WO2022143933A1 - 一种多靶点蛋白激酶抑制剂的药物组合物及其应用 - Google Patents

一种多靶点蛋白激酶抑制剂的药物组合物及其应用 Download PDF

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WO2022143933A1
WO2022143933A1 PCT/CN2021/143219 CN2021143219W WO2022143933A1 WO 2022143933 A1 WO2022143933 A1 WO 2022143933A1 CN 2021143219 W CN2021143219 W CN 2021143219W WO 2022143933 A1 WO2022143933 A1 WO 2022143933A1
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pharmaceutical composition
excipients
lubricant
filler
weight percentage
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PCT/CN2021/143219
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English (en)
French (fr)
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刘翠艳
白晶
文师龙
刘娜
谷聪
纪德华
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石药集团中奇制药技术（石家庄）有限公司
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Priority to CA3203169A priority Critical patent/CA3203169A1/en
Priority to JP2023540098A priority patent/JP2024501690A/ja
Priority to AU2021413690A priority patent/AU2021413690A1/en
Priority to EP21914663.6A priority patent/EP4272741A1/en
Priority to CN202180088568.1A priority patent/CN116744931A/zh
Priority to KR1020237026102A priority patent/KR20230128086A/ko
Priority to US18/269,123 priority patent/US20240115575A1/en
Publication of WO2022143933A1 publication Critical patent/WO2022143933A1/zh

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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
    • 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
    • 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
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K9/1664—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/2004—Excipients; Inactive ingredients
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom

Definitions

  • the present invention requires a pharmaceutical composition of a multi-target protein kinase inhibitor and its application, submitted in China on December 31, 2020, with application numbers of 202011642452.1 and July 22, 2021 in China , the priority of the invention patent application titled "a pharmaceutical composition of a multi-target protein kinase inhibitor and its application” with application number 202110829596.6, the entire contents of the two patent applications are incorporated herein by reference.
  • the application belongs to the technical field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition of a multi-target protein kinase inhibitor and its application.
  • chemotherapeutic drugs mainly act on DNA, RNA and tubulin and other common components related to the life and death of all cells, resulting in low selectivity and high toxicity.
  • Targeted therapy drugs which act on key molecules and signal transduction pathways that regulate cell growth and proliferation in tumor cells that are significantly different from normal cells, have the advantages of high selectivity to tumor cells and low toxicity to normal tissues. , has become a hot spot in antitumor drug research.
  • protein kinase family is the most important signal transduction molecule. Studies have shown that the occurrence and development of many tumors are related to the gene abnormality or excessive activation of protein kinases. Therefore, protein kinases have been become the most important target for anti-tumor therapy.
  • EGFR Epidermal growth factor receptor
  • VEGFR Vascular Endothelial Growth Factor Receptor, vascular endothelial cell growth factor receptor
  • PDGFR Platelet-derived Growth Factor Receptor, platelet-derived Growth factor receptors
  • c-Kit c-SRC, MET
  • BTK BTK
  • ALK Abl
  • FLT3 FLT3 and other tyrosine
  • serine/threonine protein kinases are the most important, and they have been classified as oncogenes or cancers protein (oncoprotein).
  • small molecule inhibitors targeting these tyrosine and serine/threonine protein kinases which are used in clinical tumor treatment.
  • Typical examples include: two EGFR inhibitors, namely Gefitinib. And erlotinib (Erlotinib), mainly for the treatment of non-small cell lung cancer; two angiogenesis inhibitors (the main targets are VEGFR and PDGFR, etc.) Sunitinib (Sunitinib) and Sorafenib (Sorafenib), Anti-angiogenesis therapy for solid tumors; Imatinib, a Bcr-Abl kinase inhibitor, is mainly used for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML).
  • CML Philadelphia chromosome-positive chronic myeloid leukemia
  • antitumor drugs targeting a single or a few kinase oncogenes or oncoproteins face the disadvantages of low efficacy and easy drug resistance.
  • Typical examples are EGFR kinase inhibitors gefitinib and erlotinib. Ni. These two drugs are only effective in 10-20% of patients with non-small cell lung cancer.
  • gefitinib and erlotinib are selective EGFR kinase inhibitors, which are mainly for the development of EGFR Patients with exon 19 deletion mutation and exon 21 L858R point mutation are most sensitive (EGFR exon 19 deletion mutation and exon 21 L858R point mutation are collectively referred to as EGFR sensitive mutations). Even for these patients with sensitizing EGFR mutations, the vast majority developed resistance after 6-9 months of treatment with gefitinib and erlotinib.
  • AML acute myeloid leukemia
  • a small molecule kinase inhibitor can not only inhibit the activity of EGFR, but also inhibit new blood vessels or other key kinases that regulate cell growth and proliferation, such as c-Kit.
  • the activity of kinase oncogenes or oncoproteins such as c-SRC, MET, BTK, ALK, Abl, FLT3, etc., will improve the efficiency of tumor treatment and reduce the incidence of drug resistance; (2) Directly target the generation of drug resistance mutations of kinases.
  • EGFR itself is prone to secondary mutation on the basis of the original mutation (ie EGFR sensitive mutation), namely the T790M mutation of EGFR, which
  • the occurrence of EGFR kinase inhibitors is one of the main reasons for the failure of EGFR inhibitors gefitinib and erlotinib. Therefore, the development of EGFR kinase inhibitors that directly target drug resistance mutations, that is, T790M mutation, is a way to overcome the drug resistance of such tumors. direct route to sex.
  • Patent WO2011147066A1 discloses compound I and its preparation method and use, which is a novel multi-target protein kinase inhibitor, the main targets include FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, etc., available in the treatment of tumor diseases.
  • the present application further finds a hydrochloride salt of compound I (for example, formula II, formula A) with better drugability than compound I, and the hydrochloride salt not only has better properties such as solubility and stability than Compound I, and in terms of solubility, hygroscopicity, stability and other aspects, the hydrochloride as a whole is more suitable for preparing medicines than other salt forms of compound I.
  • a hydrochloride salt of compound I for example, formula II, formula A
  • the hydrochloride salt not only has better properties such as solubility and stability than Compound I, and in terms of solubility, hygroscopicity, stability and other aspects, the hydrochloride as a whole is more suitable for preparing medicines than other salt forms of compound I.
  • Corresponding research and screening procedures have been documented in the PCT/CN2021/073285 patent application, the entire contents of which are incorporated into this application in its entirety.
  • a technical problem to be solved by the present application is to provide a pharmaceutical composition containing the compound represented by formula II, especially the compound represented by formula A, as an active ingredient to meet the needs of oral administration.
  • the application provides a kind of pharmaceutical composition, it comprises: as the compound shown in formula II as active ingredient and excipient,
  • n is 0-10, preferably 0-5, more preferably 3-5, still more preferably 3, 3.5, 4, 4.5 or 5, still more preferably 5.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising: a compound shown in formula A as an active ingredient and an excipient,
  • n is 0-10, Preferably it is 0-5, More preferably, it is 3-5, More preferably, it is 3, 3.5, 4, 4.5, or 5, More preferably, it is 5.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising: a compound shown in formula B as an active ingredient and an excipient,
  • the compound represented by formula B uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angles is at 8.5 ⁇ 0.2°, 11.8 ⁇ 0.2°, 19.6 ⁇ 0.2°, 25.2 ⁇ There are characteristic peaks at 0.2°, 27.2 ⁇ 0.2°; preferably, the compound represented by the formula B uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angle is at 8.5 ⁇ 0.2°, 11.8 ⁇ 0.2°, 12.6 There are characteristic peaks at ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.0 ⁇ 0.2°, 23.7 ⁇ 0.2°, 25.2 ⁇ 0.2°, 27.2 ⁇ 0.2°; further preferably, the compound represented by the formula B uses Cu-K ⁇ radiation , X-ray powder diffraction expressed in 2 ⁇ angles at 7.3 ⁇ 0.2°, 8.5 ⁇ 0.2°, 9.0 ⁇ 0.2°, 11.8 ⁇ 0.2°, 12.6 ⁇ 0.2°, 14.3 ⁇ 0.2°, 18.1 ⁇ 0.2°, 19.6 ⁇ 0.2° , 20.0 ⁇ 0.2°,
  • the single crystal of the compound represented by the formula B is irradiated with Cu-K ⁇ and belongs to the triclinic system,
  • the components and their weight percentages in the aforementioned (first aspect, second aspect, and third aspect) pharmaceutical composition are:
  • Active ingredient its weight percentage is 0.5% to 90%; or 1% to 90%; or 0.5% to 85%; or 0.5% to 80%; or 1% to 80%; or 5% to 80%; or 5 or 5% to 70%; or 5% to 65%; or 5% to 60%; or 5% to 55%; or 5% to 50%; or 5% to 45%; or 5% or 10% to 70%; or 10% to 65%; or 10% to 60%; or 15% to 60%; or 20% to 60%; or 25% to 60%; or 25% to 50%; or 25% to 45%; or 25% to 40%; the balance is excipients.
  • the components of the aforementioned (first aspect, second aspect, and third aspect) pharmaceutical composition and their weight percentages are:
  • Active ingredient its weight percentage is 1% to 90%, preferably 5% to 80%, 5% to 65%, 5% to 55%, 5% to 45% or 5% to 40%;
  • the components and their weight percentages in the aforementioned (first aspect, second aspect, and third aspect) pharmaceutical composition are:
  • Active ingredient its weight percentage is 5% to 90%; or 10% to 90%; or 10% to 80%; or 15% to 80%; or 20% to 70%; or 25% to 60%; or 25% % ⁇ 50%; or 25% ⁇ 45%; or 25% ⁇ 40%; the balance is excipients.
  • excipients refer to all the ingredients other than the active ingredients used in formulating and producing drugs.
  • additional materials generally pharmaceutically acceptable inert ingredients that have been reasonably assessed for safety.
  • excipients include, without limitation, binders, disintegrants, lubricating adjuvants (lubricants, glidants, anti-adherents), stabilizers, fillers (or diluents), and flavoring agents, Thickeners, dispersants, colorants, bacteriostatic agents, antioxidants, pH adjusters, surfactants, fragrances and coating materials (plasticizers, opacifiers, pigments) and other substances.
  • excipients can enhance the handling characteristics of a pharmaceutical formulation, such as by increasing flowability and/or tack, allowing the formulation to be manufactured to process requirements.
  • the "excipient" should have good compatibility with the active ingredient, that is, the excipient itself or the impurities contained in it will not chemically react with the structural group in the active ingredient or cause the active ingredient to degrade, resulting in Active ingredient content decreased.
  • the excipients include fillers, binders, disintegrants, flavoring agents, lubricating excipients, bacteriostatic agents, antioxidants, pH adjusters, surfactants, fragrances, solvents or one or more of the coating materials.
  • the excipients include fillers, and optionally, further include binders, disintegrants, flavoring agents, lubricating excipients, bacteriostatic agents, antioxidants, surfactants, flavors or one or more of the coating materials.
  • the excipients comprise fillers and optionally further comprise one or more of disintegrants, binders or lubricating adjuvants. In one embodiment, the excipients comprise fillers and lubricating adjuvants and optionally further comprise disintegrants and/or binders. In one embodiment, the excipient consists of a filler and a lubricating adjuvant. In another embodiment, the excipient consists of filler, lubricating adjuvant and disintegrant. In another embodiment, the excipient consists of filler, lubricating adjuvant, disintegrant and binder.
  • the pharmaceutical composition of the present application may also contain other excipients other than fillers, lubricating adjuvants and disintegrants.
  • excipients other than fillers, lubricating adjuvants and disintegrants.
  • specific examples thereof include adhesives, flavoring agents, bacteriostatic agents, pH adjusters, pigments, thickeners, dispersants, colorants, antioxidants, stabilizers, coating materials, and fragrances.
  • the weight percentage of other excipients in the pharmaceutical composition is 0%-25%, preferably 0%-20%, 0%-15%, 0%-10% or 0%-5%.
  • filler or "diluent” as used herein refers to an excipient used to increase the weight and volume of a pharmaceutical composition to facilitate shaping and dispensing.
  • the fillers described in this application may be a single filler or a mixture of two or more fillers.
  • the filler is selected from one or more of starch, pregelatinized starch, powdered sugar, magnesium hydroxide, lactose, microcrystalline cellulose, sugar alcohols or inorganic calcium salts ;
  • the sugar alcohols are selected from one or more of xylitol, sorbitol and mannitol;
  • the inorganic calcium salts are selected from calcium phosphate, calcium hydrogen phosphate, calcium carbonate and calcium sulfate one or more of.
  • the filler is selected from one of pregelatinized starch, anhydrous calcium hydrogen phosphate, calcium carbonate, microcrystalline cellulose, mannitol, or a combination of pregelatinized starch and mannitol, or A combination of microcrystalline cellulose and lactose, or a combination of pregelatinized starch and lactose, or a combination of pregelatinized starch and anhydrous calcium hydrogen phosphate, or a combination of pregelatinized starch and calcium carbonate.
  • the filler is a combination of pregelatinized starch and mannitol, a combination of microcrystalline cellulose and lactose, a combination of pregelatinized starch and anhydrous calcium hydrogen phosphate, or a combination of pregelatinized starch and carbonic acid Calcium, in the combination of two fillers, the weight ratio of the two fillers is 1:10 ⁇ 10:1; or 1:7 ⁇ 7:1; or 1:6 ⁇ 6:1, or 1:5 ⁇ 5:1; or 1:4 to 4:1; or 1:3 to 3:1; or 1:2 to 2:1; or 1:1.
  • adheresive or “adhesive” mentioned in this application refers to a viscous excipient that can make non-viscous or less viscous materials or auxiliary materials aggregate and bond into granules or compression molding, which can be solid powder or Viscous liquid.
  • the binder is selected from starch syrup, copovidone, cellulose derivatives, powdered sugar, syrup, polyvinylpyrrolidone, mucilage, polyethylene glycol 4000 and dextrin one or more;
  • the cellulose derivatives include methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose or sodium carboxymethyl cellulose;
  • the dextrins include maltose Dextrin;
  • the polyvinylpyrrolidone, also known as povidone includes povidone K30, povidone K25, povidone K90, etc.;
  • the copovidone includes copovidone VA64, copovidone VA64Fine, etc. ; Described mucilage includes Arabic mucilage, gelatin mucilage and the like.
  • disintegrant refers to an excipient used to promote the disintegration of the pharmaceutical composition in the gastrointestinal tract and increase the dissolution rate of the active ingredient. In some embodiments of the present application, no disintegrant is included in the pharmaceutical composition.
  • the pharmaceutical composition comprises a disintegrant, and the disintegrant is selected from dry starch, sodium carboxymethyl cellulose, microcrystalline cellulose, powdered cellulose, methyl cellulose , Polacrilin Potassium, Sodium Alginate, Sodium Starch Glycolate, Polyvinylpyrrolidone, Maltodextrin, Aluminum Magnesium Silicate, Corn Starch, Pregelatinized Starch, Crospovidone, Low-substituted Hypromellose, Carboxylic One or more of calcium methylcellulose, effervescent disintegrant, sodium starch glycolate and croscarmellose sodium.
  • the disintegrant is selected from dry starch, sodium carboxymethyl cellulose, microcrystalline cellulose, powdered cellulose, methyl cellulose , Polacrilin Potassium, Sodium Alginate, Sodium Starch Glycolate, Polyvinylpyrrolidone, Maltodextrin, Aluminum Magnesium Silicate, Corn Starch, Pregelatin
  • the disintegrant is selected from one or more of dry starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate and croscarmellose sodium kind.
  • the disintegrant is preferably one or more of pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate or croscarmellose sodium ; more preferably crospovidone, sodium carboxymethyl starch or croscarmellose sodium; more preferably sodium carboxymethyl starch.
  • the crospovidone includes crospovidone CL-M, crospovidone CL-SF, crospovidone CL-F, crospovidone CL and the like.
  • flavoring agent refers to the pharmaceutical excipients used to improve or shield the unpleasant smell and taste of the drug and make it difficult for the user to perceive the smell or taste of the drug. It can be further classified into sweet taste. Agents (or sweeteners), aromatics, mucilage agents and effervescent agents, etc. In some embodiments of the present application, the flavoring agent comprises one or more of a sweetening agent, an aromatic agent, a mucilage agent or an effervescent agent.
  • the sweetener is selected from the group consisting of sorbose, xylose, xylitol, glycerin, disodium glycyrrhizinate, mannose, galactose, maltose, lactose, fructose, sweetener, sodium saccharin, One or more of stevioside, glucose, sucrose, sucralose, aspartame, and neotame.
  • the fragrance agent is selected from natural volatile aromatic oils and synthetic fragrances, etc.
  • the fragrance agent is selected from cumin oil, rose oil, peppermint oil, orange peel oil, lemon oil, rose oil
  • One or more of flavor, lemon flavor, vanilla flavor, vanillin, banana flavor, pineapple flavor, and apple flavor is selected from cumin oil, rose oil, peppermint oil, orange peel oil, lemon oil, rose oil.
  • the mucilage agent is selected from one or more of starch, gum arabic, tragacanth, carboxymethyl cellulose, methyl cellulose, sodium alginate, pectin and agar kind.
  • lubricating adjuvant is a generalized lubricant, which refers to an excipient used to reduce the frictional force between particles of the pharmaceutical composition and between the particles and the die hole, and to improve the transmission and distribution of force.
  • Lubricating excipients are divided into lubricants, glidants and anti-adhesion agents according to their three functions: reducing friction, increasing particle fluidity, and resisting the adhesion between die holes and drug particles.
  • the lubricating adjuvant comprises a lubricant and/or a glidant.
  • the lubricant is selected from stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitate stearate, sodium benzoate, sodium lauryl sulfate, talc, Silicon dioxide, zinc stearate, sodium stearyl fumarate, magnesium stearoyl fumarate, magnesium lauryl sulfate, hydrogenated vegetable oil, sodium lauryl sulfate, magnesium lauryl sulfate, or polyethylene glycol one or more of the alcohols. It is preferably one or more of talc, magnesium stearate, calcium stearate or sodium stearate fumarate; more preferably magnesium stearate.
  • the glidant is selected from one or more of colloidal silica or aluminum hydroxide. Colloidal silica is preferred.
  • the pH adjusting agent is selected from one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate or potassium hydroxide.
  • the bacteriostatic agent is selected from sodium benzoate, potassium sorbate, urotropine, ethanol, benzyl alcohol, parabens, benzoic acid, sorbic acid, benzyl alcohol or phenethyl alcohol one or more of.
  • the antioxidant is selected from the group consisting of sodium bisulfite, sodium metabisulfite, sodium sulfite, dry sodium sulfite, sodium thiosulfate, ascorbic acid, methionine, thiourea, disodium EDTA, One or more of phosphoric acid, citric acid, t-butyl-p-hydroxyanisole, t-butyl-p-cresol, tocopherol, nordihydroguaiaretic acid, tocopherol or gallate.
  • the "coating material”, “coating powder”, “coating agent” or “coating premix” described in this application is a mixture of various pharmaceutical excipients, whose main functions are to color, cover taste, and protect from light. , Extend shelf life, improve appearance, etc.
  • the "film-coated tablet” or “film-coated tablet” referred to in this application refers to a tablet with a film (coating) coating on the tablet core (which is made by tableting the pharmaceutical composition of the present application).
  • the film coating can be prepared using coating materials and methods commonly used in the art.
  • film coating materials usually contain one or more of film-forming agents (or polymer materials), plasticizers, porogens, colorants, opacifiers and certain solid materials; further, the The coating material can be dissolved in a solvent to make a coating liquid.
  • the polymer material can be selected from hypromellose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, acrylic resin, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, polyethylene One or more of alcohol phthalate, cellulose acetate trimellitate, hypromellose phthalate, and polyvinyl alcohol; plasticizers can be selected from glycerol, propylene glycol, polyethylene glycol, glycerin Monoacetate, triacetin, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, castor oil, silicone oil, corn oil, liquid paraffin, etc.; Release rate modifiers) can be selected from sucrose, sodium chloride, surfactants, etc.; solid materials can be selected from talc, magnesium stearate, colloidal silicon dioxide, etc.; opacifiers include titanium dioxide; Conventional colorants in the field, for example, the colorants are selected from one or more of
  • the coating material can also be directly selected from commercially available pre-mixed coating powders, such as Opadry Series coating powder, Jacques Yi Series coating powder, Sutri Series Coating Powder, Canal Series coating powder, Aidoshow Series of coating powder, etc.
  • the coating material may be a gastric-soluble coating material or an enteric-soluble coating material.
  • the weight gain of the film coating accounts for 1-5% of the weight of the tablet core, preferably 1.5-4%, more preferably 1.5-3%.
  • the coating solvent is selected from water and ethanol, preferably water, which can be removed during drying without remaining in the final product.
  • Opadry The series of coating powder models are: Opadry 85G64788, 85F18422, 0366507, 8568918, 85F12252, 03F58908, etc.
  • the solvent is selected from one or more of water, ethanol or vegetable oil.
  • the surfactant is selected from the group consisting of polyethylene glycols, polysorbates, sorbitan monolaurate, polyoxyethylene lauryl ethers, emulsifier OP, milk bailing A.
  • the aforementioned (first aspect, second aspect, and third aspect) pharmaceutical compositions are prepared into oral formulations; preferably, the oral formulations comprise oral solid formulations and/or oral liquid formulations; further preferably Typically, the oral solid preparation is selected from one or more of capsules, tablets, granules, fine granules and powders; the oral liquid preparation is selected from oral solutions.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising: as an active ingredient a compound represented by formula II, formula A or formula B and an excipient, the excipient comprises a filler, optionally Preferably, lubricating adjuvants, disintegrants and/or binders are further included.
  • the excipients comprise fillers and lubricating adjuvants, optionally further comprising disintegrants and/or binders.
  • the excipients comprise fillers, lubricating adjuvants and disintegrants, optionally further comprising binders.
  • the excipients comprise fillers, lubricating adjuvants, disintegrants and binders.
  • the lubricating adjuvant is a lubricant, optionally, further comprising a glidant.
  • the lubricating adjuncts are lubricants and glidants.
  • the filler is selected from one or more of starch, powdered sugar, magnesium hydroxide, pregelatinized starch, lactose, microcrystalline cellulose, sugar alcohols, and inorganic calcium salts
  • the sugar alcohol filler is selected from one or more of mannitol, sorbitol and xylitol
  • the inorganic calcium salt filler is selected from calcium phosphate, calcium hydrogen phosphate, calcium sulfate and carbonic acid
  • the filler is selected from pregelatinized starch, lactose, microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate anhydrous, calcium sulfate dihydrate and calcium carbonate one or more; further preferably, the filler is selected from one or more of pregelatinized starch, lactose, microcrystalline cellulose, mannitol, anhydrous calcium hydrogen phosphate and calcium carbonate; further preferably Preferably, the
  • the filler is selected from one of pregelatinized starch, anhydrous calcium hydrogen phosphate, calcium carbonate, microcrystalline cellulose, or a combination of pregelatinized starch and mannitol, or microcrystalline
  • the weight ratio of the two fillers is 1: 10-10: 1; or 1: 7-7: 1; or 1: 6-6: 1, or 1: 5-5:1; or 1:4-4:1; or 1:3-3:1; or 1:2-2:1; or 1:1.
  • the lubricant is selected from stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitate stearate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, Talc, silicon dioxide, zinc stearate, sodium stearoyl fumarate, magnesium stearoyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate, or polyethylene glycol One or more of alcohols; preferably stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitate stearate, sodium benzoate, sodium lauryl sulfate, talc, dioxide Silicon, Zinc Stearate, Sodium Stearyl Fumarate, Magnesium Stearyl Fumarate, Magnesium Lauryl Sulfate, Macrogol 4000, Macrogol 6000,
  • the glidant is selected from one or more of colloidal silica or aluminum hydroxide; preferably colloidal silica.
  • the lubricating adjuvant is a combination of a lubricant and a glidant, and the weight ratio of the glidant to the lubricant is 1:6-6:1; or 1:5-5:1 ; or 1:4 to 4:1; or 1:3 to 3:1; or 1:2 to 2:1; or 1:1, 1:2, 1:1.5, 2:1, 2:3, 3 :1, 3:2, 4:3 or 5:3.
  • the pharmaceutical composition comprises a disintegrant selected from the group consisting of dry starch, carboxymethyl cellulose, microcrystalline cellulose, powdered cellulose, methyl cellulose, cellulose Lactrine potassium, sodium alginate, sodium starch glycolate, polyvinylpyrrolidone, maltodextrin, magnesium aluminum silicate, corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethyl One or more of calcium cellulose, effervescent disintegrant, sodium carboxymethyl starch or croscarmellose sodium; preferably dry starch, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl One or more of cellulose, croscarmellose sodium or crospovidone; preferably crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate or croscarmellose One or more of sodium; more preferably
  • the pharmaceutical composition comprises a binder selected from starch syrup, copovidone, powdered sugar, syrup, polyvinylpyrrolidone, cellulose derivatives, mucilage, One or more of polyethylene glycol 4000 and dextrin; preferably, the cellulose derivative is selected from methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose and sodium carboxymethylcellulose; more preferably copovidone, powdered sugar, polyvinylpyrrolidone, hydroxypropylmethylcellulose and sodium carboxymethylcellulose; further preferably copovidone VA64 and polyvinylpyrrolidone .
  • a binder selected from starch syrup, copovidone, powdered sugar, syrup, polyvinylpyrrolidone, cellulose derivatives, mucilage, One or more of polyethylene glycol 4000 and dextrin; preferably, the cellulose derivative is selected from methyl cellulose, hydroxypropyl methyl cellulose, hydroxy
  • the filler is selected from one of pregelatinized starch, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, or a combination of pregelatinized starch and mannitol, or microcrystalline cellulose
  • the lubricating adjuvant is a lubricant and/or a glidant, wherein the lubricant is Magnesium stearate, the glidant is colloidal silicon dioxide; optionally, the disintegrant is selected from sodium starch glycolate and croscarmellose sodium; optionally, the binding agent
  • the agent is selected from copovidone.
  • the pharmaceutical composition comprises an active ingredient, a filler, a lubricant and a glidant, wherein the filler is pregelatinized starch or microcrystalline cellulose; preferably, the adjuvant
  • the flow agent is colloidal silicon dioxide; further preferably, the lubricant is magnesium stearate; further preferably, the pharmaceutical composition further comprises a disintegrating agent, and the disintegrating agent is selected from sodium starch glycolate or Croscarmellose sodium.
  • the pharmaceutical composition comprises active ingredients, fillers, lubricants and glidants, wherein the fillers are pregelatinized starch and mannitol; preferably, the glidants is colloidal silicon dioxide; further preferably, the lubricant is magnesium stearate.
  • the pharmaceutical composition comprises an active ingredient, a filler and a lubricant, wherein the filler is microcrystalline cellulose; preferably, the lubricant is magnesium stearate.
  • the pharmaceutical composition comprises active ingredients, fillers, lubricants, glidants and disintegrants, wherein the fillers are microcrystalline cellulose and lactose; preferably, the The glidant is selected from colloidal silicon dioxide; further preferably, the disintegrant is selected from sodium starch glycolate or croscarmellose sodium; further preferably, the lubricant is magnesium stearate Or sodium stearoyl fumarate.
  • the pharmaceutical composition comprises an active ingredient, a filler, a lubricant and a glidant, wherein the filler is anhydrous calcium hydrogen phosphate or anhydrous calcium hydrogen phosphate and pregelatinized starch
  • the glidant is selected from colloidal silicon dioxide; further preferably, the lubricant is magnesium stearate; even more preferably, the pharmaceutical composition further comprises a disintegrant, so The disintegrant is selected from sodium starch glycolate or croscarmellose sodium.
  • the pharmaceutical composition comprises an active ingredient, a filler, a lubricant and a glidant, wherein the filler is calcium carbonate or a combination of calcium carbonate and pregelatinized starch; preferably, The glidant is selected from colloidal silicon dioxide; further preferably, the lubricant is magnesium stearate; even more preferably, the pharmaceutical composition further comprises a disintegrant, and the disintegrant is selected from Sodium starch glycolate or croscarmellose sodium; further preferably, the pharmaceutical composition further comprises a binder, and the binder is selected from copovidone.
  • the components of the pharmaceutical composition and their weight percentages are:
  • Active ingredient its weight percentage is 0.5% to 90%; or 1% to 90%; or 0.5% to 85%; or 5% to 80%; or 5% to 75%; or 5% to 70%; or 10 % ⁇ 70%; or 5% ⁇ 65%; or 5% ⁇ 60%; or 5% ⁇ 55%; or 5% ⁇ 50%; or 5% ⁇ 45%; or 5% ⁇ 40%; or 10% or 10% to 60%; or 15% to 60%; or 20% to 60%; or 25% to 60%; or 25% to 50%; or 25% to 45%; or 25% to 40%;
  • filler whose weight percentage is 5% to 99%; or 10% to 95%; or 15% to 95%; or 15% to 90%; or 15% to 85%; or 15% to 80%; or 20% or 25% to 90%; or 25% to 75%; or 30% to 70%; or 35% to 90%; or 35% to 70%; or 40% to 90%; or 40% or 45% to 70%; or 50% to 90%; or 50% to 70%; or 55% to 70%;
  • Disintegrant its weight percentage is 0% to 20%; 0% to 15%; or 0% to 10%; or 0% to 8%; or 0% to 6%; or 0% to 5%; or 0% % ⁇ 4%; or 0% ⁇ 3%; or 0.5% ⁇ 3%; or 1% ⁇ 3%; or 1.5% ⁇ 3%; or 2% ⁇ 3%;
  • Adhesive its weight percentage is 0% to 10%; or 0% to 6%; or 0% to 5%; or 0% to 4%; or 0% to 3%; or 0% to 2%;
  • Lubricating auxiliary materials its weight percentage is 0% to 18%; or 0.1% to 18%; or 0% to 15%; or 0.1% to 15%; or 0% to 10%; or 0.1% to 10%; or 0 or 0% to 7%; or 0% to 6%; or 1% to 6%; or 0.5% to 6%; or 0% to 5%; or 1% to 5%; or 1.5% or 2% to 4%; or 2% to 3.5%; or 2% to 3%; or 2.5% to 5%; or 3.5% to 5%; or 4% to 5%;
  • excipients whose weight percentages are 0% to 25%; or 0% to 20%; or 0% to 15%; or 0% to 10%; or 0% to 5%; and
  • the components of the pharmaceutical composition and their weight percentages are:
  • Active ingredient its weight percentage is 1% to 90%, preferably 5% to 80%, 5% to 65%, 5% to 55%, 5% to 45% or 5% to 40%;
  • filler whose weight percentage is 10% to 95%, preferably 25% to 90%, 35% to 90%, 40% to 90% or 50% to 90%;
  • Disintegrant its weight percentage is 0% to 15%, preferably 0% to 10%, 0% to 6%, 0% to 5% or 0% to 3%;
  • Lubricating auxiliary materials its weight percentage is 0% to 18%, preferably 0.1% to 18%, 0% to 15%, 0% to 10%, 0% to 6%, 0% to 5%, 0.1% to 15%, 0.1% ⁇ 10%, 0.5% ⁇ 0%, 1% ⁇ 5%, 2.5% ⁇ 5%, 3.5% ⁇ 5% or 4% ⁇ 5%;
  • the components of the pharmaceutical composition and their weight percentages are:
  • Active ingredient its weight percentage is 5% to 90%; or 10% to 90%; or 10% to 80%; or 15% to 80%; or 20% to 70%; or 25% to 60%; or 25% % ⁇ 50%; or 25% ⁇ 45%; or 25% ⁇ 40%;
  • filler whose weight percentage is 5% to 90%; or 15% to 90%; or 15% to 85%; or 25% to 85%; or 25% to 80%; or 35% to 75%; or 35% % ⁇ 70%; or 50% ⁇ 70%; or 55% ⁇ 70%;
  • Disintegrant its weight percentage is 0% to 5%; or 0% to 4%; or 0.5% to 4%; or 1% to 3%;
  • Adhesive its weight percentage is 0% to 5%; or 0% to 4%; or 0% to 3%;
  • Lubricating auxiliary materials whose weight percentage is 2% to 7%; or 2% to 6%; or 2.5% to 6%; or 3% to 5%; or 3% to 6%; or 3.5 to 6%; or 4% ⁇ 6%; or 4% ⁇ 5%; or 5% ⁇ 6%;
  • the weight percentages thereof are 0% to 10%; or 0% to 5%; and the sum of the weight percentages of the above components is 100%.
  • the lubricating adjuvant is a lubricant.
  • the lubricating adjuvant is a combination of a lubricant and a glidant, and the weight ratio of the glidant to the lubricant is 1:6-6:1; or 1:5-5:1 ; or 1:4 to 4:1; or 1:3 to 3:1; or 1:2 to 2:1; or 1:1, 1:2, 1:1.5, 2:1, 2:3, 3 :1, 3:2, 4:3 or 5:3.
  • the components of the pharmaceutical composition and their weight percentages are:
  • Active ingredient its weight percentage is 0.5% to 90%; or 1% to 90%; or 0.5% to 85%; or 5% to 80%; or 5% to 75%; or 5% to 70%; or 10 % ⁇ 70%; or 5% ⁇ 65%; or 5% ⁇ 60%; or 5% ⁇ 55%; or 5% ⁇ 50%; or 5% ⁇ 45%; or 5% ⁇ 40%; or 10% or 10% to 60%; or 15% to 60%; or 20% to 60%; or 25% to 60%; or 25% to 50%; or 25% to 45%; or 25% to 40%;
  • filler whose weight percentage is 5% to 99%; or 10% to 95%; or 15% to 95%; or 15% to 90%; or 15% to 85%; or 15% to 80%; or 20% or 25% to 90%; or 25% to 75%; or 30% to 70%; or 35% to 90%; or 35% to 70%; or 40% to 90%; or 40% or 45% to 70%; or 50% to 90%; or 50% to 70%; or 55% to 70%;
  • Disintegrant its weight percentage is 0% to 20%; 0% to 15%; or 0% to 10%; or 0% to 8%; or 0% to 6%; or 0% to 5%; or 0% % ⁇ 4%; or 0% ⁇ 3%; or 0.5% ⁇ .00%; or 1% ⁇ 3%; or 1.5% ⁇ 3%; or 2% ⁇ 3%;
  • Adhesive its weight percentage is 0% to 10%; or 0% to 6%; or 0% to 5%; or 0% to 4%; or 0% to 3%; or 0% to 2%;
  • Lubricant its weight percentage is 0% to 10%; or 0% to 8%; or 0.1% to 8%; or 0% to 6%; or 0% to 5%; or 0.1% to 5%; or 0% or 0.1% to 4%; or 0% to 3%; or 1% to 5%; or 2% to 4%; or 2% to 3%; or 1% to 4%; or 1% or 0.5% to 3%; or 1% to 3%; or 1% to 2.5%; or 1% to 2%; or 2% to 2.5%;
  • Glidant its weight percentage is 0% to 10%; or 0.5% to 10%; or 0% to 8%; or 0.5% to 8%; or 0% to 6%; or 0% to 5%; or 0.5% to 5%; or 1% to 5%; or 0% to 4%; or 1% to 4%; or 0% to 3.5%; or 0% to 3%; or 1% to 3%; or 1 % ⁇ 2.5%; or 1% ⁇ 2%; or 1.5% ⁇ 3%; or 2% ⁇ 3%; or 3%;
  • excipients whose weight percentages are 0% to 25%; or 0% to 20%; or 0% to 15%; or 0% to 10%; or 0% to 5%; and
  • the components of the pharmaceutical composition and their weight percentages are:
  • Active ingredient its weight percentage is 1% to 90%, preferably 5% to 80%, 5% to 65%, 5% to 55%, 5% to 45% or 5% to 40%;
  • filler whose weight percentage is 10% to 95%, preferably 25% to 90%, 35% to 90%, 40% to 90% or 50% to 90%;
  • Disintegrant its weight percentage is 0% to 15%, preferably 0% to 10%, 0% to 6%, 0% to 5% or 0% to 3%;
  • Lubricant whose weight percentage is 0.1% to 8%, preferably 0.1% to 5%, 0.1% to 4%, 0.5% to 3% or 1% to 3%;
  • Glidant its weight percentage is 0% to 10%, preferably 0% to 8%, 0% to 5%, 0% to 4%, or 0% to 3%;
  • the components of the pharmaceutical composition and their weight percentages are:
  • Active ingredient its weight percentage is 1% to 90%, preferably 5% to 80%, 5% to 65%, 5% to 55%, 5% to 45% or 5% to 40%;
  • filler whose weight percentage is 10% to 95%, preferably 25% to 90%, 35% to 90%, 40% to 90% or 50% to 90%;
  • Disintegrant its weight percentage is 0% to 15%, preferably 0% to 10%, .00% to 6%, 0% to 5% or 0% to 3%;
  • Lubricant whose weight percentage is 0.1% to 8%, preferably 0.1% to 5%, 0.1% to 4%, 0.5% to 3% or 1% to 3%;
  • Glidant whose weight percentage is 0.5% to 10%, preferably 0.5% to 8%, 0.5% to 5%, 1% to 5%, 1% to 4%, or 1% to 3%;
  • the components of the pharmaceutical composition and their weight percentages are:
  • Active ingredient its weight percentage is 1% to 90%, preferably 5% to 80%, 5% to 65%, 5% to 55%, 5% to 45% or 5% to 40%;
  • filler whose weight percentage is 10% to 95%, preferably 25% to 90%, 35% to 90%, 40% to 90% or 50% to 90%;
  • Disintegrant its weight percentage is 0% to 15%, preferably 0% to 10%, 0% to 6%, 0% to 5% or 0% to 3%;
  • Lubricant whose weight percentage is 1% to 5%, preferably 2% to 4%, 2% to 3% or 2% to 2.5%;
  • Glidant its weight percentage is 1% to 5%, preferably 1% to 4%, 1% to 3%, 1.5% to 3%, 2% to 3% or 3%;
  • the components of the pharmaceutical composition and their weight percentages are:
  • Active ingredient its weight percentage is 1% to 90%, preferably 5% to 80%, 5% to 65%, 5% to 55%, 5% to 45% or 5% to 40%;
  • Microcrystalline cellulose whose weight percentage is 10% to 95%, preferably 25% to 90%, 35% to 90%, 40% to 90% or 50% to 90%;
  • Disintegrant its weight percentage is 0% to 15%, preferably 0% to 10%, 0% to 6%, 0% to 5% or 0% to 3%;
  • Lubricant whose weight percentage is 0.1% to 8%, preferably 0.1% to 5%, 0.1% to 4%, 0.5% to 3% or 1% to 2%;
  • excipients whose weight percentage is 0%-25%, preferably 0%-20%, 0%-15%, 0%-10% or 0%-5%;
  • the components of the pharmaceutical composition and their weight percentages are:
  • Active ingredient its weight percentage is 5% to 90%; or 10% to 90%; or 10% to 80%; or 15% to 80%; or 20% to 70%; or 25% to 60%; or 25% % ⁇ 50%; or 25% ⁇ 45%; or 25% ⁇ 40%;
  • filler whose weight percentage is 5% to 90%; or 15% to 90%; or 15% to 85%; or 25% to 85%; or 25% to 80%; or 35% to 75%; or 35% % ⁇ 70%; or 50% ⁇ 70%; or 55% ⁇ 70%;
  • Disintegrant its weight percentage is 0% to 5%; or 0% to 4%; or 0.5% to 4%; or 1% to 3%;
  • Adhesive its weight percentage is 0% to 5%; or 0% to 4%; or 0% to 3%;
  • Lubricant whose weight percentage is 1% to 5%; or 1% to 4%; or 2% to 4%; or 2% to 3%;
  • Glidant its weight percentage is 0% to 5%; or 0% to 4%; or 1% to 4%; or 1% to 3%; or 0% to 3%; or 2% to 4%; or 3% to 4%; or 2% to 3%;
  • the weight percentages thereof are 0% to 10%; or 0% to 5%; the sum of the weight percentages of the above components is 100%.
  • the components of the pharmaceutical composition and their weight percentages are:
  • each component of the aforementioned pharmaceutical composition and its weight percentage are:
  • the filler is selected from: one of pregelatinized starch, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, calcium carbonate, or a combination of pregelatinized starch and mannitol, or The combination of microcrystalline cellulose and lactose, or the combination of pregelatinized starch and anhydrous calcium hydrogen phosphate, or the combination of pregelatinized starch and calcium carbonate;
  • the lubricating adjuvant is a lubricant and/or a glidant, wherein the The lubricant is magnesium stearate, and the glidant is colloidal silicon dioxide;
  • the disintegrating agent is selected from sodium starch glycolate and croscarmellose sodium;
  • the binder is selected from copolymerization Vidone; preferably copovidone VA64 and/or copovidone VA64Fine.
  • the filler is selected from the group consisting of a combination of pregelatinized starch and mannitol, a combination of microcrystalline cellulose and lactose, a combination of pregelatinized starch and anhydrous calcium hydrogen phosphate, a combination of pregelatinized starch
  • the combination with lactose, or the combination of pregelatinized starch and calcium carbonate, the weight ratio of the two fillers at this time is 1:10 ⁇ 10:1, preferably 1:7 ⁇ 7:1, more preferably 1:6 ⁇ 6:1, more preferably 1:5 ⁇ 5:1, more preferably 1:4 ⁇ 4:1, still more preferably 1:3 ⁇ 3:1, still more preferably 1:2 ⁇ 2:1, More preferably, it is 1:1.
  • the lubricating adjuvant is a lubricant.
  • the lubricating adjuvant is a combination of a lubricant and a glidant, and the weight ratio of the glidant to the lubricant is 1:6-6:1; or 1:5-5:1 ; or 1:4 to 4:1; or 1:3 to 3:1; or 1:2 to 2:1; or 1:1, 1:2, 1:1.5, 2:1, 2:3, 3 :1, 3:2, 4:3 or 5:3.
  • the components of the pharmaceutical composition and their weight percentages are:
  • the components of the pharmaceutical composition and their weight percentages are:
  • the filler is selected from: one of pregelatinized starch, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, calcium carbonate, or a combination of pregelatinized starch and mannitol, or A combination of microcrystalline cellulose and lactose, or a combination of pregelatinized starch and anhydrous calcium hydrogen phosphate, or a combination of pregelatinized starch and calcium carbonate;
  • the lubricant is selected from magnesium stearate or stearic fumaric acid One or more of sodium;
  • the glidant is colloidal silicon dioxide;
  • the disintegrant is selected from sodium starch glycolate and croscarmellose sodium; Ketone, preferably copovidone VA64.
  • the filler is selected from the group consisting of a combination of pregelatinized starch and mannitol, a combination of microcrystalline cellulose and lactose, a combination of pregelatinized starch and anhydrous calcium hydrogen phosphate, a combination of pregelatinized starch
  • the combination with lactose, or the combination of pregelatinized starch and calcium carbonate, preferably, the weight ratio of the two fillers is 1:10-10:1, preferably 1:7-7:1, more preferably 1:1: 6-6:1, more preferably 1:5-5:1, more preferably 1:4-4:1, still more preferably 1:3-3:1, still more preferably 1:2-2:1 , more preferably 1:1.
  • the components of the pharmaceutical composition and their weight percentages are:
  • active ingredient 50%-70% filler, 0%-4% disintegrant, 0%-3% binder, 2%-3% lubricant, 3%- 4% glidant, and 0% to 5% other excipients; or
  • the filler is selected from: pregelatinized starch or microcrystalline cellulose, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose;
  • the lubricant One or more selected from magnesium stearate or sodium stearyl fumarate;
  • the glidant is colloidal silicon dioxide;
  • the disintegrant is selected from sodium starch glycolate and cross-linked carboxymethyl Cellulose sodium;
  • the binder is copovidone, preferably copovidone VA64.
  • the filler is selected from a combination of pregelatinized starch and mannitol, a combination of microcrystalline cellulose and lactose, and preferably, the weight ratio of the two fillers is 1:10-10: 1, preferably 1:7 to 7:1, more preferably 1:6 to 6:1, further preferably 1:5 to 5:1, still more preferably 1:4 to 4:1, still more preferably 1:1 3 to 3:1, more preferably 1:2 to 2:1, still more preferably 1:1.
  • the components of the pharmaceutical composition and their weight percentages are:
  • active ingredient 50%-70% filler, 1%-3% disintegrant, 0%-3% binder, 2%-3% lubricant, 2%-3% 4% glidant, and 0% to 5% other excipients; or
  • the filler is selected from: a combination of microcrystalline cellulose and lactose; preferably, the weight ratio of the two fillers is 1:10-10:1, preferably 1:7-7 : 1, more preferably 1: 6-6: 1, more preferably 1: 5-5: 1, still more preferably 1: 4-4: 1, still more preferably 1: 3-3: 1, still more preferably 1: 2 ⁇ 2: 1, more preferably 1: 1;
  • the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate;
  • the glidant is colloidal Silicon dioxide;
  • the disintegrant is selected from sodium starch glycolate and croscarmellose sodium;
  • the binder is copovidone, preferably copovidone VA64.
  • the components of the pharmaceutical composition and their weight percentages are:
  • the filler is selected from: anhydrous calcium hydrogen phosphate or calcium carbonate, or a combination of pregelatinized starch and anhydrous calcium hydrogen phosphate, or a combination of pregelatinized starch and calcium carbonate; Described lubricant is selected from one or more in magnesium stearate or sodium stearyl fumarate; Described glidant is colloidal silicon dioxide; Described disintegrant is selected from sodium starch glycolate and cross-linked Sodium carboxymethyl cellulose; the binder is copovidone, preferably copovidone VA64.
  • the filler is selected from the combination of pregelatinized starch and anhydrous calcium hydrogen phosphate, or the combination of pregelatinized starch and calcium carbonate, preferably, the weight ratio of the two fillers is 1 : 10 ⁇ 10:1, preferably 1:7 ⁇ 7:1, more preferably 1:6 ⁇ 6:1, still more preferably 1:5 ⁇ 5:1, still more preferably 1:4 ⁇ 4:1, More preferably, it is 1:3 to 3:1, still more preferably 1:2 to 2:1, and still more preferably 1:1.
  • the components of the pharmaceutical composition and their weight percentages are:
  • the filler is pregelatinized starch; the lubricant is magnesium stearate; the glidant is colloidal silicon dioxide; the disintegration
  • the agent is selected from sodium starch glycolate and/or croscarmellose sodium; the binder is copovidone.
  • the components of the pharmaceutical composition and their weight percentages are:
  • active ingredient 50%-70% filler, 0%-3% disintegrant, 0%-3% binder, 2%-3% lubricant, 3%- 4% glidant, and 0% to 5% other excipients; or
  • the filler is pregelatinized starch; the lubricant is magnesium stearate; the glidant is colloidal silicon dioxide; the disintegration
  • the agent is selected from sodium starch glycolate and/or croscarmellose sodium; the binder is copovidone.
  • the components of the pharmaceutical composition and their weight percentages are:
  • the components of the pharmaceutical composition and their weight percentages are:
  • the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate; preferably, the glidant is selected from colloidal silicon dioxide;
  • the disintegrating agent is selected from one or both of sodium starch glycolate and croscarmellose sodium; preferably, the binder is copovidone, more preferably copovidone VA64.
  • the components of the pharmaceutical composition and their weight percentages are:
  • the weight ratio of pregelatinized starch and mannitol is 1:10-10:1, preferably 1:7-7:1, more preferably 1:6-6:1, further preferably 1 : 5 to 5: 1, more preferably 1: 4 to 4: 1, still more preferably 1: 3 to 3: 1, still more preferably 1: 2 to 2: 1.
  • the components of the pharmaceutical composition and their weight percentages are:
  • the weight ratio of pregelatinized starch and mannitol is 1:10-10:1, preferably 1:7-7:1, more preferably 1:6-6:1, further preferably 1:5- 5:1, more preferably 1:4-4:1, more preferably 1:3-3:1, still more preferably 1:2-2:1;
  • the lubricant is selected from stearic acid One or more of magnesium or sodium stearyl fumarate; preferably, the glidant is selected from colloidal silicon dioxide; preferably, the disintegrant is selected from sodium starch glycolate and cross-linked carboxylate One or both of sodium methylcellulose; preferably, the binder is copovidone, preferably copovidone VA64.
  • the components of the pharmaceutical composition and their weight percentages are:
  • the weight ratio of microcrystalline cellulose and lactose is 1:10-10:1, preferably 1:7-7:1, more preferably 1:6-6:1, further preferably 1:5-5 : 1, more preferably 1: 4 to 4: 1, still more preferably 1: 3 to 3: 1, still more preferably 1: 2 to 2: 1.
  • the components of the pharmaceutical composition and their weight percentages are:
  • the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate; preferably, the glidant is selected from colloidal silicon dioxide;
  • the disintegrating agent is selected from one or both of sodium starch glycolate and croscarmellose sodium; preferably, the binder is copovidone, preferably copovidone VA64.
  • the components of the pharmaceutical composition and their weight percentages are:
  • the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate; preferably, the glidant is selected from colloidal silicon dioxide;
  • the disintegrating agent is selected from one or both of sodium starch glycolate and croscarmellose sodium; preferably, the binder is copovidone, preferably copovidone VA64.
  • the components of the pharmaceutical composition and their weight percentages are:
  • the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate; preferably, the glidant is selected from colloidal silicon dioxide;
  • the disintegrating agent is selected from one or both of sodium starch glycolate and croscarmellose sodium; preferably, the binder is copovidone, preferably copovidone VA64.
  • the components of the pharmaceutical composition and their weight percentages are:
  • the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate; preferably, the glidant is selected from colloidal silicon dioxide;
  • the disintegrating agent is selected from one or both of sodium starch glycolate and croscarmellose sodium; preferably, the binder is copovidone, preferably copovidone VA64.
  • the components of the pharmaceutical composition and their weight percentages are:
  • the lubricant is selected from one or more of magnesium stearate or sodium stearyl fumarate; preferably, the glidant is selected from colloidal silicon dioxide;
  • the disintegrating agent is selected from one or both of sodium starch glycolate and croscarmellose sodium; preferably, the binder is copovidone, preferably copovidone VA64.
  • the components of the pharmaceutical composition and their weight percentages are:
  • the pharmaceutical composition of the above may further contain other excipients than those of the type described.
  • the other excipients are selected from the group consisting of binders, flavoring agents, bacteriostatic agents, pH adjusting agents, pigments, thickening agents, dispersing agents, coloring agents, antioxidants, stabilizers, fragrances, coating materials, and the like.
  • the weight percentage of other excipients in the pharmaceutical composition is 0%-25%, preferably 0%-20%, 0%-15%, 0%-10% or 0% ⁇ 5%.
  • the components of the pharmaceutical composition and their weight percentages are: 10%-70% of active ingredients, 30%-80% of pregelatinized starch, 0%-5% of glue state silicon dioxide, 0% to 5% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and/or croscarmellose sodium, the sum of the weight percentages of each component is 100% .
  • the components of the pharmaceutical composition and their weight percentages are: 15% to 60% of active ingredients, 40% to 80% of pregelatinized starch, 1% to 5% of colloidal silicon dioxide, 1% to 5% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and/or croscarmellose sodium, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 20% to 50% of active ingredients, 45% to 75% of pregelatinized starch, 1% to 4% of colloidal silicon dioxide, 1% to 5% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and/or croscarmellose sodium, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 25% to 45% of active ingredients, 50% to 70% of pregelatinized starch, 1% to 4% of colloidal silicon dioxide, 1% to 4% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and/or croscarmellose sodium, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 25% to 40% of active ingredients, 56% to 68% of pregelatinized starch, 1% to 4% of colloidal silicon dioxide, 2% to 4% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and/or croscarmellose sodium, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 25% to 40% of active ingredients, 56% to 68% of pregelatinized starch, 1% to 3% of colloidal silicon dioxide, 2% to 3% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and/or croscarmellose sodium, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 25% to 40% of active ingredients, 56% to 68% of pregelatinized starch, 3% to 5% of colloidal silicon dioxide and 2% to 3% of magnesium stearate, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 25% to 40% of active ingredients, 56% to 68% of pregelatinized starch, 3% to 4% of colloidal silicon dioxide and 2% to 3% of magnesium stearate, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 25%-50% active ingredients, 50%-75% microcrystalline cellulose, 0%-5% colloidal silicon dioxide, 0% to 3% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and/or croscarmellose sodium, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 25% to 40% of active ingredients, 55% to 75% of microcrystalline cellulose, 0% to 5% of colloidal silicon dioxide, 1% to 3% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and/or croscarmellose sodium, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 30% to 35% of active ingredients, 60% to 70% of microcrystalline cellulose, 0% to 3% of colloidal silicon dioxide, 1% to 2% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and/or croscarmellose sodium, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 30% to 35% of active ingredients, 60% to 70% of microcrystalline cellulose, 0% to 3% of colloidal silicon dioxide and 1% to 2% of magnesium stearate, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 5%-50% active ingredients, 5%-55% pregelatinized starch, 5%-70% mannitol, 0% to 5% of colloidal silicon dioxide, 1% to 3% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and/or croscarmellose sodium , the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 20%-50% active ingredients, 5%-55% pregelatinized starch, 5%-70% mannitol, 1%-50% 5% of colloidal silicon dioxide, 1% to 3% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and/or croscarmellose sodium, the weight percentage of each component and is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 25%-40% of active ingredients, 10%-50% of pregelatinized starch, 5%-63% of mannitol, 1%- 4% of colloidal silicon dioxide, 1% to 3% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and/or croscarmellose sodium, the weight percentage of each component is and is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 25%-40% of active ingredients, 10%-50% of pregelatinized starch, 5%-63% of mannitol, 1%- 3% of colloidal silicon dioxide, 1% to 3% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and/or croscarmellose sodium, the weight percent of each component is and is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 25%-40% of active ingredients, 10%-50% of pregelatinized starch, 5%-63% of mannitol, 3%- 4% of colloidal silicon dioxide, 2% to 3% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and/or croscarmellose sodium, the weight percent of each component is and is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 25%-40% of active ingredients, 10%-50% of pregelatinized starch, 5%-63% of mannitol, 3%- 4% of colloidal silicon dioxide and 2% to 3% of magnesium stearate, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 23%-50% active ingredient, 10%-55% microcrystalline cellulose, 10%-50% Lactose, 0% to 5% of colloidal silicon dioxide, 1% to 4% of magnesium stearate or sodium stearyl fumarate, and 0% to 5% of sodium carboxymethyl starch and/or cross-linked carboxylate Sodium methylcellulose, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 23%-40% active ingredients, 10%-50% microcrystalline cellulose, 10%-50% lactose, 1%-5% % of colloidal silicon dioxide, 1% to 4% of magnesium stearate or sodium stearyl fumarate, and 0% to 5% of sodium carboxymethyl starch and/or croscarmellose sodium, The sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 28%-35% active ingredients, 15%-45% microcrystalline cellulose, 15%-45% lactose, 1%-4% % of colloidal silicon dioxide, 2% to 3% of magnesium stearate or sodium stearyl fumarate, and 1% to 4% of sodium carboxymethyl starch and/or croscarmellose sodium, The sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 28%-35% active ingredients, 15%-45% microcrystalline cellulose, 15%-45% lactose, 1%-3% % of colloidal silicon dioxide, 2% to 3% of magnesium stearate or sodium stearyl fumarate, and 1% to 4% of sodium carboxymethyl starch and/or croscarmellose sodium, The sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 28%-35% active ingredients, 15%-45% microcrystalline cellulose, 15%-45% lactose, 3%-5% % of colloidal silicon dioxide, 2% to 4% of magnesium stearate or sodium stearyl fumarate, and 1% to 4% of sodium carboxymethyl starch and/or croscarmellose sodium, The sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 28%-35% active ingredients, 15%-45% microcrystalline cellulose, 15%-45% lactose, 3%-4% % of colloidal silicon dioxide, 2% to 3% of magnesium stearate or sodium stearyl fumarate, and 1% to 3% of sodium carboxymethyl starch and/or croscarmellose sodium, The sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 10%-90% of active ingredients, 5%-85% of anhydrous calcium hydrogen phosphate, 1%-5% colloidal silicon dioxide, 1% to 4% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and/or croscarmellose sodium, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 10%-80% active ingredients, 15%-85% anhydrous calcium hydrogen phosphate, 1%-4% colloidal silicon dioxide , 2% to 3% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and/or croscarmellose sodium, and the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 50% to 60% of active ingredients, 35% to 40% of anhydrous calcium hydrogen phosphate, and 1% to 3% of colloidal silicon dioxide , 2% to 3% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and/or croscarmellose sodium, and the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 10%-85% active ingredient, 5%-23% anhydrous calcium hydrogen phosphate, 5%-70% pregelatinized starch, 1% to 4% of colloidal silica, 1% to 4% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and/or cross-linked carboxymethyl cellulose Sodium, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 15% to 80% of active ingredients, 7% to 18% of anhydrous calcium hydrogen phosphate, 7% to 63% of pregelatinized starch, 1% to 3% of colloidal silicon dioxide, 2% to 3% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and/or croscarmellose sodium, each component The sum of the weight percentages is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 10%-82% active ingredients, 10%-85% calcium carbonate, 1%-4% colloidal Silicon dioxide, 1%-4% magnesium stearate, 0-5% copovidone VA64, and 0%-4% sodium carboxymethyl starch and/or croscarmellose sodium, each group The sum of the weight percentages is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 12%-80% active ingredients, 15%-78% calcium carbonate, 1%-3% colloidal silicon dioxide, 2% ⁇ 3% of magnesium stearate, 0-3% of copovidone VA64 and 0.5% to 4% of sodium carboxymethyl starch and/or croscarmellose sodium, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 10%-83% of active ingredients, 5%-50% of calcium carbonate, 5%-68% of pre-gel starch, 1%-4% colloidal silicon dioxide, 1%-4% magnesium stearate, 0-3% copovidone VA64 and 0%-2% sodium carboxymethyl starch and/or Croscarmellose sodium, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 12%-80% of active ingredients, 7%-45% of calcium carbonate, 7%-65% of pregelatinized starch, 1%- 3% colloidal silica, 1.5%-3% magnesium stearate, 0-2% copovidone VA64 and 0%-1% sodium carboxymethyl starch and/or croscarmellose Sodium, the sum of the weight percentages of each component is 100%.
  • the components of the pharmaceutical composition and their weight percentages are: 12%-80% of active ingredients, 7%-45% of calcium carbonate, 7%-65% of pregelatinized starch, 2%- 3% colloidal silica, 2%-3% magnesium stearate, 0-2% copovidone VA64 and 0%-1% sodium carboxymethyl starch and/or croscarmellose Sodium, the sum of the weight percentages of each component is 100%.
  • the pharmaceutical composition is made into an oral solid dosage form; preferably, the oral solid preparation is selected from capsules, tablets, powders and fine granules; more preferably capsules, tablets and fine granules Granules; more preferably capsules and tablets; even more preferably capsules.
  • the tablet is selected from a film-coated tablet or an uncoated tablet.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, a compound represented by formula II, formula A or formula B and an excipient, the excipient comprising a filler and a binding agent
  • the agent optionally, further comprises a flavoring agent.
  • the excipients comprise fillers, binders and flavoring agents.
  • the flavoring agent comprises a perfuming agent and, optionally, further comprises a sweetening agent.
  • the filler is selected from one or more of sugar alcohols; preferably, the sugar alcohol filler is selected from one or more of lactose, mannitol and sorbitol ; Preferably, the filler is selected from mannitol.
  • the binder is selected from one or more of copovidone, powdered sugar, syrup, polyvinylpyrrolidone, cellulose derivatives, mucilage and dextrin; preferably, The cellulose derivatives are selected from hydroxypropyl methylcellulose and/or sodium carboxymethylcellulose; further preferably copovidone, powdered sugar, polyvinylpyrrolidone, hydroxypropyl methylcellulose and/or Sodium carboxymethylcellulose; further preferably copovidone and/or polyvinylpyrrolidone.
  • the sweetener is selected from the group consisting of sorbose, xylose, xylitol, glycerin, disodium glycyrrhizinate, mannose, galactose, maltose, lactose, fructose, sweetener, sodium saccharin, Steviol, glucose, sucrose, sucralose, aspartame and neotame; preferably xylitol, sucralose, aspartame and neotame.
  • the fragrance is one or more of oils or essences; preferably cumin oil, rose oil, peppermint oil, orange peel oil, lemon oil, rose essence, lemon essence , one or more of vanilla essence, vanillin, banana essence, pineapple essence or apple essence; more preferably one or more of lemon essence, pineapple essence or apple essence.
  • the components of the pharmaceutical composition and their weight percentages are:
  • Active ingredient its weight percentage is 0.50% to 30%; or 0.60% to 25%; or 0.70% to 20%; or 0.80% to 15%; or 1% to 10%; or 1.50% to 8%; or 2 % ⁇ 6%; or 2.50% ⁇ 5%; or 3% ⁇ 4.50%;
  • filler whose weight percentage is 50% to 99.90%; or 60% to 99.50%; or 70% to 99%; or 80% to 99%; or 85% to 99%;
  • Adhesive its weight percentage is 0% to 10%; or 0% to 6%; or 0% to 5%; or 0% to 4%; or 0% to 3%; or 0% to 0% 2%;
  • Flavoring agent the weight percentage of which is 0% to 10%; or 0% to 6%; or 0% to 5%; or 0% to 4%; or 0% to 3%; or 0% to 0% 2%; or 0% to 1%;
  • the filler is selected from mannitol; the binder is selected from copovidone; preferably copovidone VA64 or copovidone VA64Fine; the flavoring agent is selected from sweeteners and /or aroma agent; the sweetener is selected from xylitol, sucralose, aspartame and/or neotame; the aroma agent is selected from lemon essence; each component of the pharmaceutical composition and its The weight percentages are:
  • the filler is selected from mannitol; the binder is selected from copovidone; preferably copovidone VA64; the flavoring agent is selected from lemon essence.
  • the pharmaceutical compositions of the above-described aspects may further contain other excipients than those of the type described. Specific examples thereof include disintegrating agents, bacteriostatic agents, thickening agents, dispersing agents, antioxidants, stabilizers, and the like.
  • the weight percentage of other excipients in the pharmaceutical composition is 0%-25%, preferably 0%-20%, 0%-15%, 0%-10% or 0% ⁇ 5%.
  • the pharmaceutical composition is prepared as an oral solid dosage form; preferably, the oral solid dosage form is selected from granules, powders and fine granules; more preferably, granules.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, a compound represented by formula II or formula A and an excipient, the excipient comprising a solvent, optionally, further comprising One or more of flavoring agents, bacteriostatic agents or pH adjusting agents.
  • the excipients comprise solvents and flavoring agents, and optionally, further comprise one or more of bacteriostatic agents or pH adjusting agents.
  • the excipients comprise solvents, flavouring agents and pH adjusting agents, and optionally, further comprise bacteriostatic agents.
  • the flavoring agent comprises a sweetening agent and, optionally, further comprises a flavoring agent.
  • the aforementioned sweetener is selected from the group consisting of sorbose, xylose, xylitol, glycerin, disodium glycyrrhizinate, mannose, galactose, maltose, lactose, fructose, sweetener, sodium saccharin, stevia One or more of glycosides, glucose, sucralose, sucralose, aspartame and/or neotame; preferably one or more of xylitol, sucralose, aspartame and/or neotame one or more.
  • the aforementioned fragrances are one or more of oils or essences; preferably cumin oil, rose oil, peppermint oil, orange peel oil, lemon oil, rose essence, lemon essence, One or more of vanilla essence, vanillin, banana essence, pineapple essence or apple essence; more preferably one or more of lemon essence, pineapple essence or apple essence.
  • the aforementioned solvent is selected from the group consisting of water, ethanol and vegetable oil; preferably water; more preferably purified water.
  • the aforementioned bacteriostatic agent is selected from one or more of sodium benzoate, potassium sorbate, urotropine, ethanol, benzyl alcohol or parabens; preferably sodium benzoate, sorbitan One or more of potassium acid, urotropine, ethanol, benzyl alcohol, methylparaben, ethylparaben or propylparaben; more preferably sodium benzoate, potassium sorbate , one or more of methylparaben, ethylparaben or propylparaben.
  • the aforementioned pH adjusting agent is one or more of sodium hydroxide, sodium bicarbonate, and sodium carbonate.
  • the components of the pharmaceutical composition and their weight percentages are:
  • Active ingredient its weight percentage is 0.10% to 40%; or 0.10% to 35%; or 0.10% to 30%; or 0.50% to 25%; or 0.50% to 20%; or 1% to 10%;
  • Solvent whose weight percentage is 90% to 99.99%; or 95% to 99.99%; or 96% to 99.99%; or 97% to 99.99%;
  • Sweetener its weight percentage is 0% to 5%; or 0.01% to 4%; or 0.05% to 3%; or 0.10% to 2%; or 0.10% to 1%; or 0.10% to 0.50%;
  • Fragrance its weight percentage is 0%-5%; or 0.01%-4%; or 0.05%-3%; or 0.05%-2%; or 0.05%-1.50%; or 0.05%-1%;
  • Bacteriostatic agent its weight percentage is 0% to 6%; or 0% to 5%; or 0% to 4%; or 0% to 3%; or 0% to 2.50%; or 0% to 2%; or 0% ⁇ 1.50%; or 0% ⁇ 1%; or 0% ⁇ 0.50%;
  • excipients whose weight percentages are 0% to 25%; or 0% to 20%; or 0% to 15%; or 0% to 10%; or 0% to 5%;
  • the solvent is water; the fragrance is lemon essence; the sweetener is neotame, and the pH adjuster is sodium hydroxide.
  • the components of the pharmaceutical composition and their weight percentages are:
  • the pharmaceutical compositions of the above-described aspects may further contain other excipients than those of the type described. Specific examples thereof include thickeners, dispersants, surfactants, antioxidants, stabilizers, and the like.
  • the weight percentage of other excipients in the pharmaceutical composition is 0%-25%, preferably 0%-20%, 0%-15%, 0%-10% or 0% ⁇ 5%.
  • the pharmaceutical composition is formulated as an oral solution.
  • the pharmaceutical composition may be formulated in single-dose form or in multiple-dose form.
  • the single-dose form of the oral solution is 1-30 mL, preferably 1-20 mL, more preferably 1-15 mL, further preferably 1-10 mL, further preferably 1 mL, 2 mL, 3 mL , 4mL, 5mL, 6mL, 7mL, 8mL, 9mL or 10mL.
  • the multi-dose form of the oral solution is 2-500 mL, preferably 2-250 mL, more preferably 5-250 mL, still more preferably 10-200 mL, still more preferably 15-150 mL, further Preferably it is 20-100 mL, More preferably, it is 20-50 mL, More preferably, it is 30-50 mL.
  • the pharmaceutical compositions described above contain 0.001-1000 mg of active ingredients, preferably 0.1-800 mg, more preferably 1-500 mg, further preferably 10-300 mg, further Preferably 10-200mg, more preferably 10-100mg dosage range, for example, the pharmaceutical composition in single dosage form contains 5mg, 10mg, 20mg, 25mg, 30mg, 50mg, 60mg, 100mg, 150mg, 200mg, 250mg, 300mg, 500 mg, etc.; wherein the active ingredient is in the form of a hydrochloride salt ( eg , C24H29N9.3HCl in some aspects of the application).
  • a hydrochloride salt eg , C24H29N9.3HCl in some aspects of the application.
  • each preparation unit of the oral preparation, oral solid preparation or oral solution described above may contain 0.001-1000 mg of active ingredient, preferably 0.1-800 mg, and further Preferably 1-500mg, more preferably 10-300mg, still more preferably 10-200mg, still more preferably 10-100mg dosage range, for example, the oral preparation in single dosage form contains 5mg, 10mg, 20mg, 25mg, 30mg, 50mg, 60mg of active ingredient , 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 500 mg, etc.; wherein the active ingredient is in the form of a hydrochloride salt (eg, C 24 H 29 N 9 ⁇ 3HCl in some aspects of the application).
  • a hydrochloride salt eg, C 24 H 29 N 9 ⁇ 3HCl in some aspects of the application.
  • the present application provides a method for preparing the above-mentioned pharmaceutical composition, which comprises: (1) weighing: weighing the active ingredients and excipients according to the prescribed amount; (2) mixing: placing the active ingredients and excipients in a Mix well in mixing container.
  • the pharmaceutical composition is made into capsules, and the preparation method includes: (1) weighing the active ingredients and excipients according to the prescription; (2) adding the active ingredients and excipients Mixing in a mixing container produces a mixed powder; (3) using the above mixed powder to fill a capsule.
  • the excipient of the pharmaceutical composition includes an external lubricant; the pharmaceutical composition is made into a capsule, and the preparation method includes: (1) weighing the active ingredient and the excipient according to the prescription amount (2) adding active ingredient and excipients other than adding lubricant into a mixing container and mixing to produce mixed powder; (3) using the above-mentioned mixed powder for granulation; (4) by step (3) obtained The granules are mixed with an external lubricant; (5) the mixture obtained in step (4) is filled into capsules.
  • the pharmaceutical composition is made into a tablet, and the preparation method includes: (1) weighing the active ingredient and the excipient according to the prescription; (2) mixing the active ingredient and the excipient (3) use the above-mentioned mixed powder for granulation; (4) mix the granules obtained in step (3) with an external lubricant; (5) perform tablet compression; and optionally Optionally, a coating step is further included.
  • the pharmaceutical composition is made into granules, and the preparation method includes: (1) weighing the active ingredient and the excipient according to the prescribed amount; (2) adding the excipient and the active ingredient to the Mixing in a mixing vessel produces a premix; (3) adding water to make a soft material; (4) granulating and drying; (5) granulating.
  • the pharmaceutical composition is made into an oral liquid preparation, and the preparation method includes: (1) weighing the active ingredient and the excipient according to the prescribed amount; (2) mixing the excipient and the active ingredient Add to mixing container, stir and mix; (3) sterilization; (4) filling.
  • a preparation method of the above-mentioned solid oral preparation which comprises: packing the pharmaceutical composition obtained by the above-mentioned preparation method into a packaging bag according to a packaged dose to prepare a powder or fine granule.
  • the above "mixing container” should be understood in a broad sense, which includes both flexible mixers (including but not limited to flexible bags such as clean plastic bags, ziplock bags, etc.) and rigid mixers (including but not limited to mixers, hoppers, etc.) mixer, etc.). Those skilled in the art can select a suitable mixer according to the batch and weight to carry out the corresponding premixing and blending operations.
  • granulation should be understood in a broad sense, including the use of a mortar for granulation, optionally, granulation may be further assisted by a sieving operation, or the sieving operation may be assisted to make the obtained granules meet the requirements, and also include:
  • the granulation operation is carried out using mechanical equipment, such as a dry granulator, etc. Those skilled in the art can select appropriate tools or machinery equipment to carry out the corresponding granulation operation according to the batch and weight.
  • the application provides the aforementioned pharmaceutical composition or the aforementioned solid oral preparation for inhibiting FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, Use of the activity of one or more of c-SRC, FGFR1, KDR, MET and PDGFR ⁇ kinases.
  • the present application provides the use of the aforementioned pharmaceutical composition or the aforementioned oral preparation for preparing a medicine.
  • the medicament is for the treatment or prevention of a disease mediated by a protein kinase selected from the group consisting of: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2 One or more of , ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFR ⁇ kinases.
  • a protein kinase selected from the group consisting of: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2
  • a protein kinase selected from the group consisting of: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2
  • a protein kinase selected from the group consisting of: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEG
  • the protein kinase-mediated disease is a tumor disease, preferably a hematological tumor or a solid tumor, more preferably a leukemia or lung cancer, more preferably an acute myeloid leukemia such as FLT3 mutation-positive acute myeloid Leukemia (further such as FLT3-ITD-mutated or FLT3-TKD-mutated acute myeloid leukemia), chronic myeloid leukemia (eg Ph-positive chronic myeloid leukemia), or non-small cell lung cancer (eg, EGFR activating mutation non-small cell lung cancer) ).
  • an acute myeloid leukemia such as FLT3 mutation-positive acute myeloid Leukemia (further such as FLT3-ITD-mutated or FLT3-TKD-mutated acute myeloid leukemia), chronic myeloid leukemia (eg Ph-positive chronic myeloid leukemia), or non-small cell lung cancer (eg, EGFR activating mutation non-small cell lung cancer) ).
  • the medicament is used for the treatment or prevention of acute myeloid leukemia; preferably, the acute myeloid leukemia is selected from relapsed and/or refractory acute myeloid leukemia, or, the acute myeloid leukemia Myeloid leukemia selected from FLT3-ITD-mutated and/or TKD-mutated acute myeloid leukemia, relapsed and/or refractory acute myeloid leukemia that has failed treatment with a type II FLT3 inhibitor (eg, sorafenib), or, DEK - CAN-positive acute myeloid leukemia coexisting with FLT3-ITD mutation; more preferably, said acute myeloid leukemia is FLT3-ITD high-mutated acute myeloid leukemia; and/or said acute myeloid leukemia has a poor prognosis There are 0 to 2 factors; and/or the FAB type of the acute myeloid leukemia is M2, M4,
  • the present application provides the use of the aforementioned pharmaceutical composition or the aforementioned oral preparation for preparing a drug as a protein kinase inhibitor, wherein the protein kinase is selected from: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn One or more of , Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFR ⁇ kinases.
  • the protein kinase inhibitor drug is an anti-tumor drug
  • the tumor is preferably a solid tumor or a hematological tumor, more preferably a leukemia or lung cancer, more preferably an acute myeloid leukemia such as FLT3 mutation-positive Acute myeloid leukemia (further such as FLT3-ITD-mutated or FLT3-TKD-mutated acute myeloid leukemia), chronic myeloid leukemia (eg Ph-positive chronic myeloid leukemia), or non-small cell lung cancer (eg, non-small cell lung cancer (eg, non-small cell lung cancer) Small Cell Lung Cancer).
  • FLT3 mutation-positive Acute myeloid leukemia further such as FLT3-ITD-mutated or FLT3-TKD-mutated acute myeloid leukemia
  • chronic myeloid leukemia eg Ph-positive chronic myeloid leukemia
  • non-small cell lung cancer eg, non-small cell lung cancer (eg
  • the protein kinase inhibitor drug is an anti-tumor drug
  • the tumor is selected from the group consisting of non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, epidermal squamous cancer, breast cancer, colorectal cancer, liver cancer, gastric cancer, and malignant melanoma; further preferably, the disorder is selected from human non-small cell lung cancer, human acute myeloid leukemia, human chronic myeloid leukemia, human chronic myeloid leukemia , human epidermal squamous cell carcinoma, human breast cancer, human colorectal cancer, human liver cancer, human gastric cancer, and human malignant melanoma.
  • the application provides the purposes of the aforementioned pharmaceutical composition or the aforementioned oral preparation in the preparation of a medicine for the treatment or prevention of a disorder; , Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFR ⁇ kinase in one or more than one of the resulting disorders; more preferably, the disorder is selected from from non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, epidermal squamous cell carcinoma, breast cancer, colorectal cancer, liver cancer, gastric cancer, and malignant melanoma; further preferably, the disorder is selected from Human non-small cell lung cancer, human acute myeloid leukemia, human chronic myeloid leukemia, human chronic myeloid leukemia, human epidermal squamous cell carcinoma, human breast cancer, human colorectal cancer, human liver cancer,
  • the application provides the above-mentioned pharmaceutical composition or the above-mentioned oral preparation, which is used for the treatment of protein kinase-related diseases, and the protein kinase is selected from: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, One or more of Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFR ⁇ kinases.
  • the protein kinase-related disease is selected from the group consisting of non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, epidermal squamous cell carcinoma, breast cancer, colorectal cancer, liver cancer, Gastric cancer, and malignant melanoma; further preferably, the disorder is selected from human non-small cell lung cancer, human acute myeloid leukemia, human chronic myeloid leukemia, human chronic myeloid leukemia, human epidermal squamous cell carcinoma, human breast cancer, human Colorectal cancer, human liver cancer, human gastric cancer, and human malignant melanoma.
  • the present application provides a method for treating a protein kinase-mediated disease, comprising using the aforementioned pharmaceutical composition or the aforementioned oral formulation to a subject in need thereof, the protein kinase being selected from the group consisting of FLT3, EGFR, One or more of Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFR ⁇ kinases.
  • the protein kinase-related disease is selected from the group consisting of non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, epidermal squamous cell carcinoma, breast cancer, colorectal cancer, liver cancer, Gastric cancer, and malignant melanoma; further preferably, the disorder is selected from human non-small cell lung cancer, human acute myeloid leukemia, human chronic myeloid leukemia, human chronic myeloid leukemia, human epidermal squamous cell carcinoma, human breast cancer, human Colorectal cancer, human liver cancer, human gastric cancer, and human malignant melanoma.
  • the therapeutically effective amount of the active ingredient is 0.001 to 1000 mg, preferably 1 to 800 mg, or 1 to 500 mg, or 20 to 400 mg, or 100-350 mg, most preferably 150-310 mg, the therapeutically effective amount in the form of the hydrochloride salt (eg, C24H29N9.3HCl in some embodiments of the present application).
  • Administration can be single dose or divided doses.
  • Oral formulation refers to a pharmaceutical formulation for oral administration.
  • Oral solid formulation refers to a solid pharmaceutical formulation for oral administration.
  • oral solution formulation or “oral solution” as used herein refers to a pharmaceutical formulation in a solution state for oral administration.
  • the subject of administration may be a human or a non-human mammal, more preferably a human.
  • a pharmaceutical composition comprising: as an active ingredient a compound represented by formula II, formula A or formula B and an excipient
  • a pharmaceutical composition comprising as an active ingredient a compound such as Compounds represented by formula II, formula A or formula B and excipients.
  • the amount of the compound represented by Formula I, Formula II, Formula A or Formula B or a pharmaceutically acceptable salt thereof in the formulation can be adjusted appropriately, or the ratio with the excipient (mass ratio) is adjusted to obtain pharmaceutical compositions or oral preparations containing different specifications or different drug weights, which also fall within the scope of the present application.
  • the preparation method of the pharmaceutical composition is simple, the preparation process is smooth, and there are no harsh requirements for the equipment and operation techniques used, and it is more suitable for industrial production; (2) After screening, it was found that the application described Some of the pharmaceutical compositions described above are suitable for direct mixing or dry granulation, which can simplify the preparation process of solid preparations; (3) compared with other prescriptions, the oral preparations made from the above-mentioned pharmaceutical compositions meet the preparation standards and requirements, such as oral solid preparations
  • the preparation eg, capsule, tablet
  • the pharmaceutical composition and/or oral preparation, especially the oral solid preparation also has excellent stability, In influencing factor tests, accelerated tests and/or long-term tests, the maximum single-unit cost of the investigated pharmaceutical compositions and/or oral formulations (especially oral solid formulations, such as capsules and tablets, more particularly, capsules)
  • octadecylsilane-bonded silica gel as the filler (the applicable pH value should be greater than 10.0), and use 20mmol/L disodium hydrogen phosphate solution (adjust the pH value to 10.0 with sodium hydroxide)-acetonitrile (65:35) as Mobile phase; the detection wavelength is 287nm, and the column temperature is 30°C.
  • the number of theoretical plates should not be less than 3000.
  • Determination method Take about 20 mg of the sample, accurately weigh it, put it in a 100 mL volumetric flask, add a diluent (50% methanol water) to dissolve and dilute to the mark, shake well, accurately measure 10 ⁇ L, inject it into a liquid chromatograph, and record the chromatogram ; Take another appropriate amount of reference substance, and measure with the same method. According to the external standard method to calculate the peak area, namely.
  • Test method After the instrument is balanced, take an appropriate amount of the test sample (about 200 mg), accurately weigh it, add it to a titration cup, use anhydrous methanol as a solvent, and directly measure it with a water titrant. Each test sample is measured twice and averaged. value.
  • pH 1.2 hydrochloric acid solution add 7.65 ml of hydrochloric acid, add 1000 ml of water, and shake well to get it.
  • Phosphate buffer solution of pH 4.5 take 6.8 g of potassium dihydrogen phosphate, dilute it with water to 1000 ml, and shake well.
  • Phosphate buffer at pH 6.8 take 6.8 g of potassium dihydrogen phosphate and 0.896 g of sodium hydroxide, dilute with water to 1000 ml, and shake well.
  • Preparation of reference solution take an appropriate amount of the compound of formula 1, accurately weigh, add solvent to dissolve and dilute to make a solution containing about 10 ⁇ g of compound of formula 1 per 1 ml, measure the absorbance at 287nm wavelength, and calculate.
  • the thickness of the test sample is generally about 1 mm, and the weight (m2) is precisely weighed.
  • Weight gain percentage (m3-m2)/(m2-m1) ⁇ 100%
  • Deliquescence Absorbs sufficient water to form a liquid.
  • the weight gain is not less than 15%.
  • Moisture gain is less than 15% but not less than 2%.
  • the weight gain of hygroscopicity is less than 2% but not less than 0.2%.
  • hygroscopic weight gain is less than 0.2%.
  • Light tube type Cu target, metal ceramic X-ray tube;
  • X-ray wavelength CuK ⁇ , K ⁇ 2 /K ⁇ 1 intensity ratio: 0.5;
  • Total scan time about 5min.
  • Heating rate 10.0 (K/min);
  • Atmosphere N 2 , 20.0ml/min/N 2 , 50.0ml/min
  • Detection instrument AVIII BRUKER 600 superconducting nuclear magnetic resonance spectrometer
  • compound B reference substance was taken, accurately weighed, placed in a 100 mL volumetric flask, dissolved and diluted to the mark by adding pH1.2 hydrochloric acid solution, shaken up, and used as the reference substance stock solution; accurately measure the reference substance stock solution and dilute it For the solution of 10ug/mL, as the reference solution.
  • Determination method Take appropriate amount of reference solution and test solution respectively, measure the absorbance at 287nm wavelength according to UV-Vis spectrophotometry, and calculate the dissolution amount of each grain with absorbance according to the external standard method.
  • Compound I of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and to those skilled in the art. Say the obvious equivalent alternative. Preferred embodiments include, but are not limited to, the preparation examples of the present application.
  • Hydrochloric acid after adding concentrated hydrochloric acid, add 2L acetone, keep the temperature at 40 ⁇ 5°C, continue the reaction for 1h, then stir and cool down to 10 ⁇ 5°C for 2 hours, filter with suction, wash the filter cake with 300mL acetone, and get yellow or pale Yellow hydrochloride 74.7g.
  • the samples were taken for DSC and TGA tests, and the chromatograms are shown in Figure 2, respectively.
  • the DSC spectrum shows that there is no obvious melting point, and the TGA spectrum shows that the sample begins to lose crystal water at about 40 °C; it begins to lose acid at about 140 °C.
  • the specific methods are: 1) Weighing or material preparation: Weigh the active ingredient (API) Compound B and the corresponding filler, glidant, lubricant (internally added, externally added) according to the prescription amount; 2) Pre-mixing 1: Add active ingredients, fillers, glidants and lubricants (internally added) into the mixing container in turn to carry out pre-mixing; 3) Depolymerization: Depolymerize the obtained mixed powder; 4) Pre-mix 2 : The mixed powder after the depolymerization treatment is added into the mixing container, and premixed again; 5) Dry granulation: the premixed powder is again premixed to be pressed by a tablet machine, and granulated after the pressing is completed; 6) Total mixing: add the granules obtained in step 5) into a mixing container, add lubricant (extra), and mix; 7) Capsule filling: select a suitable type of capsule shell for filling according to
  • results show: within the scope of the application, adjust the weight percent of colloidal silicon dioxide and magnesium stearate (internally added), and the obtained prescription does not have phenomena such as sticking, flower pieces, agglomeration and/or layering,
  • the process of pressing large tablets before granulation is smooth, that is, the tablet pressing process meets the requirements, the dissolution is fast, the preparation requirements are met, and the prescriptions are all qualified.
  • Example 2 Referring to the preparation method of Example 1, and adjusting the dosage of the filler, the following pharmaceutical composition can be obtained.
  • the specific prescription and test results are shown in Table 4.
  • the weight percentage of magnesium stearate (internally added) and magnesium stearate (externally added) are both 1%; each recipe is made into 100 capsules, and the total weight is 16g.
  • Example 1 on the basis of Example 1, with the recipe obtained by adding a disintegrant, the process of pressing large tablets before granulation is smooth, slightly sticky or non-sticky, and there is no phenomenon such as flower pieces, agglomeration and/or delamination. , that is, the tableting process meets the requirements, the dissolution is rapid, the formulation requirements are met, and the prescription is qualified, that is, the effect is equivalent to that without disintegrant. Therefore, whether or not to add a disintegrant has little effect on the formulation of a single filler (pregelatinized starch).
  • Example 2 Referring to the recipe and preparation method of Example 1, using pregelatinized starch and mannitol as combined fillers, the following pharmaceutical compositions can be obtained. The specific prescription and test results are shown in Table 6.
  • the weight percentage of magnesium stearate (internally added) and magnesium stearate (externally added) are both 1%; each recipe is made into 100 capsules, and the total weight is 16g.
  • Example 1 Referring to the preparation method of Example 1, using microcrystalline cellulose and lactose as combined fillers, the following pharmaceutical compositions can be obtained.
  • the specific prescription and test results are shown in Table 7 and Table 8, respectively.
  • results show that: using the combined filler of microcrystalline cellulose and lactose, the process of pressing large tablets before granulation is smooth, without sticking and punching, and there is no phenomenon of flower chips, agglomeration and/or delamination, that is, the tablet pressing process meets the requirements.
  • the dissolution is fast, meets the preparation requirements, and the prescriptions are all qualified.
  • Example 15 Referring to the preparation method and loading amount of Example 15, using microcrystalline cellulose as a single filler, according to the formulation composition and weight percentage in Table 9, the pharmaceutical composition was prepared. The specific prescription and experimental results are shown in Table 9 below.
  • the obtained formulation (Example 16) meets the requirements in the granulation process without adding a disintegrant; Silicon dioxide), the obtained recipe (Example 17) still meets the requirements in the granulation process, that is, the process of pressing large tablets before the granulation of the obtained recipe is smooth, slightly sticky or non-sticky, and there are no flower pieces, agglomeration and and/or delamination.
  • Example 16 and Example 17 For the formulations of Example 16 and Example 17, the dissolution results show that although the dissolution is slightly slower at 15 minutes, the dissolution at 30 minutes meets the requirements, and can be selected according to drug needs.
  • Example 15 Referring to the formulation composition and preparation method of Example 15, and adjusting the weight ratio of the combined filler, the following pharmaceutical composition (100 capsules) can be obtained.
  • the specific prescription and test results are shown in Table 10.
  • the weight percentage of magnesium stearate (internally added) and magnesium stearate (externally added) are both 1%; each recipe is made into 100 capsules, and the total weight is 18g.
  • Example 15 changing the type of disintegrant and adjusting the ratio of the two fillers, the following pharmaceutical composition (100 capsules) can be obtained.
  • the specific prescription and test results are shown in Table 11.
  • the weight percentage of magnesium stearate (internally added) and magnesium stearate (externally added) are both 1%; each recipe is made into 100 capsules, and the total weight is 18g.
  • the disintegrant is sodium carboxymethyl starch
  • the process of pressing large tablets before granulation of the obtained prescription is smooth, without sticking and punching, and there are no phenomena such as flower tablets, agglomeration and/or delamination, that is, the tableting process conforms to the
  • the obtained prescriptions have good dissolution effect, meet the preparation requirements, and the prescriptions are all qualified. Therefore, in the case of satisfying the compatibility of raw and auxiliary materials, the selection and replacement of disintegrants can be carried out according to the medication needs.
  • Example 15 Referring to the preparation method of Example 15 and the prescription composition of Example 20, using sodium starch glycolate as a disintegrant, and adjusting its dosage, the following pharmaceutical composition (100 capsules) can be obtained.
  • the specific formulation composition and test results are shown in Table 12.
  • the weight percentage of magnesium stearate (internally added) and magnesium stearate (externally added) are both 1%; each recipe is made into 100 capsules, and the total weight is 18g.
  • Example 15 Referring to the preparation method of Example 15 and the prescription composition of Example 20, and changing the type of lubricant, the following composition (100 capsules) can be obtained.
  • the specific prescription and test results are shown in Table 13.
  • Example 14 Referring to the prescription and preparation method of Example 1, and replacing the filler, the following pharmaceutical composition (100 capsules) can be obtained. The specific prescription and test results are shown in Table 14.
  • the weight percentage of magnesium stearate (internally added) and magnesium stearate (externally added) are both 1%; 100 tablets are made according to the prescription, and the total weight is 10g.
  • Example 25 Referring to the preparation method of Example 1 and the formulation composition of Example 25, adjusting the ratio of each component, or further increasing the disintegrant, the following pharmaceutical composition can be obtained.
  • the specific prescription and test results are shown in the table.
  • the weight percentage of magnesium stearate (internally added) and magnesium stearate (externally added) are both 1%; each recipe is made into 100 capsules, and the total weight is calculated according to the amount of each capsule; "/" means no detection.
  • Example 25 Referring to the preparation method of Example 1 or Example 15, and the formulation composition of Example 25, the following pharmaceutical composition can be obtained by replacing a single filler with a combination of two fillers.
  • the specific prescription and test results are shown in Table 16.
  • Example 30 the weight percentages of magnesium stearate (internally added) and magnesium stearate (externally added) are both 1%; in Example 32, magnesium stearate (internally added) and stearic acid The weight percentages of magnesium (additional) are 0.5% and 1% respectively; 100 capsules are made according to the prescription, and the total weight is calculated according to the filling amount of each capsule.
  • Example 25 The results show that compared with Example 25, using the combination of two fillers (for example, the combination of anhydrous calcium hydrogen phosphate and pregelatinized starch), or further adjusting the ratio of each component, has a better effect on the granulation process (non-sticky There was no impact on the results of punching, no flower flakes, agglomeration and/or delamination, etc.) and dissolution results, and all prescriptions were qualified.
  • two fillers for example, the combination of anhydrous calcium hydrogen phosphate and pregelatinized starch
  • Example 15 or Example 30 replacing the filler, or further adding a disintegrant and/or replacing the disintegrating agent, or further adding a binder, the following pharmaceutical compositions can be obtained.
  • the specific prescription and test results are shown in Table 17.
  • the weight percentages of magnesium stearate (internally added) and magnesium stearate (externally added) are both 1%; each recipe is made into 100 capsules, and the total weight is calculated according to the amount of each capsule.
  • Example 15 or Example 30 adding a second filler, or further adding a disintegrant and/or a binder, the following pharmaceutical composition can be obtained.
  • the specific prescription and test results are shown in Table 18.
  • the weight percentages of magnesium stearate (internally added) and magnesium stearate (externally added) are both 1%; each recipe is made into 100 capsules, and the total weight is calculated according to the amount of each capsule.
  • the above-mentioned qualified pharmaceutical composition prescriptions can be made into preparations containing different specifications of active ingredients, and exemplary prescriptions include (made into 100 capsules):
  • Example 39-2 is the same as that of Example 1.
  • Example 39-5 is the same as that of Example 11.
  • Examples 39-8 and 39-9 refer to the preparation method of Example 1, and the filler ratio and gelatin hollow capsules can be appropriately adjusted according to the required specifications and loadings.
  • Example 39-7 was prepared using the direct mixing process, and the specific methods were: 1) material preparation: weigh the active ingredient (API) compound B and various excipients according to the recipe; 2) premix 1: colloidal silicon dioxide sieve and mix with the active ingredient, and place in a mixing container; 3) premix 2: add pregelatinized starch and mannitol to the above-mentioned mixed powder, shake and mix well; 4) total mixing: add magnesium stearate to the above-mentioned mixed powder Step 3) In the obtained mixed powder, shake and mix evenly; 5) Capsule filling: select a suitable type of capsule shell according to the filling amount for filling and filling.
  • API active ingredient
  • premix 1 colloidal silicon dioxide sieve and mix with the active ingredient, and place in a mixing container
  • premix 2 add pregelatinized starch and mannitol to the above-mentioned mixed powder, shake and mix well
  • total mixing add magnesium stearate to the above-mentioned mixed powder Step 5)
  • the filler ratio and gelatin hollow capsules can be appropriately adjusted according to the required specifications and loadings.
  • the filler ratio and gelatin hollow capsules can be appropriately adjusted according to the required specifications and loadings.
  • each prescription is made into 100 tablets respectively; the weight percentage of coating powder is the weight of coating powder/total tablet core weight; the model of coating powder: Opadry 85G68918, the specific composition is polyvinyl alcohol, titanium dioxide, talcum powder, Polyethylene glycol, soybean lecithin.
  • the dry granulation process is used, and the specific methods are: 1) material preparation: weigh the active ingredient (API) compound A and the corresponding filler, glidant, and lubricant according to the recipe quantity; 2) premix 1: mix the active ingredient, filling 3) Depolymerization: depolymerize the obtained mixed powder; 4) Premix 2: depolymerize the mixed powder after depolymerization Add into the mixing container, and premix again; 5) granulation; 6) total mixing: mix the granules obtained in step 5) with lubricant (externally added); 7) tableting: use a tableting machine for tableting; 8) Coating: The tablet obtained in step 5) is coated.
  • API active ingredient
  • premix 1 mix the active ingredient, filling
  • Depolymerization depolymerize the obtained mixed powder
  • Premix 2 depolymerize the mixed powder after depolymerization Add into the mixing container, and premix again; 5) granulation; 6) total mixing: mix the
  • the specific methods are: 1) material preparation: weigh the active ingredient (API) compound B and the corresponding excipients according to the recipe quantity; 2) premix 1: add the active ingredients and various excipients into the mixing container in turn, and carry out premixing. Mixing; 3) Making soft material: adding appropriate amount of water to make suitable soft material; 4) granulating: using for granulation; 5) drying: drying at 45°C; 6) granulating.
  • API active ingredient
  • premix 1 add the active ingredients and various excipients into the mixing container in turn, and carry out premixing. Mixing; 3) Making soft material: adding appropriate amount of water to make suitable soft material; 4) granulating: using for granulation; 5) drying: drying at 45°C; 6) granulating.
  • the specific methods are: 1) Weighing: Weigh the active ingredient (API) Compound B and the corresponding sweetener according to the prescribed amount; 2) Dosing: first place the active ingredient and the sweetener in a beaker, and add the solvent while adding the solvent. Stir, after stirring evenly, use sodium hydroxide to adjust the pH of the solution to 4-5; 3) Filtration: filter and sterilize the prepared solution; 4) Filling: fill the filtered solution according to the required dosage ; 5) Roll cover.
  • the inner bag is a medicinal low-density polyethylene bag
  • the outer bag is a polyester/aluminum/polyethylene compound bag for pharmaceutical packaging.
  • Samples were taken at the end of the 3rd, 6th, 9th, 12th and 18th months, and other inspection indicators were tested after comparing the appearance. The results were compared with the 0th month.
  • the experimental results are shown in the following table:
  • the salt sample obtained in Preparation Example 2 was tested according to the kinase inhibitory activity evaluation described in the biological evaluation of patent application WO 2011/147066.
  • the test results show that the sample can inhibit the expression of FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET and PDGFR ⁇ kinases.
  • Activity, some kinase test results are shown in the table below.
  • Kinase IC50 (nM) Kinase IC50 (nM) FLT3(h) 26 Lyn(h) 7 FLT3-ITD(h) 3-10 Ret(h) 10 EGFR(h) 42 Yes 4 Abl(h) 25 c-SRC(h) 176 Fyn(h) 34 FGFR1(h) 247
  • the salt samples obtained in Preparation Example 2 were tested (specifically for FLT3-ITD acute myeloid leukemia, EGFR activating mutation non-small cell lung cancer) , or Ph-positive chronic myeloid leukemia).
  • the test results show that in the MV4-11 (FLT3-ITD mutation) subcutaneous tumor model experiment (refer to Example 4 of WO2011/147066 to establish a model), the sample (orally once a day, administered for 21 days) was administered at a dose of 5 mg. Tumor growth was completely inhibited at 10 mg/kg and 20 mg/kg, which resulted in complete tumor regression.
  • the sample can dose-dependently inhibit the growth of human non-small cell lung cancer HCC827 at 7.5mg/kg, 15mg/kg, 30mg/kg
  • the K562 (BCR-Abl gene rearrangement) subcutaneous tumor model experiment (a model similar to the MV4-11 subcutaneous tumor model), the sample (orally once a day for 18 days) was administered at a dose of 70 mg/kg It can effectively inhibit tumor growth, and the tumor inhibition rate reaches 71.3%.
  • Capsule samples from Examples 39-1, 39-2, 39-7, 39-8, and 39-9, and tablet samples from Example 40 were taken according to example packaging conditions (aluminum foil and polyamide/aluminum/polyvinyl chloride cold Stamping and forming solid pharmaceutical composite hard sheet packaging), placed in a constant temperature and humidity box at 40 °C ⁇ 2 °C, relative humidity 75% RH ⁇ 5% RH, for 6 months of accelerated test, at 0, 1, 2, 3. Sampling at the end of 6 months, carry out key project investigation, and the test results of representative examples (Example 39-2, 39-7, 39-8 and Example 40) (other examples are proportional amplification or proportional adjustment) , not all data presented, results are similar) see Tables 30-33.
  • the accelerated test results show that the three examples of pharmaceutical compositions placed in the package are placed in the package under the conditions of 40 ⁇ 2 ° C and relative humidity of 75% RH ⁇ 5% RH for 6 months. No increase in related substances or slight increase. The content is basically unchanged; other inspection items at each time point are in compliance with the regulations, and the crystal form of the active ingredient has not changed.
  • the capsule samples of Examples 39-1 and 39-9 also remained stable in the accelerated test, and there was no significant change in drug properties, related substances, drug content, dissolution rate, microbial limit, etc.
  • the tablet sample of Example 40 was in the accelerated test. It also remained stable in drug properties, related substances, drug content, microbial limits, etc. There were no significant changes.
  • Examples 39-1, 39-2, 39-7, 39-8 and 39-9 Take the capsule samples of Examples 39-1, 39-2, 39-7, 39-8 and 39-9, according to the example packaging conditions (aluminum foil and polyamide/aluminum/polyvinyl chloride cold stamping to form a solid pharmaceutical composite hard sheet packaging), placed in a constant temperature and humidity box at 30°C ⁇ 2°C and relative humidity of 65%RH ⁇ 5%RH, for 30 months of accelerated test, at 3, 6, 9, 12, 18, 24, 30 Samples were taken at the end of the month, and the test results of the representative examples (Examples 39-7 and 39-8) (other examples were scaled up or scaled, not all data are presented, the results are similar) are shown in Tables 34-35.

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Abstract

一种包含多靶点蛋白激酶抑制剂化合物的药物组合物及其应用。药物组合物包含作为活性成分的式II、式A或式B所示的化合物及赋形剂。所述的药物组合物具有制备方法简便、制剂过程顺利、适于工业化生产的特点，且由该药物组合物制成口服制剂，特别是口服固体制剂具有有利的溶出度、含量均匀度等制剂性质和优良的稳定性，适于作为药品使用和存储。

Description

一种多靶点蛋白激酶抑制剂的药物组合物及其应用
相关申请的引用
本发明要求2020年12月31日在中国提交的、名称为“一种多靶点蛋白激酶抑制剂的药物组合物及其应用”、申请号为202011642452.1和2021年7月22日在中国提交的、名称为“一种多靶点蛋白激酶抑制剂的药物组合物及其应用”、申请号为202110829596.6的发明专利申请的优先权，通过引用的方式将两篇专利申请的全部内容并入本文。
技术领域
本申请属于药物制剂技术领域，具体涉及一种多靶点蛋白激酶抑制剂的药物组合物及其应用。
背景技术
恶性肿瘤是威胁人类生命健康的最重大疾病之一，已成为仅次于心血管疾病的人类第二大死因。化疗是除手术和放疗之外最重要的恶性肿瘤治疗手段。传统的化疗药物主要作用于DNA、RNA和微管蛋白等与所有细胞生死相关的共有组分，致使其选择性低、毒性大。而靶向治疗药物，即作用于肿瘤细胞中与正常细胞有巨大差异的调控细胞生长增殖的关键分子及其信号转导通路，具有对肿瘤细胞的选择性高、对正常组织的毒性低等优点，已成为抗肿瘤药物研究的热点。
在众多的细胞信号转导通路调控分子中，蛋白激酶家族是最重要的信号转导分子，研究表明，许多肿瘤的发生和发展都与蛋白激酶的基因异常或过度激活有关，因此，蛋白激酶已成为最重要的抗肿瘤治疗靶点。在蛋白激酶家族成员中，以EGFR(Epidermal Growth Factor Receptor，表皮生长因子受体)、VEGFR(Vascular Endothelial Growth Factor Receptor，血管内皮细胞生长因子受体)、PDGFR(Platelet Derived Growth Factor Receptor，血小板衍生的生长因子受体)、c-Kit、c-SRC、MET、BTK、ALK、Abl、FLT3等酪氨酸、丝/苏氨酸蛋白激酶最为重要，它们已被列为癌基因(oncogene)或癌蛋白(oncoprotein)。
目前已有多个针对这些酪氨酸、丝/苏氨酸蛋白激酶的小分子抑制剂，应用于临床肿瘤治疗，典型的例子包括：两个EGFR的抑制剂，即吉非替尼(Gefitinib)和埃罗替尼(Erlotinib)，主要用于治疗非小细胞肺癌；两个新生血管抑制剂(主要靶点为VEGFR和PDGFR等)舒尼替尼(Sunitinib)和索拉非尼(Sorafenib)，用于实体肿瘤的抗新生血管治疗；Bcr-Abl激酶抑制剂伊马替尼(Imatinib)，主要用于费城染色体阳性的慢性髓细胞白血病(CML)的治疗。
随着越来越多靶向抗肿瘤药物应用于临床，一些问题也逐渐引起人们的重视。一方面，针对单个或少数几个激酶癌基因或癌蛋白的抗肿瘤药物，面临着有效率低、易产生耐药性等缺点，典型的例子如EGFR激酶抑制剂吉非替尼和埃罗替尼。这两种药物只对10-20％的非小细胞肺癌患者有效，关于其作用机制的研究发现，吉非替尼和埃罗替尼属于选择性的EGFR激酶抑制剂，它们主要对于发生了EGFR 19外显子缺失突变和21外显子L858R点突变的患者最敏感(EGFR 19外显子缺失突变和21外显子L858R点突变合称为EGFR敏感突变)。即使对于这些EGFR敏感突变的患者，在使用吉非替尼和埃罗替尼治疗6-9个月后，绝大部分都产生了耐药性。研究表明，产生耐药性的原因有多种，其中主要包括(1)EGFR敏感突变基础上又发生了二次突变，即EGFR的T790M突变；(2)MET基因(MET为酪氨酸激酶)发生了扩增。另一方面，现有蛋白激酶抑制剂还集中在EGFR、FGFR、VEGFR、JAK、PI3K和CDK等小部分激酶靶点，对其他激酶成员发掘尚不够，在抑制剂骨架结构和作用机制方面还有较大的探索空间。此外，虽然靶向药物相比传统抗肿瘤药物具有低毒、特异性强的特点，但在小分子激酶抑制剂的临床试验过程中仍观察到了不同程度的毒副作用，例如，据报道，Midostaurin在急性髓系白血病(AML)治疗过程中的常见不良反应主要有：白细胞减少、恶心呕吐、黏膜炎、头痛、皮肤瘀点、肌肉骨骼疼痛、鼻出血、高血糖、上呼吸道感染等。
研究新的抗肿瘤药物以解决小分子激酶抑制剂的有效率低、耐药性及安全性问题是当前抗肿瘤靶向药物研发的工作重点。目前人们正在探索有效的解决策略，其中最有前景的方法主要包括：(1)同时靶向多个与肿瘤发生发展相关的激酶的多激酶抑制剂。例如，EGFR在人类多种肿瘤组织中过度表达或异常过度激活，如果某小分子激酶抑制剂不仅能抑制EGFR的活性，也能抑制新生血管或其它调控 细胞生长增殖的关键激酶例如c-Kit、c-SRC、MET、BTK、ALK、Abl、FLT3等激酶癌基因或癌蛋白的活性，将可提高肿瘤治疗的有效率、降低耐药性的发生率；(2)直接靶向产生耐药突变的激酶。例如，如前所述，使用EGFR抑制剂吉非替尼和埃罗替尼后，EGFR本身容易在原来突变(即EGFR敏感突变)基础上又发生二次突变，即EGFR的T790M突变，该突变的发生是导致EGFR抑制剂吉非替尼和埃罗替尼失效的主要原因之一，因此，研发直接靶向耐药突变即针对T790M突变的EGFR激酶抑制剂，是一条克服这类肿瘤耐药性的直接途径。
专利WO2011147066A1公开了化合物I及其制备方法和用途，其是一种新型多靶点蛋白激酶抑制剂，主要作用靶标包括FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes等，可用于肿瘤疾病的治疗。
Figure PCTCN2021143219-appb-000001
发明内容
技术问题
本申请在化合物I的基础上，进一步发现了成药性较化合物I更好的化合物I的盐酸盐(例如，式II、式A)，所述盐酸盐不仅溶解度、稳定性等性能优于化合物I，而且从溶解性、吸湿性、稳定性等多方面考量，该盐酸盐整体比化合物I的其他盐型更适合用于制备药物。相应的研究和筛选过程已记载在PCT/CN2021/073285专利申请中，该申请的全部内容作为整体被引入本申请。鉴于化合物I在肿瘤疾病的治疗中具有良好的应用前景，寻求一种具有优异的制剂性质的包含化合物I或其药学上可接受的盐(例如，式II、式A)的药物组合物成为本领域技术人员亟待解决的问题。
Figure PCTCN2021143219-appb-000002
本申请所要解决的一个技术问题是提供一种满足口服给药需要的、包含作为活性成分的式II所示化合物，特别是式A所示化合物的药物组合物。
解决方案
在探索合乎需要的包含式II所示化合物，特别是式A所示化合物的药物组合物和/或口服制剂的持续研究的过程中，本申请的发明人对药物组合物的成分进行了缜密的筛选实验，并且已经发现特定的药物组合物的处方组成能够解决以上技术问题，从而完成了本申请。
一方面，本申请提供了一种药物组合物，其包含：作为活性成分的如式II所示的化合物和赋形剂，
Figure PCTCN2021143219-appb-000003
其中，m为1～5，优选为1～3；n为0～10，优选为0～5，进一步优选为3～5，进一步优选为3、3.5、4、4.5或5，更进一步优选为5。
第二方面，本申请提供了一种药物组合物，其包含：作为活性成分的如式A所示的化合物和赋形剂，
Figure PCTCN2021143219-appb-000004
其中，n为0～10，优选为0～5，进一步优选为3～5，进一步优选为3、3.5、4、4.5或5，更进一步优选为5。
第三方面，本申请提供了一种药物组合物，其包含：作为活性成分的如式B所示的化合物和赋形剂，
Figure PCTCN2021143219-appb-000005
在本申请的一些实施方案中，所述式B所示的化合物使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射在8.5±0.2°、11.8±0.2°、19.6±0.2°、25.2±0.2°、27.2±0.2°处具有特征峰；优选地，所述式B所示的化合物使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射在8.5±0.2°、11.8±0.2°、12.6±0.2°、19.6±0.2°、20.0±0.2°、23.7±0.2°、25.2±0.2°、27.2±0.2°处具有特征峰；进一步优选地，所述式B所示的化合物使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射在7.3±0.2°、8.5±0.2°、9.0±0.2°、11.8±0.2°、12.6±0.2°、14.3±0.2°、18.1±0.2°、19.6±0.2°、20.0±0.2°、21.1±0.2°、21.9±0.2°、23.7±0.2°、25.2±0.2°、 26.1±0.2°、27.2±0.2°或者7.3±0.2°、8.5±0.2°、9.1±0.2°、11.8±0.2°、12.6±0.2°、14.3±0.2°、18.1±0.2°、19.6±0.2°、20.0±0.2°、21.1±0.2°、21.9±0.2°、23.7±0.2°、25.2±0.2°、26.1±0.2°、27.2±0.2°处具有特征峰；更进一步优选地，所述式B所示的化合物使用Cu-Kα辐射，具有基本上如图1所示的X射线粉末衍射谱图。
本申请的一些实施方案中，所述式B所示的化合物的单晶使用Cu-Kα辐射，属三斜晶系，
Figure PCTCN2021143219-appb-000006
空间群，其单胞参数为：
Figure PCTCN2021143219-appb-000007
Figure PCTCN2021143219-appb-000008
本申请的一些实施方案中，前述(第一方面、第二方面、第三方面)药物组合物中的各组分及其重量百分比为：
活性成分，其重量百分比为0.5％～90％；或者1％～90％；或者0.5％～85％；或者0.5％～80％；或者1％～80％；或者5％～80％；或者5％～75％；或者5％～70％；或者5％～65％；或者5％～60％；或者5％～55％；或者5％～50％；或者5％～45％；或者5％～40％；或者10％～70％；或者10％～65％；或者10％～60％；或者15％～60％；或者20％～60％；或者25％～60％；或者25％～50％；或者25％～45％；或者25％～40％；余量为赋形剂。
本申请的一些实施方案中，前述(第一方面、第二方面、第三方面)药物组合物的各组分及其重量百分比为：
活性成分，其重量百分比为1％～90％，优选5％～80％、5％～65％、5％～55％、5％～45％或5％～40％；
赋形剂，其重量百分比为1％～99％，优选5％～95％、10％～90％、20％～80％或30％～70％；且以上各组分重量百分比之和为100％。
本申请的一些实施方案中，前述(第一方面、第二方面、第三方面)药物组合物中的各组分及其重量百分比为：
活性成分，其重量百分比为5％～90％；或者10％～90％；或者10％～80％；或者15％～80％；或者20％～70％；或者25％～60％；或者25％～50％；或者25％～45％；或者25％～40％；余量为赋形剂。
本申请所述的“赋形剂”，也可称为“药学上可接受的辅料”、“辅料”或“附加剂”，是指除活性成分以外，在调配处方和生产药品时使用的所有附加物料的总称，一般为可药用的惰性成分，在安全性方面已进行了合理的评估。赋形剂的实例非限制性地包括粘合剂、崩解剂、润滑辅料(润滑剂、助流剂、抗粘着剂)、稳定剂、填充剂(或称稀释剂)，以及矫味剂、增稠剂、分散剂、着色剂、抑菌剂、抗氧化剂、pH调节剂、表面活性剂、香料及包衣材料(增塑剂、遮光剂、色素)等物质。例如，赋形剂能增强药物制剂的操作特性，例如通过增加流动性和/或粘着性而使制剂制备符合工艺要求。进一步的，所述“赋形剂”应具备与活性成分良好的相容性，即赋形剂本身或所含杂质不会与活性成分中的结构基团产生化学反应或导致活性成分降解，造成活性成分含量下降。
本申请的一些实施方案中，所述赋形剂包含填充剂、粘合剂、崩解剂、矫味剂、润滑辅料、抑菌剂、抗氧化剂、pH调节剂、表面活性剂、香料、溶剂或包衣材料中的一种或多种。
本申请的一些实施方案中，所述赋形剂包含填充剂，任选地，进一步包含粘合剂、崩解剂、矫味剂、润滑辅料、抑菌剂、抗氧化剂、表面活性剂、香料或包衣材料中的一种或多种。
本申请的一些实施方案中，所述赋形剂包含填充剂并任选地进一步包含崩解剂、粘合剂或润滑辅料中的一种或多种。在一个实施方案中，所述赋形剂包含填充剂及润滑辅料并任选地进一步包含崩解剂和/或粘合剂。在一个实施方案中，所述赋形剂由填充剂及润滑辅料组成。在另一个实施方案中，所述赋形剂由填充剂、润滑辅料和崩解剂组成。在另一个实施方案中，所述赋形剂由填充剂、润滑辅料、崩解剂和粘合剂组成。
本申请的药物组合物还可含有除填充剂、润滑辅料和崩解剂以外的其它赋形剂。作为其具体实例，可以举出：粘合剂、矫味剂、抑菌剂、pH调节剂、色素、增稠剂、分散剂、着色剂、抗氧化剂、稳定剂、包衣材料及香料等。优选地，其它赋形剂在所述药物组合物中的重量百分比为0％～25％，优选0％～20％、0％～15％、0％～10％或0％～5％。
本申请所述的“填充剂”或“稀释剂”是指用于增加药物组合物的重量和体积，以便于成型和分剂量的赋形剂。本申请所述的填充剂可以为单一填充剂，也可为两种或更多种填充剂的混合物。本申请的一些实施方案中，所述填充剂选自淀粉、预胶化淀粉、糖粉、氢氧化镁、乳糖、微晶纤维素、糖醇类或无机钙盐类中的一种或多种；优选地，所述糖醇类选自木糖醇、山梨醇和甘露醇中的一种或多种；优选地，所述无机钙盐类选自磷酸钙、磷酸氢钙、碳酸钙和硫酸钙中的一种或多种。在一个实施方案中，所述填充剂选自预胶化淀粉、无水磷酸氢钙、碳酸钙、微晶纤维素、甘露醇中的一种，或预胶化淀粉和甘露醇的组合，或微晶纤维素和乳糖的组合，或预胶化淀粉和乳糖的组合，或预胶化淀粉和无 水磷酸氢钙的组合，或预胶化淀粉和碳酸钙的组合。在一个实施方案中，所述填充剂为预胶化淀粉和甘露醇的组合、微晶纤维素和乳糖的组合、预胶化淀粉和无水磷酸氢钙的组合、或预胶化淀粉和碳酸钙，在两种填充剂的组合中，两种填充剂的重量比为1∶10～10∶1；或者1∶7～7∶1；或者1∶6～6∶1，或者1∶5～5∶1；或者1∶4～4∶1；或者1∶3～3∶1；或者1∶2～2∶1；或者1∶1。
本申请所述的“粘合剂”或“黏合剂”是指能使无粘性或粘性较小的物料或辅料聚集粘结成颗粒或压缩成型的具有粘性的赋形剂，可以是固体粉末或粘稠液体。本申请的一些实施方案中，所述粘合剂选自淀粉浆、共聚维酮、纤维素衍生物、糖粉、糖浆、聚乙烯基吡咯烷酮、胶浆、聚乙二醇4000和糊精中的一种或多种；所述纤维素衍生物包括甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素或羧甲基纤维素钠；所述糊精包括麦芽糖糊精；所述聚乙烯基吡咯烷酮，也称为聚维酮，包括聚维酮K30、聚维酮K25、聚维酮K90等；所述共聚维酮包括共聚维酮VA64、共聚维酮VA64Fine等；所述胶浆包括阿拉伯胶浆、明胶胶浆等。
本申请所述的“崩解剂”是指用于促进药物组合物在胃肠道中的崩解和增加活性成分的溶出速度的赋形剂。本申请的一些实施方案中，所述药物组合物中不包含崩解剂。本申请的一些实施方案中，所述药物组合物包含崩解剂，且所述崩解剂选自干淀粉、羧甲基纤维素钠、微晶纤维素、粉状纤维素、甲基纤维素、波拉克林钾、海藻酸钠、淀粉羟乙酸钠、聚乙烯吡咯烷酮、麦芽糖糊精、硅酸铝镁、玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙纤维素、羧甲基纤维素钙、泡腾崩解剂、羧甲淀粉钠和交联羧甲基纤维素钠中的一种或多种。优选地，所述崩解剂选自干淀粉、预胶化淀粉、交联聚维酮、低取代羟丙纤维素、羧甲淀粉钠和交联羧甲基纤维素钠中的一种或多种。在一个实施方案中，所述崩解剂优选为预胶化淀粉、交联聚维酮、低取代羟丙纤维素、羧甲淀粉钠或交联羧甲纤维素钠中的一种或多种；进一步优选为交联聚维酮、羧甲淀粉钠或交联羧甲基纤维素钠；更优选为羧甲淀粉钠。所述交联聚维酮包括交联聚维酮CL-M、交联聚维酮CL-SF、交联聚维酮CL-F、交联聚维酮CL等。
本申请所述的“矫味剂”或“调味剂”是指用以改善或屏蔽药物不良气味和味道，使服用者难以察觉药物的气味或味道的药用辅料，其可以进一步分为甜味剂(或称甜剂)、芳香剂、胶浆剂和泡腾剂等。本申请的一些实施方案中，所述矫味剂包含甜味剂、芳香剂、胶浆剂或泡腾剂中的一种或多种。
本申请的一些实施方案中，所述甜味剂选自山梨糖、木糖、木糖醇、甘油、甘草酸二钠、甘露糖、半乳糖、麦芽糖、乳糖、果糖、甜精、糖精钠、甜菊糖甙、葡萄糖、蔗糖、三氯蔗糖、阿司帕坦和纽甜中的一种或多种。
本申请的一些实施方案中，所述芳香剂选自天然挥发性芳香油和人工合成香精等，例如所述芳香剂选自小茴香油、玫瑰油、薄荷油、橙皮油、柠檬油、玫瑰香精、柠檬香精、香草香精、香草醛、香蕉香精、菠萝香精和苹果香精中的一种或多种。
本申请的一些实施方案中，所述胶浆剂选自淀粉、阿拉伯胶、西黄耆胶、羧甲基纤维素、甲基纤维素、海藻酸钠、果胶和琼脂中的一种或多种。
本申请所述的“润滑辅料”是一种广义的润滑剂，是指用于减少药物组合物的颗粒间及颗粒与模孔间的摩擦力，改善力的传递和分布的赋形剂。润滑辅料根据其减少摩擦、增加颗粒流动性、抗模孔与药物颗粒间的粘着三个方面的作用，又分为润滑剂、助流剂和抗粘着剂。
本申请的一些实施方案中，所述润滑辅料包含润滑剂和/或助流剂。
本申请的一些实施方案中，所述润滑剂选自硬脂酸、硬脂酸镁、硬脂酸钙、棕榈酸、棕榈酸硬脂酸甘油酯、苯甲酸钠、月桂基硫酸钠、滑石粉、二氧化硅、硬脂酸锌、硬脂酰富马酸钠、硬脂酰富马酸镁、月桂醇硫酸镁、氢化植物油、十二烷基硫酸钠、十二烷基硫酸镁或聚乙二醇类中的一种或多种。优选为滑石粉、硬脂酸镁、硬脂酸钙或硬脂富马酸钠中的一种或多种；进一步优选为硬脂酸镁。
本申请的一些实施方案中，所述助流剂选自胶态二氧化硅或氢氧化铝中的一种或多种。优选为胶态二氧化硅。
本申请的一些实施方案中，所述pH调节剂选自氢氧化钠、碳酸钠、碳酸氢钠或氢氧化钾中的一种或多种。
本申请的一些实施方案中，所述抑菌剂选自苯甲酸钠、山梨酸钾、乌洛托品、乙醇、苯甲醇、尼泊金酯类、苯甲酸、山梨酸、苯甲醇或苯乙醇中的一种或多种。
本申请的一些实施方案中，所述抗氧化剂选自亚硫酸氢钠、焦亚硫酸钠、亚硫酸钠、干燥亚硫酸钠、硫代硫酸钠、抗坏血酸、甲硫氨酸、硫脲、乙二胺四醋酸二钠、磷酸、枸橼酸、叔丁基对羟基茴香醚、叔丁基对甲酚、生育酚、去甲双氢愈创木酸、生育酚或棓酸酯类中的一种或多种。
本申请所述的“包衣材料”、“包衣粉”、“包衣剂”或“包衣预混剂”是多种药用辅料的混合物，主要作用是上色、遮味、避光、延长保质期、改善外观等。本申请所述的“薄膜包衣片剂”或“薄膜衣片剂” 是指在片芯(其由本申请的药物组合物经压片制成)外包上薄膜(包)衣的片剂。所述薄膜包衣可使用本领域常用的包衣材料和方法制备。例如，薄膜包衣材料通常包含成膜剂(或称高分子材料)、增塑剂、致孔剂、着色剂、遮光剂和某些固体物料中的一种或多种；进一步地，所述包衣材料可溶于溶剂中制成包衣液。其中高分子材料可选自羟丙甲纤维素、羟丙纤维素、甲基纤维素、羟乙基纤维素、丙烯酸树脂、乙基纤维素、醋酸纤维素、醋酸纤维素酞酸酯、聚乙烯醇酞酸酯、醋酸纤维素苯三酸酯、羟丙甲纤维素酞酸酯和聚乙烯醇等中的一种或多种；增塑剂可选自甘油、丙二醇、聚乙二醇、甘油单醋酸酯、甘油三醋酸酯、癸二酸二丁酯、邻苯二甲酸二丁酯、邻苯二甲酸二乙酯、蓖麻油、硅油、玉米油、液状石蜡等；致孔剂(也称释放速度调节剂)可选自蔗糖、氯化钠、表面活性剂等；固体物料可选自滑石粉、硬脂酸镁、胶态二氧化硅等；遮光剂包括二氧化钛；还可视情况使用本领域常规的着色剂，例如所述着色剂选自苋菜红、胭脂红、柠檬黄、可溶性靛蓝、桔黄G、伊红、品红、美蓝、苏丹黄或红汞中的一种或多种。包衣材料也可直接选用市售预混包衣粉，例如欧巴代
Figure PCTCN2021143219-appb-000009
系列包衣粉、雅克宜
Figure PCTCN2021143219-appb-000010
系列包衣粉、苏特丽
Figure PCTCN2021143219-appb-000011
系列包衣粉、苏丽丝
Figure PCTCN2021143219-appb-000012
系列包衣粉、爱多秀
Figure PCTCN2021143219-appb-000013
系列包衣粉等。所述包衣材料可以是胃溶性包衣材料，也可以是肠溶性包衣材料。所述薄膜包衣增重占片芯重量的1～5％，优选1.5～4％，更优选为1.5％～3％。包衣溶剂选自水和乙醇，优选为水，其可在干燥期间去除而并不保留于最终产物中。例如，欧巴代
Figure PCTCN2021143219-appb-000014
系列包衣粉型号有：欧巴代85G64788，85F18422，0366507，8568918，85F12252，03F58908等。
本申请的一些实施方案中，所述溶剂选自水、乙醇或植物油中的一种或多种。
本申请的一些实施方案中，所述表面活性剂选自聚乙二醇类、聚山梨酯类、失水山梨醇单月桂酸酯类、聚氧乙烯月桂醇醚类、乳化剂OP、乳百灵A、西士马哥-1000、普流罗尼、单油酸甘油酯、单硬脂酸甘油酯、软皂、硬皂、单硬脂酸铝、硬脂酸钙、油酸三乙醇胺从、月桂醇硫酸钠、鲸硬醇硫酸钠、硫酸化蓖麻油、丁二酸二辛酯磺酸钠、洁尔灭、新洁尔灭、氯化苯甲烃铵、氯化苯麦洛和溴化十六烷三甲胺中的一种或多种。
本申请的一些实施方案中，前述(第一方面、第二方面、第三方面)药物组合物制成口服制剂；优选地，所述口服制剂包含口服固体制剂和/或口服液体制剂；进一步优选地，所述口服固体制剂选自胶囊剂、片剂、颗粒剂、细粒剂和散剂中的一种或多种；所述口服液体制剂选自口服溶液剂。
第四方面，本申请提供了一种药物组合物，其包含：作为活性成分的如式II、式A或式B所示的化合物和赋形剂，所述赋形剂包含填充剂，任选地，进一步包含润滑辅料、崩解剂和/或粘合剂。
在本申请的一些实施方案中，所述赋形剂包含填充剂和润滑辅料，任选地，进一步包含崩解剂和/或粘合剂。
在本申请的一些实施方案中，所述赋形剂包含填充剂、润滑辅料和崩解剂，任选地，进一步包含粘合剂。
在本申请的一些实施方案中，所述赋形剂包含填充剂、润滑辅料、崩解剂和粘合剂。
本申请的一些实施方案中，所述润滑辅料为润滑剂，任选地，进一步包含助流剂。
本申请的一些实施方案中，所述润滑辅料为润滑剂和助流剂。
本申请的一些实施方案中，所述填充剂选自淀粉、糖粉、氢氧化镁、预胶化淀粉、乳糖、微晶纤维素、糖醇类、无机钙盐类中的一种或多种；优选地，所述糖醇类填充剂选自甘露醇、山梨醇和木糖醇中的一种或多种，所述无机钙盐类填充剂选自磷酸钙、磷酸氢钙、硫酸钙和碳酸钙中的一种或多种；优选地，所述填充剂选自预胶化淀粉、乳糖、微晶纤维素、甘露醇、山梨醇、无水磷酸氢钙、二水硫酸钙和碳酸钙中的一种或多种；进一步优选地，所述填充剂选自预胶化淀粉、乳糖、微晶纤维素、甘露醇、无水磷酸氢钙和碳酸钙中的一种或多种；进一步优选地，所述填充剂选自预胶化淀粉、乳糖、微晶纤维素、无水磷酸氢钙或甘露醇中的一种或多种；进一步优选地，所述填充剂选自预胶化淀粉、乳糖、微晶纤维素或甘露醇中的一种或多种。
本申请的一些实施方案中，所述填充剂选自预胶化淀粉、无水磷酸氢钙、碳酸钙、微晶纤维素中的一种，或预胶化淀粉和甘露醇的组合，或微晶纤维素和乳糖的组合，或预胶化淀粉和无水磷酸氢钙的组合，或预胶化淀粉和碳酸钙的组合，或预胶化淀粉和乳糖的组合；优选地，所述填充剂选自预胶化淀粉、无水磷酸氢钙、微晶纤维素中的一种，或预胶化淀粉和甘露醇的组合，或微晶纤维素和乳糖的组合，或预胶化淀粉和无水磷酸氢钙的组合，或预胶化淀粉和碳酸钙的组合；进一步优选地，所述填充剂选自：预胶化淀粉或微晶纤维素中的一种，或预胶化淀粉和甘露醇的组合，或微晶纤维素和乳糖的组合，或预胶化淀粉和无水磷酸氢钙的组合，或预胶化淀粉和碳酸钙的组合；进一步优选地，所述填充剂选自：预胶化淀粉或微晶纤维素中的一种，或预胶化淀粉和甘露醇的组合，或微晶纤维素和 乳糖的组合。
本申请的一些实施方案中，所述预胶化淀粉和甘露醇的组合、微晶纤维素和乳糖的组合、预胶化淀粉和无水磷酸氢钙的组合、预胶化淀粉和乳糖的组合、或预胶化淀粉和碳酸钙的组合中，两种填充剂的重量比为1∶10～10∶1；或者1∶7～7∶1；或者1∶6～6∶1，或者1∶5～5∶1；或者1∶4～4∶1；或者1∶3～3∶1；或者1∶2～2∶1；或者1∶1。
本申请的一些实施方案中，所述润滑剂选自硬脂酸、硬脂酸镁、硬脂酸钙、棕榈酸、棕榈酸硬脂酸甘油酯、苯甲酸钠、月桂基硫酸钠、氢化植物油、滑石粉、二氧化硅、硬脂酸锌、硬脂酰富马酸钠、硬脂酰富马酸镁、月桂醇硫酸镁、十二烷基硫酸钠、十二烷基硫酸镁或聚乙二醇类中的一种或多种；优选为硬脂酸、硬脂酸镁、硬脂酸钙、棕榈酸、棕榈酸硬脂酸甘油酯、苯甲酸钠、月桂基硫酸钠、滑石粉、二氧化硅、硬脂酸锌、硬脂酰富马酸钠、硬脂酰富马酸镁、月桂醇硫酸镁、聚乙二醇4000、聚乙二醇6000、十二烷基硫酸钠或十二烷基硫酸镁中的一种或多种；进一步优选为硬脂酸、硬脂酸镁、硬脂酸钙、棕榈酸、棕榈酸硬脂酸甘油酯、苯甲酸钠、月桂基硫酸钠、滑石粉、二氧化硅、硬脂酸锌、硬脂酰富马酸钠、硬脂酰富马酸镁或月桂醇硫酸镁中的一种或多种；进一步优选为滑石粉、硬脂酸镁、硬脂酸钙或硬脂酰富马酸钠中的一种或多种；更进一步优选为硬脂酸镁。
本申请的一些实施方案中，所述助流剂选自胶态二氧化硅或氢氧化铝中的一种或多种；优选为胶态二氧化硅。
本申请的一些实施方案中，所述润滑辅料为润滑剂和助流剂的组合，所述助流剂与润滑剂的重量比为1∶6～6∶1；或者1∶5～5∶1；或者1∶4～4∶1；或者1∶3～3∶1；或者1∶2～2∶1；或者1∶1、1∶2、1∶1.5、2∶1、2∶3、3∶1、3∶2、4∶3或5∶3。
本申请的一些实施方案中，所述药物组合物包含崩解剂，所述崩解剂选自干淀粉、羧甲基纤维素、微晶纤维素、粉状纤维素、甲基纤维素、波拉克林钾、海藻酸钠、淀粉羟乙酸钠、聚乙烯吡咯烷酮、麦芽糖糊精、硅酸铝镁、玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙纤维素、羧甲基纤维素钙、泡腾崩解剂、羧甲淀粉钠或交联羧甲基纤维素钠中的一种或多种；优选为干淀粉、预胶化淀粉、羧甲淀粉钠、低取代羟丙纤维素、交联羧甲纤维素钠或交联聚维酮中的一种或多种；优选为交联聚维酮、低取代羟丙纤维素、羧甲淀粉钠或交联羧甲纤维素钠中的一种或多种；进一步优选为交联聚维酮、羧甲淀粉钠或交联羧甲基纤维素钠；更优选为羧甲淀粉钠或交联羧甲基纤维素钠。
本申请的一些实施方案中，所述药物组合物包含粘合剂，所述粘合剂选自淀粉浆、共聚维酮、糖粉、糖浆、聚乙烯基吡咯烷酮、纤维素衍生物、胶浆、聚乙二醇4000和糊精中的一种或多种；优选地，所述纤维素衍生物选自甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素和羧甲基纤维素钠；进一步优选为共聚维酮、糖粉、聚乙烯基吡咯烷酮、羟丙基甲基纤维素和羧甲基纤维素钠；进一步优选为共聚维酮VA64和聚乙烯基吡咯烷酮。
本申请的一些实施方案中，所述填充剂选自预胶化淀粉、微晶纤维素、无水磷酸氢钙中的一种，或预胶化淀粉和甘露醇的组合，或微晶纤维素和乳糖的组合，或预胶化淀粉和无水磷酸氢钙的组合，或预胶化淀粉和碳酸钙的组合；所述润滑辅料为润滑剂和/或助流剂，其中所述润滑剂为硬脂酸镁，所述助流剂为胶态二氧化硅；任选地，所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠；任选地，所述粘合剂选自共聚维酮。
本申请的一些实施方案中，所述药物组合物包含活性成分、填充剂、润滑剂和助流剂，其中，所述填充剂为预胶化淀粉或微晶纤维素；优选地，所述助流剂为胶态二氧化硅；进一步优选地，所述润滑剂为硬脂酸镁；进一步优选地，所述药物组合物进一步包含崩解剂，所述崩解剂选自羧甲淀粉钠或交联羧甲基纤维素钠。
本申请的一些实施方案中，所述药物组合物包含活性成分、填充剂、润滑剂和助流剂，其中，所述填充剂为预胶化淀粉和甘露醇；优选地，所述助流剂为胶态二氧化硅；进一步优选地，所述润滑剂为硬脂酸镁。
本申请的一些实施方案中，所述药物组合物包含活性成分、填充剂和润滑剂，其中，所述填充剂为微晶纤维素；优选地，所述润滑剂为硬脂酸镁。
本申请的一些实施方案中，所述药物组合物包含活性成分、填充剂、润滑剂、助流剂和崩解剂，其中，所述填充剂为微晶纤维素和乳糖；优选地，所述助流剂选自胶态二氧化硅；进一步优选地，所述崩解剂选自羧甲淀粉钠或交联羧甲基纤维素钠；更进一步优选地，所述润滑剂为硬脂酸镁或硬脂酰富马酸钠。
本申请的一些实施方案中，所述药物组合物包含活性成分、填充剂、润滑剂和助流剂，其中，所述填充剂为无水磷酸氢钙或无水磷酸氢钙和预胶化淀粉的组合；优选地，所述助流剂选自胶态二氧化 硅；进一步优选地，所述润滑剂为硬脂酸镁；更进一步优选地，所述药物组合物进一步包含崩解剂，所述崩解剂选自羧甲淀粉钠或交联羧甲基纤维素钠。
本申请的一些实施方案中，所述药物组合物包含活性成分、填充剂、润滑剂和助流剂，其中，所述填充剂为碳酸钙或碳酸钙和预胶化淀粉的组合；优选地，所述助流剂选自胶态二氧化硅；进一步优选地，所述润滑剂为硬脂酸镁；更进一步优选地，所述药物组合物进一步包含崩解剂，所述崩解剂选自羧甲淀粉钠或交联羧甲基纤维素钠；更进一步优选地，所述药物组合物进一步包含粘合剂，所述粘合剂选自共聚维酮。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
活性成分，其重量百分比为0.5％～90％；或者1％～90％；或者0.5％～85％；或者5％～80％；或者5％～75％；或者5％～70％；或者10％～70％；或者5％～65％；或者5％～60％；或者5％～55％；或者5％～50％；或者5％～45％；或者5％～40％；或者10％～65％；或者10％～60％；或者15％～60％；或者20％～60％；或者25％～60％；或者25％～50％；或者25％～45％；或者25％～40％；
填充剂，其重量百分比为5％～99％；或者10％～95％；或者15％～95％；或者15％～90％；或者15％～85％；或者15％～80％；或者20％～80％；或者25％～90％；或者25％～75％；或者30％～70％；或者35％～90％；或者35％～70％；或者40％～90％；或者40％～70％；或者45％～70％；或者50％～90％；或者50％～70％；或者55％～70％；
崩解剂，其重量百分比为0％～20％；0％～15％；或者0％～10％；或者0％～8％；或者0％～6％；或者0％～5％；或者0％～4％；或者0％～3％；或者0.5％～3％；或者1％～3％；或者1.5％～3％；或者2％～3％；
粘合剂，其重量百分比为0％～10％；或者0％～6％；或者0％～5％；或者0％～4％；或者0％～3％；或者0％～2％；
润滑辅料，其重量百分比为0％～18％；或者0.1％～18％；或者0％～15％；或者0.1％～15％；或者0％～10％；或者0.1％～10％；或者0％～8％；或者0％～7％；或者0％～6％；或者1％～6％；或者0.5％～6％；或者0％～5％；或者1％～5％；或者1.5％～4.5％；或者2％～4％；或者2％～3.5％；或者2％～3％；或者2.5％～5％；或者3.5％～5％；或者4％～5％；
其它赋形剂，其重量百分比为0％～25％；或者0％～20％；或者0％～15％；或者0％～10％；或者0％～5％；且
以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
活性成分，其重量百分比为1％～90％，优选5％～80％、5％～65％、5％～55％、5％～45％或5％～40％；
填充剂，其重量百分比为10％～95％，优选25％～90％、35％～90％、40％～90％或50％～90％；
崩解剂，其重量百分比为0％～15％，优选0％～10％、0％～6％、0％～5％或0％～3％；
润滑辅料，其重量百分比为0％～18％，优选0.1％～18％、0％～15％、0％～10％、0％～6％、0％～5％、0.1％～15％、0.1％～10％、0.5％～0％、1％～5％、2.5％～5％、3.5％～5％或4％～5％；
其它赋形剂，其重量百分比为0％～25％，优选0％～20％、0％～15％、0％～10％或0％～5％；且以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
活性成分，其重量百分比为5％～90％；或者10％～90％；或者10％～80％；或者15％～80％；或者20％～70％；或者25％～60％；或者25％～50％；或者25％～45％；或者25％～40％；
填充剂，其重量百分比为5％～90％；或者15％～90％；或者15％～85％；或者25％～85％；或者25％～80％；或者35％～75％；或者35％～70％；或者50％～70％；或者55％～70％；
崩解剂，其重量百分比为0％～5％；或者0％～4％；或者0.5％～4％；或者1％～3％；
粘合剂，其重量百分比为0％～5％；或者0％～4％；或者0％～3％；
润滑辅料，其重量百分比为2％～7％；或者2％～6％；或者2.5％～6％；或者3％～5％；或者3％～6％；或者3.5～6％；或者4％～6％；或者4％～5％；或者5％～6％；
其它赋形剂，其重量百分比为0％～10％；或者0％～5％；且以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述润滑辅料为润滑剂。
本申请的一些实施方案中，所述润滑辅料为润滑剂和助流剂的组合，所述助流剂与润滑剂的重量比为1∶6～6∶1；或者1∶5～5∶1；或者1∶4～4∶1；或者1∶3～3∶1；或者1∶2～2∶1；或者1∶1、1∶2、1∶1.5、2∶1、2∶3、3∶1、3∶2、4∶3或5∶3。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
活性成分，其重量百分比为0.5％～90％；或者1％～90％；或者0.5％～85％；或者5％～80％；或者 5％～75％；或者5％～70％；或者10％～70％；或者5％～65％；或者5％～60％；或者5％～55％；或者5％～50％；或者5％～45％；或者5％～40％；或者10％～65％；或者10％～60％；或者15％～60％；或者20％～60％；或者25％～60％；或者25％～50％；或者25％～45％；或者25％～40％；
填充剂，其重量百分比为5％～99％；或者10％～95％；或者15％～95％；或者15％～90％；或者15％～85％；或者15％～80％；或者20％～80％；或者25％～90％；或者25％～75％；或者30％～70％；或者35％～90％；或者35％～70％；或者40％～90％；或者40％～70％；或者45％～70％；或者50％～90％；或者50％～70％；或者55％～70％；
崩解剂，其重量百分比为0％～20％；0％～15％；或者0％～10％；或者0％～8％；或者0％～6％；或者0％～5％；或者0％～4％；或者0％～3％；或者0.5％～.00％；或者1％～3％；或者1.5％～3％；或者2％～3％；
粘合剂，其重量百分比为0％～10％；或者0％～6％；或者0％～5％；或者0％～4％；或者0％～3％；或者0％～2％；
润滑剂，其重量百分比为0％～10％；或者0％～8％；或者0.1％～8％；或者0％～6％；或者0％～5％；或者0.1％～5％；或者0％～4％；或者0.1％～4％；或者0％～3％；或者1％～5％；或者2％～4％；或者2％～3％；或者1％～4％；或者1％～3.5％；或者0.5％～3％；或者1％～3％；或者1％～2.5％；或者1％～2％；或者2％～2.5％；
助流剂，其重量百分比为0％～10％；或者0.5％～10％；或者0％～8％；或者0.5％～8％；或者0％～6％；或者0％～5％；或者0.5％～5％；或者1％～5％；或者0％～4％；或者1％～4％；或者0％～3.5％；或者0％～3％；或者1％～3％；或者1％～2.5％；或者1％～2％；或者1.5％～3％；或者2％～3％；或者3％；
其它赋形剂，其重量百分比为0％～25％；或者0％～20％；或者0％～15％；或者0％～10％；或者0％～5％；且
以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
活性成分，其重量百分比为1％～90％，优选5％～80％、5％～65％、5％～55％、5％～45％或5％～40％；
填充剂，其重量百分比为10％～95％，优选25％～90％、35％～90％、40％～90％或50％～90％；
崩解剂，其重量百分比为0％～15％，优选0％～10％、0％～6％、0％～5％或0％～3％；
润滑剂，其重量百分比为0.1％～8％，优选0.1％～5％、0.1％～4％、0.5％～3％或1％～3％；
助流剂，其重量百分比为0％～10％，优选0％～8％、0％～5％、0％～4％、或0％～3％；
其它赋形剂，其重量百分比为0％～25％，优选0％～20％、0％～15％、0％～10％或0％～5％；且以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
活性成分，其重量百分比为1％～90％，优选5％～80％、5％～65％、5％～55％、5％～45％或5％～40％；
填充剂，其重量百分比为10％～95％，优选25％～90％、35％～90％、40％～90％或50％～90％；
崩解剂，其重量百分比为0％～15％，优选0％～10％、.00％～6％、0％～5％或0％～3％；
润滑剂，其重量百分比为0.1％～8％，优选0.1％～5％、0.1％～4％、0.5％～3％或1％～3％；
助流剂，其重量百分比为0.5％～10％，优选0.5％～8％、0.5％～5％、1％～5％、1％～4％、或1％～3％；
其它赋形剂，其重量百分比为0％～25％，优选0％～20％、0％～15％、0％～10％或0％～5％；且以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
活性成分，其重量百分比为1％～90％，优选5％～80％、5％～65％、5％～55％、5％～45％或5％～40％；
填充剂，其重量百分比为10％～95％，优选25％～90％、35％～90％、40％～90％或50％～90％；
崩解剂，其重量百分比为0％～15％，优选0％～10％、0％～6％、0％～5％或0％～3％；
润滑剂，其重量百分比为1％～5％，优选2％～4％、2％～3％或2％～2.5％；
助流剂，其重量百分比为1％～5％，优选1％～4％、1％～3％、1.5％～3％、2％～3％或3％；
其它赋形剂，其重量百分比为0％～25％，优选0％～20％、0％～15％、0％～10％或0％～5％；且以上各组分重量百分比之和为100％。
本发明的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
活性成分，其重量百分比为1％～90％，优选5％～80％、5％～65％、5％～55％、5％～45％或5％～40％；
微晶纤维素，其重量百分比为10％～95％，优选25％～90％、35％～90％、40％～90％或50％～90％；
崩解剂，其重量百分比为0％～15％，优选0％～10％、0％～6％、0％～5％或0％～3％；
润滑剂，其重量百分比为0.1％～8％，优选0.1％～5％、0.1％～4％、0.5％～3％或1％～2％；
其它赋形剂，其重量百分比为0％～25％，优选0％～20％、0％～15％、0％～10％或0％～5％；
且以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：。
活性成分，其重量百分比为5％～90％；或者10％～90％；或者10％～80％；或者15％～80％；或者20％～70％；或者25％～60％；或者25％～50％；或者25％～45％；或者25％～40％；
填充剂，其重量百分比为5％～90％；或者15％～90％；或者15％～85％；或者25％～85％；或者25％～80％；或者35％～75％；或者35％～70％；或者50％～70％；或者55％～70％；
崩解剂，其重量百分比为0％～5％；或者0％～4％；或者0.5％～4％；或者1％～3％；
粘合剂，其重量百分比为0％～5％；或者0％～4％；或者0％～3％；
润滑剂，其重量百分比为1％～5％；或者1％～4％；或者2％～4％；或者2％～3％；
助流剂，其重量百分比为0％～5％；或者0％～4％；或者1％～4％；或者1％～3％；或者0％～3％；或者2％～4％；或者3％～4％；或者2％～3％；
其它赋形剂，其重量百分比为0％～10％；或者0％～5％；以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
0.5％～90％的活性成分、5％～99％的填充剂、0％～20％的崩解剂、0％～10％的粘合剂、0.1％～15％的润滑辅料、以及0％～25％的其它赋形剂；或者
5％～80％的活性成分、10％～95％的填充剂、0％～15％的崩解剂、0％～6％的粘合剂、0.50％～10％的润滑辅料、以及0％～15％的其它赋形剂；或者
5％～80％的活性成分、15％～85％的填充剂、0％～5％的崩解剂、0％～4％的粘合剂、0％～7％的润滑辅料、以及0％～10％的其它赋形剂；或者
5％～80％的活性成分、15％～80％的填充剂、0％～4％的崩解剂、0％～3％的粘合剂、1％～6％的润滑辅料、以及0％～5％的其它赋形剂；以上各组分重量百分比之和为100％。
本申请的一些方案中，前述药物组合物的各组分及其重量百分比为：
5％～90％的活性成分、5％～90％的填充剂、0％～5％的崩解剂、0％～5％的粘合剂、1％～7％的润滑辅料、以及0％～5％的其它赋形剂；或者
10％～90％的活性成分、15％～90％的填充剂、0％～5％的崩解剂、0％～4％的粘合剂、1％～6％的润滑辅料、以及0％～5％的其它赋形剂；或者
10％～80％的活性成分、15％～85％的填充剂、0％～5％的崩解剂、0％～4％的粘合剂、3％～5％的润滑辅料、以及0％～5％的其它赋形剂；或者
10％～80％的活性成分、15％～85％的填充剂、0％～5％的崩解剂、0％～4％的粘合剂、3.5％～6％的润滑辅料、以及0％～5％的其它赋形剂；或者
10％～80％的活性成分、15％～85％的填充剂、0％～5％的崩解剂、0％～4％的粘合剂、4％～6％的润滑辅料、以及0％～5％的其它赋形剂；或者
25％～60％的活性成分、35％～70％的填充剂、0％～4％的崩解剂、0％～3％的粘合剂、5％～6％的润滑辅料、以及0％～5％的其它赋形剂；或者
以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述填充剂选自：预胶化淀粉、微晶纤维素、无水磷酸氢钙、碳酸钙中的一种，或预胶化淀粉和甘露醇的组合，或微晶纤维素和乳糖的组合，或预胶化淀粉和无水磷酸氢钙的组合，或预胶化淀粉和碳酸钙的组合；所述润滑辅料为润滑剂和/或助流剂，其中所述润滑剂为硬脂酸镁，所述助流剂为胶态二氧化硅；所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠；所述粘合剂选自共聚维酮；优选为共聚维酮VA64和/或共聚维酮VA64Fine。
本申请的一些实施方案中，所述填充剂选自预胶化淀粉和甘露醇的组合、微晶纤维素和乳糖的组合、预胶化淀粉和无水磷酸氢钙的组合、预胶化淀粉和乳糖的组合、或预胶化淀粉和碳酸钙的组合，此时两种填充剂的重量比为1∶10～10∶1，优选为1∶7～7∶1，进一步优选为1∶6～6∶1，进一步优选为1∶5～5∶1，进一步优选为1∶4～4∶1，进一步优选为1∶3～3∶1，更进一步优选为1∶2～2∶1，更进一步优选为1∶1。
本申请的一些实施方案中，所述润滑辅料为润滑剂。
本申请的一些实施方案中，所述润滑辅料为润滑剂和助流剂的组合，所述助流剂与润滑剂的重量比为1∶6～6∶1；或者1∶5～5∶1；或者1∶4～4∶1；或者1∶3～3∶1；或者1∶2～2∶1；或者1∶1、1∶2、1∶1.5、2∶1、2∶3、3∶1、3∶2、4∶3或5∶3。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
0.50％～90％的活性成分、5％～99％的填充剂、0％～20％的崩解剂、0％～10％的粘合剂、0％～10％的 润滑剂、0％～10％的助流剂、以及0％～25％的其它赋形剂；或者
5％～80％的活性成分、10％～95％的填充剂、0％～10％的崩解剂、0％～6％的粘合剂、0％～5％的润滑剂、0％～5％的助流剂、以及0％～25％的其它赋形剂；或者
5％～80％的活性成分、15％～85％的填充剂、0％～6％的崩解剂、0％～5％的粘合剂、1％～4％的润滑剂、0％～4％的助流剂、以及0％～15％的其它赋形剂；或者
5％～80％的活性成分、15％～80％的填充剂、0％～5％的崩解剂、0％～4％的粘合剂、1％～3.50％的润滑剂、0％～3.50％的助流剂、以及0％～10％的其它赋形剂；或者
5％～80％的活性成分、15％～80％的填充剂、0％～4％的崩解剂、0％～3％的粘合剂、1％～3％的润滑剂、0％～3％的助流剂、以及0％～5％的其它赋形剂；以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
5％～90％的活性成分、5％～90％的填充剂、0％～5％的崩解剂、0％～5％的粘合剂、1％～5％的润滑剂、0％～5％的助流剂、以及0％～5％的其它赋形剂；或者
5％～90％的活性成分、5％～90％的填充剂、0％～5％的崩解剂、0％～5％的粘合剂、1％～4％的润滑剂、0％～4％的助流剂、以及0％～5％的其它赋形剂；或者
10％～90％的活性成分、15％～90％的填充剂、0％～5％的崩解剂、0％～4％的粘合剂、1％～3％的润滑剂、0％～3％的助流剂、以及0％～5％的其它赋形剂；或者
10％～90％的活性成分、15％～90％的填充剂、0％～4％的崩解剂、0％～3％的粘合剂、1％～3％的润滑剂、0％～3％的助流剂、以及0％～5％的其它赋形剂；或者
以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述填充剂选自：预胶化淀粉、微晶纤维素、无水磷酸氢钙、碳酸钙中的一种，或预胶化淀粉和甘露醇的组合，或微晶纤维素和乳糖的组合，或预胶化淀粉和无水磷酸氢钙的组合，或预胶化淀粉和碳酸钙的组合；所述润滑剂选自硬脂酸镁或硬脂富马酸钠中的一种或多种；所述助流剂为胶态二氧化硅；所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠；所述粘合剂为共聚维酮，优选为共聚维酮VA64。
本申请的一些实施方案中，所述填充剂选自预胶化淀粉和甘露醇的组合、微晶纤维素和乳糖的组合、预胶化淀粉和无水磷酸氢钙的组合、预胶化淀粉和乳糖的组合、或预胶化淀粉和碳酸钙的组合，优选的，两种填充剂的重量比为1∶10～10∶1，优选为1∶7～7∶1，进一步优选为1∶6～6∶1，进一步优选为1∶5～5∶1，进一步优选为1∶4～4∶1，进一步优选为1∶3～3∶1，更进一步优选为1∶2～2∶1，更进一步优选为1∶1。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
5％～45％的活性成分、50％～90％的填充剂、0％～5％的崩解剂、0％～5％的粘合剂、1％～5％的润滑剂、0％～5％的助流剂、以及0％～5％的其它赋形剂；或者
5％～40％的活性成分、50％～90％的填充剂、0％～5％的崩解剂、0％～3％的粘合剂、2％～4％的润滑剂、1％～4％的助流剂、以及0％～5％的其它赋形剂；或者
5％～40％的活性成分、50％～90％的填充剂、0％～5％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、2％～4％的助流剂、以及0％～5％的其它赋形剂；或者
5％～40％的活性成分、50％～90％的填充剂、0％～5％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、3％～4％的助流剂、以及0％～5％的其它赋形剂；或者
20％～45％的活性成分、50％～75％的填充剂、0％～5％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、3％～4％的助流剂、以及0％～5％的其它赋形剂；或者
25％～40％的活性成分、50％～70％的填充剂、0％～4％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、3％～4％的助流剂、以及0％～5％的其它赋形剂；或者
25％～40％的活性成分、50％～70％的填充剂、2％～3％的润滑剂以及3％～4％的助流剂；
以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述填充剂选自：预胶化淀粉或微晶纤维素，或预胶化淀粉和甘露醇的组合，或微晶纤维素和乳糖的组合；所述润滑剂选自硬脂酸镁或硬脂富马酸钠中的一种或多种；所述助流剂为胶态二氧化硅；所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠；所述粘合剂为共聚维酮，优选为共聚维酮VA64。
本申请的一些实施方案中，所述填充剂选自预胶化淀粉和甘露醇的组合、微晶纤维素和乳糖的组合，优选的，两种填充剂的重量比为1∶10～10∶1，优选为1∶7～7∶1，进一步优选为1∶6～6∶1，进一步优选为1∶5～5∶1，进一步优选为1∶4～4∶1，进一步优选为1∶3～3∶1，更进一步优选为1∶2～2∶1，更进一步优选 为1∶1。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
5％～45％的活性成分、50％～90％的填充剂、0％～5％的崩解剂、0％～5％的粘合剂、1％～5％的润滑剂、0％～5％的助流剂、以及0％～5％的其它赋形剂；或者
15％～45％的活性成分、50％～70％的填充剂、1％～5％的崩解剂、0％～3％的粘合剂、2％～4％的润滑剂、3％～4％的助流剂、以及0％～5％的其它赋形剂；或者
25％～40％的活性成分、50％～70％的填充剂、1％～3％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、2％～4％的助流剂、以及0％～5％的其它赋形剂；或者
25％～40％的活性成分、50％～70％的填充剂、1％～3％的崩解剂、2％～3％的润滑剂以及2％～4％的助流剂；
以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述填充剂选自：微晶纤维素和乳糖的组合；优选的，两种填充剂的重量比为1∶10～10∶1，优选为1∶7～7∶1，进一步优选为1∶6～6∶1，进一步优选为1∶5～5∶1，进一步优选为1∶4～4∶1，进一步优选为1∶3～3∶1，更进一步优选为1∶2～2∶1，更进一步优选为1∶1；所述润滑剂选自硬脂酸镁或硬脂富马酸钠中的一种或多种；所述助流剂为胶态二氧化硅；所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠；所述粘合剂为共聚维酮，优选为共聚维酮VA64。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
10％～90％的活性成分、5％～90％的填充剂、0％～5％的崩解剂、0％～5％的粘合剂、1％～4％的润滑剂、1％～4％的助流剂、以及0％～5％的其它赋形剂；或者
10％～90％的活性成分、5％～90％的填充剂、0％～5％的崩解剂、0％～4％的粘合剂、1％～3％的润滑剂、1％～3％的助流剂、以及0％～5％的其它赋形剂；或者
15％～70％的活性成分、20％～80％的填充剂、0％～5％的崩解剂、0％～4％的粘合剂、1％～3％的润滑剂、1％～3％的助流剂、以及0％～5％的其它赋形剂；或者
15％～70％的活性成分、20％～80％的填充剂、0％～4％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、2％～3％的助流剂、以及0％～5％的其它赋形剂；或者
15％～70％的活性成分、20％～80％的填充剂、0％～4％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂以及2％～3％的助流剂；
以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述填充剂选自：无水磷酸氢钙或碳酸钙，或预胶化淀粉和无水磷酸氢钙的组合，或预胶化淀粉和碳酸钙的组合；所述润滑剂选自硬脂酸镁或硬脂富马酸钠中的一种或多种；所述助流剂为胶态二氧化硅；所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠；所述粘合剂为共聚维酮，优选为共聚维酮VA64。
本申请的一些实施方案中，所述填充剂选自预胶化淀粉和无水磷酸氢钙的组合、或预胶化淀粉和碳酸钙的组合，优选的，两种填充剂的重量比为1∶10～10∶1，优选为1∶7～7∶1，进一步优选为1∶6～6∶1，进一步优选为1∶5～5∶1，进一步优选为1∶4～4∶1，进一步优选为1∶3～3∶1，更进一步优选为1∶2～2∶1，更进一步优选为1∶1。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
0.50％～90％的活性成分、5％～99％的填充剂、0％～20％的崩解剂、0％～10％的粘合剂、0％～10％的润滑剂、0％～10％的助流剂、以及0％～25％的其它赋形剂；或者
5％～80％的活性成分、10％～95％的填充剂、0％～10％的崩解剂、0％～6％的粘合剂、0％～5％的润滑剂、0％～5％的助流剂、以及0％～25％的其它赋形剂；或者
5％～80％的活性成分、15％～85％的填充剂、0％～6％的崩解剂、0％～5％的粘合剂、1％～4％的润滑剂、0％～4％的助流剂、以及0％～15％的其它赋形剂；或者
5％～80％的活性成分、15％～80％的填充剂、0％～5％的崩解剂、0％～4％的粘合剂、1％～3.50％的润滑剂、0％～3.50％的助流剂、以及0％～10％的其它赋形剂；或者
5％～80％的活性成分、15％～80％的填充剂、0％～4％的崩解剂、0％～3％的粘合剂、1％～3％的润滑剂、0％～3％的助流剂、以及0％～5％的其它赋形剂；或者
5％～80％的活性成分、15％～80％的填充剂、0％～4％的崩解剂、0％～3％的粘合剂、1％～3％的润滑剂、1％～5％的助流剂、以及0％～5％的其它赋形剂；或者
5％～80％的活性成分、15％～80％的填充剂、0％～4％的崩解剂、0％～3％的粘合剂、1％～3％的润滑 剂、1％～3％的助流剂、以及0％～5％的其它赋形剂；或者
以上各组分重量百分比之和为100％；其中，所述填充剂为预胶化淀粉；所述润滑剂为硬脂酸镁；所述助流剂为胶态二氧化硅；所述崩解剂选自羧甲淀粉钠和/或交联羧甲基纤维素钠；所述粘合剂为共聚维酮。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
20％～45％的活性成分、40％～80％的填充剂、0％～5％的崩解剂、0％～5％的粘合剂、2％～5％的润滑剂、1％～5％的助流剂、以及0％～5％的其它赋形剂；或者
20％～45％的活性成分、40％～80％的填充剂、0％～3％的崩解剂、0％～3％的粘合剂、2％～4％的润滑剂、1％～4％的助流剂、以及0％～5％的其它赋形剂；或者
20％～45％的活性成分、40％～80％的填充剂、0％～3％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、2％～4％的助流剂、以及0％～5％的其它赋形剂；或者
20％～45％的活性成分、40％～80％的填充剂、0％～3％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、3％～4％的助流剂、以及0％～5％的其它赋形剂；或者
25％～40％的活性成分、50％～75％的填充剂、0％～3％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、3％～4％的助流剂、以及0％～5％的其它赋形剂；或者
25％～40％的活性成分、50％～70％的填充剂、0％～3％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、3％～4％的助流剂、以及0％～5％的其它赋形剂；或者
以上各组分重量百分比之和为100％；其中，所述填充剂为预胶化淀粉；所述润滑剂为硬脂酸镁；所述助流剂为胶态二氧化硅；所述崩解剂选自羧甲淀粉钠和/或交联羧甲基纤维素钠；所述粘合剂为共聚维酮。
本发明的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
5％～65％的活性成分、35％～90％的预胶化淀粉、0％～6％的崩解剂、0.1％～5％的润滑剂、1％～5％的助流剂、以及0％～25％的其它赋形剂；或者
5％～55％的活性成分、40％～90％的预胶化淀粉、0％～5％的崩解剂、0.1％～4％的润滑剂、1％～5％的助流剂、以及0％～20％的其它赋形剂；或者
5％～40％的活性成分、50％～90％的预胶化淀粉、0％～3％的崩解剂、1％～3％的润滑剂、1％～5％的助流剂、以及0％～15％的其它赋形剂；或者5％～40％的活性成分、50％～90％的预胶化淀粉、0％～3％的崩解剂、1％～3％的润滑剂、1％～5％的胶态二氧化硅、以及0％～10％的其它赋形剂；或者5％～40％的活性成分、50％～90％的预胶化淀粉、0％～3％的崩解剂、1％～3％的硬脂酸镁、1％～5％的胶态二氧化硅、以及0％～5％的其它赋形剂；或者
5％～40％的活性成分、50％～90％的预胶化淀粉、0％～3％的羧甲淀粉钠或交联羧甲基纤维素钠、1％～3％的硬脂酸镁、以及1％～5％的胶态二氧化硅；
以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
20％～45％的活性成分、40％～80％的预胶化淀粉、0％～5％的崩解剂、0％～5％的粘合剂、2％～5％的润滑剂、1％～5％的助流剂、以及0％～5％的其它赋形剂；或者
20％～45％的活性成分、40％～80％的预胶化淀粉、0％～3％的崩解剂、0％～3％的粘合剂、2％～4％的润滑剂、1％～4％的助流剂、以及0％～5％的其它赋形剂；或者
20％～45％的活性成分、40％～80％的预胶化淀粉、0％～3％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、2％～4％的胶态二氧化硅、以及0％～5％的其它赋形剂；或者
20％～45％的活性成分、40％～80％的预胶化淀粉、0％～3％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、3％～4％的胶态二氧化硅、以及0％～5％的其它赋形剂；或者
25％～40％的活性成分、50％～75％的预胶化淀粉、0％～3％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、3％～4％的胶态二氧化硅、以及0％～5％的其它赋形剂；或者
25％～40％的活性成分、50％～70％的预胶化淀粉0％～3％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂以及3％～4％的胶态二氧化硅；以上各组分重量百分比之和为100％；
优选地，所述润滑剂选自硬脂酸镁或硬脂富马酸钠中的一种或多种；优选地，所述助流剂选自胶态二氧化硅；优选地，所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠中的一种或两种；优选地，所述粘合剂为共聚维酮，更优选为共聚维酮VA64。
本发明的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
5％～65％的活性成分、10％～95％的填充剂(预胶化淀粉和甘露醇)、0％～6％的崩解剂、0.1％～5％ 的润滑剂、1％～5％的助流剂、以及0％～25％的其它赋形剂；或者
5％～65％的活性成分、5％～30％的预胶化淀粉、5％～65％的甘露醇、0％～6％的崩解剂、0.1％～5％的润滑剂、1％～5％的助流剂、以及0％～20％的其它赋形剂；或者
5％～55％的活性成分、5％～30％的预胶化淀粉、5％～65％的甘露醇、0％～5％的崩解剂、0.1％～4％的润滑剂、1％～5％的助流剂、以及0％～15％的其它赋形剂；或者
5％～40％的活性成分、5％～30％的预胶化淀粉、5％～65％的甘露醇、0％～3％的崩解剂、1％～3％的润滑剂、1％～5％的助流剂、以及0％～10％的其它赋形剂；或者
5％～40％的活性成分、5％～30％的预胶化淀粉、5％～65％的甘露醇、0％～3％的崩解剂、1％～3％的润滑剂、1％～5％的胶态二氧化硅、以及0％～10％的其它赋形剂；或者
5％～40％的活性成分、5％～30％的预胶化淀粉、5％～65％的甘露醇、0％～3％的崩解剂、1％～3％的硬脂酸镁、1％～5％的胶态二氧化硅、以及0％～5％的其它赋形剂；或者
5％～40％的活性成分、5％～30％的预胶化淀粉、5％～65％的甘露醇、0％～3％的羧甲淀粉钠或交联羧甲基纤维素钠、1％～3％的硬脂酸镁、以及1％～5％的胶态二氧化硅；
以上各组分重量百分比之和为100％；
优选地，预胶化淀粉和甘露醇的重量比为重量比为1∶10～10∶1，优选为1∶7～7∶1，进一步优选为1∶6～6∶1，进一步优选为1∶5～5∶1，进一步优选为1∶4～4∶1，进一步优选为1∶3～3∶1，更进一步优选为1∶2～2∶1。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
5％～45％的活性成分、50％～90％的填充剂(预胶化淀粉和甘露醇)、0％～3％的崩解剂、0％～4％的粘合剂、2％～4％的润滑剂、2.5％～5％的助流剂、以及0％～5％的其它赋形剂；或者
5％～45％的活性成分、5％～60％的预胶化淀粉、5％-65％的甘露醇、0％～3％的崩解剂、0％～3％的粘合剂、2％～4％的润滑剂、2.5％～5％的助流剂、以及0％～5％的其它赋形剂；或者
25％～45％的活性成分、5％～55％的预胶化淀粉、5％-65％的甘露醇、0％～3％的崩解剂、0％～3％的粘合剂、2％～4％的润滑剂、3％～4％的助流剂、以及0％～5％的其它赋形剂；以上各组分重量百分比之和为100％；
优选地，预胶化淀粉和甘露醇的重量比为1∶10～10∶1，优选为1∶7～7∶1，进一步优选为1∶6～6∶1，进一步优选为1∶5～5∶1，进一步优选为1∶4～4∶1，进一步优选为1∶3～3∶1，更进一步优选为1∶2～2∶1；优选地，所述润滑剂选自硬脂酸镁或硬脂富马酸钠中的一种或多种；优选地，所述助流剂选自胶态二氧化硅；优选地，所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠中的一种或两种；优选地，所述粘合剂为共聚维酮，优选为共聚维酮VA64。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
5％～65％的活性成分、10％～95％的填充剂(微晶纤维素和乳糖)、0％～6％的崩解剂、0.1％～5％的润滑剂、0.5％～5％的助流剂、以及0％～25％的其它赋形剂；或者
5％～65％的活性成分、5％～50％的微晶纤维素、5％～45％的乳糖、0％～6％的崩解剂、0.1％～5％的润滑剂、0.5％～5％的助流剂、以及0％～20％的其它赋形剂；或者
5％～55％的活性成分、15％～45％的微晶纤维素、10％～45％的乳糖、0％～5％的崩解剂、0.1％～4％的润滑剂、0.5％～5％的助流剂、以及0％～15％的其它赋形剂；或者
5％～40％的活性成分、15％～45％的微晶纤维素、10％～45％的乳糖、0％～3％的崩解剂、1％～2％的润滑剂、0.5％～5％的助流剂、以及0％～10％的其它赋形剂；或者
5％～40％的活性成分、15％～45％的微晶纤维素、10％～45％的乳糖、0％～3％的崩解剂、1％～2％的润滑剂、0.5％～5％的胶态二氧化硅、以及0％～10％的其它赋形剂；或者
5％～40％的活性成分、15％～45％的微晶纤维素、10％～45％的乳糖、0％～3％的崩解剂、1％～2％的硬脂酸镁、0.5％～5％的胶态二氧化硅、以及0％～5％的其它赋形剂；或者
5％～40％的活性成分、15％～45％的微晶纤维素、10％～45％的乳糖、0％～3％的羧甲淀粉钠或交联羧甲基纤维素钠、1％～2％的硬脂酸镁、以及0.5％～5％的胶态二氧化硅；
以上各组分重量百分比之和为100％；
优选地，微晶纤维素和乳糖的重量比为1∶10～10∶1，优选为1∶7～7∶1，进一步优选为1∶6～6∶1，进一步优选为1∶5～5∶1，进一步优选为1∶4～4∶1，进一步优选为1∶3～3∶1，更进一步优选为1∶2～2∶1。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
20％～45％的活性成分、50％～75％的填充剂(微晶纤维素和乳糖)、0％～5％的崩解剂、0％～5％的粘合剂、2％～4％的润滑剂、2％～4％的助流剂、以及0％～5％的其它赋形剂；或者
20％～45％的活性成分、50％～75％的填充剂(微晶纤维素和乳糖)、1％～4％的崩解剂、0％～4％的 粘合剂、2％～3％的润滑剂、3％～4％的助流剂、以及0％～5％的其它赋形剂；或者
20％～45％的活性成分、15％～50％的微晶纤维素、15％～45％的乳糖、1％～4％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、3％～4％的助流剂、以及0％～5％的其它赋形剂；或者
25％～45％的活性成分、15％～50％的微晶纤维素、15％～45％的乳糖、1％～3％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、3％～4％的助流剂、以及0％～5％的其它赋形剂；或者以上各组分重量百分比之和为100％；
优选地，所述润滑剂选自硬脂酸镁或硬脂富马酸钠中的一种或多种；优选地，所述助流剂选自胶态二氧化硅；优选地，所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠中的一种或两种；优选地，所述粘合剂为共聚维酮，优选为共聚维酮VA64。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
10％～90％的活性成分、5％～85％的无水磷酸氢钙、0％～3％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、1％～3％的助流剂、以及0％～5％的其它赋形剂；或者
10％～80％的活性成分、15％～85％的无水磷酸氢钙、0％～3％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、1％～3％的助流剂、以及0％～5％的其它赋形剂；且以上各组分重量百分比之和为100％；
优选地，所述润滑剂选自硬脂酸镁或硬脂富马酸钠中的一种或多种；优选地，所述助流剂选自胶态二氧化硅；优选地，所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠中的一种或两种；优选地，所述粘合剂为共聚维酮，优选为共聚维酮VA64。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
15％～80％的活性成分、5％～20％的无水磷酸氢钙、5％～60％的预胶化淀粉、0％～3％的崩解剂、0％～3％的粘合剂、1.5％～3％的润滑剂、2％～3％的助流剂、以及0％～5％的其它赋形剂；
且以上各组分重量百分比之和为100％；
优选地，所述润滑剂选自硬脂酸镁或硬脂富马酸钠中的一种或多种；优选地，所述助流剂选自胶态二氧化硅；优选地，所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠中的一种或两种；优选地，所述粘合剂为共聚维酮，优选为共聚维酮VA64。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
10％～80％的活性成分、15％～75％的碳酸钙、0％～5％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、2％～3％的助流剂、以及0％～5％的其它赋形剂；或者
10％～80％的活性成分、15％～75％的碳酸钙、0.5％～4％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、2％～3％的助流剂、以及0％～5％的其它赋形剂；
且以上各组分重量百分比之和为100％；
优选地，所述润滑剂选自硬脂酸镁或硬脂富马酸钠中的一种或多种；优选地，所述助流剂选自胶态二氧化硅；优选地，所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠中的一种或两种；优选地，所述粘合剂为共聚维酮，优选为共聚维酮VA64。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
10％～80％的活性成分、5％～40％的碳酸钙、5％～60％的预胶化淀粉、0％～2％的崩解剂、0％～3％的粘合剂、2％～3％的润滑剂、2％～3％的助流剂、以及0％～5％的其它赋形剂；或者
10％～80％的活性成分、、5％～40％的碳酸钙、5％～60％的预胶化淀粉、0％～2％的崩解剂、0％～2％的粘合剂、2％～3％的润滑剂、2％～3％的助流剂、以及0％～5％的其它赋形剂；
且以上各组分重量百分比之和为100％；
优选地，所述润滑剂选自硬脂酸镁或硬脂富马酸钠中的一种或多种；优选地，所述助流剂选自胶态二氧化硅；优选地，所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠中的一种或两种；优选地，所述粘合剂为共聚维酮，优选为共聚维酮VA64。
本发明的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
5％～65％的活性成分、10％～95％的微晶纤维素、0％～6％的崩解剂、0.1％～5％的润滑剂、0％～10％的助流剂、以及0％～25％的其它赋形剂；或者
5％～55％的活性成分、20％～85％的微晶纤维素、0％～5％的崩解剂、0.1％～4％的润滑剂、0％～8％的助流剂、以及0％～20％的其它赋形剂；或者
5％～45％的活性成分、30％～75％的微晶纤维素、0％～4％的崩解剂、1％～3％的润滑剂、0％～3％的助流剂、以及0％～10％的其它赋形剂；
以上各组分重量百分比之和为100％。
在本申请的一些实施方案中，上述(第四方面)的药物组合物还可含有除所述类型赋形剂以外的 其它赋形剂。所述其它赋形剂选自：粘合剂、矫味剂、抑菌剂、pH调节剂、色素、增稠剂、分散剂、着色剂、抗氧化剂、稳定剂、香料及包衣材料等。在本申请的实施方案中，其它赋形剂在所述药物组合物中的重量百分比为0％～25％，优选0％～20％、0％～15％、0％～10％或0％～5％。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：10％～70％的活性成分、30％～80％的预胶化淀粉、0％～5％的胶态二氧化硅、0％～5％的硬脂酸镁、以及0％～5％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：15％～60％的活性成分、40％～80％的预胶化淀粉、1％～5％的胶态二氧化硅、1％～5％的硬脂酸镁、以及0％～5％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：20％～50％的活性成分、45％～75％的预胶化淀粉、1％～4％的胶态二氧化硅、1％～5％的硬脂酸镁、以及0％～5％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：25％～45％的活性成分、50％～70％的预胶化淀粉、1％～4％的胶态二氧化硅、1％～4％的硬脂酸镁、以及0％～4％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：25％～40％的活性成分、56％～68％的预胶化淀粉、1％～4％的胶态二氧化硅、2％～4％的硬脂酸镁、以及0％～4％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：25％～40％的活性成分、56％～68％的预胶化淀粉、1％～3％的胶态二氧化硅、2％～3％的硬脂酸镁、以及0％～4％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：25％～40％的活性成分、56％～68％的预胶化淀粉、3％～5％的胶态二氧化硅以及2％～3％的硬脂酸镁，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：25％～40％的活性成分、56％～68％的预胶化淀粉、3％～4％的胶态二氧化硅以及2％～3％的硬脂酸镁，各组分重量百分比之和为100％。
在本申请的另一些实施方案中，所述药物组合物的各组分及其重量百分比为：25％～50％的活性成分、50％～75％的微晶纤维素、0％～5％的胶态二氧化硅、0％～3％的硬脂酸镁、以及0％～5％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：25％～40％的活性成分、55％～75％的微晶纤维素、0％～5％的胶态二氧化硅、1％～3％的硬脂酸镁、以及0％～5％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：30％～35％的活性成分、60％～70％的微晶纤维素、0％～3％的胶态二氧化硅、1％～2％的硬脂酸镁、以及0％～4％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：30％～35％的活性成分、60％～70％的微晶纤维素、0％～3％的胶态二氧化硅以及1％～2％的硬脂酸镁，各组分重量百分比之和为100％。
在本申请的另一些实施方案中，所述药物组合物的各组分及其重量百分比为：5％～50％的活性成分、5％～55％的预胶化淀粉、5％～70％的甘露醇、0％～5％的胶态二氧化硅、1％～3％的硬脂酸镁、以及0％～5％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选地，所述药物组合物的各组分及其重量百分比为：20％～50％的活性成分、5％～55％的预胶化淀粉、5％～70％的甘露醇、1％～5％的胶态二氧化硅、1％～3％的硬脂酸镁、以及0％～5％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：25％～40％的活性成分、10％～50％的预胶化淀粉、5％～63％的甘露醇、1％～4％的胶态二氧化硅、1％～3％的硬脂酸镁、以及0％～5％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：25％～40％的活性成分、10％～50％的预胶化淀粉、5％～63％的甘露醇、1％～3％的胶态二氧化硅、1％～3％的硬脂酸镁、以及0％～5％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：25％～40％的活性成分、10％～50％的预胶化淀粉、5％～63％的甘露醇、3％～4％的胶态二氧化硅、2％～3％的硬脂酸镁、以及0％～5％的羧甲基淀 粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：25％～40％的活性成分、10％～50％的预胶化淀粉、5％～63％的甘露醇、3％～4％的胶态二氧化硅、以及2％～3％的硬脂酸镁，各组分重量百分比之和为100％。
在本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：23％～50％的活性成分、10％～55％的微晶纤维素、10％～50％的乳糖、0％～5％的胶态二氧化硅、1％～4％的硬脂酸镁或硬脂富马酸钠、以及0％～5％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：23％～40％的活性成分、10％～50％的微晶纤维素、10％～50％的乳糖、1％～5％的胶态二氧化硅、1％～4％的硬脂酸镁或硬脂富马酸钠、以及0％～5％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：28％～35％的活性成分、15％～45％的微晶纤维素、15％～45％的乳糖、1％～4％的胶态二氧化硅、2％～3％的硬脂酸镁或硬脂富马酸钠、以及1％～4％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：28％～35％的活性成分、15％～45％的微晶纤维素、15％～45％的乳糖、1％～3％的胶态二氧化硅、2％～3％的硬脂酸镁或硬脂富马酸钠、以及1％～4％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：28％～35％的活性成分、15％～45％的微晶纤维素、15％～45％的乳糖、3％～5％的胶态二氧化硅、2％～4％的硬脂酸镁或硬脂富马酸钠、以及1％～4％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：28％～35％的活性成分、15％～45％的微晶纤维素、15％～45％的乳糖、3％～4％的胶态二氧化硅、2％～3％的硬脂酸镁或硬脂富马酸钠、以及1％～3％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
在本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：10％～90％的活性成分、5％～85％的无水磷酸氢钙、1％～5％的胶态二氧化硅、1％～4％的硬脂酸镁、以及0％～5％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：10％～80％的活性成分、15％～85％的无水磷酸氢钙、1％～4％的胶态二氧化硅、2％～3％的硬脂酸镁、以及0％～4％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：50％～60％的活性成分、35％～40％的无水磷酸氢钙、1％～3％的胶态二氧化硅、2％～3％的硬脂酸镁、以及0％～4％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
在本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：10％～85％的活性成分、5％～23％的无水磷酸氢钙、5％～70％的预胶化淀粉、1％～4％的胶态二氧化硅、1％～4％的硬脂酸镁、以及0％～4％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：15％～80％的活性成分、7％～18％的无水磷酸氢钙、7％～63％的预胶化淀粉、1％～3％的胶态二氧化硅、2％～3％的硬脂酸镁、以及0％～4％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
在本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：10％～82％的活性成分、10％～85％的碳酸钙、1％～4％的胶态二氧化硅、1％～4％的硬脂酸镁、0-5％的共聚维酮VA64以及0％～4％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：12％～80％的活性成分、15％～78％的碳酸钙、1％～3％的胶态二氧化硅、2％～3％的硬脂酸镁、0-3％的共聚维酮VA64以及0.5％～4％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
在本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：10％～83％的活性成分、5％～50％的碳酸钙、5％-68％的预胶化淀粉、1％～4％的胶态二氧化硅、1％～4％的硬脂酸镁、0-3％的共聚维酮VA64以及0％～2％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：12％～80％的活性成分、7％～45％的碳酸钙、7％-65％的预胶化淀粉、1％～3％的胶态二氧化硅、1.5％～3％的硬脂酸镁、0-2％的共聚维酮VA64以及0％～1％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
优选的，所述药物组合物的各组分及其重量百分比为：12％～80％的活性成分、7％～45％的碳酸钙、7％-65％的预胶化淀粉、2％～3％的胶态二氧化硅、2％～3％的硬脂酸镁、0-2％的共聚维酮VA64以及 0％～1％的羧甲基淀粉钠和/或交联羧甲基纤维素钠，各组分重量百分比之和为100％。
在本申请的一些实施方案中，所述药物组合物制成口服固体剂型；优选地，所述口服固体制剂选自胶囊、片剂、散剂和细粒剂；进一步优选为胶囊、片剂和细粒剂；进一步优选为胶囊和片剂；更进一步优选为胶囊。
在本申请的一些实施方案中，所述片剂选自薄膜衣片剂或不包衣的片剂。
第五方面，本申请提供了一种药物组合物，其包含，作为活性成分的如式II、式A或式B所示的化合物和赋形剂，所述赋形剂包含填充剂和粘合剂，任选地，进一步包含矫味剂。
在本申请的一些实施方案中，所述赋形剂包含填充剂、粘合剂和矫味剂。
本申请的一些实施方案中，所述矫味剂包含芳香剂，任选地，进一步包含甜味剂。
本申请的一些实施方案中，所述填充剂选自糖醇类中的一种或多种；优选地，所述糖醇类填充剂选自乳糖、甘露醇和山梨醇中的一种或多种；优选地，所述填充剂选自甘露醇。
本申请的一些实施方案中，所述粘合剂选自共聚维酮、糖粉、糖浆、聚乙烯基吡咯烷酮、纤维素衍生物、胶浆和糊精中的一种或多种；优选地，所述纤维素衍生物选自羟丙基甲基纤维素和/或羧甲基纤维素钠；进一步优选为共聚维酮、糖粉、聚乙烯基吡咯烷酮、羟丙基甲基纤维素和/或羧甲基纤维素钠；进一步优选为共聚维酮和/或聚乙烯基吡咯烷酮。
本申请的一些实施方案中，所述甜味剂选自山梨糖、木糖、木糖醇、甘油、甘草酸二钠、甘露糖、半乳糖、麦芽糖、乳糖、果糖、甜精、糖精钠、甜菊糖甙、葡萄糖、蔗糖、三氯蔗糖、阿司帕坦和纽甜；优选为木糖醇、三氯蔗糖、阿司帕坦和纽甜。
本申请的一些实施方案中，所述芳香剂为油类或香精类中的一种或多种；优选为小茴香油、玫瑰油、薄荷油、橙皮油、柠檬油、玫瑰香精、柠檬香精、香草香精、香草醛、香蕉香精、菠萝香精或苹果香精中的一种或多种；进一步优选为柠檬香精、菠萝香精或苹果香精中的一种或多种。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
活性成分，其重量百分比为0.50％～30％；或者0.60％～25％；或者0.70％～20％；或者0.80％～15％；或者1％～10％；或者1.50％～8％；或者2％～6％；或者2.50％～5％；或者3％～4.50％；
填充剂，其重量百分比为50％～99.90％；或者60％～99.50％；或者70％～99％；或者80％～99％；或者85％～99％；
粘合剂，其重量百分比为其重量百分比为0％～10％；或者0％～6％；或者0％～5％；或者0％～4％；或者0％～3％；或者0％～2％；
矫味剂，其重量百分比为其重量百分比为0％～10％；或者0％～6％；或者0％～5％；或者0％～4％；或者0％～3％；或者0％～2％；或者0％～1％；
其它赋形剂，其重量百分比为0％～25％；或者0％～20％；或者0％～15％；或者0％～10％；或者0％～5％；或者0.10％～3％；或者0.10％～2％；或者0.10％～1％；以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述填充剂选自甘露醇；所述粘合剂选自共聚维酮；优选共聚维酮VA64或共聚维酮VA64Fine；所述矫味剂选自甜味剂和/或芳香剂；所述甜味剂选自木糖醇、三氯蔗糖、阿司帕坦和/或纽甜；所述芳香剂选自柠檬香精；所述药物组合物的各组分及其重量百分比为：
0.50％～30％的活性成分、50％～99.90％的填充剂、0％～10％的粘合剂、0％～10％的矫味剂、以及0％～25％的其它赋形剂；或者
0.60％～25％的活性成分、60％～99.50％的填充剂、0％～8％的粘合剂、0％～6％的矫味剂、以及0％～15％的其它赋形剂；或者
0.70％～20％的活性成分、70％～99％的填充剂、2％～8％的粘合剂、0％～3％的矫味剂、以及0％～10％的其它赋形剂；或者
1％～10％的活性成分、85％～99％的填充剂、3％～8％的粘合剂、0％～1％的矫味剂、以及0％～2％的其它赋形剂；
1％～5％的活性成分、85％～95％的填充剂、4％～8％的粘合剂、0％～1％的矫味剂、以及0％～2％的其它赋形剂；
以上各组分重量百分比之和为100％。
优选地，所述药物组合物中，所述填充剂选自甘露醇；所述粘合剂选自共聚维酮；优选为共聚维酮VA64；所述矫味剂选自柠檬香精。
在本申请的一些实施方案中，上述各方面所述的药物组合物还可含有除所述类型赋形剂以外的其它赋形剂。作为其具体实例，可以举出：崩解剂、抑菌剂、增稠剂、分散剂、抗氧化剂及稳定剂等。 在本申请的实施方案中，其它赋形剂在所述药物组合物中的重量百分比为0％～25％，优选0％～20％、0％～15％、0％～10％或0％～5％。
在本申请的一些实施方案中，所述药物组合物制成口服固体剂型；优选地，所述口服固体制剂选自颗粒剂、散剂和细粒剂；进一步优选为颗粒剂。
第六方面，本发明提供了一种药物组合物，其包含，作为活性成分的如式II或式A所示的化合物及赋形剂，所述赋形剂包含溶剂，任选地，进一步包含矫味剂、抑菌剂或pH调节剂中的一种或多种。
本申请的一些实施方案中，所述赋形剂包含溶剂和矫味剂，任选地，进一步包含抑菌剂或pH调节剂中的一种或多种。
本申请的一些实施方案中，所述赋形剂包含溶剂、矫味剂和pH调节剂，任选地，进一步包含抑菌剂。
本申请的一些实施方案中，所述矫味剂包含甜味剂，任选地，进一步包含芳香剂。
本申请的一些实施方案中，前述甜味剂选自山梨糖、木糖、木糖醇、甘油、甘草酸二钠、甘露糖、半乳糖、麦芽糖、乳糖、果糖、甜精、糖精钠、甜菊糖甙、葡萄糖、蔗糖、三氯蔗糖、阿司帕坦和/或纽甜中的一种或多种；优选为木糖醇、三氯蔗糖、阿司帕坦和/或纽甜中的一种或多种。
本申请的一些实施方案中，前述芳香剂为油类或香精类中的一种或多种；优选为小茴香油、玫瑰油、薄荷油、橙皮油、柠檬油、玫瑰香精、柠檬香精、香草香精、香草醛、香蕉香精、菠萝香精或苹果香精中的一种或多种；进一步优选为柠檬香精、菠萝香精或苹果香精中的一种或多种。
本申请的一些实施方案中，前述溶剂选自水、乙醇和植物油；优选为水；进一步优选为纯化水。
本申请的一些实施方案中，前述抑菌剂选自苯甲酸钠、山梨酸钾、乌洛托品、乙醇、苯甲醇或尼泊金酯类中的一种或多种；优选为苯甲酸钠、山梨酸钾、乌洛托品、乙醇、苯甲醇、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯或对羟基苯甲酸丙酯中的一种或多种；进一步优选为苯甲酸钠、山梨酸钾、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯或对羟基苯甲酸丙酯中的一种或多种。
本申请的一些实施方案中，前述pH调节剂为氢氧化钠、碳酸氢钠、碳酸钠中的一种或多种。
本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
活性成分，其重量百分比为0.10％～40％；或者0.10％～35％；或者0.10％～30％；或者0.50％～25％；或者0.50％～20％；或者1％～10％；
溶剂，其重量百分比为90％～99.99％；或者95％～99.99％；或者96％～99.99％；或者97％～99.99％；
甜味剂，其重量百分比为0％～5％；或者0.01％～4％；或者0.05％～3％；或者0.10％～2％；或者0.10％～1％；或者0.10％～0.50％；
芳香剂，其重量百分比为0％～5％；或者0.01％～4％；或者0.05％～3％；或者0.05％～2％；或者0.05％～1.50％；或者0.05％～1％；
抑菌剂，其重量百分比为0％～6％；或者0％～5％；或者0％～4％；或者0％～3％；或者0％～2.50％；或者0％～2％；或者0％～1.50％；或者0％～1％；或者0％～0.50％；
其它赋形剂，其重量百分比为0％～25％；或者0％～20％；或者0％～15％；或者0％～10％；或者0％～5％；
以及pH调节剂；
其中，pH调节剂以达到pH＝4～6所需实际用量为准，以上各组分重量百分比之和为100％。
本申请的一些实施方案中，所述溶剂为水；所述芳香剂为柠檬香精；所述甜味剂为纽甜，所述pH调节剂为氢氧化钠。本申请的一些实施方案中，所述药物组合物的各组分及其重量百分比为：
0.10％～10％的活性成分、90％～99.99％的溶剂、0％～5％的甜味剂、0％～5％的芳香剂、0％～6％的抑菌剂、以及0％～25％的其它赋形剂；或者
0.10％～5％的活性成分、95％～99.99％的溶剂、0.05％～3％的甜味剂、0.05％～3％的芳香剂、0％～4％的抑菌剂、以及0％～25％的其它赋形剂；或者
0.50％～4％的活性成分、96％～99.99％的溶剂、0.10％～2％的甜味剂、0.05％～2％的芳香剂、0％～2.50％的抑菌剂、以及0％～25％的其它赋形剂；或者
1％～3％的活性成分、97％～99.99％的溶剂、0.10％～1％的甜味剂、0％～1％的芳香剂、0％～1％的抑菌剂、以及0％～25％的其它赋形剂；
以及pH调节剂；
其中，pH调节剂以达到pH＝4～6所需实际用量为准，以上各组分重量百分比之和为100％。
在本申请的一些实施方案中，上述各方面所述的药物组合物还可含有除所述类型赋形剂以外的其 它赋形剂。作为其具体实例，可以举出：增稠剂、分散剂、表面活性剂、抗氧化剂、稳定剂等。在本申请的实施方案中，其它赋形剂在所述药物组合物中的重量百分比为0％～25％，优选0％～20％、0％～15％、0％～10％或0％～5％。
本申请的一些实施方案中，所述药物组合物制成口服溶液剂。
本申请的一些实施方案中，所述药物组合物可制成单剂量形式或多剂量形式。
本申请的一些实施方案中，所述口服溶液剂的单剂量形式为1～30mL，优选为1～20mL，进一步优选为1～15mL，进一步优选为1～10mL，进一步优选为1mL、2mL、3mL、4mL、5mL、6mL、7mL、8mL、9mL或10mL。
本申请的一些实施方案中，所述口服溶液剂的多剂量形式为2～500mL，优选为2～250mL，进一步优选为5～250mL，进一步优选为10～200mL，进一步优选为15～150mL，进一步优选为20～100mL，进一步优选为20～50mL，进一步优选为30～50mL。
本申请的一些实施方案中，以上所述(第一至第六方面)的药物组合物中含有0.001-1000mg的活性成分，优选0.1～800mg，进一步优选1～500mg，进一步优选10～300mg，进一步优选10～200mg，更进一步优选10～100mg剂量范围，例如单剂量形式的药物组合物中包含活性成分5mg、10mg、20mg、25mg、30mg、50mg、60mg、100mg、150mg、200mg、250mg、300mg、500mg等；其中，所述活性成分以盐酸盐形式(例如，本申请的一些方案中以C 24H 29N 9·3HCl)计。
本申请的一些实施方案中，以上所述(第一至第六方面)口服制剂、口服固体制剂或口服溶液剂的每个制剂单位中可含有0.001-1000mg的活性成分，优选0.1～800mg，进一步优选1～500mg，进一步优选10～300mg，进一步优选10～200mg，更进一步优选10～100mg剂量范围，例如单剂量形式的口服制剂中包含活性成分5mg、10mg、20mg、25mg、30mg、50mg、60mg、100mg、150mg、200mg、250mg、300mg、500mg等；其中，所述活性成分以盐酸盐形式(例如，本申请的一些方案中以C 24H 29N 9·3HCl)计。
第七方面，本申请提供了上述药物组合物的制备方法，其包括：(1)称量：按处方量称量活性成分和赋形剂；(2)混合：将活性成分及赋形剂于混合容器中混合均匀。
本申请的一些实施方案中，所述药物组合物制成胶囊剂，所述制备方法包括：(1)按处方量称量活性成分和赋形剂；(2)将活性成分和赋形剂加入混合容器中进行混合产生混粉；(3)使用上述混粉灌装胶囊。
本申请的一些实施方案中，所述药物组合物的赋形剂包括外加润滑剂；所述药物组合物制成胶囊剂，所述制备方法包括：(1)按处方量称量活性成分和赋形剂；(2)将活性成分和除外加润滑剂以外的赋形剂加入混合容器中进行混合产生混粉；(3)使用上述混粉进行制粒；(4)将步骤(3)得到的颗粒与外加润滑剂混合；(5)将步骤(4)制得的混合物灌装胶囊。
本申请的一些实施方案中，所述药物组合物制成片剂，所述制备方法，其包括：(1)按处方量称量活性成分和赋形剂；(2)将活性成分和赋形剂加入混合容器中进行混合，产生混粉；(3)使用上述混粉进行制粒；(4)将步骤(3)得到的颗粒与外加润滑剂混合；(5)进行压片；以及任选地，进一步包含包衣步骤。
本申请的一些实施方案中，所述药物组合物制成颗粒剂，所述制备方法包括：(1)按处方量称量活性成分和赋形剂；(2)将赋形剂和活性成分加入混合容器中进行混合产生预混物；(3)加水制成软材；(4)制粒，干燥；(5)整粒。
本申请的一些实施方案中，所述药物组合物制成口服液体制剂，所述制备方法包括：(1)按处方量称量活性成分和赋形剂；(2)将赋形剂和活性成分加入混合容器中，搅拌混匀；(3)除菌；(4)灌装。
本申请的一些实施方案中，提供上述固体口服制剂的制备方法，其包括：将由上述制备方法得到的所述的药物组合物按包装剂量装入包装袋中，制成散剂或细粒剂。上述“混合容器”应做广义的理解，其既包括柔性的混合器(包括但不限于柔性的袋如洁净塑料袋、自封袋等)也包括刚性的混合器(包括但不限于混合机、料斗混合机等)。本领域技术人员可根据批量和重量选择适宜的混合器进行相应的预混和总混操作。
上述“制粒”步骤应作广义的理解，既包括使用研钵进行制粒，任选地，可进一步辅助过筛操作进行整粒，或者辅助过筛操作使制得的颗粒符合需要，也包括使用机器设备进行制粒操作，例如干法制粒机等。本领域技术人员可根据批量和重量选择适宜的工具或机器设备进行相应的制粒操作。
第八方面，本申请提供了前述的药物组合物或前述的固体口服制剂用于抑制FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes、VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET和PDGFRα激酶中一个或多个的活性的用途。
第九方面，本申请提供了前述的药物组合物或前述的口服制剂用于制备作为药物的用途。
在本申请的一些实施方案中，所述药物用于治疗或预防蛋白激酶介导的疾病，所述蛋白激酶选自：FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes、VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET和PDGFRα激酶中一个或多个。
在本申请的一些实施方案中，所述蛋白激酶介导的疾病为肿瘤疾病，优选血液瘤或实体瘤，进一步优选为白血病或肺癌，更优选为急性髓性白血病如FLT3突变阳性的急性髓性白血病(进一步如FLT3-ITD突变或FLT3-TKD突变的急性髓性白血病)、慢性髓性白血病(如Ph阳性的慢性髓性白血病)、或非小细胞肺癌(如EGFR激活突变的非小细胞肺癌)。在本申请的一些实施方案中，所述药物用于治疗或预防急性髓性白血病；优选地，所述急性髓性白血病选自复发和/或难治性急性髓性白血病，或者，所述急性髓性白血病选自FLT3-ITD突变和/或TKD突变的急性髓性白血病，II型FLT3抑制剂(例如索拉非尼)治疗失败的复发和/或难治性急性髓性白血病，或者，DEK-CAN阳性与FLT3-ITD突变同时存在的急性髓性白血病；更优选地，所述急性髓性白血病为FLT3-ITD high突变的急性髓性白血病；和/或所述急性髓性白血病的预后不良因素为0～2种；和/或所述急性髓性白血病的FAB分型为M2、M4、M5型，优选M5型。更进一步地，前述在制备用于治疗或预防急性髓性白血病的药物中的用途详述于专利申请PCT/CN2020/127449中，在此将该专利申请PCT/CN2020/127449的公开内容并入这里，如同在本申请中公开的一样。
第十方面，本申请提供了前述的药物组合物或前述的口服制剂用于制备作为蛋白激酶抑制剂药物的用途，所述蛋白激酶选自：FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes、VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET和PDGFRα激酶中一个或多个。
在本申请的一些实施方案中，所述蛋白激酶抑制剂药物为抗肿瘤药物，所述肿瘤优选实体瘤或血液瘤，进一步优选为白血病或肺癌，更优选为急性髓性白血病如FLT3突变阳性的急性髓性白血病(进一步如FLT3-ITD突变或FLT3-TKD突变的急性髓性白血病)、慢性髓性白血病(如Ph阳性的慢性髓性白血病)、或非小细胞肺癌(如EGFR激活突变的非小细胞肺癌)。
在本申请的一些实施方案中，所述蛋白激酶抑制剂药物为抗肿瘤药物，所述肿瘤选自选自非小细胞肺癌、急性髓性白血病、慢性粒细胞白血病、慢性髓性白血病、表皮鳞癌、乳腺癌、结直肠癌、肝癌、胃癌、和恶性黑色素瘤；进一步优选地，所述病症选自人非小细胞肺癌、人急性髓性白血病、人慢性粒细胞白血病、人慢性髓性白血病、人表皮鳞癌、人乳腺癌、人结直肠癌、人肝癌、人胃癌、和人恶性黑色素瘤。
第十一方面，本申请提供了前述的药物组合物或前述的口服制剂在制备用于治疗或预防病症的药物中的用途；优选地，所述病症是由FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes、VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET和PDGFRα激酶中的一个或多于一个导致的病症；更优选地，所述病症选自非小细胞肺癌、急性髓性白血病、慢性粒细胞白血病、慢性髓性白血病、表皮鳞癌、乳腺癌、结直肠癌、肝癌、胃癌、和恶性黑色素瘤；进一步优选地，所述病症选自人非小细胞肺癌、人急性髓性白血病、人慢性粒细胞白血病、人慢性髓性白血病、人表皮鳞癌、人乳腺癌、人结直肠癌、人肝癌、人胃癌、和人恶性黑色素瘤。
第十二方面，本申请提供了上述的药物组合物或上述的口服制剂，其用于治疗蛋白激酶相关疾病，所述蛋白激酶选自：FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes、VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET和PDGFRα激酶中一个或多个。
在本申请的一些实施方案中，所述蛋白激酶相关疾病选自非小细胞肺癌、急性髓性白血病、慢性粒细胞白血病、慢性髓性白血病、表皮鳞癌、乳腺癌、结直肠癌、肝癌、胃癌、和恶性黑色素瘤；进一步优选地，所述病症选自人非小细胞肺癌、人急性髓性白血病、人慢性粒细胞白血病、人慢性髓性白血病、人表皮鳞癌、人乳腺癌、人结直肠癌、人肝癌、人胃癌、和人恶性黑色素瘤。。
第十三方面，本申请提供了一种治疗蛋白激酶介导的疾病的方法，其包括向需要其的对象使用前述的药物组合物或前述的口服制剂，所述蛋白激酶选自FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes、VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET和PDGFRα激酶中一个或多个。
在本申请的一些实施方案中，所述蛋白激酶相关疾病选自非小细胞肺癌、急性髓性白血病、慢性粒细胞白血病、慢性髓性白血病、表皮鳞癌、乳腺癌、结直肠癌、肝癌、胃癌、和恶性黑色素瘤；进 一步优选地，所述病症选自人非小细胞肺癌、人急性髓性白血病、人慢性粒细胞白血病、人慢性髓性白血病、人表皮鳞癌、人乳腺癌、人结直肠癌、人肝癌、人胃癌、和人恶性黑色素瘤。。
前述各方面的药物、口服制剂、口服固体制剂或口服溶液剂在发挥治疗作用时，活性成分的治疗有效量为0.001～1000mg，优选为1～800mg，或1～500mg，或20～400mg，或100-350mg，最优选150～310mg，所述治疗有效量以盐酸盐形式(例如，在本申请的一些实施方案中以C 24H 29N 9·3HCl)计。可以单剂量施用或分剂量施用。
除非另外指出，否则所有的百分数都以药物组合物及其口服制剂的总重量的重量％给出。
本申请所述的“口服制剂”是指用于口服施用的药物制剂。
本申请所述的“口服固体制剂”是指用于口服施用的呈固态的药物制剂。
本申请所述的“口服溶液制剂”或“口服溶液剂”是指用于口服施用的呈溶液状态的药物制剂。
在本申请的实施方案中，给药对象可以是人或非人哺乳动物，更优选人。
在本申请的实施方案中，术语“包含”、“包括”和“含有”一般表示开放性的含义，但是在其范围内也包括“由......组成”所限定的封闭性的情况。例如，“一种药物组合物，其包含：作为活性成分的如式II、式A或式B所示的化合物及赋形剂”也包括“一种药物组合物，其由作为活性成分的如式II、式A或式B所示的化合物及赋形剂组成”的情况。
在本申请的范围中，任一特征的各种选项可以与其它特征的各种选项相互组合，从而构成许多不同的实施方案。本申请意欲包括由所有技术特征的各种选项所组成的所有可能的实施方案。
在本申请的范围中，可对如式I、式II、式A或式B所示的化合物或其药学上可接受的盐在处方中的用量进行适当的调整，或者与赋形剂的比例(质量比)进行调整，以得到含有不同规格或不同药物重量的药物组合物或口服制剂，其也落入本申请的范围。
经过缜密的研究试验，本申请取得了以下有益技术效果中的一种或多种：
(1)所述药物组合物的制备方法简便，制剂过程顺利，对所采用的仪器设备和操作工艺均无苛刻的要求，更适合于工业化生产；(2)经过筛选，发现了本申请所述的一些药物组合物适于直接混合或干法制粒，可简化固体制剂的制备过程；(3)同其它处方相比，由上述药物组合物制成的口服制剂符合制剂标准和要求，例如口服固体制剂(例如，胶囊剂、片剂)具有良好的溶出度、含量均匀度和稳定性；(4)所述药物组合物和/或口服制剂，特别是口服固体制剂，还具备优良的稳定性，在影响因素试验、加速试验和/或长期试验中，被考察药物组合物和/或口服制剂(特别是口服固体制剂，例如，胶囊剂和片剂，更特别地，是胶囊剂)的最大单杂、总杂、含量、晶型等均无明显改变，故适宜长期储存。
附图说明
图1：制备例2所得式B所示化合物的XRPD谱图。
图2：制备例2所得式B所示化合物的差热-热重联用分析(DSC-TGA)图。
具体实施方式
检测方法：
1、含量(化合物B的游离碱含量检测)
检测仪器：高效液相色谱仪/Waters e2695-2489
分析方法：
用十八烷基硅烷键合硅胶为填充剂(pH值适用范围应大于10.0)，以20mmol/L磷酸氢二钠溶液(用氢氧化钠调pH值至10.0)-乙腈(65∶35)为流动相；检测波长为287nm，柱温为30℃。理论板数应不低于3000。
测定法取样品约20mg，精密称定，置100mL量瓶中，加稀释剂(50％甲醇水)使溶解并稀释至刻度，摇匀，精密量取10μL，注入液相色谱仪，记录色谱图；另取对照品适量，同法测定。按外标法以峰面积计算，即得。
2、水分(化合物B的水分含量检测)
检测仪器：卡式水分滴定仪/915KF Ti-Touch
测试方法：仪器平衡后，取供试品适量(约200mg)，精密称定，加入滴定杯中，以无水甲醇为溶剂，用水分滴定液直接测定，每个供试品测定两次取平均值。
3、溶解度
检测仪器：紫外分光光度计/Evolution 300
测试方法：
选择pH1.2、pH4.5、pH6.8和水做为溶剂，溶剂配制方法具体如下：
(1)pH1.2盐酸溶液：盐酸7.65ml，加水1000ml，摇匀，即得。
(2)pH4.5磷酸盐缓冲液：取磷酸二氢钾6.8g，用水稀释至1000ml，摇匀即得。
(3)pH6.8磷酸盐缓冲液：取磷酸二氢钾6.8g，氢氧化钠0.896g，用水稀释至1000ml，摇匀即得。
(4)水：纯化水
样品制备：
取具塞试管，分别精密加入10ml各pH值溶出介质，加入过量原料药，直至形成过饱和溶液，记录加入量，摇匀，密塞，于摇床中振摇24小时，分别于不同时间点取出2ml溶液，离心，取上清液，滤过，取续滤液，待用。
取上述不同溶剂下饱和溶液，加溶剂稀释一定体积，于287nm波长处测定吸光度。
对照品溶液制备：取式1化合物对照品适量，精密称定，加溶剂使溶解并稀释制成每1ml中约含式1化合物10μg的溶液，于287nm波长处测定吸光度，计算得到。
4、引湿性
检测仪器：XPE105DR
测试方法：
(1)取干燥的具塞玻璃称量瓶，于试验前一天置于适宜的25℃±1℃恒温干燥器(下部放置氯化铵或硫酸铵饱和溶液)或人工气候箱(设定温度为25℃±1℃，相对湿度为80％士2％)内，精密称定重量(m1)。
(2)取供试品适量，平铺于上述称量瓶中，供试品厚度一般约为1mm，精密称定重量(m2)。
(3)将称量瓶敞口，并与瓶盖同置于上述恒温恒湿条件下24小时。
(4)盖好称量瓶盖子，精密称定重量(m3)。
增重百分率＝(m3-m2)/(m2-m1)×100％
(5)引湿性特征描述与引湿性增重的界定：
潮解：吸收足量水分形成液体。
极具引湿性：引湿增重不小于15％。
有引湿性：引湿增重小于15％但不小于2％。
略有引湿性：引湿增重小于2％但不小于0.2％。
无或几乎无引湿性：引湿增重小于0.2％。
5、X-射线粉末衍射(X-Ray Powder Diffraction，XRPD)
检测仪器：PANalytical Empyrean型粉末X-射线衍射仪
测试条件：
光管类型：Cu靶，金属陶瓷X光管；
X-射线波长：CuKα，
Figure PCTCN2021143219-appb-000015
Kα 2/Kα 1强度比例：0.5；
电压电流：45kV，40mA；
扫描范围：3-40°2θ；
扫描总时间：约5min。
6、差热-热重联用分析(DSC-TGA)
检测仪器：NETZSCH STA 449F3
测试条件：
温度范围：20℃-350℃；
升温速率：10.0(K/min)；
样品支架/热电偶：DSC/TG Cp S/S
坩埚：DSC/TG pan Al 2O 3
气氛：N 2，20.0ml/min/N 2，50.0ml/min
校正/测量范围：020/5000μV
7、核磁共振波谱(Nuclear Magnetic Resonance spectroscopy，NMRS)
检测仪器：AVIII BRUKER 600型超导核磁共振谱仪
内容及测试溶剂： 1H-NMR，测试溶剂为H 2D。
8、单晶
单晶衍射数据使用Rigaka XtaLAB Synergy-R(Micro-Max007HF Cu mode，
Figure PCTCN2021143219-appb-000016
Hypix 6000HE detector)型单晶衍射仪在120.00(10)K温度下收集。单晶样品的显微照片使用上海测维PXS9-T型体视显微镜拍摄。
9、溶出度
检查方法：溶出度与释放度测定法第二法(加沉降篮)(中国药典2020年版四部通则0931)
取本品6粒，照溶出度与释放度测定法第二法，以pH1.2盐酸溶液900mL为溶出介质，转速为每分钟50转，依法操作，经30分钟时，取溶液10mL，滤过，取续滤液，加pH1.2盐酸溶液稀释为相当于含量API为10ug/mL的溶液作为供试品溶液。另取化合物B对照品约25mg，精密称定，置100mL量瓶中，加pH1.2盐酸溶液使溶解并稀释至刻度，摇匀，作为对照品贮备液；精密量取对照品贮备液并稀释为10ug/mL的溶液，作为对照品溶液。
测定方法：分别取对照品溶液和供试品溶液适量，按照紫外-可见分光光度法在287nm波长处测定吸光度，按外标法以吸光度计算每粒的溶出量。
10、原辅料相容性试验
原辅料相容性试验考察条件及时间
Figure PCTCN2021143219-appb-000017
11、影响因素试验
影响因素试验考察条件及时间
Figure PCTCN2021143219-appb-000018
12、加速和长期稳定性试验
稳定性试验考察条件及时间
Figure PCTCN2021143219-appb-000019
下面通过部分实施例对本申请进行详细说明，但本申请并不限于下述实施例。对于本领域技术人员显而易见的修改意图落入本申请权利要求的范围内。
实施例中未注明具体条件者，按照常规条件或制造商建议条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。除非另行定义，文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。
本申请的化合物I可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其它化学合成方法的结合所形成的实施方式以及对于本领域技术上人员来说显而易见 的等同替换方式。优选的实施方式包括但不限于本申请的制备例。
为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
制备例1式I化合物的制备
Figure PCTCN2021143219-appb-000020
参考专利文献WO 2011/147066中实施例90所记载的方法，制备得到式I所示化合物100g。
制备例2化合物B的制备
将制备例1所得芳胺基嘌呤衍生物(90g，0.203mol)和800mL纯化水、400mL丙酮加入反应器中，搅拌升温至40±5℃后，向反应器中流加(74g，0.731mol)浓盐酸，加完浓盐酸后，再加入2L丙酮，保持温度40±5℃，继续反应1h，然后搅拌降温至10±5℃析晶2h，抽滤，滤饼用300mL丙酮洗涤，得黄色或淡黄色盐酸盐74.7g。 1H-NMR(600MHz，D 2O)δ：1.556(d，6H)，2.896(s，3H)，3.058(t，2H)，3.187(t，2H)，3.586(d，2H)，3.749(d，2H)，4.701(s，1H)，7.062(d，2H)，7.377(d，2H)，7.968(t，1H)，8.086(s，1H)，8.431(d，1H)，8.636(d，1H)，9.171(s，1H)。所得盐酸盐呈现良好的结晶性，其XRPD表征谱图如附图1所示，主要衍射峰数据如下：
峰位置2θ角(°) 相对峰强度％ 峰位置2θ角(°) 相对峰强度％
7.300 20.96 20.027 26.40
8.504 40.4 21.140 22.06
9.052 14.65 21.913 14.4
11.814 34.65 23.701 25.54
12.579 13.44 25.162 62.26
14.300 15.86 26.137 15.54
18.136 18.09 27.165 100
19.641 29.87    
取样品进行DSC和TGA测试，图谱分别如附图2所示。DSC图谱显示无明显熔点，TGA图谱显示，样品在40℃左右开始失结晶水；140℃左右开始失酸。
通过HPLC计算自由碱含量、水分测定(见下表)，可以推断得到该盐酸盐的碱/酸/H 2O为1∶3∶5。
Figure PCTCN2021143219-appb-000021
取制备例2样品培养单晶(参照PCT/CN2021/073285的方法)，单晶X-射线衍射表征结果显示：该晶体属于三斜晶系，
Figure PCTCN2021143219-appb-000022
空间群，其单胞参数为：
Figure PCTCN2021143219-appb-000023
Figure PCTCN2021143219-appb-000024
该晶体的不对称单元由式1化合物阳离子、三个氯离子和五个水分子组成。且经对比，该单晶的XRPD图谱与图1基本一致。
实施例1化合物B的胶囊
表1实施例1处方(制成100粒)
Figure PCTCN2021143219-appb-000025
Figure PCTCN2021143219-appb-000026
使用干法制粒工艺，具体方法为：1)称量或备料：按照处方量称取活性成分(API)化合物B以及相应的填充剂、助流剂、润滑剂(内加、外加)；2)预混合1：将活性成分、填充剂、助流剂和润滑剂(内加)依次加入混合容器内，进行预混；3)解聚：将得到的混粉进行解聚；4)预混合2：将解聚处理后的混粉加入混合容器内，再次进行预混；5)干法制粒：将再次预混后的混粉使用压片机进行片状物压制，压制完成后进行制粒；6)总混合：将第5)步制得的颗粒加入混合容器内，加入润滑剂(外加)，进行混合；7)胶囊填充：根据装量选择适宜型号的胶囊壳进行灌装。
表2实施例1检测结果
Figure PCTCN2021143219-appb-000027
结果显示：制粒前压大片过程顺利，不粘冲，溶出快速，满足制剂要求，处方合格。
实施例2-5化合物B的胶囊
参照实施例1的制备方法，调整助流剂和润滑剂的比例，并根据总量调整API和预胶化淀粉的用量(API：预胶化淀粉(w/w)＝1∶1.58)，可得以下药物组合物。具体处方及检测结果见表3。
表3实施例2-5处方及检测结果
Figure PCTCN2021143219-appb-000028
注：①外加硬脂酸镁的重量百分比均为1％；②表中数据为重量百分比，下同。
结果显示：在本申请的范围内，调整胶态二氧化硅和硬脂酸镁(内加)的重量百分比，所得处方均未出现粘冲、花片、聚团和/或分层等现象，制粒前压大片过程顺利，即压片环节符合要求，溶出快速，满足制剂要求，处方均合格。
实施例6-9化合物B的胶囊
参照实施例1的制备方法，调整填充剂的用量，可得以下药物组合物。具体处方及检测结果见表4。
表4实施例6-9处方及检测结果
Figure PCTCN2021143219-appb-000029
注：硬脂酸镁(内加)和硬脂酸镁(外加)的重量百分比均为1％；各处方分别制成100粒，重量总计均为16g。
结果显示：在实施例1处方的基础上，在本申请的范围内，调整预胶化淀粉的用量，对压片现象及溶出度结果无明显影响，即所得处方制粒前压大片过程顺利，轻微粘冲或不粘冲，且均未出现花片、聚团和/或分层等现象，即压片环节符合要求，溶出快速，满足制剂要求，处方均合格。
实施例10化合物B的胶囊
参照实施例1的制备方法，在第6)步增加崩解剂，可得以下药物组合物。具体处方及检测结果见表5。
表5实施例10处方(制成100粒)及检测结果
Figure PCTCN2021143219-appb-000030
结果显示：在实施例1的基础上，添加崩解剂所得的处方，制粒前压大片过程顺利，轻微粘冲或不粘冲，且未出现花片、聚团和/或分层等现象，即压片环节符合要求，溶出快速，满足制剂要求，处方合格，即效果与不加崩解剂的效果相当。因此，是否添加崩解剂对单一填充剂(预胶化淀粉)处方的效果影响不大。
实施例11-14化合物B的胶囊
参照实施例1的处方及制备方法，使用预胶化淀粉和甘露醇作为组合填充剂，可得以下药物组合物。具体处方及检测结果见表6。
表6实施例11-14处方及检测结果
Figure PCTCN2021143219-appb-000031
注：硬脂酸镁(内加)和硬脂酸镁(外加)的重量百分比均为1％；各处方分别制成100粒，重量总计均为16g。
结果显示：使用预胶化淀粉和甘露醇组成的组合填充剂，在本申请的范围内，调整两者的重量比例，对压片现象及溶出度结果无明显影响，即所得处方制粒前压大片过程顺利，轻微粘冲或不粘冲，且均未出现花片、聚团和/或分层等现象，即压片环节符合要求，满足制剂要求，处方均合格；而且，在不添加崩解剂的情况下，也能实现快速溶出。
实施例15化合物B的胶囊
参照实施例1的制备方法，使用微晶纤维素和乳糖作为组合填充剂，可得以下药物组合物。具体处方及检测结果分别见表7和表8。
表7实施例15处方(制成100粒)
Figure PCTCN2021143219-appb-000032
Figure PCTCN2021143219-appb-000033
注：硬脂酸镁(内加)和硬脂酸镁(外加)的重量百分比均为1％；
表8实施例15检测结果
Figure PCTCN2021143219-appb-000034
结果显示：使用微晶纤维素和乳糖的组合填充剂，制粒前压大片过程顺利，不粘冲，且未出现花片、聚团和/或分层等现象，即压片环节符合要求，溶出快速，满足制剂要求，处方均合格。
实施例16-17化合物B的胶囊
参照实施例15的制备方法及装量，使用微晶纤维素作为单一填充剂，按表9中的处方组成和重量百分比，进行药物组合物的制备。具体处方及实验结果如下表9。
表9实施例16-17处方及检测结果
Figure PCTCN2021143219-appb-000035
注：各处方分别制成100粒，重量总计均为18g。
结果显示：当微晶纤维素作为单一填充剂使用时，在不添加崩解剂的情况下，所得处方(实施例16)在制粒过程符合要求；而且，即使不添加助流剂(胶态二氧化硅)，所得处方(实施例17)在制粒过程中依然符合要求，即所得处方制粒前压大片过程顺利，轻微粘冲或不粘冲，且均未出现花片、聚团和/或分层等现象。
对于实施例16和实施例17的处方，溶出度结果显示，虽然15min时溶出稍慢，但30min时溶出度符合要求，可根据用药需求进行选择。
实施例18-19化合物B的胶囊
参照实施例15的处方组成及制备方法，调整组合填充剂的重量比例，可得以下药物组合物(100粒)。具体处方及检测结果见表10。
表10实施例18-19处方及检测结果
Figure PCTCN2021143219-appb-000036
Figure PCTCN2021143219-appb-000037
注：硬脂酸镁(内加)和硬脂酸镁(外加)的重量百分比均为1％；各处方分别制成100粒，重量总计均为18g。
结果显示：调整组合填充剂中两种填充剂的比例，在本申请的范围内，所得处方制粒前压大片过程顺利，不粘冲，且均未出现花片、聚团和/或分层等现象，即压片环节符合要求，满足制剂要求。采用重量比1∶1的乳糖/微晶纤维素(实施例18)的处方时，15min内溶出较快；采用重量比2∶1的乳糖/微晶纤维素(实施例19)的处方时，15min内溶出稍慢，但30min内溶出度符合要求。
实施例20-21化合物B的胶囊
参照实施例15的处方组成及制备方法，更换崩解剂的种类，调整两种填充剂的比例，可得以下药物组合物(100粒)。具体处方及检测结果见表11。
表11实施例20-21处方及检测结果
Figure PCTCN2021143219-appb-000038
注：硬脂酸镁(内加)和硬脂酸镁(外加)的重量百分比均为1％；各处方分别制成100粒，重量总计均为18g。
结果显示：当崩解剂选用羧甲淀粉钠时，所得处方制粒前压大片过程顺利，不粘冲，且均未出现花片、聚团和/或分层等现象，即压片环节符合要求，所得处方均有较好的溶出效果，满足制剂要求，处方均合格。因此，在满足原辅料兼容性的情况下，可根据用药需求，进行崩解剂的选择和替换。
实施例22-23化合物B的胶囊
参照实施例15的制备方法和实施例20的处方组成，使用羧甲淀粉钠为崩解剂，调整其用量，可得以下药物组合物(100粒)。具体处方组成及检测结果见表12。
表12实施例22-23处方及检测结果
Figure PCTCN2021143219-appb-000039
注：硬脂酸镁(内加)和硬脂酸镁(外加)的重量百分比均为1％；各处方分别制成100粒，重量总计均为18g。
结果显示：调整崩解剂用量，所得处方制粒前压大片过程顺利，不粘冲，且均未出现花片、聚团和/或分层等现象，即压片环节符合要求，所得处方均有较好的溶出效果，满足制剂要求，处方均合 格。
实施例24化合物B的胶囊
参照实施例15的制备方法和20的处方组成，更换润滑剂的种类，可得以下组合物(100粒)。具体处方及检测结果见表13。
表13实施例24处方及检测结果
Figure PCTCN2021143219-appb-000040
注：硬脂富马酸钠(内加)和硬脂酸镁(外加)的重量百分比均为1％；
结果显示：与实施例20相比，更换润滑剂对制粒过程(不粘冲、未出现花片、聚团和/或分层等现象)及溶出度结果无显著影响，从价格上，更优选硬脂酸镁。
实施例25化合物B的胶囊
参照实施例1的处方及制备方法，更换填充剂，可得以下药物组合物(100粒)。具体处方及检测结果见表14。
表14实施例25处方及检测结果
Figure PCTCN2021143219-appb-000041
注：硬脂酸镁(内加)和硬脂酸镁(外加)的重量百分比均为1％；按处方制成100粒，重量总计均为10g。
结果显示：与实施例1相比，将填充剂替换为钙盐(例如，无水磷酸氢钙)对制粒过程(不粘冲、未出现花片、聚团和/或分层等现象)及溶出度结果无影响，处方合格。
实施例26-29化合物B的胶囊
参照实施例1的制备方法和实施例25的处方组成，调整各组分的比例，或者进一步增加崩解剂，可得以下药物组合物。具体处方及检测结果见表。
表15实施例26-29处方及检测结果
Figure PCTCN2021143219-appb-000042
Figure PCTCN2021143219-appb-000043
注：硬脂酸镁(内加)和硬脂酸镁(外加)的重量百分比均为1％；各处方分别制成100粒，总重量总计根据每粒装量分别折算；“/”表示未检测。
结果显示：与实施例25相比，调整各组分的比例，或者进一步增加崩解剂，对制粒过程(轻微粘冲或不粘冲、未出现花片、聚团和/或分层等现象)均无影响，虽然15min溶出度偏低，但30min可实现80％以上的溶出，可根据实际需要选择，各处方合格。
实施例30-32化合物B的胶囊
参照实施例1或实施例15的制备方法，以及实施例25的处方组成，将单一填充剂替换为两种填充剂的组合，可得以下药物组合物。具体处方及检测结果见表16。
表16实施例30-32处方及检测结果
Figure PCTCN2021143219-appb-000044
注：实施例30和31中，硬脂酸镁(内加)和硬脂酸镁(外加)的重量百分比均为1％；实施例32中，硬脂酸镁(内加)和硬脂酸镁(外加)的重量百分比分别为0.5％和1％；按处方制成100粒，总重量总计根据每粒装量分别折算。
结果显示：与实施例25相比，使用两种填充剂的组合(例如，无水磷酸氢钙和预胶化淀粉的组合)，或者进一步调整各组分的比例，对制粒过程(不粘冲、未出现花片、聚团和/或分层等现象)及溶出度结果均无影响，各处方均合格。
实施例33-34化合物B的胶囊
参照实施例1、实施例15或实施例30的处方及制备方法，更换填充剂，或进一步加入崩解剂和/或更换崩解剂，或进一步增加粘合剂，可得以下药物组合物。具体处方及检测结果见表17。
表17实施例33-34处方及检测结果
Figure PCTCN2021143219-appb-000045
注：硬脂酸镁(内加)和硬脂酸镁(外加)的重量百分比均为1％；各处方分别制成100粒，总重量总计根据每粒装量分别折算。
结果显示：以上处方组成和比例的调整，对制粒过程(不粘冲、未出现花片、聚团和/或分层等现象)及溶出度结果均无影响，各处方均合格。
实施例35-38化合物B的胶囊
参照实施例1、实施例15或实施例30的处方及制备方法，增加第二种填充剂，或进一步加入崩解剂和/或粘合剂，可得以下药物组合物。具体处方及检测结果见表18。
表18实施例35-38处方及检测结果
Figure PCTCN2021143219-appb-000046
注：硬脂酸镁(内加)和硬脂酸镁(外加)的重量百分比均为1％；各处方分别制成100粒，总重量总计根据每粒装量分别折算。
结果显示：以上处方组成和比例的调整，对制粒过程(不粘冲、未出现花片、聚团和/或分层等现象)及溶出度结果均无影响，各处方均合格。
实施例39化合物B的胶囊
上述合格的药物组合物处方可以制成含不同规格活性成分的制剂，示例性处方包括(制成100粒)：
表19实施例39处方(单一填充剂)
Figure PCTCN2021143219-appb-000047
注：参照实施例1的处方和制备方法，根据所需规格和装量可适当调整填充剂比例和明胶空心胶囊；实施例39-2与实施例1处方相同。
表20实施例39处方(组合填充剂)
Figure PCTCN2021143219-appb-000048
注：参照实施例11的处方和实施例1的制备方法，根据所需规格和装量可适当调整填充剂比例和明胶空心胶囊；实施例39-5与实施例11处方相同。
表21实施例39处方(组合填充剂)
Figure PCTCN2021143219-appb-000049
Figure PCTCN2021143219-appb-000050
注：实施例39-8和39-9参照实施例1的制备方法，根据所需规格和装量可适当调整填充剂比例和明胶空心胶囊。
使用直接混合工艺制备实施例39-7，具体方法为：1)备料：按照处方量称取活性成分(API)化合物B以及各种赋形剂；2)预混合1：将胶态二氧化硅与活性成分过筛混合，置于混合容器内；3)预混合2：将预胶化淀粉、甘露醇加入上述混粉中，振摇混合均匀；4)总混合：将硬脂酸镁加入上述步骤3)所得混粉中，振摇混合均匀；5)胶囊填充：根据装量选择适宜型号的胶囊壳进行填充灌装。
表22实施例39处方(组合填充剂)
Figure PCTCN2021143219-appb-000051
注：参照实施例15的处方和制备方法，根据所需规格和装量可适当调整填充剂比例和明胶空心胶囊。
表23实施例39处方(单一填充剂)
Figure PCTCN2021143219-appb-000052
注：参照实施例1的处方和制备方法，根据所需规格和装量可适当调整填充剂比例和明胶空心胶囊。
实施例40化合物B的片剂
表24实施例40处方(制成100片)
Figure PCTCN2021143219-appb-000053
Figure PCTCN2021143219-appb-000054
注：各处方分别制成100片；包衣粉的重量百分比，为包衣粉重量/片芯总重；包衣粉型号：欧巴代85G68918，具体组成为聚乙烯醇、二氧化钛、滑石粉、聚乙二醇、大豆磷脂。
使用干法制粒工艺，具体方法为：1)备料：按照处方量称取活性成分(API)化合物A以及相应的填充剂、助流剂、润滑剂；2)预混合1：将活性成分、填充剂、助流剂和润滑剂(内加)依次加入混合容器内，进行预混；3)解聚：将得到的混粉进行解聚；4)预混合2：将解聚处理后的混粉加入混合容器内，再次进行预混；5)制粒；6)总混：将步骤5)制得的颗粒与润滑剂(外加)进行混合；7)压片：使用压片机进行压片；8)包衣：将第5)步制得的片子进行包衣。
表25实施例40检测结果
Figure PCTCN2021143219-appb-000055
结果显示：制得的片剂含量均匀，边缘无明显磨损，硬度符合要求，且溶出快速，处方合格。
实施例41化合物B的颗粒剂
表26实施例41处方(制成100袋)
Figure PCTCN2021143219-appb-000056
具体方法为：1)备料：按照处方量称取活性成分(API)化合物B以及相应的赋形剂；2)预混合1：将活性成分及各种赋形剂依次加入混合容器内，进行预混；3)制软材：加入适量水，制成适宜软材；4)制粒：使用进行制粒；5)干燥：45℃进行干燥；6)整粒。
表27实施例41检测结果
Figure PCTCN2021143219-appb-000057
结果显示：制得的颗粒剂含量均匀，溶化性能良好，且溶液澄清，处方合格。
实施例42化合物B的口服溶液剂
表28实施例42处方(制成100mL)
Figure PCTCN2021143219-appb-000058
具体方法为：1)称量：按照处方量称取活性成分(API)化合物B以及相应的甜味剂；2)配液：先将活性成分、甜味剂置于烧杯内，边加入溶剂边搅拌，搅拌均匀后，使用氢氧化钠将溶液调至pH为4-5；3)过滤：将配好的溶液过滤除菌；4)灌装：将过滤好的溶液按所需剂量进行灌装；5)轧盖。
表29实施例42检测结果
处方 外观 含量 pH
实施例42 澄清溶液 99.7％ 4.55
结果显示：制得的口服溶液剂型含量均匀，溶液澄清透明，处方合格。
测试例1溶解度测试
取制备例2所得盐与制备例1样品在以下介质中进行溶解度测试，结果如下表所示：
Figure PCTCN2021143219-appb-000059
测试例2吸湿性测
取制备例2所得盐与制备例1样品分别在25±1℃，相对湿度为80％士2％，进行吸湿性试验，结果如下表所示：
Figure PCTCN2021143219-appb-000060
测试例3加速稳定性测试
取制备例2所得盐分别在25±2℃，60％±5％RH，敞口放置10天及40±2℃；75％±5％RH，敞口放置10天，进行加速试验，结果如下：
Figure PCTCN2021143219-appb-000061
测试例4：长期稳定性测试
取制备例2所得盐样品适量，内包为药用低密度聚乙烯袋，外包为聚酯/铝/聚乙烯药品包装用复合袋，在温度25±2℃，相对湿度60％±5％，分别于第3、6、9、12和18个月末取样，比较外观后测试其它考察指标，结果与0个月比较，实验结果见下表：
时间 性状 水分(％) 酸度 有关物质(％) 含量(％)
0月 黄色结晶性粉末 13.9 3.1 0.33 100.9
3月 黄色结晶性粉末 13.9 3.3 0.34 100.4
6月 黄色结晶性粉末 14.3 3.3 0.34 100.8
9月 黄色结晶性粉末 14.3 3.3 0.31 101.7
12月 黄色结晶性粉末 13.9 3.3 0.34 99.6
18月 黄色结晶性粉末 14.2 3.3 0.26 100.2
测试例5：生物活性测试
根据专利申请WO 2011/147066的生物学评价中记载的激酶抑制活性评价，对制备例2所得的盐样品进行测试。测试结果表明，所述样品能够抑制FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes、VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET和PDGFRα激酶的活性，部分激酶测试结果见下表。
激酶 IC 50(nM) 激酶 IC 50(nM)
FLT3(h) 26 Lyn(h) 7
FLT3-ITD(h) 3-10 Ret(h) 10
EGFR(h) 42 Yes 4
Abl(h) 25 c-SRC(h) 176
Fyn(h) 34 FGFR1(h) 247
Hck(h) 93 KDR(h) 323
Lck(h) 37    
根据专利申请WO 2011/147066的生物学评价中记载的体内抗肿瘤实验，对制备例2所得的盐样品进行测试(分别具体针对FLT3-ITD的急性髓性白血病、EGFR激活突变的非小细胞肺癌、或Ph阳性的慢性髓性白血病)。测试结果表明，在MV4-11(FLT3-ITD突变)皮下瘤模型实验中(参考WO2011/147066的例4建立模型)，所述样品(每天口服一次，给药21天)在给药剂量为5mg/kg时可以完全抑制肿瘤生长，而在给药剂量为10mg/kg和20mg/kg时，可以引起肿瘤的完全消退。在非小细胞肺癌模型中(参考WO 2011/147066的例3建立模型)，所述样品可剂量依赖性地抑制人非小细胞肺癌HCC827的生长，在7.5mg/kg、15mg/kg、30mg/kg三个剂量组(每天口服一次，给药30天)均引起肿瘤缩小(与起始肿瘤相比)，其中，30mg/kg组可引起肿瘤的近乎完全消退。在K562(BCR-Abl基因重排)皮下瘤模型实验中(以类似于MV4-11皮下瘤模型建立模型)，所述样品(每天口服一次，给药18天)在给药剂量为70mg/kg时可以有效抑制肿瘤生长，抑瘤率达到71.3％。
针对化合物I的盐酸盐及其它盐型的相应研究已经记载在PCT/CN202I/073285专利申请中，该申请的全部内容作为整体被引入本申请。
实验例1原辅料相容性试验
将活性成分(式B化合物)分别与本申请提及的各种赋形剂混合均匀，置10ml注射剂瓶中，在光照4500lux±500 lux/外周湿度、高温60℃±2℃/外周湿度、高湿90％±5％RH、温度25℃±2℃条件下分别放置14天和28天或30天，进行杂质含量的检测，检验活性成分与各种赋形剂的相容性。
结果显示，经过14天和28天或30天的加速相容性试验，活性成分与本申请提及的各种赋形剂的相容性良好，均未发生最大单杂和总杂的明显增长，除碳酸钙样品发生轻微变色外，其他混合样品的颜色未发生明显变化。
实验例2加速试验
取实施例39-1、39-2、39-7、39-8和39-9的胶囊样品，实施例40的片剂样品，按示例包装条件(铝箔和聚酰胺/铝/聚氯乙烯冷冲压成型固体药用复合硬片包装)，置于40℃±2℃、相对湿度75％RH±5％RH的恒温恒湿箱中，进行6个月的加速试验，于0、1、2、3、6个月末取样，进行重点项目考察，代表性实施例(实施例39-2、39-7、39-8和实施例40)的试验结果(其它实施例为等比放大或按比例调整，未全部呈现数据，结果类似)见表30-33。
表30实施例39-2(铝铝包装)批加速试验结果
Figure PCTCN2021143219-appb-000062
表31实施例39-7(铝铝包装)批加速试验结果
Figure PCTCN2021143219-appb-000063
Figure PCTCN2021143219-appb-000064
表32实施例39-8(铝铝包装)批加速试验结果
Figure PCTCN2021143219-appb-000065
表33实施例40(铝铝包装)批加速试验结果
Figure PCTCN2021143219-appb-000066
结果显示：加速试验结果表明，置于包装内的三个实施例药物组合物在40±2℃，相对湿度75％RH±5％RH的条件下放置6个月后有关物质无增加或略有增加，含量基本不变；各时间点的其他考察项目均符合规定，活性成分的晶型未发生变化。实施例39-1和39-9的胶囊样品在加速试验中也保持稳定，药物性状、有关物质、药物含量、溶出度、微生物限量等均无明显变化，实施例40的片剂样品在加速试验中也保持稳定，药物性状、有关物质、药物含量、微生物限量等均无明显变化。
实验例3长期试验
取实施例39-1、39-2、39-7、39-8和39-9的胶囊样品，按示例包装条件(铝箔和聚酰胺/铝/聚氯乙烯冷冲压成型固体药用复合硬片包装)，置于30℃±2℃、相对湿度65％RH±5％RH的恒温恒湿箱中，进行30个月的加速试验，于3、6、9、12、18、24、30个月末取样，代表性实施例(实施例39-7和39-8)的试验结果(其它实施例为等比放大或按比例调整，未全部呈现数据，结果类似)，结果见表34-35。
表34实施例39-7(铝铝包装)批长期试验结果
Figure PCTCN2021143219-appb-000067
Figure PCTCN2021143219-appb-000068
表35实施例39-8(铝铝包装)批长期试验结果
Figure PCTCN2021143219-appb-000069
结果显示：长期试验结果表明，置于包装内的两个实施例药物组合物在30±2℃，相对湿度65％RH±5％RH的条件下放置30个月后，有关物质无增加或略有增加，含量基本不变；各时间点的其他考察项目均符合规定。实施例39-1、39-2和39-9的胶囊样品在长期试验中也保持稳定，药物性状、有关物质、药物含量、溶出度、微生物限量等均无明显变化。

Claims (20)

  1. 一种药物组合物，其包含作为活性成分的如式II所示的化合物及赋形剂，
    Figure PCTCN2021143219-appb-100001
    其中，m为1～5；n为0～10。
  2. 如权利要求1所述的药物组合物，其特征在于，所述化合物为式A所示化合物，
    Figure PCTCN2021143219-appb-100002
    其中，n为0～10。
  3. 如权利要求2所述的药物组合物，其特征在于，所述化合物为式B所示化合物，
    Figure PCTCN2021143219-appb-100003
    优选地，所述式B所示的化合物使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射在8.5±0.2°、11.8±0.2°、19.6±0.2°、25.2±0.2°、27.2±0.2°处具有特征峰。
  4. 如权利要求1至3任一项所述的药物组合物，其特征在于，所述药物组合物中的各组分及其重量百分比为：
    活性成分，其重量百分比为0.5％～90％；或者1％～90％；或者0.5％～85％；或者0.5％～80％；或者 1％～80％；或者5％～80％；或者5％～75％；或者5％～70％；或者5％～65％；或者5％～60％；或者5％～55％；或者5％～50％；或者5％～45％；或者5％～40％；或者10％～70％；或者10％～65％；或者10％～60％；或者15％～60％；或者20％～60％；或者25％～60％；或者25％～50％；或者25％～45％；或者25％～40％；
    余量为赋形剂；
    优选地，所述药物组合物中的各组分及其重量百分比为：
    活性成分，其重量百分比为5％～90％；或者10％～90％；或者10％～80％；或者15％～80％；或者20％～70％；或者25％～60％；或者25％～50％；或者25％～45％；或者25％～40％；余量为赋形剂。
  5. 如权利要求1至3任一项所述的药物组合物，其特征在于，所述赋形剂包括填充剂、粘合剂、崩解剂、矫味剂、润滑辅料、抑菌剂、抗氧化剂、pH调节剂、表面活性剂、香料、稳定剂、增稠剂、分散剂、着色剂、溶剂或包衣材料中的一种或多种。
  6. 如权利要求1至3任一项所述的药物组合物，所述赋形剂包含填充剂，任选地，进一步包含崩解剂和润滑辅料；或者所述赋形剂包含填充剂和润滑辅料，任选地，进一步包含崩解剂和/或粘合剂。
  7. 如权利要求6所述的药物组合物，其特征在于，所述填充剂选自淀粉、糖粉、氢氧化镁、预胶化淀粉、乳糖、微晶纤维素、糖醇类、无机钙盐类中的一种或多种；优选地，所述填充剂选自淀粉、糖粉、氢氧化镁、预胶化淀粉、乳糖、微晶纤维素、甘露醇、山梨醇、木糖醇、磷酸钙、磷酸氢钙、硫酸钙和碳酸钙中的一种或多种；进一步优选地，所述填充剂为预胶化淀粉、无水磷酸氢钙、碳酸钙、微晶纤维素、甘露醇中的一种，或预胶化淀粉和甘露醇的组合，或微晶纤维素和乳糖的组合，或预胶化淀粉和无水磷酸氢钙的组合，或预胶化淀粉和碳酸钙的组合，或预胶化淀粉与乳糖的组合；更进一步优选地，所述填充剂为预胶化淀粉和甘露醇的组合、微晶纤维素和乳糖的组合、预胶化淀粉和无水磷酸氢钙的组合、或预胶化淀粉和碳酸钙的组合，其中，两种填充剂的重量比为1∶10～10∶1；或者1∶7～7∶1；或者1∶6～6∶1，或者1∶5～5∶1；或者1∶4～4∶1；或者1∶3～3∶1；或者1∶2～2∶1；或者1∶1。
  8. 如权利要求6所述的药物组合物，其特征在于，所述药物组合物包含润滑辅料，所述润滑辅料为润滑剂或润滑剂和助流剂；优选地，所述润滑剂选自硬脂酸、硬脂酸镁、硬脂酸钙、棕榈酸、棕榈酸硬脂酸甘油酯、苯甲酸钠、月桂基硫酸钠、氢化植物油、滑石粉、二氧化硅、硬脂酸锌、硬脂酰富马酸钠、硬脂酰富马酸镁、月桂醇硫酸镁、十二烷基硫酸钠、十二烷基硫酸镁或聚乙二醇中的一种或多种；
    优选地，所述助流剂选自胶态二氧化硅或氢氧化铝中的一种或多种。
  9. 如权利要求6所述的药物组合物，其特征在于，所述药物组合物不包含崩解剂；或者所述药物组合物包含崩解剂，且所述崩解剂选自干淀粉、羧甲基纤维素、微晶纤维素、粉状纤维素、甲基纤维素、波拉克林钾、海藻酸钠、淀粉羟乙酸钠、聚乙烯吡咯烷酮、麦芽糖糊精、硅酸铝镁、玉米淀粉、预胶化淀粉、交联聚维酮、低取代羟丙纤维素、羧甲基纤维素钙、泡腾崩解剂、羧甲淀粉钠和交联羧甲基纤维素钠中的一种或多种。
  10. 如权利要求6所述的药物组合物，其特征在于，所述药物组合物不包含粘合剂；或者所述药 物组合物包含粘合剂，且所述粘合剂选自淀粉浆、共聚维酮、糖粉、糖浆、聚乙烯吡咯烷酮、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、胶浆、聚乙二醇4000、羟丙基纤维素、乙基纤维素和糊精中的一种或多种。
  11. 如权利要求6所述的药物组合物，其特征在于，所述填充剂选自预胶化淀粉、微晶纤维素、无水磷酸氢钙中的一种，或预胶化淀粉和甘露醇的组合，或微晶纤维素和乳糖的组合，或预胶化淀粉和无水磷酸氢钙的组合，或预胶化淀粉和碳酸钙的组合；所述润滑辅料为润滑剂和/或助流剂，其中所述润滑剂为硬脂酸镁，所述助流剂为胶态二氧化硅；所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠；所述粘合剂选自共聚维酮。
  12. 如权利要求6所述的药物组合物，其特征在于，所述药物组合物的各组分及其重量百分比为：
    活性成分，其重量百分比为0.5％～90％；或者1％～90％；或者0.5％～85％；或者5％～80％；或者5％～75％；或者5％～70％；或者10％～70％；或者5％～65％；或者5％～60％；或者5％～55％；或者5％～50％；或者5％～45％；或者5％～40％；或者10％～65％；或者10％～60％；或者15％～60％；或者20％～60％；或者25％～60％；或者25％～50％；或者25％～45％；或者25％～40％；
    填充剂，其重量百分比为5％～99％；或者10％～95％；或者15％～95％；或者15％～90％；或者15％～85％；或者15％～80％；或者20％～80％；或者25％～90％；或者25％～75％；或者30％～70％；或者35％～90％；或者35％～70％；或者40％～90％；或者40％～70％；或者45％～70％；或者50％～90％；或者50％～70％；或者55％～70％；
    崩解剂，其重量百分比为0％～20％；0％～15％；或者0％～10％；或者0％～8％；或者0％～6％；或者0％～5％；或者0％～4％；或者0％～3％；或者0.5％～3％；或者1％～3％；或者1.5％～3％；或者2％～3％；
    粘合剂，其重量百分比为0％～10％；或者0％～6％；或者0％～5％；或者0％～4％；或者0％～3％；或者0％～2％；
    润滑辅料，其重量百分比为0％～18％；或者0.1％～18％；或者0％～15％；或者0.1％～15％；或者0％～10％；或者0.1％～10％；或者0％～8％；或者0％～7％；或者0％～6％；或者1％～6％；或者0.5％～6％；或者0％～5％；或者1％～5％；或者1.5％～4.5％；或者2％～4％；或者2％～3.5％；或者2％～3％；或者2.5％～5％；或者3.5％～5％；或者4％～5％；
    其它赋形剂，其重量百分比为0％～25％；或者0％～20％；或者0％～15％；或者0％～10％；或者0％～5％；
    且以上各组分重量百分比之和为100％；
    优选地，所述药物组合物的各组分及其重量百分比为：
    活性成分，其重量百分比为5％～90％；或者10％～90％；或者10％～80％；或者15％～80％；或者20％～70％；或者25％～60％；或者25％～50％；或者25％～45％；或者25％～40％；
    填充剂，其重量百分比为5％～90％；或者15％～90％；或者15％～85％；或者25％～85％；或者25％～80％；或者35％～75％；或者35％～70％；或者50％～70％；或者55％～70％；
    崩解剂，其重量百分比为0％～5％；或者0％～4％；或者0.5％～4％；
    粘合剂，其重量百分比为0％～5％；或者0％～4％；或者0％～3％；
    润滑辅料，其重量百分比为2％～7％；或者2％～6％；或者2.5％～6％；或者3％～5％；或者3％～6％；或者3.5～6％；或者4％～6％；或者4％～5％；或者5％～6％；
    其它赋形剂，其重量百分比为0％～10％；或者0％～5％；
    且以上各组分重量百分比之和为100％；
    进一步优选地，所述润滑辅料为润滑剂；或者所述润滑辅料为润滑剂和助流剂，所述助流剂与润滑剂的重量比为1∶6～6∶1；或者1∶5～5∶1；或者1∶4～4∶1；或者1∶3～3∶1；或者1∶2～2∶1；或者1∶1、1∶2、1∶1.5、2∶1、2∶3、3∶1、3∶2、4∶3或5∶3。
  13. 如权利要求6所述的药物组合物，其特征在于，所述药物组合物的各组分及其重量百分比为：
    活性成分，其重量百分比为0.5％～90％；或者1％～90％；或者0.5％～85％；或者5％～80％；或者5％～75％；或者5％～70％；或者10％～70％；或者5％～65％；或者5％～60％；或者5％～55％；或者5％～50％；或者5％～45％；或者5％～40％；或者10％～65％；或者10％～60％；或者15％～60％；或者20％～60％；或者25％～60％；或者25％～50％；或者25％～45％；或者25％～40％；
    填充剂，其重量百分比为5％～99％；或者10％～95％；或者15％～95％；或者15％～90％；或者15％～85％；或者15％～80％；或者20％～80％；或者25％～90％；或者25％～75％；或者30％～70％；或者35％～90％；或者35％～70％；或者40％～90％；或者40％～70％；或者45％～70％；或者50％～90％；或者50％～70％；或者55％～70％；
    崩解剂，其重量百分比为0％～20％；0％～15％；或者0％～10％；或者0％～8％；或者0％～6％；或者0％～5％；或者0％～4％；或者0％～3％；或者0.5％～.00％；或者1％～3％；或者1.5％～3％；或者2％～3％；
    粘合剂，其重量百分比为0％～10％；或者0％～6％；或者0％～5％；或者0％～4％；或者0％～3％；或者0％～2％；
    润滑剂，其重量百分比为0％～10％；或者0％～8％；或者0.1％～8％；或者0％～6％；或者0％～5％；或者0.1％～5％；或者0％～4％；或者0.1％～4％；或者0％～3％；或者1％～5％；或者2％～4％；或者2％～3％；或者1％～4％；或者1％～3.5％；或者0.5％～3％；或者1％～3％；或者1％～2.5％；或者1％～2％；或者2％～2.5％；
    助流剂，其重量百分比为0％～10％；或者0.5％～10％；或者0％～8％；或者0.5％～8％；或者0％～6％；或者0％～5％；或者0.5％～5％；或者1％～5％；或者0％～4％；或者1％～4％；或者0％～3.5％；或者0％～3％；或者1％～3％；或者1％～2.5％；或者1％～2％；或者1.5％～3％；或者2％～3％；或者3％；
    其它赋形剂，其重量百分比为0％～25％；或者0％～20％；或者0％～15％；或者0％～10％；或者0％～5％；
    且以上各组分重量百分比之和为100％；
    优选地，所述药物组合物的各组分及其重量百分比为：
    活性成分，其重量百分比为5％～90％；或者10％～90％；或者10％～80％；或者15％～80％；或者20％～70％；或者25％～60％；或者25％～50％；或者25％～45％；或者25％～40％；
    填充剂，其重量百分比为5％～90％；或者15％～90％；或者15％～85％；或者25％～85％；或者25％～80％；或者35％～75％；或者35％～70％；或者50％～70％；或者55％～70％；
    崩解剂，其重量百分比为0％～5％；或者0％～4％；或者0.5％～4％；
    粘合剂，其重量百分比为0％～5％；或者0％～4％；或者0％～3％；
    润滑剂，其重量百分比为1％～5％；或者1％～4％；或者2％～4％；或者2％～3％；
    助流剂，其重量百分比为0％～5％；或者0％～4％；或者1％～4％；或者1％～3％；或者0％～3％；或者2％～4％；或者3％～4％；或者2％～3％；
    其它赋形剂，其重量百分比为0％～10％；或者0％～5％；
    且以上各组分重量百分比之和为100％。
  14. 如权利要求6所述的药物组合物，其特征在于，所述药物组合物的各组分及其重量百分比为：
    0.5％～90％的活性成分、5％～99％的填充剂、0％～20％的崩解剂、0％～10％的粘合剂、0.1％～15％的润滑辅料、以及0％～25％的其它赋形剂；或者
    5％～80％的活性成分、10％～95％的填充剂、0％～15％的崩解剂、0％～6％的粘合剂、0.50％～10％的润滑辅料、以及0％～15％的其它赋形剂；或者
    5％～80％的活性成分、15％～85％的填充剂、0％～5％的崩解剂、0％～4％的粘合剂、0％～7％的润滑辅料、以及0％～10％的其它赋形剂；或者
    5％～80％的活性成分、15％～80％的填充剂、0％～4％的崩解剂、0％～3％的粘合剂、1％～6％的润滑辅料、以及0％～5％的其它赋形剂；
    且以上各组分重量百分比之和为100％；
    优选地，所述药物组合物的各组分及其重量百分比为：
    5％～90％的活性成分、5％～90％的填充剂、0％～5％的崩解剂、0％～5％的粘合剂、1％～7％的润滑辅料、以及0％～5％的其它赋形剂；或者
    10％～90％的活性成分、15％～90％的填充剂、0％～5％的崩解剂、0％～4％的粘合剂、1％～6％的润滑辅料、以及0％～5％的其它赋形剂；
    且以上各组分重量百分比之和为100％。
  15. 如权利要求6所述的药物组合物，其特征在于，所述药物组合物的各组分及其重量百分比为：
    0.50％～90％的活性成分、5％～99％的填充剂、0％～20％的崩解剂、0％～10％的粘合剂、0％～10％的润滑剂、0％～10％的助流剂、以及0％～25％的其它赋形剂；或者
    5％～80％的活性成分、10％～95％的填充剂、0％～10％的崩解剂、0％～6％的粘合剂、0％～5％的润滑剂、0％～5％的助流剂、以及0％～25％的其它赋形剂；或者
    5％～80％的活性成分、15％～85％的填充剂、0％～6％的崩解剂、0％～5％的粘合剂、1％～4％的润滑剂、0％～4％的助流剂、以及0％～15％的其它赋形剂；或者
    5％～80％的活性成分、15％～80％的填充剂、0％～5％的崩解剂、0％～4％的粘合剂、1％～3.50％的润滑剂、0％～3.50％的助流剂、以及0％～10％的其它赋形剂；或者
    5％～80％的活性成分、15％～80％的填充剂、0％～4％的崩解剂、0％～3％的粘合剂、1％～3％的润滑剂、0％～3％的助流剂、以及0％～5％的其它赋形剂；
    且以上各组分重量百分比之和为100％；
    优选地，所述药物组合物的各组分及其重量百分比为：
    5％～90％的活性成分、5％～90％的填充剂、0％～5％的崩解剂、0％～5％的粘合剂、1％～5％的润滑剂、0％～5％的助流剂、以及0％～5％的其它赋形剂；或者
    5％～90％的活性成分、5％～90％的填充剂、0％～5％的崩解剂、0％～5％的粘合剂、1％～4％的润滑剂、0％～4％的助流剂、以及0％～5％的其它赋形剂；或者
    10％～90％的活性成分、15％～90％的填充剂、0％～5％的崩解剂、0％～4％的粘合剂、1％～3％的润滑剂、0％～3％的助流剂、以及0％～5％的其它赋形剂；
    且以上各组分重量百分比之和为100％。
  16. 如权利要求12-15任一项所述的药物组合物，其特征在于，所述填充剂选自：预胶化淀粉、微晶纤维素、无水磷酸氢钙、碳酸钙中的一种，或预胶化淀粉和甘露醇的组合，或微晶纤维素和乳糖的组合，或预胶化淀粉和无水磷酸氢钙的组合，或预胶化淀粉和碳酸钙的组合；所述润滑辅料为润滑剂或润滑剂和助流剂；所述润滑剂选自硬脂酸镁或硬脂富马酸钠中的一种或多种；所述助流剂为胶态二氧化硅；所述崩解剂选自羧甲淀粉钠和交联羧甲基纤维素钠；所述粘合剂为共聚维酮。
  17. 如权利要求6所述的药物组合物，其特征在于，所述药物组合物制成口服固体剂型；优选地，所述口服固体制剂选自胶囊、片剂、散剂和细粒剂中的一种或多种。
  18. 如权利要求6所述的药物组合物，其包含活性成分0.001～1000mg。
  19. 如权利要求1-18任一项所述的药物组合物用于抑制FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes、VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET和PDGFRα激酶中一个或多个的活性的用途。
  20. 如权利要求1-18任一项所述的药物组合物用于制备药物的用途；
    优选地，所述药物用于治疗蛋白激酶介导的疾病，所述蛋白激酶选自：FLT3、EGFR、Abl、Fyn、Hck、Lck、Lyn、Ret、Yes、VEGFR2、ALK、BTK、c-KIT、c-SRC、FGFR1、KDR、MET和PDGFRα激酶中一个或多个；进一步优选地，所述蛋白激酶介导的疾病为肿瘤疾病，所述肿瘤疾病优选为实体瘤或血液瘤；进一步优选为白血病或肺癌，更优选为急性髓性白血病或非小细胞肺癌；更进一步优选为FLT3突变阳性的急性髓性白血病或EGFR激活突变的非小细胞肺癌。
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