p-toluenesulfonic acid monohydrate of the compound of formula (I), mannitol, microcrystalline cellulose, the first part of cross-linked sodium carboxymethyl cellulose and/or other pharmaceutically acceptable carriers to obtain a pharmaceutical composition.
  • the preparation method is to mix p-toluenesulfonic acid monohydrate of the compound of formula (I), mannitol, microcrystalline cellulose, the first part of cross-linked sodium carboxymethyl cellulose and/or other pharmaceutically acceptable carriers to obtain a pharmaceutical composition; add an aqueous solution of hydroxypropyl cellulose to perform wet granulation and then dry.
  • the preparation method comprises mixing p-toluenesulfonic acid monohydrate of the compound of formula (I), mannitol, microcrystalline cellulose, a first portion of cross-linked sodium carboxymethyl cellulose and/or other pharmaceutically acceptable carriers to obtain a pharmaceutical composition; adding an aqueous solution of hydroxypropyl cellulose to perform wet granulation and then drying; externally adding colloidal silicon dioxide and a second portion of cross-linked sodium carboxymethyl cellulose and further mixing with the dried granules obtained in the previous step.
  • the preparation method is to mix the p-toluenesulfonic acid monohydrate of the compound of formula (I), mannitol, microcrystalline cellulose, the first part of cross-linked sodium carboxymethyl cellulose and/or other pharmaceutically acceptable carriers to obtain a pharmaceutical composition; add an aqueous solution of hydroxypropyl cellulose for wet granulation and then dry; add colloidal silicon dioxide and the second part of cross-linked sodium carboxymethyl cellulose and further mix with the dried granules obtained in the previous step; add magnesium stearate for total mixing to obtain a pharmaceutical composition.
  • the components of the pharmaceutical composition are separately or mixed before and/or after mixing. Pass through 30-100 mesh sieve.
  • the components of the pharmaceutical composition are individually or mixedly passed through a 30-50 mesh sieve before and/or after mixing.
  • the components of the pharmaceutical composition are individually or mixedly passed through a 40-mesh sieve before and/or after mixing.
  • the mixing speed of the components of the pharmaceutical composition is 10 to 100 rpm;
  • the mixing speed of the components of the pharmaceutical composition is 10 to 50 rpm;
  • the mixing speed of the components of the pharmaceutical composition is 20 to 30 rpm.
  • a third aspect of the present invention provides use of a pharmaceutical composition in the preparation of a FGFR4 inhibitor drug.
  • the pharmaceutical composition is used in the preparation of a drug for treating liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma associated with FGFR4.
  • the present invention provides a method for treating liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma associated with FGFR4, the method comprising administering an effective therapeutic amount of the pharmaceutical composition to a patient in need of treatment.
  • a fifth aspect of the present invention provides a pharmaceutical composition for use as a FGFR4 inhibitor drug.
  • the pharmaceutical composition of the present invention can be prepared by a powder direct filling process or a wet granulation process.
  • the drug solubility, content uniformity, content of related substances and physicochemical stability all meet clinical needs and meet the needs of clinical research and drug marketing.
  • the wet granulation process is suitable for industrialization and solves the problem of drug accessibility.
  • Figure 1 Shows the uncomminuted API morphology.
  • FIG. 1 Shows the drug substance form of Trial 1.
  • Figure 5 Dissolution curves of magnesium stearate in different proportions of direct mixing process, the horizontal axis represents time (minutes), and the vertical axis represents dissolution (%).
  • Figure 6 Dissolution curves of formulation and process screening batches, the horizontal axis represents time (minutes) and the vertical axis represents dissolution (%).
  • the term "acid salt” refers to a pharmaceutically acceptable salt, which is generally an inorganic acid salt or an organic acid salt as known to those of ordinary skill in the art.
  • the inorganic acid salt may be hydrochloride, sulfate, hydrobromide, hydrofluoride, hydroiodide or phosphate;
  • the organic acid salt may be acetate, dichloroacetate, trichloroacetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, 1,5-naphthalene disulfonate, naphthalene-2-sulfonate, ethane-1,2-disulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzoate, decanoate, hexanoate, caprylate, cinnamate, citrate,
  • solvate refers to a compound composed of a solvent and a solute.
  • the solvent may be an organic solvent or other liquid, and the solute may be an ion, molecule or other substance.
  • the solvent compound may be a solid, a liquid or a gas.
  • a solvate refers to a complex formed by the dissolution of an active substance in a solvent, the mutual combination of solvent molecules and active substance molecules or ions, etc., so that the active ingredient changes its original state;
  • the organic solvent includes but is not limited to: alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides or sulfoxide organic solvents, or mixtures thereof, or aqueous solutions thereof.
  • the organic solvent may be methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether or 2-methoxyethyl ether, or mixtures thereof, or aqueous solutions thereof.
  • the term "pharmaceutical composition” refers to a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable crystal forms, salt forms or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • free base of a compound of formula (I) refers to a compound of formula (I),
  • active ingredient refers to the free base of the compound of formula (I) or its acid salt; the active ingredient is preferably an anhydrate, hydrate or solvate of the free base of the compound of formula (I) or its acid salt; the solvent is selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides or sulfoxides, or mixtures thereof, or aqueous solutions thereof.
  • the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether or 2-methoxyethyl ether, or mixtures thereof, or aqueous solutions thereof.
  • API refers to the p-toluenesulfonate monohydrate salt of the compound of formula (I).
  • the pharmaceutical composition of the present invention may include one or more pharmaceutically acceptable carriers, including but not limited to fillers, glidants, adhesives, foaming agents, lubricants, disintegrants, diluents, stabilizers, buffers, adjuvants, carriers, emulsifiers, viscosity modifiers, surfactants, preservatives, flavoring agents or coloring agents.
  • pharmaceutically acceptable carriers including but not limited to fillers, glidants, adhesives, foaming agents, lubricants, disintegrants, diluents, stabilizers, buffers, adjuvants, carriers, emulsifiers, viscosity modifiers, surfactants, preservatives, flavoring agents or coloring agents.
  • Medically acceptable excipients can be described in the examples of R.C. Luo P.J. Shesky's Handbook of Pharmaceutical Excipients.
  • filler refers to any pharmaceutically acceptable substance or composition added to a formulation to increase volume. Suitable fillers include, but are not limited to, mannitol, lactose, microcrystalline cellulose, mannitol, silicified microcrystalline cellulose, and dibasic calcium phosphate.
  • glidant refers to a compound or composition added to a formulation to improve the interaction between various factors, which will improve the flowability of the powder. Suitable glidants include (but are not limited to) colloidal silicon dioxide and talc.
  • binder refers to a pharmaceutically acceptable compound or composition added to a formulation to hold the active pharmaceutical ingredient and the inactive ingredients together in a cohesive mixture. Dry binders used for direct compaction must exhibit cohesive and adhesive forces so that the particles agglomerate when compacted. Binders used for wet granulation are hydrophilic and soluble in water, and are typically dissolved in water to form a wet mass that is then granulated.
  • Suitable binders include (but are not limited to) Plasdone, Plasdone K29/32, Plasdone S-630, hydroxypropyl cellulose, methylcellulose, polyvinyl pyrrolidone, aluminum stearate, hydroxypropyl methylcellulose and the like. These binders may additionally act as water chelators (e.g., Plasdone).
  • lubricant refers to any pharmaceutically acceptable agent that reduces surface friction, lubricates the surface of particles, reduces the tendency for static electricity to accumulate, and/or reduces the brittleness of particles.
  • lubricants can act as anti-agglomeration agents.
  • Conventional lubricants include stearic acid and related compounds such as magnesium stearate, sodium stearyl fumarate, and sodium stearyl fumarate.
  • Alternative lubricants include glyceryl dibehenate, colloidal silicon dioxide, talc, other hydrogenated vegetable oils, and polyols. Examples of suitable alternative lubricants include, but are not limited to, glyceryl dibehenate.
  • disintegrant refers to a substance added to a composition to help it break up (disintegrate) and release the agent.
  • disintegrants include, but are not limited to, non-sugar water-soluble polymers such as croscarmellose sodium, sodium starch glycolate, crospovidone, sodium starch glycolate, and the like.
  • D10, D50, D90 are parameters indicating the particle size of the active ingredient, and their specific meanings are as follows:
  • D10 refers to the particle size at which the cumulative distribution of active ingredient particles is 10%, that is, the volume content of particles smaller than this particle size accounts for 10% of all particles.
  • D50 refers to the particle size at which the cumulative distribution of active ingredient particles accounts for 50%. Also called the median diameter or median particle size, this is a typical value that represents the particle size, which accurately divides the population into two equal parts, that is, 50% of the particles exceed this value and 50% of the particles are below this value. If the D50 of a sample is 5 ⁇ m, it means that among all the particles of the sample, particles larger than 5 ⁇ m account for 50% and particles smaller than 5 ⁇ m also account for 50%.
  • D90 refers to the particle size at which the cumulative distribution of active ingredient particles is 90%, that is, the volume content of particles smaller than this particle size accounts for 90% of all particles. The same applies to the others.
  • the preparation process of the raw material drug is as follows: weigh 5 mg of the free form compound of formula (I) and dissolve it in 0.5 mL of ethyl acetate; weigh 1.67 mg of p-toluenesulfonic acid and dissolve it in 0.1 mL of tetrahydrofuran; slowly add the p-toluenesulfonic acid solution to the solution of the compound of formula (I) under stirring, stir overnight, filter, and dry the filter cake in a vacuum drying oven at 40°C.
  • the XRPD diffraction angle (2 ⁇ ) and related intensity data ( ⁇ 0.2°) are as follows:
  • the unit cell is P1
  • the unit cell volume is P1
  • Octadecylsilane bonded silica gel was used as filler (Waters C18, 4.6 ⁇ 150 mm, 3.5 ⁇ m chromatographic column or chromatographic column with equivalent performance); 0.1 vol% trifluoroacetic acid solution was used as mobile phase A, 0.1 vol% trifluoroacetic acid acetonitrile solution was used as mobile phase B, mobile phase A-mobile phase B (70:30) was used for isocratic elution, the detection wavelength was 232 nm, the flow rate was 1.0 mL per minute, the column temperature was 40° C., the injection volume was 10 ⁇ L, and the running time was 10 minutes.
  • Chromatographic conditions octadecylsilane bonded silica gel as filler (Waters SunFire C18, 4.6 ⁇ 150mm, 3.5 ⁇ m chromatographic column or chromatographic column with equivalent performance), 10mmol/L ammonium formate solution as mobile phase A, acetonitrile as mobile phase B, detection wavelength of 232nm, flow rate of 1.0mL per minute, column temperature of 40°C, injection volume of 10 ⁇ L. Gradient elution was performed according to the table below, running time of 50.0 minutes, and post-running time of 5 minutes.
  • Weighing method weigh the initial sample weight W1, then weigh the sample weight W2 after being placed under high humidity conditions for a certain period of time, and calculate the percentage of moisture absorption and weight gain based on the weight difference.
  • the calculation formula is: (W2-W1)/W1*100%.
  • the inventors first studied the physical and chemical properties of the API.
  • the specific operation is as follows: the API and different excipients are mixed in different proportions, placed under different conditions, and taken out at different time points to observe their appearance, hygroscopicity, and Weight gain, API content and related substance content, etc.
  • the specific experimental design is shown in the table below.
  • excipients used are pharmaceutically acceptable excipients for oral solid preparations and have been included in the current edition of the Chinese Pharmacopoeia. The properties of each excipient are stable. Unless otherwise specified in the following examples, the API used is the same as that in Example 1.
  • Test items: X appearance, content;
  • the API alone is not easy to absorb moisture, but the API impurities increase slightly when exposed to high humidity conditions of 25°C/92.5%RH.
  • the API impurities are stable when exposed to high temperature of 60°C, light and open conditions of 40°C/75%RH. This indicates that sealed storage of this product is beneficial to increase the stability of the API.
  • the impurity levels of the above three binary mixtures are comparable to those of individual APIs under other conditions and can be used for formulation development. However, it is recommended that the products be protected from light and attention should be paid to the stability data of subsequent products.
  • material fluidity and capsule dissolution are used as the main evaluation indicators, and pharmaceutically acceptable pharmaceutical excipients with good compatibility with the raw materials are selected for capsules, and prescription screening is performed within the conventional dosage range to optimize the types of excipients.
  • colloidal silicon dioxide has good compatibility with the API, and colloidal silicon dioxide is selected as the preferred glidant.
  • Adding an appropriate amount of lubricant to the preparation product can reduce the friction between the material and the equipment and improve the fluidity of the material.
  • Magnesium stearate and sodium stearyl fumarate are used as lubricants below.
  • the compatibility results of the binary mixture of API and lubricant in a weight ratio of 10:1 were used as the basis for the screening of lubricant types.
  • the compatibility results of API and lubricant are shown in the table below.
  • disintegrants it is not necessary to add disintegrants to promote drug dissolution when using the powder direct mixing capsule process.
  • an appropriate amount of disintegrant is added to the prescription to avoid this risk.
  • Cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone and sodium starch glycolate are used as disintegrants.
  • the compatibility results of the binary mixture of the API and disintegrant in a weight ratio of 1:1 were used as the basis for screening the type of disintegrant.
  • the compatibility results of the API and disintegrant are shown in the table below.
  • the specifications of the preparation of the present invention are determined to be 5 mg, 20 mg and 100 mg, and the dosage form is a capsule. Excipients with good compatibility with the raw material drug are selected, and the process is initially screened with the 100 mg specification, and the final process is determined to be direct powder filling.
  • the filler type and dosage were investigated with material fluidity and product dissolution behavior as indicators, and the 100mg specification prescription was preliminarily determined.
  • the 5mg and 20mg specifications adopted equal proportion prescriptions, referring to the 100mg specification prescription. While the proportions of other excipients remained unchanged, only the amount of filler anhydrous calcium hydrogen phosphate was adjusted to a suitable filling amount, and the prescription was preliminarily determined with material fluidity and product dissolution behavior as indicators.
  • the first consideration is to adopt a powder direct filling process that is easy to produce, scale up and has good repeatability.
  • this preparation process has high requirements for the powder fluidity of the raw material and excipient mixture, the inventors therefore determined the dissolution characteristics and powder properties of the total mixed powder of different specifications of raw material prescriptions based on the 100 mg specification.
  • the API was mechanically pulverized, and samples were taken at different pulverization times.
  • the particle size distribution was determined using a Malvern Mastersizer 2000 laser particle size analyzer, and the particle morphology was observed using a polarizing microscope.
  • the particle size determination parameters are described in Table 13, and the particle size results are shown in Table 14.
  • PSD is the abbreviation of Particle Size Distribution.
  • PLM Polarizing Microscope
  • composition of the above-mentioned preparations of various specifications weigh the raw material, anhydrous calcium hydrogen phosphate, colloidal silicon dioxide 200, cross-linked carboxymethyl cellulose sodium and magnesium stearate, and place them in appropriate ziplock bags respectively.
  • the raw material drug, anhydrous calcium hydrogen phosphate, colloidal silicon dioxide 200, cross-linked carboxymethyl cellulose sodium and magnesium stearate are sieved through a 40-mesh sieve for later use.
  • the raw material drug used in the test is first pulverized and pre-treated before sieving.
  • the sieved API, anhydrous calcium hydrogen phosphate, colloidal silicon dioxide 200 and cross-linked sodium carboxymethyl cellulose were placed in a hopper mixer at a mixing speed of 20 rpm and a mixing time of 15 min.
  • the sieved magnesium stearate was placed in a hopper mixer and mixed at a speed of 20 rpm for 5 minutes. After mixing, the blended powder was taken out.
  • the powder properties of the blended powder are shown in the table below.
  • the total mixed powder is placed in the capsule machine and filled into gelatin capsules according to various specifications.
  • the process parameters of each step are detailed in Table 20 below.
  • the filling volume using the vacuum cannula is relatively stable, and the locking length and appearance are intact.
  • the cannula needs to be cleaned to ensure normal filling, which makes filling more difficult.
  • RRT is the abbreviation for Relative Retention Time.
  • This embodiment further screens and optimizes the prescription and process to obtain a pharmaceutical composition with good content uniformity and dissolution, and there is no situation where the prescription material adheres to the cannula or the pressing wheel, which can meet the requirements of industrial production.
  • composition 5-1 was prepared by direct mixing. During the process, it was shown that there was no sticking phenomenon after 20 minutes of operation, but the material fluidity was poor and the filling amount fluctuated relatively greatly and would exceed the filling limit. Then, 1.0% of magnesium stearate was additionally added to the remaining material, that is, the total proportion was about 1.5%, and a second filling was performed. After 20 minutes of operation, there was no sticking phenomenon, but the filling limit was exceeded. Capsules close to the target value were selected twice for sample dissolution testing. The results are shown in FIG5 . The 1.5% magnesium stearate was not completely released after dissolution. Therefore, the formulation of about 1.5% magnesium stearate in the direct mixing method may affect the dissolution.
  • composition 5-2 was prepared by dry granulation. During the process, a small amount of material adhered to the pressing wheel during the dry granulation stage with strong adhesion, which required regular cleaning. After capsule filling, samples were sent for dissolution testing. The results are shown in FIG6 . The dissolution results were similar to those of the 100 mg specification prescription (4-100) in Example 4.
  • composition 5-3 In pharmaceutical composition 5-3, the filler anhydrous calcium hydrogen phosphate was replaced with silicified microcrystalline cellulose, and the proportion of magnesium stearate was increased from 0.5% internally and externally to 0.75% internally and externally. The preparation process showed that a small amount of material still adhered to the pressing wheel during the dry granulation stage with strong adhesion.
  • composition 5-4 was prepared by wet granulation. The process showed that the wet granulation process was relatively smooth and the material fluidity was relatively good. After capsule filling, the samples were sent for dissolution testing. The results are shown in Figure 6. The dissolution results are similar to those of the 100 mg specification prescription (4-100) in Example 4.
  • the Carle coefficient of the prescription material obtained by wet granulation is significantly reduced, the fluidity of the material is greatly improved, and it has better content uniformity.
  • the preparation was carried out by referring to the production process of test number 5-4 in Example 5.
  • the specific capsule content, moisture, impurities, content uniformity and dissolution results are shown in the table below.

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Abstract

一种FGFR4抑制剂组合物，其制备方法和在药学上的应用，所述FGFR4抑制剂组合物包含具有如下结构的式(I)化合物游离碱或其酸式盐作为活性成分，采用合适的填充剂及其它药学上可接受载体，开发出适合工业化生产的制剂工艺，可以获得药物流动性、溶出度、含量均匀度、有关物质含量和物理化学稳定性等均符合临床需求的药物制剂，从而满足临床研究和药物上市的需求，解决了药物可及性问题，有望加速开发成新一代FGFR4抑制剂。

Description

一种FGFR4抑制剂组合物、其制备方法和在药学上的应用 技术领域
本发明属于药物开发领域，具体涉及一种FGFR4抑制剂组合物、其制备方法和在药学上的应用。
背景技术
成纤维细胞生长因子(FGF)是一个有22种具有不同生物学活性的结构相关多肽的一个家族，FGF的相应受体(FGFR)属于受体酪氨酸激酶的一个家族RPTK。目前已经有FGFR1，FGFR2，FGFR3以及FGFR4四种受体被发现，它们与相应的配体FGF的相互作用会导致受体二聚化和自我磷酸化，从而启动下游包括MAPK和AKT在内多种信号传导级联反应。
肝细胞癌(HCC)是导致中国癌症相关死亡的主要起因之一，也是每年发病人数增长最快的癌症之一。目前的一线治疗方案是索拉芬妮，且没有被批准的二线药物，仍然需要具有抗肿瘤剂的靶向药物。在5～10％的肝细胞癌病人中带有FGF19的过表达，而FGFR4是人肝细胞中存在的优势FGFR，并且其在肝细胞中的高表达被认为与肝细胞肿瘤的侵袭性相关。因此FGFR4在肝癌中有非常重要的作用。另外，FGF19以及FGFR4的相互作用也被认为与其他癌症类型(比如胃癌，前列腺癌，肺癌，结肠直肠癌，胰腺癌，卵巢癌)的侵袭性有关。
目前高选择性FGFR4抑制剂能有效治疗FGFR4信号通路异常导致的癌症疾病，并可避免FGFR1-3抑制导致的高血磷症等相关副作用，高选择性FGFR4的小分子抑制剂在肿瘤靶向治疗领域具有重大应用前景，FGFR4抑制剂作为良好药物候选药物将可以满足国内外肝癌及其他肿瘤靶向药物的需求，并带来安全性好和特异性更强的优点。
上海和誉生物医药科技有限公司(Abbisko Therapeutics Co.,Ltd)在长期的研究过程中发明了一种具有高选择性FGFR4抑制效果的小分子化合物(WO2018113584A1)，其代表性化合物如下：
中文名称为：N-((3S,4S)-3-((6-(2,6-二氟-3,5-二甲氧苯基)-8-(3-甲氧基-3-甲基吖丁啶-1-基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢-2H-吡喃-4-基)丙烯酰胺(称式(I)化合物，或 称式(I)化合物游离碱)，该化合物能显著提高FGFR4靶点的抑制作用和对于其他FGFR1-3激酶受体的选择性，能够用于对肝癌、前列腺癌、胰腺癌、食管癌、胃癌、肺癌、乳腺癌、卵巢癌、结肠癌、皮肤癌、神经胶质母细胞瘤或横纹肌肉瘤等的治疗。
为了适应临床前和临床开发制剂需求，上海和誉生物医药科技有限公司又开发出了式(I)化合物对甲苯磺酸盐，该盐型化合物可以大大改善游离态式(I)化合物的溶解性和生物利用度等物化性能。
但是，在临床制剂的进一步开发过程中发现，式(I)化合物对甲苯磺酸盐的溶出特性和流动性不佳，工业生产困难。因此，迫切需要对制剂处方和制备工艺进行优化，进一步开发出药物溶出度、流动性、有关物质含量或物理化学稳定性等都能够满足工业化生产要求的药物制剂，满足药物临床研究以及上市的需求。
发明内容
本发明的目的在于提供一种FGFR4抑制剂组合物以解决药物可及性问题，满足药物临床研究以及药物上市的需求。具体的，发明人通过筛选合适填充剂及辅料来提高物料流动性，获得可以粉末直灌或湿法制粒的制剂处方，并优化了灌装工艺或湿法制粒流程，大大改善了药物的均一性，制剂的溶出特性满足临床要求。本发明采用的粉末灌装工艺或湿法制粒工艺简单、质量稳定，效能较高，可工业化生产，解决了药物可及性问题，满足药物临床研究以及上市的需求。
本发明第一方面提供一种药物组合物，所述药物组合物包含式(I)化合物游离碱或其酸式盐作为活性成分、药学上可接受的填充剂、以及其它药学上可接受载体，
所述药学上可接受的填充剂为磷酸氢钙、甘露醇、乳糖、微晶纤维素或硅化微晶纤维素中的一种或多种。
作为优选的方案，所述活性成分的含量以式(I)化合物对甲苯磺酸盐一水合物计，为药物组合物总重量的0.1～60wt％。
作为进一步优选的方案，所述活性成分的含量以式(I)化合物对甲苯磺酸盐一水合物计，为药物组合物总重量的1.0～50wt％。
作为更进一步优选的方案，所述活性成分的含量以式(I)化合物对甲苯磺酸盐一水合物计，为药物组合物总重量的5.0～40wt％。
作为优选的方案，所述其它药学上可接受载体为助流剂、润滑剂、粘合剂和崩解剂中的一种或多种。
作为优选的方案，所述助流剂为胶态二氧化硅，所述助流剂的含量为药物组合物总重量的0.1～5.0wt％。
作为进一步优选的方案，所述助流剂的含量为药物组合物总重量的0.5～4.0wt％。
作为更进一步优选的方案，所述助流剂的含量为药物组合物总重量的0.8～2.0wt％。
作为优选的方案，所述润滑剂为硬脂酸镁和/或硬脂富马酸钠，所述润滑剂的含量为药物组合物总重量的0.1～5.0wt％。
作为进一步优选的方案，所述润滑剂的含量为药物组合物总重量的0.2～3.0wt％。
作为更进一步优选的方案，所述润滑剂的含量为药物组合物总重量的0.3～1.5wt％。
作为更进一步优选的方案，所述润滑剂的含量为药物组合物总重量的0.3～1.0wt％。
作为优选的方案，所述粘合剂为羟丙纤维素、甲基纤维素、羟丙基甲基纤维素、聚乙烯吡咯啶酮、聚维酮和/或羧甲淀粉钠，所述粘合剂的含量为药物组合物总重量的0.0～20.0wt％。
作为进一步优选的方案，所述粘合剂的含量为药物组合物总重量的0.0～10.0wt％。
作为更进一步优选的方案，所述粘合剂的含量为药物组合物总重量的0.0～4.0wt％。
作为优选的方案，所述崩解剂为交联羧甲基纤维素钠和/或羧甲淀粉钠，所述崩解剂的含量为药物组合物总重量的0.5～20.0wt％。
作为进一步优选的方案，所述崩解剂的含量为药物组合物总重量的1.0～10.0wt％。
作为更进一步优选的方案，所述崩解剂的含量为药物组合物总重量的2.0～6.0wt％。
作为优选的方案，所述药学上可接受的填充剂为无水磷酸氢钙。
作为优选的方案，所述药学上可接受的填充剂为甘露醇或微晶纤维素中的一种或多种。
作为更优选的方案，所述药学上可接受的填充剂为甘露醇和微晶纤维素的混合物。
作为更优选的方案，所述药学上可接受的填充剂中甘露醇和微晶纤维素的质量比为1:(1±0.2)，优选为1:1。
作为优选的方案，所述药学上可接受的填充剂的含量为药物组合物总重量的1.0～98.0wt％。
作为进一步优选的方案，所述药学上可接受的填充剂的含量为药物组合物总重量的20.0～95.0wt％。
作为更进一步优选的方案，所述药学上可接受的填充剂的含量为药物组合物总重量的40.0～90.0wt％。
作为更进一步优选的方案，所述药学上可接受的填充剂的含量为药物组合物总重量的50.0～70wt％。
作为进一步优选的方案，所述药物组合物的单位剂型包含活性成分、助流剂、润滑剂、粘合剂和崩解剂，
其中，所述活性成分的含量为药物组合物总重量的5.0～40.0wt％，和/或
所述助流剂的含量为药物组合物总重量的0.8～2.0wt％，和/或
所述润滑剂的含量为药物组合物总重量的0.3～1.0wt％，和/或
所述粘合剂的含量为药物组合物总重量的0.0～4.0wt％，和/或
所述崩解剂的含量为药物组合物总重量的2.0～6.0wt％。
作为更进一步优选的方案，所述药物组合物的单位剂型包含活性成分、胶态二氧化硅、硬脂酸镁、羟丙纤维素和交联羧甲基纤维素钠，
其中，所述活性成分的含量为药物组合物总重量的5.0～40.0wt％，和/或
所述胶态二氧化硅的含量为药物组合物总重量的0.8～2.0wt％，和/或
所述硬脂酸镁的含量为药物组合物总重量的0.3～1.0wt％，和/或
所述羟丙纤维素的含量为药物组合物总重量的0.0～4.0wt％，和/或
所述交联羧甲基纤维素钠的含量为药物组合物总重量的2.0～6.0wt％。
作为优选的方案，所述药物组合物的单位剂型还包括填充剂，其中，所述填充剂的含量为药物组合物总重量的40.0～90.0wt％。
作为优选的方案，所述药物组合物的单位剂型还包括磷酸氢钙作为填充剂，其中，所述磷酸氢钙的含量为药物组合物总重量的40.0～90.0wt％。
作为优选的方案，所述药物组合物的单位剂型还包括甘露醇和微晶纤维素作为填充剂，其中，所述甘露醇和微晶纤维素的含量为药物组合物总重量的40.0～90.0wt％，其中，所述的甘露醇和微晶纤维素的质量比为1:1。
作为优选的方案，所述药物组合物中各组分的含量之和不足100％时，调节填充剂的含量使得所述药物组合物中各组分的含量之和为100wt％。
作为优选的方案，所述药物组合物中各组分的含量之和为100wt％。
作为优选的方案，所述活性成分为式(I)化合物游离碱或其酸式盐的无水物、水合物或溶剂合物。
作为进一步优选的方案，所述活性成分为式(I)化合物游离碱或其酸式盐的溶剂合物，所述溶剂选自醇类、氯代烷烃、酮类、醚类、环醚类、酯类、烷烃类、环烷烃类、苯类、酰胺类或亚砜类有机溶剂，或其混合物，或其水溶液。
作为更进一步优选的方案，所述活性成分为式(I)化合物游离碱或其酸式盐的溶剂合物，所述溶剂选自甲醇、乙醇、正丙醇、异丙醇、二氯甲烷、乙腈、丙酮、1,4-二氧六环、四氢呋喃、N,N-二甲基甲酰胺、乙酸乙酯、乙酸异丙酯、甲基叔丁基醚或2-甲氧基乙醚，或其混合物，或其水溶液。
作为进一步优选的方案，所述活性成分为式(I)化合物游离碱或其酸式盐的无水物或水合物。
作为更进一步优选的方案，所述活性成分为式(I)化合物游离碱或其酸式盐的无水物。
作为更进一步优选的方案，所述活性成分为式(I)化合物游离碱或其酸式盐的水合物，所述水合物每个分子中包含1～3个水分子。
作为最更进一步优选的方案，所述活性成分为式式(I)化合物游离碱或其酸式盐的水合物，所述水合物每个分子中包含1个水分子。
作为更进一步优选的方案，所述活性成分为式(I)化合物对甲苯磺酸盐的水合物，所述水合物每个分子中包含1～3个水分子。
作为最更进一步优选的方案，所述活性成分为式(I)化合物对甲苯磺酸盐的水合物，所述水合物每个分子中包含1个水分子。
作为优选的方案，所述活性成分为式(I)化合物对甲苯磺酸盐一水合物。
作为进一步优选的方案，所述式(I)化合物对甲苯磺酸盐一水合物的X-射线粉末衍射图包括5个或以上位于9.02±0.2°、10.60±0.2°、12.04±0.2°、12.72±0.2°、15.32±0.2°、17.18±0.2°、17.68±0.2°、18.56±0.2°、19.60±0.2°、20.60±0.2°、21.22±0.2°、22.90±0.2°、23.82±0.2°、24.12±0.2°、24.60±0.2°、24.90±0.2°、25.58±0.2°、27.78±0.2°、29.04±0.2°、31.48±0.2°、36.60±0.2°和38.16±0.2°的衍射角(2θ)处的峰。
作为进一步优选的方案，所述式(I)化合物对甲苯磺酸盐一水合物的X-射线粉末衍射图包括5个或以上位于17.68±0.2°、22.9±0.2°、19.6±0.2°、17.18±0.2°、9.02±0.2°、24.9±0.2°、12.72±0.2°、21.22±0.2°、18.56±0.2°、10.6±0.2°、23.82±0.2°、24.12±0.2°、24.6±0.2°、25.58±0.2°、15.32±0.2°的衍射角(2θ)处的峰。
作为进一步优选的方案，所述式(I)化合物对甲苯磺酸盐一水合物的X-射线粉末衍射图具有表A所示的2θ特征峰。
表A

作为优选的方案，所述活性成分为式(I)化合物对甲苯磺酸盐一水合物，粒径(D90)为5～330μm。
作为进一步优选的方案，所述活性成分为式(I)化合物对甲苯磺酸盐一水合物，粒径(D90)为10～200μm。
作为更进一步优选的方案，所述活性成分为式(I)化合物对甲苯磺酸盐一水合物，粒径(D90)为20～150μm。
作为优选的方案，所述活性成分为式(I)化合物对甲苯磺酸盐一水合物，粒径(D50)为2～200μm。
作为进一步优选的方案，所述活性成分为式(I)化合物对甲苯磺酸盐一水合物，粒径(D50)为4～100μm。
作为更进一步优选的方案，所述活性成分为式(I)化合物对甲苯磺酸盐一水合物，粒径(D50)为6～50μm。
作为更进一步优选的方案，所述活性成分为式(I)化合物对甲苯磺酸盐一水合物，粒径(D50)为6～25μm。
作为优选的方案，所述药物组合物中各组分的含量之和不足100％时调节填充剂的含量使得所述药物组合物中各组分的含量之和为100wt％。
作为进一步优选的方案，所述活性成分、药学上可接受的填充剂、助流剂、润滑剂、粘合剂和崩解剂的含量之和为100wt％。
作为优选的方案，所述药物组合物通过粉末直灌、干法制粒或湿法制粒工艺获得。
作为进一步优选的方案，所述药物组合物通过湿法制粒工艺获得。
作为优选的方案，所述药物组合物为胶囊剂或片剂。
作为进一步优选的方案，所述药物组合物的单位剂型包含1mg～500mg活性成分，以式(I)化合物游离碱计。
作为更进一步优选的方案，所述药物组合物的单位剂型包含1mg～200mg活性成分，以式(I)化合物游离碱计。
作为再更进一步优选的方案，所述药物组合物的单位剂型包含1mg、5mg、20mg、50mg、60mg、80mg、100mg或200mg活性成分，以式(I)化合物游离碱计。
本发明第二方面提供一种本发明第一方面所述的药物组合物的制备方法，所述制备方法包括以下步骤：活性成分式(I)化合物游离碱或其酸式盐与药学上可接受的填充剂混合得到所述药物组合物，
且任选地，在混合前、混合时或混合后加入其它药学上可接受载体；
任选地，对上述制备得到的药物组合物进行粉末灌装、干法制粒或湿法制粒得到胶囊剂或压片得到片剂。
作为优选的方案，所述制备方法为式(I)化合物游离碱或其酸式盐与药学上可接受的填充剂混合得到所述药物组合物，在混合前或混合时加入其它药学上可接受载体。
作为优选的方案，所述制备方法为式(I)化合物游离碱或其酸式盐与药学上可接受的填充剂混合得到所述药物组合物，在混合后加入其它药学上可接受载体。
作为进一步优选的方案，所述制备方法为式(I)化合物游离碱或其酸式盐与药学上可接受的填充剂混合得到所述药物组合物，在混合前、混合时或混合时均加入其它药学上可接受载体。
作为进一步优选的方案，所述制备方法中药物组合物的活性成分在混合之前单独经粉碎预处理。
作为更进一步优选的方案，所述制备方法包括对前述制备得到的药物组合物进行 灌装得到胶囊剂。
作为更进一步优选的方案，所述制备方法包括对前述制备得到的药物组合物进行压片得到片剂。
作为优选的方案，所述其它药学上可接受载体为助流剂、润滑剂、粘合剂和崩解剂中的一种或多种。
作为进一步优选的方案，所述制备方法为将式(I)化合物对甲苯磺酸一水合物、磷酸氢钙、交联羧甲基纤维素钠、胶态二氧化硅和/或其它药学上可接受载体混合得到所述药物组合物。
作为更进一步优选的方案，所述制备方法为将式(I)化合物对甲苯磺酸一水合物、磷酸氢钙、交联羧甲基纤维素钠、胶态二氧化硅和/或其它药学上可接受载体混合得到所述药物组合物；
且将硬脂酸镁和/或硬脂富马酸钠与前述药物组合物进一步混合得到药物组合物。
作为进一步优选的方案，所述制备方法为将式(I)化合物对甲苯磺酸一水合物、甘露醇、微晶纤维素、第一部分交联羧甲基纤维素钠和/或其它药学上可接受载体混合得药物组合物。
作为更进一步优选的方案，所述制备方法为将式(I)化合物对甲苯磺酸一水合物、甘露醇、微晶纤维素、第一部分交联羧甲基纤维素钠和/或其它药学上可接受载体混合得药物组合物；加入羟丙纤维素的水溶液进行湿法制粒后干燥。
作为再更进一步优选的方案，所述制备方法为将式(I)化合物对甲苯磺酸一水合物、甘露醇、微晶纤维素、第一部分交联羧甲基纤维素钠和/或其它药学上可接受载体混合得药物组合物；加入羟丙纤维素的水溶液进行湿法制粒后干燥；外加入胶态二氧化硅和第二部分交联羧甲基纤维素钠进一步与前步得到的干燥后的颗粒混合。
作为再更进一步优选的方案，所述制备方法为将式(I)化合物对甲苯磺酸一水合物、甘露醇、微晶纤维素、第一部分交联羧甲基纤维素钠和/或其它药学上可接受载体混合得药物组合物；加入羟丙纤维素的水溶液进行湿法制粒后干燥；外加入胶态二氧化硅和第二部分交联羧甲基纤维素钠进一步与前步得到的干燥后的颗粒混合；加入硬脂酸镁进行总混合得到药物组合物。
作为更进一步优选的方案，所述药物组合物的组分在混合前和/或混合后各自或混 合过30～100目筛。
作为更进一步优选的方案，所述药物组合物的组分在混合前和/或混合后各自或混合过30～50目筛。
作为更进一步优选的方案，所述药物组合物的组分在混合前和/或混合后各自或混合过40目筛。
作为更进一步优选的方案，所述药物组合物组分的的混合的速度为10～100rpm；
作为更进一步优选的方案，所述药物组合物组分的的混合的速度为10～50rpm；
作为更进一步优选的方案，所述药物组合物组分的的混合的速度为20～30rpm。
本发明第三方面提供一种药物组合物在制备FGFR4抑制剂药物中的应用。
作为更进一步优选的方案，所述药物组合物的应用为在制备治疗与FGFR4有关的肝癌、前列腺癌、胰腺癌、食管癌、胃癌、肺癌、乳腺癌、卵巢癌、结肠癌、皮肤癌、神经胶质母细胞瘤或横纹肌肉瘤的药物中的应用。
本发明第四方面提供一种与FGFR4有关的肝癌、前列腺癌、胰腺癌、食管癌、胃癌、肺癌、乳腺癌、卵巢癌、结肠癌、皮肤癌、神经胶质母细胞瘤或横纹肌肉瘤的治疗方法，所述治疗方法包括给予需要治疗的患者有效治疗量的药物组合物。
本发明第五方面提供一种药物组合物，其用作在FGFR4抑制剂药物。
本发明的药物组合物，可采用粉末直接灌装工艺或湿法制粒工艺制备，药物溶出度、含量均匀度、有关物质含量和物理化学稳定性等均符合临床需求，满足临床研究和药物上市的需求，尤其湿法制粒工艺适合工业化，解决了药物可及性问题。
附图说明：
图1：示出未粉碎原料药形态。
图2：示出试验1原料药形态。
图3：示出试验2原料药形态。
图4：示出试验3原料药形态。
图5：直混工艺不同比例硬脂酸镁溶出曲线图，横坐标表示时间(分钟)，纵坐标表示溶出度(％)。
图6：处方及工艺筛选批次溶出曲线图，横坐标表示时间(分钟)，纵坐标表示溶出度(％)。
具体实施方式
具体定义
详细说明：除非有相反陈述或特别说明，下列用在说明书和权利要求书中的术语具有下述含义。
如本文所用，术语“酸式盐”是指药学上可接受盐，就本领域普通技术人员所知，一般为无机酸盐或有机酸盐。所述无机酸盐可以为盐酸盐、硫酸盐、氢溴酸盐、氢氟酸盐、氢碘酸盐或磷酸盐；所述有机酸盐可以为醋酸盐、二氯醋酸盐、三氯醋酸盐、三氟乙酸盐、苯磺酸盐、对甲苯磺酸盐、4-氯苯磺酸盐、1,5-萘二磺酸盐、萘-2-磺酸盐、乙烷-1,2-二磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐、苯甲酸盐、癸酸盐、己酸盐、辛酸盐、肉桂酸盐、柠檬酸盐、环己烷氨基磺酸盐、樟脑磺酸盐、天门冬氨酸盐、樟脑酸盐、葡萄糖酸盐、葡糖醛酸盐、谷氨酸盐、异抗坏血酸盐、乳酸盐、苹果酸盐、扁桃酸盐、焦谷氨酸盐、酒石酸盐、十二烷基硫酸盐、二苯甲酰酒石酸盐、蚁酸盐、富马酸盐、半乳糖酸盐、龙胆酸盐、乙酰氧肟酸盐、丙二酸盐、丁二酸盐、戊二酸盐、己二酸盐、癸二酸盐、2-酮戊二酸盐、乙醇酸盐、马尿酸盐、羟乙基磺酸盐、乳糖酸盐、抗坏血酸盐、天冬氨酸盐、月桂酸盐、马来酸盐、烟酸盐、油酸盐、乳清酸盐、草酸盐、琥铂酸、棕榈酸盐、双羟萘酸盐、丙酸盐、4-乙酰氨基苯甲酸盐、4-氨基苯甲酸盐、水杨酸盐、4-氨基水杨酸盐、2,5-二羟基苯甲酸盐、1-羟基-2-萘甲酸盐、硬脂酸盐、硫氰酸盐、十一碳烯酸盐或琥珀酸盐。
如本文所用，术语“溶剂合物”是指由溶剂和溶解物组成的化合物。溶剂可以是有机溶剂或其他液体，而溶解物可以是离子、分子或其他物质。溶剂化合物可以是固体、液体或气体。就本发明而言，溶剂合物是指活性物质在溶剂中溶解，溶剂分子与活性物质分子或离子等的相互结合，使活性成分改变了原来的状态而生成的络合物；所述有机溶剂包括但不限于：醇类、氯代烷烃、酮类、醚类、环醚类、酯类、烷烃类、环烷烃类、苯类、酰胺类或亚砜类有机溶剂，或其混合物，或其水溶液。具体的，所述有机溶剂可以是甲醇、乙醇、正丙醇、异丙醇、二氯甲烷、乙腈、丙酮、1,4-二氧六环、四氢呋喃、N,N-二甲基甲酰胺、乙酸乙酯、乙酸异丙酯、甲基叔丁基醚或2-甲氧基乙醚，或其混合物，或其水溶液。
如本文所用，术语“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的晶型、盐型或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
术语“式(I)化合物游离碱”是指如下式(I)化合物，
术语“活性成分”是指式(I)化合物游离碱或其酸式盐；所述活性成分优选为式(I)化合物游离碱或其酸式盐的无水物、水合物或溶剂合物；所述溶剂选自醇类、氯代烷烃、酮类、醚类、环醚类、酯类、烷烃类、环烷烃类、苯类、酰胺类或亚砜类有机溶剂，或其混合物，或其水溶液。优选的，所述有机溶剂选自甲醇、乙醇、正丙醇、异丙醇、二氯甲烷、乙腈、丙酮、1,4-二氧六环、四氢呋喃、N,N-二甲基甲酰胺、乙酸乙酯、乙酸异丙酯、甲基叔丁基醚或2-甲氧基乙醚，或其混合物，或其水溶液。
术语“原料药”或“API”为式(I)化合物对甲苯磺酸盐一水合物。
本发明药物组合物可包括一种或多种药学上可接受的载体，这些载体包括但不限于：填充剂、助流剂、黏合剂、发泡剂、润滑剂、崩解剂、稀释剂、稳定剂、缓冲剂、佐剂、载剂、乳化剂、粘度调节剂、表面活性剂、防腐剂、调味剂或着色剂。医学上可接受的赋形剂可参见R.C.罗P.J.舍斯基《药用辅料手册》的实例描述。
如本文所用，术语“填充剂”是指添加至配制品中以增加容积的任何医药学上可接受的物质或组合物。适合填充剂包括(但不限于)甘露糖醇、乳糖、微晶纤维素、甘露醇、硅化微晶纤维素和磷酸氢钙。
如本文所用，术语“助流剂”是指添加至配制品中以改善各因素之间的交互作用，会使得粉末的流动性变好的化合物或组合物。适合助流剂包括(但不限于)胶态二氧化硅、滑石粉。
如本文所用，术语“黏合剂”或“粘合剂”是指添加至配制品中以使活性医药成分及无活性成分以内聚混合物形式保持在一起的医药学上可接受的化合物或组合物。用于直接压实的干式黏合剂须展现内聚及黏着力，使得当压实时，粒子聚结。用于湿式造粒的黏合剂为亲水的且可溶于水中，且通常溶解于水中以形成湿物质，该湿物质接着造粒。适合黏合剂的实例包括(但不限于)普维酮、Plasdone K29/32、Plasdone S-630、羟丙基纤维素、甲基纤维素、聚乙烯吡咯啶酮、硬脂酸铝、羟丙基甲基纤维素及其类似物。这些黏合剂有可能另外充当水螯合剂(例如普维酮)。
如本文所用，术语“润滑剂”是指降低表面摩擦、润滑颗粒表面、降低静电累积的趋势和/或降低颗粒易脆性的任何医药学上可接受的试剂。因此，润滑剂可充当抗聚结剂。常规润滑剂包括硬脂酸及相关化合物，诸如硬脂酸镁、硬酯富马酸钠及硬脂酰反丁烯二酸钠。可替代润滑剂包括甘油二山嵛酸酯、胶态二氧化硅、滑石、其他氢化植 物油或三酸甘油酯。适合可替代润滑剂的实例包括(但不限于)甘油二山嵛酸酯。
如本文所用，术语“崩解剂”是指添加至组合物中以帮助其分裂(崩解)且释放药剂的物质。崩解剂的实例包括(但不限于)非糖水溶性聚合物，诸如：交联羧甲纤维素钠、羧甲淀粉钠、交联聚维酮、羟基乙酸淀粉钠及其类似物。
如本文所用，术语“D10、D50、D90”是表示活性成分粒径大小的参数，具体含义如下：
D10是指活性成分颗粒累积分布为10％的粒径，即小于此粒径的颗粒体积含量占全部颗粒的10％。
D50是指活性成分颗粒累积分布为50％的粒径。也叫中位径或中值粒径，这是一个表示粒度大小的典型值，该值准确地将总体划分为二等份，也就是说有50％的颗粒超过此值，有50％的颗粒低于此值。如果一个样品的D50＝5μm，说明在组成该样品的所有粒径的颗粒中，大于5μm的颗粒占50％，小于5μm的颗粒也占50％。
D90是指活性成分颗粒累积分布为90％的粒径。即小于此粒径的颗粒体积含量占全部颗粒的90％。其他以此类推。
2.分析方法
本发明制剂研究中胶囊溶出测定方法如下表：
3.物料信息

原料药的制备过程如下：称取5mg游离态式(I)化合物，溶于0.5mL乙酸乙酯中；称取1.67mg对甲苯磺酸，溶于0.1mL四氢呋喃中；搅拌下将对甲苯磺酸溶液缓慢加入式(I)化合物溶液中，搅拌过夜，过滤，滤饼于40℃真空干燥箱进行干燥。XRPD衍射角(2θ)和相关强度数据(±0.2°)如下：
表A
晶胞为P1，晶胞体积为
4.设备信息
5.含量均匀度测定方法
在灌装过程中随机取出本申请实施例4～6制备的胶囊剂样本10～11粒，分别测定每粒以标示量为100％的相对含量，计算其平均值和标准差(SD％)以及标示量与均值之差的绝对值(A)，由CP＝A+2.2S计算本申请处方的含量均匀度CP(CP≤15.0满足中国药典要求)。
色谱条件：用十八烷基硅烷键合硅胶为填充剂(WatersC18，4.6×150mm，3.5μm色谱柱或效能相当的色谱柱)；以0.1vol％的三氟乙酸溶液为流动相A，以0.1vol％的三氟乙酸乙腈溶液为流动相B，以流动相A-流动相B(70:30)进行等度洗脱，检测波长为232nm，流速为每分钟1.0mL，柱温为40℃，进样量为10μL，运行时间10分钟。
6.有关物质测定方法
色谱条件：以十八烷基硅烷键合硅胶为填充剂(Waters SunFire C18，4.6×150mm，3.5μm色谱柱或效能相当的色谱柱)，以10mmol/L甲酸铵溶液为流动相A，以乙腈为流动相B，检测波长为232nm，流速为每分钟1.0mL，柱温40℃，进样量为10μL。按下表进行梯度洗脱，运行时间50.0分钟，后运行时间5分钟。
7.吸湿增重测定
称重法：称量初始样品的重量W1，再称量高湿条件下放置一定时间后样品的重量W2，根据重量差值计算吸湿增重的百分比，计算公式为：(W2-W1)/W1*100％。
以下实施例对本发明做进一步详细、完整地说明，其仅用于阐明本发明的特定实施方案，而不应被解读为以任何方式限制本发明的范围。
实施例1
(原辅料物性研究)
发明人首先对原料药的理化性质进行了研究。具体操作如下：将原料药和不同辅料以不同比例混合，放置不同条件，分别于不同时间点取出后观察其外观性状、吸湿 增重、原料药含量和有关物质含量等，具体实验设计见下表。
所用辅料均为口服固体制剂的药学上可接受的辅料，且均已收载入中国药典现行版，各辅料性质稳定。以下实施例除非特别注明，所用原料药(或称API)与实施例1相同。
表1原辅料信息和相应重量比例
表2实验条件和检测项目
备注：[1]：检测项目：X＝外观性状、含量；
[2]：检测项目：Y＝吸湿增重。
试验结果：
表3原料药与辅料混合物的外观性状结果

表4原料药与以下辅料混合后的样品的吸湿增重重量变化百分比
表5原料药与以下辅料混合后的样品含量检测结果

备注：上述表中“d”是day(天)的缩写简称，下表中意思相同。有关物质结果参见实施例2中原料药与各辅料相容性汇总结果。
在上述不同放置条件下，将原料药和不同辅料以不同比例混合，有关物质含量变化情况如下：
(1)单独原料药不易吸湿，但暴露于25℃/92.5％RH高湿度条件下原料药杂质略有增长，暴露于高温60℃、光照和40℃/75％RH开口条件下原料药杂质稳定。提示本品密封贮存有利于增加原料药的稳定性。
(2)原料药与各辅料的二元混合物在25℃/92.5％RH和40℃/75％RH开口条件下与单独原料药的杂质水平相当，说明各辅料在该条件下均不影响原料药的化学稳定性，相容性良好，对外观和吸湿性产生影响极小。
(3)原料药与聚维酮K30或羟丙纤维素EXF或交联聚维酮XL-10的二元混合物在60℃条件下放置，曾有一单个杂质(RRT＝0.30)增加明显，考虑到这两个辅料在高温条件下对原料药化学稳定性的影响，因此，这两种辅料在处方中的应用不作为优选考虑的方案。
(4)在光照条件下暴露10天，观察到以下主要杂质生成情况：
a)原料药的单个杂质(RRT＝0.44)由<0.05％增加至0.07％；
b)原料药与无水磷酸氢钙二元混合物的单个杂质(RRT＝0.44)由<0.05％增加至0.17％；
c)原料药与交联羧甲基纤维素钠二元混合物的单个杂质(RRT＝0.27)由<0.05％增加至0.14％，另一单个杂质(RRT＝0.44)由<0.05％增加至0.13％；
d)原料药与羧甲淀粉钠二元混合物的单个杂质(RRT＝0.27)由<0.05％增加至0.10％，另一单个杂质(RRT＝0.44)由<0.05％增加至0.13％。
上述三个二元混合物在其它条件下与单独原料药的杂质水平相当，可以用于制剂开发，但提示产品需避光并关注后续产品的稳定性数据。
实施例2
(药用辅料的筛选)
本实施例以物料流动性和胶囊溶出度等项目为主要评价指标，选用胶囊剂，且与原料药相容性良好的药学上可接受的药用辅料，在常规用量范围内进行处方筛选，优化辅料种类。
一、填充剂的筛选
选择微晶纤维素102和无水磷酸氢钙复配或单一无水磷酸氢钙作为填充剂，主要考察不同填充剂对流动性和溶出的影响。
将原料药和填充剂以1:5重量比例的二元混合物的相容性结果，作为填充剂种类筛选依据。
具体处方组成、溶出检测结果、总混粉粉体特性、原料药与填充剂的相容性结果分别见下列各表。
表6不同填充剂原料药胶囊处方组成
表7不同填充剂胶囊溶出检测结果
表8不同填充剂总混粉粉体学特性数据
表9原料药与填充剂相容性结果
试验结果：
1)由上述实验结果可知，在60℃(开口)和40℃/75％RH(开口)条件下，四种填充剂均与原料药无明显的相容性问题。在光照(开口)条件下原料药与无水磷酸氢钙二元混合物的杂质略微增加，但此问题基本可以通过产品避光保存规避。因此，无水磷酸氢钙可用于处方的筛选。
2)填充剂的筛选结果显示在粉末流动性方面：两个处方粉末流动性测定结果无明显差异，均可满足粉末直灌的要求。在溶出度方面：单一无水磷酸氢钙仅需30分钟能达到95％的溶出，而微晶纤维素102和无水磷酸氢钙复配处方在60分钟仅能达到93％的溶出度，可见采用单一无水磷酸氢钙的处方在溶出度方面有显著优势。
3)综合考虑填充剂应用于本发明产品的优势与风险，首选用单一无水磷酸氢钙作为填充剂，以保证溶出速度；其次也可选用甘露醇和/或微晶纤维素作为可接受的填充剂。
二、助流剂的筛选
以下采用胶态二氧化硅作为助流剂进行测试。
表10原料药与助流剂相容性结果
试验结论：
由上述实验结果可知，胶态二氧化硅与原料药相容性良好，选择胶态二氧化硅作为优选的助流剂。
三、润滑剂的筛选
制剂产品中加入适量的润滑剂可降低物料与设备之间的摩擦力，并可以提高物料的流动性。以下采用硬脂酸镁和硬脂富马酸钠作为润滑剂。
将原料药和润滑剂以10:1重量比例的二元混合物的相容性结果，作为润滑剂种类筛选依据。原料药与润滑剂的相容性结果见下表。
表11原料药与润滑剂相容性结果
试验结论：
由上述实验结果可知，两种润滑剂均与原料药在放样条件下放置30天，有关物质没有明显的变化，因此，可以判断两种润滑剂与原料药无明显的相容性问题，但在制备过程发现处方中加入0.5wt％硬脂酸镁时不存在物料粘填充杆及溶出缓慢的问题。因此，硬脂酸镁作为优选的润滑剂。
四、崩解剂的筛选
采用粉末直混灌胶囊工艺，理论上不需要加入崩解剂来促进药物的溶出，但实际中考虑到产品长期储存过程中可能存在胶囊内容物吸湿结块导致溶出变慢的风险，因此处方加入适量崩解剂以规避这种风险。以下采用交联羧甲基纤维素钠、交联聚维酮及羧甲淀粉钠作为崩解剂。
将原料药和崩解剂以1:1重量比例的二元混合物的相容性结果，作为崩解剂种类筛选依据。原料药与崩解剂的相容性结果见下表。
表12原料药与崩解剂相容性结果
试验结论：
由上述实验结果可知，所选崩解剂均与原料药无明显的相容性问题，最终选择交联羧甲基纤维素钠作为优选处方的崩解剂。
实施例3
(原料药粒径的考察)
1.处方开发过程
本发明制剂规格确定为5mg、20mg和100mg，剂型为胶囊剂。选择了与原料药相容性良好的辅料，首先以100mg规格进行了工艺的初步筛选，确定了最终工艺为粉末直灌。
在此基础上以物料流动性，产品溶出行为为指标，考察了填充剂种类和用量，初步确定了100mg规格处方。5mg规格和20mg规格采用等比例处方，参考100mg规格处方，在其它辅料比例不变的情况下，仅调整填充剂无水磷酸氢钙用量至适合装量，以物料流动性，产品溶出行为为指标初步确定了处方。
2.制剂工艺的选择
为了满足临床实验用药和药物产品雏形设计的要求，首先考虑采用易于生产、放大和重复性好的粉末直接灌装工艺。但因为该制剂工艺对原辅料混合物的粉末流动性要求较高。因此，发明人以100mg规格为基础测定了不同规格原料药处方总混粉的溶出特性和粉体学特性。
3.原料药粒径的测定
将原料药进行机械粉碎，分别于不同粉碎时间取样，使用Malvern Mastersizer 2000激光粒度分析仪测定粒径分布，并使用偏光显微镜观察粒子形态。粒径测定参数如表13所述，粒径结果见表14。
表13 PSD检测参数
备注：“PSD”是Particle Size Distribution(粒径分布)的缩写简称。
表14原料药粒径分布
备注：“PLM”是Polarizing Microscope(偏光显微镜)的缩写简称。
4.粒径对溶出影响
分别使用上述三种粉碎后不同粒径的原料药制备100mg规格胶囊，测定溶出和粉体学特性。处方组成见表15，溶出结果见表16，粉体学测定结果见表17。
表15 100mg胶囊处方组成

表16 100mg胶囊溶出结果
备注：“RSD”是Relative Standard Deviation(相对标准偏差)的缩写简称。
表17粉体学特性测定结果
5.试验结论：
当原料药未处理时，制剂组合物溶出不完全。当原料药经过机械粉碎后，粒径显著减小，溶出均快速且完全，3个不同粒径分布的原料制备的胶囊溶出均合格，且3个处方的流动性均可满足粉末直灌的要求。
实施例4
(5mg、20mg、100mg胶囊)
1.处方组成(表18)

备注：胶囊制剂规格以式(I)化合物游离碱为计算标准，原料药为式(I)化合物对甲苯磺酸盐一水合物。
2.生产工艺
1)称量
根据上述各规格制剂的处方组成称取原料药、无水磷酸氢钙、胶态二氧化硅200、交联羧甲基纤维素钠和硬脂酸镁，分别置于合适的自封袋中。
2)过筛
将原料药、无水磷酸氢钙、胶态二氧化硅200、交联羧甲基纤维素钠和硬脂酸镁过40目筛备用。作为优选的技术方案，试验所用原料药先经粉碎预处理后再过筛。
3)混合
将过筛后的原料药、无水磷酸氢钙、胶态二氧化硅200和交联羧甲基纤维素钠置于料斗混合机中，混合转速20rpm，混合时间15min。
4)润滑
将过筛后的硬脂酸镁置于料斗混合机中，开始混合，混合转速20rpm，混合5min。混合完成后将共混粉取出，共混粉粉体性质详见下表。
表19 5mg、20mg、100mg规格总混粉粉体学特性数据
5)灌装
将总混粉置于胶囊机中，按各规格灌装于明胶胶囊中。各步骤工艺参数详见下表20。
表20各步骤工艺参数

在灌装过程中，使用真空插管灌装装量相对稳定且锁合长度及外观完好，但由于处方物料粘附性较强，当发现真空插管内壁被过多物料粘附后需对插管进行清洁，才能保证灌装正常进行，灌装难度较大。
3.制剂分析
因5mg和20mg为等比例处方，以5mg规格胶囊为代表考察相关性质。
表21 5mg及100mg规格胶囊溶出度结果
表22 5mg含量规格胶囊原料药及有关物质含量结果(％)

备注：*检测30天样品时换了色谱柱，RRT 0.71和0.74两个未知杂质(API中工艺杂质)未能达到基线分离，积成一个峰。“RRT”为Relative Retention Time(相对保留时间)的缩写简称。
表23 100mg含量规格胶囊原料药及有关物质含量结果(％)
备注：*检测30天样品时换了色谱柱，RRT0.71和0.74两个未知杂质(API中工艺杂质)未能达到基线分离，积成一个峰。
表24 5mg和20mg胶囊含量均匀度结果

4.试验结论
(1)5mg规格与100mg规格处方在60℃、开口，40℃/75％RH、闭口，40℃/75％RH、开口，及光照、开口条件下放置10天与30天，杂质及含量无明显变化，说明该制剂产品在加速条件下化学性质稳定。
(2)5mg规格与100mg规格处方在60℃、开口，40℃/75％RH、开口，及光照、开口条件下放置10天与30天，溶出无明显变化(因40℃/75％RH、开口条件样品溶出稳定，故未检测40℃/75％RH、闭口条件样品溶出)，说明该制剂产品在加速实验条件下溶出性质稳定。
(3)5mg规格处方在60℃、开口，40℃/75％RH、开口条件下放置30天，手性纯度无变化，说明该制剂产品在加速条件下手性纯度稳定。
(4)通过加速稳定性实验，可以预期该制剂产品具有良好的稳定性，具有较长的保存期及较宽的保存条件。
(5)胶囊粒重、粒重差异与含量均匀度均符合要求，工艺选择合理，可工业化。
试验结论：5mg、20mg、100mg规格胶囊罐装顺利，且溶出特性、胶囊含量均匀度、含量及有关物质均符合要求，但由于处方物料粘附性较强，灌装难度较大的问题，仍有待进一步研究以获得工业化生产方法。
实施例5
(处方及工艺优化)
本实施例进一步对处方及工艺进行筛选优化，以获得含量均匀度、溶出度均良好的药物组合物，且不存在处方物料粘附插管或压轮的情况，可满足工业化生产要求。
1.处方组成(表25)

2.生产工艺(表26)
具体总混粉粉体特性、胶囊含量均匀度结果见下表。
表27总混粉粉体学特性数据

表28胶囊含量均匀度结果
3.试验结论
(1)药物组合物5-1采取直接混合的方式进行制备，工艺过程中显示，运行20分钟不存在粘压针的现象，但物料流动性差因而装量波动相对较大且会超出装量限度，然后在剩余物料中额外加入1.0％的硬脂酸镁，即总占比约为1.5％下进行第二次灌装，运行20分钟不存在粘压针的现象，但会超出装量限度，分别挑选两次接近目标值的胶囊送样测试溶出，结果如图5所示，1.5％的硬脂酸镁溶出并未完全释放，因而在直混方式下约为1.5％占比的硬脂酸镁的处方可能会影响溶出。
(2)药物组合物5-2采取干法制粒的方式进行制备，工艺过程中显示，干法制粒阶段少量物料黏附在压轮上且附着力较强，需要定期清理，胶囊灌装后送样测试溶出，结果如图6所示，溶出结果与实施例4中100mg规格处方(4-100)相似。
(3)药物组合物5-3将填充剂无水磷酸氢钙更换为硅化微晶纤维素，硬脂酸镁比例由内加外加各0.5％提高至内加外加各0.75％，制备过程显示，干法制粒阶段物料仍然会有少量物料黏附在压轮上且附着力较强。
(4)药物组合物5-4采取湿法制粒方式进行制备，工艺过程中显示，湿法制粒过程相对顺利，物料流动性相对较好，胶囊灌装胶囊灌装后送样测试溶出，结果如图6所示，溶出结果与实施例4中100mg规格处方(4-100)相似。
综上所述，相对于直接混合或干法制粒，湿法制粒获得的处方物料卡尔系数有了明显的降低，物料的流动性有较大的改善，同时具有较好的含量均匀度。
实施例6
(50mg、60mg、100mg胶囊)
1.处方组成(表29)
2.生产工艺
参照实施例5中试验编号5-4的生产工艺进行制备。具体胶囊含量、水分、杂质、含量均匀度、溶出结果见下表。
表30胶囊含量、水分、杂质数据汇总表
表31胶囊含量均匀度结果

表32溶出结果

3.试验结论
由上述试验验结果可知，本实施例提供的不同规格处方，水分结果为报告值；杂质结果显示各个批次与API相比并无新增异常杂质，且各个批次都满足单个杂质≤0.2％且总杂≤2.0％的要求。含量均匀度结果皆满足A+2.2S≤15.0，AV≤15.0，符合中美药典接受标准，且均具有良好的溶出度。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述公开内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (30)

  1. 一种药物组合物，其特征在于，所述药物组合物包含式(I)化合物游离碱或其酸式盐作为活性成分、药学上可接受的填充剂、以及其它药学上可接受载体，
    其中，所述药学上可接受的填充剂为磷酸氢钙、甘露醇、乳糖、微晶纤维素或硅化微晶纤维素中的一种或多种。
  2. 根据权利要求1所述的药物组合物，其特征在于，所述活性成分的含量以式(I)化合物对甲苯磺酸盐一水合物计，为药物组合物总重量的0.1～60wt％；
    优选地，所述活性成分的含量以式(I)化合物对甲苯磺酸盐一水合物计，为药物组合物总重量的1.0～50wt％；
    更优选地，所述活性成分的含量以式(I)化合物对甲苯磺酸盐一水合物计，为药物组合物总重量的5.0～40wt％。
  3. 根据权利要求1所述的药物组合物，其特征在于，所述其它药学上可接受载体为助流剂、润滑剂、粘合剂和崩解剂中的一种或多种。
  4. 根据权利要求3所述的药物组合物，其特征在于，所述助流剂为胶态二氧化硅，所述助流剂的含量为药物组合物总重量的0.1～5.0wt％；
    优选地，所述助流剂的含量为药物组合物总重量的0.5～4.0wt％；
    更优选地，所述助流剂的含量为药物组合物总重量的0.8～2.0wt％。
  5. 根据权利要求3所述的药物组合物，其特征在于，所述润滑剂为硬脂酸镁和/或硬脂富马酸钠，所述润滑剂的含量为药物组合物总重量的0.1～5.0wt％；
    优选地，所述润滑剂的含量为药物组合物总重量的0.2～3.0wt％；
    更优选地，所述润滑剂的含量为药物组合物总重量的0.3～1.5wt％；
    更优选地，所述润滑剂的含量为药物组合物总重量的0.3～1.0wt％。
  6. 根据权利要求3所述的药物组合物，其特征在于，所述粘合剂为羟丙纤维素、甲基纤维素、羟丙基甲基纤维素、聚乙烯吡咯啶酮、聚维酮和/或羧甲淀粉钠，所述粘合剂的含量为药物组合物总重量的0.0～20.0wt％；
    优选地，所述粘合剂的含量为药物组合物总重量的0.0～10.0wt％；
    更优选地，所述粘合剂的含量为药物组合物总重量的0.0～4.0wt％。
  7. 根据权利要求3所述的药物组合物，其特征在于，所述崩解剂为交联羧甲基纤维素钠和/或羧甲淀粉钠，所述崩解剂的含量为药物组合物总重量的0.5～20.0wt％；
    优选地，所述崩解剂的含量为药物组合物总重量的1.0～10.0wt％；
    更优选地，所述崩解剂的含量为药物组合物总重量的2.0～6.0wt％。
  8. 根据权利要求1所述的药物组合物，其特征在于，所述药学上可接受的填充剂为无水磷酸氢钙。
  9. 根据权利要求1所述的药物组合物，其特征在于，所述药学上可接受的填充剂为甘露醇或微晶纤维素中的一种或多种；
    优选地，所述药学上可接受的填充剂为甘露醇和微晶纤维素的混合物。
  10. 根据权利要求3所述的药物组合物，其特征在于，所述药学上可接受的填充剂的含量为药物组合物总重量的1.0～98.0wt％；
    优选地，所述药学上可接受的填充剂的含量为药物组合物总重量的20.0～95.0wt％；
    更优选地，所述药学上可接受的填充剂的含量为药物组合物总重量的40.0～90.0wt％。
  11. 根据权利要求1-10任一项所述的药物组合物，其特征在于，所述药物组合物的单位剂型包含活性成分、助流剂、润滑剂、粘合剂和崩解剂，
    其中，所述活性成分的含量为药物组合物总重量的5.0～40.0wt％，和/或
    所述助流剂的含量为药物组合物总重量的0.8～2.0wt％，和/或
    所述润滑剂的含量为药物组合物总重量的0.3～1.0wt％，和/或
    所述粘合剂的含量为药物组合物总重量的0.0～4.0wt％，和/或
    所述崩解剂的含量为药物组合物总重量的2.0～6.0wt％。
  12. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物的单位剂型包含活性成分、胶态二氧化硅、硬脂酸镁、羟丙纤维素和交联羧甲基纤维素钠，
    其中，所述活性成分的含量为药物组合物总重量的5.0～40.0wt％，和/或
    所述胶态二氧化硅的含量为药物组合物总重量的0.8～2.0wt％，和/或
    所述硬脂酸镁的含量为药物组合物总重量的0.3～1.0wt％，和/或
    所述羟丙纤维素的含量为药物组合物总重量的0.0～4.0wt％，和/或
    所述交联羧甲基纤维素钠的含量为药物组合物总重量的2.0～6.0wt％。
  13. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物中各组分的含量之和不足100％时，调节填充剂的含量使得所述药物组合物中各组分的含量之和为100wt％。
  14. 根据权利要求1所述的药物组合物，其特征在于，所述活性成分为式(I)化合物游离碱或其酸式盐的无水物、水合物或溶剂合物；
    优选地，所述活性成分为式(I)化合物游离碱或其酸式盐的溶剂合物，所述溶剂选自醇类、氯代烷烃、酮类、醚类、环醚类、酯类、烷烃类、环烷烃类、苯类、酰胺类或亚砜类有机溶剂，或其混合物，或其水溶液；
    更优选地，所述活性成分为式(I)化合物游离碱或其酸式盐的溶剂合物，所述溶剂选自甲醇、乙醇、正丙醇、异丙醇、二氯甲烷、乙腈、丙酮、1,4-二氧六环、四氢呋喃、N,N-二甲基甲酰胺、乙酸乙酯、乙酸异丙酯、甲基叔丁基醚或2-甲氧基乙醚，或其混合物，或其水溶液；
    优选地，所述活性成分为式(I)化合物游离碱或其酸式盐的无水物或水合物；
    更优选地，所述活性成分为式(I)化合物游离碱或其酸式盐的无水物；
    更优选地，所述活性成分为式(I)化合物游离碱或其酸式盐的水合物，所述水合物每个分子中包含1～3个水分子；
    更优选地，所述活性成分为式(I)化合物对甲苯磺酸盐的水合物，所述水合物每个分子中包含1～3个水分子；
    更优选地，所述活性成分为式(I)化合物对甲苯磺酸盐的水合物，所述水合物每个分子中包含1个水分子。
  15. 根据权利要求14所述的药物组合物，其特征在于，所述活性成分为式(I)化合物对甲苯磺酸盐一水合物。
  16. 根据权利要求15所述的药物组合物，其特征在于，所述式(I)化合物对甲苯磺酸盐一水合物的X-射线粉末衍射图包括5个或以上位于选自9.02±0.2°、10.60±0.2°、12.04±0.2°、12.72±0.2°、15.32±0.2°、17.18±0.2°、17.68±0.2°、18.56±0.2°、19.60±0.2°、20.60±0.2°、21.22±0.2°、22.90±0.2°、23.82±0.2°、24.12±0.2°、24.60±0.2°、24.90±0.2°、 25.58±0.2°、27.78±0.2°、29.04±0.2°、31.48±0.2°、36.60±0.2°和38.16±0.2°的衍射角(2θ)处的峰。
  17. 根据权利要求15所述的药物组合物，其特征在于，所述活性成分为式(I)化合物对甲苯磺酸盐一水合物，粒径(D90)为5～330μm；优选地，粒径(D90)为10～200μm；更优选地，粒径(D90)为20～150μm。
  18. 根据权利要求15所述的药物组合物，其特征在于，所述活性成分为式(I)化合物对甲苯磺酸盐一水合物，粒径(D50)为2～200μm；优选地，粒径(D50)为4～100μm；更优选地，粒径(D50)为6～50μm；更优选地，粒径(D50)为6～25μm。
  19. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物通过粉末直灌、干法制粒或湿法制粒工艺获得；优选地，所述药物组合物通过湿法制粒工艺获得。
  20. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物为胶囊剂或片剂。
  21. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物的单位剂型包含1mg～500mg活性成分，以式(I)化合物游离碱计；
    优选地，药物组合物的单位剂型包含1mg～200mg活性成分，以式(I)化合物游离碱计；
    更优选地，药物组合物的单位剂型包含1mg、5mg、20mg、50mg、60mg、80mg、100mg或200mg活性成分，以式(I)化合物游离碱计。
  22. 一种权利要求1所述的药物组合物的制备方法，其特征在于，所述制备方法包括以下步骤：
    活性成分式(I)化合物游离碱或其酸式盐与药学上可接受的填充剂混合得到所述药物组合物，
    且任选地，在混合前、混合时或混合后加入其它药学上可接受载体；
    任选地，对上述制备得到的药物组合物进行粉末灌装、干法制粒或湿法制粒得到胶囊剂或压片得到片剂。
  23. 根据权利要求22所述的制备方法，其特征在于，所述其它药学上可接受载体为助流剂、润滑剂、粘合剂和崩解剂中的一种或多种。
  24. 根据权利要求22所述的制备方法，其特征在于，所述制备方法包括以下步骤：
    将式(I)化合物对甲苯磺酸一水合物、磷酸氢钙、交联羧甲基纤维素钠、胶态二氧化硅和/或其它药学上可接受载体混合得药物组合物；
    任选地，将硬脂酸镁和/或硬脂富马酸钠与前述药物组合物进一步混合得到药物组合物。
  25. 根据权利要求22所述的制备方法，其特征在于，所述制备方法包括以下步骤：将式(I)化合物对甲苯磺酸一水合物、甘露醇、微晶纤维素、第一部分交联羧甲基纤维素钠和/或其它药学上可接受载体混合得药物组合物；
    任选地，加入羟丙纤维素的水溶液进行湿法制粒后干燥；
    任选地，外加入胶态二氧化硅和第二部分交联羧甲基纤维素钠进一步与前步得到的干燥后的颗粒混合；
    任选地，加入硬脂酸镁进行总混合得到所述药物组合物。
  26. 根据权利要求22所述的制备方法，其特征在于，所述药物组合物的组分在混合前和/或混合后各自或混合过30～100目筛；优选地，过30～50目筛；更优选地，过40目筛；特别地，所述药物组合物的活性成分在混合之前单独经粉碎预处理。
  27. 根据权利要求22所述的制备方法，其特征在于，所述药物组合物组分的混合的速度为10～100rpm；优选地，混合的速度为10～50rpm；更优选地，混合的速度为20～30rpm。
  28. 权利要求1所述的药物组合物在制备FGFR4抑制剂药物中的应用。
  29. 权利要求1所述的药物组合物在制备治疗与FGFR4有关的肝癌、前列腺癌、胰腺癌、食管癌、胃癌、肺癌、乳腺癌、卵巢癌、结肠癌、皮肤癌、神经胶质母细胞瘤或横纹肌肉瘤的药物中的应用。
  30. 一种与FGFR4有关的肝癌、前列腺癌、胰腺癌、食管癌、胃癌、肺癌、乳腺 癌、卵巢癌、结肠癌、皮肤癌、神经胶质母细胞瘤或横纹肌肉瘤的治疗方法，所述治疗方法包括给予需要治疗的患者有效治疗量的权利要求1所述的药物组合物。
PCT/CN2024/098046 2023-06-09 2024-06-07 一种fgfr4抑制剂组合物、其制备方法和在药学上的应用 Ceased WO2024251252A1 (zh)

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