WO2023186031A1 - 多靶点蛋白激酶抑制剂的药物组合物及其用途和制备方法 - Google Patents

多靶点蛋白激酶抑制剂的药物组合物及其用途和制备方法 Download PDF

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WO2023186031A1
WO2023186031A1 PCT/CN2023/085194 CN2023085194W WO2023186031A1 WO 2023186031 A1 WO2023186031 A1 WO 2023186031A1 CN 2023085194 W CN2023085194 W CN 2023085194W WO 2023186031 A1 WO2023186031 A1 WO 2023186031A1
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Prior art keywords
pharmaceutical composition
lubricant
ionic
filler
nonionic
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PCT/CN2023/085194
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English (en)
French (fr)
Inventor
唐琳
赫玉霞
周付刚
史凯
齐鹏成
冯雪
班萌
李少茹
王洁敏
陈雪桃
Original Assignee
石药集团中奇制药技术（石家庄）有限公司
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Application filed by 石药集团中奇制药技术（石家庄）有限公司 filed Critical 石药集团中奇制药技术（石家庄）有限公司
Priority to CN202380011150.XA priority Critical patent/CN117177756A/zh
Publication of WO2023186031A1 publication Critical patent/WO2023186031A1/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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition of a multi-target protein kinase inhibitor and its use and preparation method.
  • PTKs Protein tyrosine kinases
  • PTKs transfer the ⁇ -phosphate group on adenosine triphosphate to the protein tyrosine residue of the substrate, phosphorylating the phenolic hydroxyl group
  • PTKs If PTKs are out of control during the regulation process, it will affect the correct activation of its downstream signaling pathways, causing dysfunction in cell proliferation regulation and leading to many diseases.
  • excessive tyrosine kinase activity can phosphorylate receptors and activate downstream signals, leading to cell proliferation. Excessive transformation, proliferation, resistance to cell apoptosis, promotion of cell survival and formation of malignant tumors.
  • EGFR Epidermal Growth Factor Receptor
  • FGFR Fibroblast Growth Factor Receptors
  • PDGFR Platelet-derived Growth Factor Receptor
  • RET Rearranged during Transfection
  • EGFR includes EGFR (ErbB-1), human epidermal growth factor receptor type 2 HER-2 (ErbB-2), human epidermal growth factor receptor type 3 HER3 (ErbB-3), and human epidermal growth factor receptor type 4 HER4 (ErbB-4), among which, EGFR and HER-2 are the targets most closely related to tumors among the EGFR family members. Studies have shown that EGFR shows overexpression, gene mutation or gene fusion in a variety of tumors, such as lung cancer, gastric cancer, epidermoid cancer, renal cancer, ovarian cancer, etc.
  • FGFR mainly includes four subtypes: FGFR1/2/3/4, which are overexpressed or overactivated through gene amplification, mutation, fusion or ligand induction, and have a negative impact on tumor cell proliferation, invasion and migration, and tumor vascularization. important role. Studies have found that FGFRs exhibit mutations, overexpression, or overactivation in a variety of tumors, such as lung cancer, gastric cancer, biliary tract cancer (eg, intrahepatic cholangiocarcinoma), colorectal cancer, liver cancer, etc.
  • FGFR1/2/3/4 which are overexpressed or overactivated through gene amplification, mutation, fusion or ligand induction, and have a negative impact on tumor cell proliferation, invasion and migration, and tumor vascularization. important role. Studies have found that FGFRs exhibit mutations, overexpression, or overactivation in a variety of tumors, such as lung cancer, gastric cancer, biliary tract cancer (eg, intrahepatic cholangiocarcinoma
  • RET normal physiological functions include kidney development, development of the nervous system, maintenance and renewal of sperm stem cells, differentiation of myeloid mononuclear cells, formation of lymphoid tissue, etc., in human intestinal ganglion cells, neuroblastoma, pheochromocytoma, thyroid Expressed in medullary carcinoma, thyroid C cells, melanoma and other cells.
  • RET through in-depth research on RET, it has been found that excessive activation of RET in tumors can significantly promote the proliferation, survival, invasion, metastasis and tumor inflammation of a variety of tumors.
  • RET plays an important role in thyroid cancer (such as medullary thyroid carcinoma) , papillary thyroid cancer), lung cancer (e.g., non-small cell lung cancer), colorectal cancer, pancreatic cancer, melanoma, etc. have shown overexpression.
  • thyroid cancer such as medullary thyroid carcinoma
  • papillary thyroid cancer e.g., papillary thyroid cancer
  • lung cancer e.g., non-small cell lung cancer
  • colorectal cancer e.g., pancreatic cancer, melanoma, etc. have shown overexpression.
  • Tumors are often related to imbalances in the regulation of multiple signal transduction pathways and multiple targets.
  • Single-target drug treatment of tumors may not necessarily achieve the expected therapeutic effect, and its application is also limited by drug side effects and drug resistance. Therefore, many Target drugs have become a new drug research direction.
  • multi-target drugs can act on multiple tumor-related targets. Even if their activity against a single target may be reduced compared with single-target drugs, they may benefit from multi-target regulation. The resulting synergistic effect may make the total effect greater than the sum of the individual effects, resulting in better efficacy and smaller adverse reactions.
  • CN106660970B discloses a compound represented by Formula 1 (Example 22), which is a multi-target inhibitor with the activity of inhibiting RET, KDR, EGFR, FGFR1, FLT-1 and other protein tyrosine kinases.
  • the technical problem to be solved by this application is to provide a pharmaceutical composition that meets the requirements of preparation and oral administration and contains the compound represented by Formula 2 as an active ingredient.
  • the present application provides a pharmaceutical composition suitable for oral administration, which includes: as an active ingredient, a compound represented by Formula 2 and an excipient,
  • excipients which may also be called “pharmaceutically acceptable excipients", “auxiliary materials” or “additives”, refer to all ingredients, other than active ingredients, used in formulating prescriptions and producing drugs.
  • auxiliary materials or “additives” refer to all ingredients, other than active ingredients, used in formulating prescriptions and producing drugs.
  • additional materials generally pharmaceutically acceptable inert ingredients that have been reasonably evaluated in terms of safety.
  • excipients include, but are not limited to, fillers (or diluents), disintegrants, lubricating excipients (lubricants, glidants, anti-adhesive agents), binders, stabilizers, flavoring agents, extenders, Thickeners, dispersants, colorants, bacteriostatic agents, antioxidants, pH regulators, surfactants, spices and coating materials (including plasticizers, opacifiers, pigments, etc.) and other substances.
  • excipients can enhance the handling characteristics of pharmaceutical formulations, such as by increasing flowability and/or adhesion, allowing formulation preparation to meet process requirements.
  • excipient should have good compatibility with the active ingredient, that is, the excipient itself or the impurities contained therein will not react chemically with the structural groups in the active ingredient or cause degradation of the active ingredient, resulting in The content of active ingredients decreases.
  • the excipients can also be divided into ionic excipients and nonionic excipients.
  • nonionic excipients refer to excipients that do not contain metal ions, for example, nonionic excipients.
  • Excipients include nonionic fillers Fillers, nonionic lubricants, nonionic disintegrants, nonionic glidants, etc.; among them, for example, nonionic fillers include microcrystalline cellulose, pregelatinized starch, lactose, mannitol, starch, etc. , non-ionic lubricants include stearic acid, hydrogenated vegetable oil, etc., non-ionic disintegrants include crospovidone, low-substituted hydroxypropylcellulose, etc., and non-ionic glidants include colloidal silica;
  • the "ionic excipient" mentioned above refers to an excipient containing metal ions.
  • Ionic excipients include ionic fillers, ionic lubricants, ionic disintegrants, etc., among which, for example, ionic fillers Including calcium hydrogen phosphate, calcium carbonate, etc., ionic lubricants include magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, etc.
  • Fillers or “diluents” as used herein refer to excipients used to increase the weight and volume of pharmaceutical compositions to facilitate shaping and dosing.
  • the filler described in this application can be a single filler or a mixture of two or more fillers.
  • Disintegrant refers to an excipient used to promote the disintegration of a pharmaceutical composition in the gastrointestinal tract and increase the dissolution rate of active ingredients.
  • lubricating excipient is a broad lubricant, which refers to an excipient used to reduce the friction between particles of the pharmaceutical composition and between the particles and the die holes, and improve the transmission and distribution of force.
  • Lubricating excipients are divided into lubricants, flow aids and anti-adhesion agents based on their three functions: reducing friction, increasing particle fluidity, and resisting adhesion between die holes and drug particles.
  • the pharmaceutical composition is formulated for oral administration.
  • the oral preparation is an oral solid preparation.
  • the pharmaceutical composition or oral preparation does not dissolve 85% of the time in the dissolution test. More than 60 minutes.
  • the time for the pharmaceutical composition or oral formulation to dissolve 85% in a dissolution test does not exceed 55 minutes; preferably 50 minutes; more preferably 45 minutes.
  • the content of the active ingredient in the pharmaceutical composition or oral preparation is determined to be 100% ⁇ 10%; preferably 100% ⁇ 5%; more preferably 100% ⁇ 3%.
  • the excipient includes a disintegrant, which is a nonionic disintegrant.
  • the excipients further comprise non-ionic excipients, optionally further comprising ionic excipients.
  • the excipients comprise a disintegrant and a filler, the disintegrant is a non-ionic disintegrant, optionally the excipients further comprise a glidant and/or a lubricant. agent.
  • the nonionic disintegrant comprises dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low-substituted hydroxypropylcellulose, or crospovidone.
  • the nonionic disintegrating agent comprises crospovidone, optionally further comprising another nonionic disintegrating agent, the other nonionic disintegrating agent
  • the agent is selected from dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch or low-substituted hydroxypropyl cellulose.
  • the weight percentage of the disintegrant in the pharmaceutical composition is 5% to 40%; preferably 7% to 40%; preferably 8% to 35%; further preferably 8% to 40%; More preferably, it is 10% to 40%; further preferably, 8% to 30%; further preferably, 8% to 25%; further preferably, 8% to 20%; further preferably, 8% to 15%; further preferably, 10% ⁇ 15%.
  • the excipients comprise nonionic disintegrants and nonionic fillers, optionally further comprising nonionic glidants, ionic fillers and/or ionic lubricants.
  • the excipients comprise nonionic disintegrants, nonionic fillers, and nonionic glidants, optionally further comprising nonionic lubricants, ionic fillers, and/or Or ionic lubricant.
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angles (°) has characteristic diffraction peaks ( ⁇ 0.2°) at the following positions: 9.8, 12.4, 18.8, 20.3, 24.6.
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angle (°) has characteristic diffraction peaks ( ⁇ 0.2°) at the following positions: 8.1, 9.8, 12.4, 18.8, 19.3, 20.3, 24.6, 28.6 ,29.9.
  • the powder X-ray diffraction pattern expressed in 2 ⁇ angle (°) has characteristic diffraction peaks ( ⁇ 0.2°) at the following positions: 8.1, 9.8, 12.4, 16.1, 18.8, 19.3, 20.3, 24.6 ,28.6,29.9,30.9.
  • Cu-K ⁇ radiation is used, with an X-ray powder diffraction pattern substantially as shown in Figure 1 or Figure 2.
  • the DSC curve of the crystalline form of the compound represented by Formula 2 (form I) has endothermic peaks at 231.0 ⁇ 5°C and 284.2 ⁇ 5°C respectively.
  • the TGA curve of the crystalline form of the compound represented by Formula 2 begins to decompose at 205.6 ⁇ 5°C.
  • the weight percentage of the nonionic disintegrant in the pharmaceutical composition is 8% to 40%; preferably 8% to 30%; preferably 10% % ⁇ 40%; preferably 10% ⁇ 35%; preferably 10% ⁇ 30%; preferably 15% ⁇ 40%; preferably 15% ⁇ 30%; preferably 20% ⁇ 30%; preferably 20% ⁇ 40%; preferably 25% to 40%; preferably 30% to 40%.
  • the weight percentage of the filler in the pharmaceutical composition is: 10% to 85%; or 10% to 80%; or 15% to 75%; Or 17% to 68%; or 15% to 70%; or 15% to 65%; or 20% to 65%; or 30% to 65%; or 30% to 60%; or 30% to 55%; or 30% to 50%; or 35% to 50%; or 40% to 55%.
  • the weight percentage of lubricant in the pharmaceutical composition is: 0% to 6%; or 0% to 5%; or 0% to 4%; or 0 % ⁇ 3.5%; or 0% ⁇ 3%; or 0% ⁇ 2.5%; or 0% ⁇ 2%; or 0% ⁇ 1.5%; or 0% ⁇ 1%; or,
  • the weight percentage of lubricant in the pharmaceutical composition is: 1% to 6%; or 1% to 5%; or 1.5% to 5%; or 1% to 4%; or 1.5% to 4%; or 1 % to 3.5%; or 1.5% to 3.5%; or 1% to 3%; or 1% to 2%; or 1.5% to 3%; or 2% to 3.5%.
  • the pharmaceutical composition includes a lubricant, and wherein the lubricant is a nonionic lubricant, wherein the nonionic lubricant is present in the pharmaceutical composition in a weight percentage of 1% ⁇ 6%, preferably 1% to 5%, preferably 1% to 4%, more preferably 1% to 3.5%, even more preferably 1% to 3%, even more preferably 1% to 2%.
  • the pharmaceutical composition includes a lubricant, and wherein the lubricant includes both a nonionic lubricant and an ionic lubricant, wherein the nonionic lubricant is in the pharmaceutical composition
  • the weight percentage is 1% to 4%, preferably 1% to 3.5%, more preferably 1% to 3%, further preferably 1% to 2%;
  • the weight percentage of the active ingredient in the pharmaceutical composition is ⁇ 40% (for example, 40% to 70%, 40% to 68%), and the ionic lubricant in the pharmaceutical composition is The weight percentage is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably ⁇ 0.5%; or
  • the weight percentage of the active ingredient in the pharmaceutical composition is less than 40% (for example, 15% ⁇ active ingredient weight percentage ⁇ 40%, 16% ⁇ active ingredient weight percentage ⁇ 40%, 16% to 35%, 16% to 34%), the weight percentage of the ionic lubricant in the pharmaceutical composition is ⁇ 2%, preferably ⁇ 1.5 %, preferably ⁇ 1%, preferably ⁇ 0.8%, more preferably ⁇ 0.7%, even more preferably ⁇ 0.6%, even more preferably ⁇ 0.5%.
  • the pharmaceutical composition includes a lubricant, and wherein the lubricant is an ionic lubricant, and the weight percentage of the active ingredient in the pharmaceutical composition is ⁇ 40% (preferably ⁇ 35%; Preferably ⁇ 34%, such as 15% to 35%, 15% to 34%, 20% to 34%, 20% to 35%, 20% to 33.5%), the ionic lubricant is in the pharmaceutical composition
  • the weight percentage is 1% to 3%; preferably 1% to 2.5%, preferably 1% to 2%, preferably 1% to 1.5%.
  • the weight percentage of the glidant in the pharmaceutical composition is: 0% to 8%; or 0% to 7%; or 0% to 6%; or 0% to 5.5%; or 0 % ⁇ 5%; or 0% ⁇ 4%; or 0% ⁇ 3%; or 0% ⁇ 2%; or 0% ⁇ 1.5%; or 0% ⁇ 1%; or 0% ⁇ 0.5%; or,
  • the weight percentage of the glidant in the pharmaceutical composition is 3% to 8%; or 3% to 7%; or 3% to 6%; or 3% to 5.5%; or 3% to 5%; or 3.5 % to 7%; or 4% to 7%; or 4.5% to 7%; or 5% to 7%; or 4% to 7%; or 4% to 6%.
  • the nonionic disintegrant is selected from dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low-substituted hydroxypropylcellulose, or crospovidone one or more;
  • the nonionic disintegrant is selected from one of dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low-substituted hydroxypropylcellulose or cross-linked povidone. , or a combination of crospovidone and one or more of dry starch, microcrystalline cellulose, polyvinylpyrrolidone, corn starch, pregelatinized starch or low-substituted hydroxypropylcellulose;
  • the non-ionic disintegrant is selected from crospovidone, a combination of crospovidone and low-substituted hydroxypropylcellulose.
  • the filler comprises a non-ionic filler, optionally further comprising an ionic filler;
  • the nonionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose;
  • the nonionic filler is selected from one of microcrystalline cellulose, or pregelatinized starch, mannitol or lactose; or is selected from a combination of two nonionic fillers, including microcrystalline fiber.
  • a combination of starch and starch, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a pregelatinized The combination of starch and lactose, or the combination of microcrystalline cellulose and dextrin, or the combination of microcrystalline cellulose and powdered sugar, or the combination of microcrystalline cellulose and sucrose.
  • the pharmaceutical composition includes a lubricant, and when the lubricant includes a nonionic lubricant, the nonionic lubricant is selected from the group consisting of stearic acid, palmitic acid, and glycerin palmitate stearate.
  • the nonionic lubricant is selected from the group consisting of stearic acid, palmitic acid, and glycerin palmitate stearate.
  • esters, glyceryl behenate, hydrogenated vegetable oil, talc or polyethylene glycols preferably stearic acid; and/or
  • the ionic lubricant is selected from the group consisting of magnesium stearate, calcium stearate, sodium benzoate, sodium lauryl sulfate, zinc stearate, sodium stearyl fumarate, One or more of magnesium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate or magnesium lauryl sulfate; preferably magnesium stearate or sodium stearyl fumarate; more preferably Magnesium stearate.
  • the pharmaceutical composition includes a glidant, and wherein the glidant is a nonionic glidant; preferably, the nonionic glidant is selected from colloidal silica.
  • the excipients include fillers, disintegrants, lubricants, and glidants, wherein the disintegrants are nonionic disintegrants and the lubricants include nonionic lubricants.
  • the agent optionally, further contains an ionic lubricant.
  • the excipients include fillers, disintegrants, lubricants, and glidants, wherein the disintegrant is a nonionic disintegrant and the lubricant is an ionic lubricant.
  • the filler includes a nonionic filler, and the glidant is a nonionic glidant.
  • the present application provides a pharmaceutical composition suitable for oral administration, which contains a compound shown in formula 2 as an active ingredient, a filler Agent, disintegrant, lubricant and glidant, wherein the disintegrant is a non-ionic disintegrant,
  • the compound represented by Formula 2 is as defined in the first aspect above.
  • the weight percentage of the nonionic lubricant in the pharmaceutical composition is 1% to 6%, preferably 1% to 6%. 5%, preferably 1% to 4%, more preferably 1% to 3.5%, even more preferably 1% to 3%, even more preferably 1% to 2%.
  • the lubricant comprises a nonionic lubricant, optionally, further comprising an ionic lubricant; preferably, when an ionic lubricant is included, and the weight of the active ingredient in the pharmaceutical composition
  • the percentage is ⁇ 40% (for example, 40% to 70%, 40% to 68%)
  • the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably ⁇ 0.8%, and further preferably ⁇ 0.7 %, more preferably ⁇ 0.6%, even more preferably ⁇ 0.5%.
  • the lubricant comprises a nonionic lubricant, optionally, further comprising an ionic lubricant; preferably, when an ionic lubricant is included, and the weight of the active ingredient in the pharmaceutical composition
  • the ionic lubricant is The weight percentage in the pharmaceutical composition is ⁇ 2%, preferably ⁇ 1.5%, preferably ⁇ 1%, preferably ⁇ 0.8%, more preferably ⁇ 0.7%, further preferably ⁇ 0.6%, even more preferably ⁇ 0.5% .
  • the lubricant comprises a nonionic lubricant, optionally further comprising an ionic lubricant; preferably, when an ionic lubricant is included, the ionic lubricant is in the pharmaceutical composition
  • the weight percentage is less than 1%, more preferably ⁇ 0.8%, still more preferably ⁇ 0.7%, still more preferably ⁇ 0.6%, even more preferably ⁇ 0.5%, and even more preferably 0% to 0.5%.
  • the filler comprises a non-ionic filler, optionally further comprising an ionic filler; preferably, the filler is a non-ionic filler.
  • the nonionic filler includes one or more of microcrystalline cellulose, pregelatinized starch, mannitol, or lactose.
  • the nonionic filler comprises microcrystalline cellulose, optionally further comprising starch, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar, or sucrose. one or more;
  • the non-ionic filler comprises pregelatinized starch, optionally further comprising one or more of microcrystalline cellulose, starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose. kind;
  • the non-ionic filler includes lactose, optionally further including one or more of microcrystalline cellulose, pregelatinized starch, starch, mannitol, xylitol, dextrin, powdered sugar or sucrose. kind;
  • the nonionic filler includes mannitol, optionally, further including one or more of microcrystalline cellulose, pregelatinized starch, lactose, starch, xylitol, dextrin, powdered sugar or sucrose. kind.
  • the non-ionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose.
  • the nonionic filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose, or the nonionic filler is a combination of two nonionic fillers , including a combination of microcrystalline cellulose and starch, or a combination of microcrystalline cellulose and pregelatinized starch, or a combination of microcrystalline cellulose and lactose, or a combination of microcrystalline cellulose and mannitol, or pregelatinized starch The combination with mannitol, or the combination of pregelatinized starch and lactose, or the combination of microcrystalline cellulose and dextrin, or the combination of microcrystalline cellulose and powdered sugar, or the combination of microcrystalline cellulose and sucrose; further preferred
  • the nonionic filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose, or a combination of microcrystalline cellulose and starch, or microcrystalline cellulose and pregelatin
  • microcrystalline cellulose and lactose or the combination of microcrystalline cellulose and mannitol, or the combination of pregelatinized starch and mannitol, or the combination of pregelatinized starch and lactose.
  • the weight ratio of the two fillers is 1:10 ⁇ 10:1; or 1:9 ⁇ 9:1; or 1:8 ⁇ 8:1; 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 ionic filler is selected from one or more of calcium sulfate, calcium hydrogen phosphate, or calcium phosphate.
  • the weight ratio of the non-ionic filler and the ionic filler is 1000 ⁇ 1:1; or 900 ⁇ 1:1; 800 ⁇ 1: 1; or 700 ⁇ 1:1; or 600 ⁇ 1:1; or 500 ⁇ 1:1; or 300 ⁇ 1:1, or 200 ⁇ 1:1; or 100 ⁇ 1:1; or 50 ⁇ 1:1 ; Or 20 ⁇ 1:1; Or 10 ⁇ 1:1.
  • the weight percentage of the filler in the pharmaceutical composition is: 10% to 85%; or 10% to 80%; or 15% to 75%; or 17% to 68%; or 15% to 70%; or 15% to 65%; or 20% to 65%; or 30% to 65%; or 30% to 60%; or 30% to 55%; or 30% to 50%; or 35 % ⁇ 50%; or 40% ⁇ 55%.
  • the nonionic disintegrant comprises crospovidone, optionally, further comprising another nonionic disintegrant selected from Dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch or low-substituted hydroxypropylcellulose.
  • the weight percentage of the crospovidone in the pharmaceutical composition is 5% to 20%, more preferably 5% to 18%; further preferably 7% to 18%, further preferably 8% ⁇ 15%, more preferably 5% to 15%, even more preferably 10% to 15%.
  • the weight percentage of the other nonionic disintegrant in the pharmaceutical composition is 0% to 20%, preferably 5% to 20%, preferably 5% to 10%, preferably 0% to 10% %, preferably 10% to 20%.
  • the nonionic disintegrant is selected from dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low-substituted hydroxypropylcellulose, or crospovidone One or more; preferably, the nonionic disintegrant is selected from dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low-substituted hydroxypropylcellulose or cross-linked One of povidone, or a combination of crospovidone and one or more of dry starch, microcrystalline cellulose, polyvinylpyrrolidone, corn starch, pregelatinized starch or low-substituted hydroxypropylcellulose ; Preferred is a combination of crospovidone, crospovidone and low-substituted hydroxypropylcellulose.
  • the weight percentage of the crospovidone in the pharmaceutical composition is 5% to 20%; more preferably, it is 7% to 18%; further preferably, it is 8% to 15%; further preferably, it is 5% ⁇ 15%; more preferably 10% ⁇ 15%.
  • the weight percentage of the disintegrant in the pharmaceutical composition is: 5% to 35%; or 5% to 30%; or 5% to 25%; or 6% to 25%; Or 7% to 20%; or 5% to 20%; or 8% to 20%; or 8% to 18%; or 8% to 15%; or 10% to 15%.
  • the lubricant comprises a non-ionic lubricant, optionally further comprising an ionic lubricant.
  • the nonionic lubricant comprises stearic acid, optionally further comprising palmitic acid, palmitic acid stearic acid
  • stearic acid optionally further comprising palmitic acid, palmitic acid stearic acid
  • glyceryl esters hydrogenated vegetable oil, talc, glyceryl behenate or polyethylene glycols.
  • the ionic lubricant is selected from the group consisting of magnesium stearate, calcium stearate, sodium benzoate, sodium lauryl sulfate, zinc stearate, sodium stearyl fumarate, magnesium stearyl fumarate , one or more of magnesium lauryl sulfate, sodium lauryl sulfate or magnesium lauryl sulfate; preferably magnesium stearate or sodium stearyl fumarate; more preferably magnesium stearate.
  • the lubricant comprises stearic acid, optionally, further comprising another lubricant (i.e., a combination of stearic acid and another lubricant) selected from Magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitate stearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, zinc stearate, stearyl fumarate Sodium sulfate, magnesium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate or polyethylene glycols.
  • the other lubricant is magnesium stearate, sodium stearyl fumarate or hydrogenated vegetable oil; more preferably, it is magnesium stearate.
  • the lubricant is selected from stearic acid, a combination of stearic acid and magnesium stearate, a combination of stearic acid and sodium stearyl fumarate, or a combination of stearic acid and hydrogenated vegetable oil. Combination; more preferred is stearic acid, or a combination of stearic acid and magnesium stearate.
  • the weight percentage of the stearic acid in the pharmaceutical composition is 1% to 4%; further preferably, it is 1% to 3.5%; further preferably, it is 1% to 3%; further preferably It is 1% ⁇ 2%.
  • the other lubricant is an ionic lubricant (for example, magnesium stearate, calcium stearate, sodium benzoate, sodium lauryl sulfate, zinc stearate, sodium stearyl fumarate, sodium stearate, etc.
  • magnesium lipofumarate magnesium lauryl sulfate, sodium lauryl sulfate or magnesium lauryl sulfate; preferably magnesium stearate or sodium stearyl fumarate
  • the active ingredient is in the pharmaceutical composition
  • the weight percentage of the ionic lubricant is ⁇ 40% (for example, 40% to 70%, 40% to 68%)
  • the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.8%. ⁇ 0.7%, preferably ⁇ 0.6%, preferably ⁇ 0.5%.
  • the weight percentage of the stearic acid in the pharmaceutical composition is 1% to 4%; further preferably, it is 1% to 3.5%; further preferably, it is 1% to 3%; further preferably It is 1% ⁇ 2%.
  • the other lubricant is an ionic lubricant (for example, magnesium stearate, calcium stearate, sodium benzoate, sodium lauryl sulfate, zinc stearate, sodium stearyl fumarate, sodium stearate, etc.
  • the active ingredient is in the pharmaceutical composition
  • the weight percentage of active ingredient is ⁇ 40% (for example, 15% ⁇ weight percentage of active ingredient ⁇ 40%, 16% ⁇ weight percentage of active ingredient ⁇ 40%, 16% ⁇ 35%, 16% ⁇ 34%)
  • the ionic lubrication is ⁇ 2%, preferably ⁇ 1.5%, preferably ⁇ 1%, preferably ⁇ 0.8%, more preferably ⁇ 0.7%, further preferably ⁇ 0.6%, even more preferably is ⁇ 0.5%.
  • the weight percentage of the stearic acid in the pharmaceutical composition is 1% to 4%; further preferably, it is 1% to 3.5%; further preferably, it is 1% to 3%; further preferably It is 1% ⁇ 2%.
  • the other lubricant is a non-ionic lubricant (for example, palmitic acid, glyceryl palmitate stearate, glyceryl behenate, hydrogenated vegetable oil, talc or polyethylene glycols
  • hydrogenated vegetable oil the weight percentage of the nonionic lubricant in the pharmaceutical composition is ⁇ 4%; preferably ⁇ 3.5%; preferably ⁇ 3%; preferably ⁇ 2.5%; preferably ⁇ 2%; preferably ⁇ 1.5%; preferably ⁇ 1%; preferably ⁇ 0.5%.
  • the weight percentage of the stearic acid in the pharmaceutical composition is 1% to 4%; further preferably, it is 1% to 3.5%; further preferably, it is 1% to 3%; further preferably It is 1% ⁇ 2%.
  • the weight percentage of the other lubricant in the pharmaceutical composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably 0% to 0.5%, Preferably it is ⁇ 0.5%.
  • the glidant is a non-ionic glidant; preferably, the weight percentage of the glidant in the pharmaceutical composition is 3% to 8%; or 3% to 7% ; Or 3% to 6%; Or 3% to 5.5%; Or 3% to 5%; Or 3.5% to 7%; Or 4% to 7%; Or 4.5% to 7%; Or 5% to 7%; Or 4% to 7%; or 4% to 6%.
  • the glidant is a nonionic glidant; preferably, the nonionic glidant is selected from colloidal silica.
  • the weight percentage of the colloidal silica in the pharmaceutical composition is: 3% to 8%; or 3% to 7%; or 3% to 6%; or 3% to 5.5%; or 3% to 5%; or 3.5% to 7%; or 4% to 7%; or 4.5% to 7%; or 5% to 7%; or 4% to 7%; or 4% to 7%; or 4% to 6%.
  • the filler in the pharmaceutical composition, includes a nonionic filler; the disintegrant is a nonionic disintegrant; and the glidant is a nonionic glidant. ;
  • the lubricant includes a nonionic lubricant, optionally, further including an ionic lubricant;
  • nonionic filler nonionic disintegrant, nonionic lubricant, ionic lubricant and nonionic glidant are as defined above.
  • the weight percentage of the nonionic lubricant in the pharmaceutical composition is 1% to 4%, preferably 1% to 3.5%, more preferably 1% to 3%, even more preferably 1% to 3.5%. 2%; the weight percentage of ionic lubricant in the pharmaceutical composition is not higher than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably 0% to 0.5%, preferably is ⁇ 0.5%.
  • the filler includes a non-ionic filler, optionally, further comprising an ionic filler;
  • the lubricant includes stearic acid, optionally, further comprising another lubricant selected from the group consisting of magnesium stearate, calcium stearate, palmitic acid, and glyceryl palmitate stearate.
  • Glyceryl behenate sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium stearyl fumarate, magnesium lauryl sulfate, lauryl sulfate Sodium, magnesium lauryl sulfate or polyethylene glycols; wherein the weight percentage of the stearic acid in the pharmaceutical composition is 1% to 4%, preferably 1% to 3.5%, and further preferably 1% to 3%, more preferably 1% to 2%; the weight percentage of the other lubricant in the pharmaceutical composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.7%.
  • the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7% , preferably ⁇ 0.6%, preferably ⁇ 0.5%;
  • the disintegrant is a nonionic disintegrant, and the nonionic disintegrant is selected from dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, and low-substituted hydroxypropyl cellulose. Or one of crospovidone, or one of crospovidone and dry starch, microcrystalline cellulose, corn starch, powdered cellulose, pregelatinized starch or low-substituted hydroxypropyl cellulose, or A combination of multiple types; wherein, the weight percentage of the disintegrant in the pharmaceutical composition is 5% to 35%, preferably 7% to 30%, preferably 8% to 30%, preferably 8% to 8%. 20%, preferably 8% to 18%, preferably 8% to 15%, preferably 10% to 30%, preferably 10% to 20%, preferably 10% to 15%;
  • the glidant is colloidal silica
  • the non-ionic filler or the ionic filler is as defined above.
  • the weight percentage of the glidant in the pharmaceutical composition is 3% to 8%; or 3% to 7%; or 3% to 6%; or 3% to 5.5%; or 3% to 5%; or 3.5% to 7%; or 4% to 7%; or 4.5% to 7%; or 5% to 7%; or 4% to 7%; or 4% to 6%.
  • the non-ionic filler contains microcrystalline cellulose, optionally further containing one of starch, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose, or variety;
  • the non-ionic filler comprises pregelatinized starch, optionally further comprising one or more of microcrystalline cellulose, starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose. kind;
  • the nonionic filler includes mannitol, optionally, further including one or more of microcrystalline cellulose, pregelatinized starch, lactose, starch, xylitol, dextrin, powdered sugar or sucrose. kind.
  • the nonionic filler includes one or more of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; further preferably, the nonionic filler is selected from microcrystalline cellulose. , one of pregelatinized starch, mannitol or lactose, or a combination selected from two nonionic fillers, including a combination of microcrystalline cellulose and starch, a combination of microcrystalline cellulose and pregelatinized starch, A combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose.
  • the weight ratio of the two nonionic fillers is 1:10 to 10:1; or 1:9 to 9:1; Or 1:8 ⁇ 8:1; 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 weight ratio of the non-ionic filler to the ionic filler is 1000 to 1:1; or 900 to 1:1; 800 to 1:1; or 700 ⁇ 1:1; or 600 ⁇ 1:1; or 500 ⁇ 1:1; or 300 ⁇ 1:1, or 200 ⁇ 1:1; or 100 ⁇ 1:1; or 50 ⁇ 1:1; or 20 ⁇ 1:1; or 10 ⁇ 1:1.
  • the filler includes a non-ionic filler, optionally, further comprising an ionic filler;
  • the lubricant is selected from stearic acid, a combination of stearic acid and magnesium stearate, a combination of stearic acid and calcium stearate, or a combination of stearic acid and zinc stearate, or stearic acid and stearic acid.
  • the percentage is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably 0% to 0.5%, preferably ⁇ 0.5%; preferably, when the active ingredient is in the pharmaceutical composition
  • the weight percentage is ⁇ 40% (for example, 40% to 70%, 40% to 68%), the magnesium stearate, calcium stearate, sodium stearyl fumarate or zinc stearate is in the drug
  • the weight percentage in the composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇
  • the weight percentage of the glidant in the pharmaceutical composition is 3% to 8%; or 3% to 7%; or 3% to 6%; or 3% to 5.5%; or 3% to 5%; or 3.5% to 7%; or 4% to 7%; or 4.5% to 7%; or 5% to 7%; or 4% to 7%; or 4% to 6%.
  • the non-ionic filler contains microcrystalline cellulose, optionally further containing one of starch, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose, or variety;
  • the non-ionic filler includes lactose, optionally further including one or more of microcrystalline cellulose, pregelatinized starch, starch, mannitol, xylitol, dextrin, powdered sugar or sucrose. kind;
  • the nonionic filler includes mannitol, optionally, further including one or more of microcrystalline cellulose, pregelatinized starch, lactose, starch, xylitol, dextrin, powdered sugar or sucrose. kind.
  • the nonionic filler includes one or more of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; further preferably, the nonionic filler is selected from microcrystalline cellulose. , one of pregelatinized starch, mannitol or lactose, or a combination selected from two nonionic fillers, including a combination of microcrystalline cellulose and starch, a combination of microcrystalline cellulose and pregelatinized starch, A combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose.
  • the weight ratio of the two nonionic fillers is 1:10 to 10:1; or 1:9 to 9:1; Or 1:8 ⁇ 8:1; 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 weight ratio of the non-ionic filler and the ionic filler is 1000 ⁇ 1:1; or 900 ⁇ 1:1; 800 ⁇ 1: 1; or 700 ⁇ 1:1; or 600 ⁇ 1:1; or 500 ⁇ 1:1; or 300 ⁇ 1:1, or 200 ⁇ 1:1; or 100 ⁇ 1:1; or 50 ⁇ 1:1 ; Or 20 ⁇ 1:1; Or 10 ⁇ 1:1.
  • the filler includes a non-ionic filler, optionally, further comprising an ionic filler;
  • the disintegrant is a non-ionic disintegrant, the non-ionic disintegrant includes crospovidone, optionally, further includes another disintegrant, and the other disintegrant is selected from Self-drying starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch or low-substituted hydroxypropylcellulose; wherein the weight percentage of the cross-linked povidone in the pharmaceutical composition is 5 % to 20%, further preferably 5% to 15%; further preferably 7% to 15%; further preferably 8% to 15%; further preferably 10% to 15%; the other disintegrant is The weight percentage in the pharmaceutical composition is 0% to 20%, preferably 5% to 15%, preferably 0% to 15%, preferably 0% to 10%, preferably 5% to 10%, preferably 10% ⁇ 20%;
  • the weight percentage of the glidant in the pharmaceutical composition is 3% to 8%; or 3% to 7%; or 3% to 6%; or 3% to 5.5%; or 3% to 5%; or 3.5% to 7%; or 4% to 7%; or 4.5% to 7%; or 5% to 7%; or 4% to 7%; or 4% to 6%.
  • the non-ionic filler contains microcrystalline cellulose, optionally further containing one of starch, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose, or variety;
  • the non-ionic filler comprises pregelatinized starch, optionally further comprising one or more of microcrystalline cellulose, starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose. kind;
  • the non-ionic filler includes lactose, optionally further including one or more of microcrystalline cellulose, pregelatinized starch, starch, mannitol, xylitol, dextrin, powdered sugar or sucrose. kind;
  • the nonionic filler includes mannitol, optionally, further including one or more of microcrystalline cellulose, pregelatinized starch, lactose, starch, xylitol, dextrin, powdered sugar or sucrose. kind.
  • the nonionic filler includes one or more of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; further Preferably, the nonionic filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose, or a combination of two nonionic fillers, including microcrystalline cellulose. Combination with starch, combination of microcrystalline cellulose with pregelatinized starch, combination of microcrystalline cellulose with lactose, combination of microcrystalline cellulose with mannitol, combination of pregelatinized starch with mannitol, or pregelatinization A combination of starch and lactose.
  • the weight ratio of the two nonionic fillers is 1:10 to 10:1; or 1:9 to 9:1; Or 1:8 ⁇ 8:1; 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 weight ratio of the non-ionic filler and the ionic filler is 1000 ⁇ 1:1; or 900 ⁇ 1:1; 800 ⁇ 1: 1; or 700 ⁇ 1:1; or 600 ⁇ 1:1; or 500 ⁇ 1:1; or 300 ⁇ 1:1, or 200 ⁇ 1:1; or 100 ⁇ 1:1; or 50 ⁇ 1:1 ; Or 20 ⁇ 1:1; Or 10 ⁇ 1:1.
  • the filler includes a non-ionic filler, optionally, further comprising an ionic filler;
  • the lubricant is selected from stearic acid, a combination of stearic acid and magnesium stearate, a combination of stearic acid and calcium stearate, or a combination of stearic acid and zinc stearate, or stearic acid and stearic acid.
  • the percentage is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably 0% to 0.5%, preferably ⁇ 0.5%; preferably, when the active ingredient is in the pharmaceutical composition
  • the weight percentage is ⁇ 40% (for example, 40% to 70%, 40% to 68%), the magnesium stearate, calcium stearate, sodium stearyl fumarate or zinc stearate is in the drug
  • the weight percentage in the composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇
  • the disintegrant is a non-ionic disintegrant, and the non-ionic disintegrant includes crospovidone, optionally, further comprising another disintegrant, and the other disintegrant is selected from Self-drying starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch or low-substituted hydroxypropylcellulose; wherein the weight percentage of the cross-linked povidone in the pharmaceutical composition is 5 % to 20%, further preferably 5% to 15%; further preferably 7% to 15%; further preferably 8% to 15%; further preferably 10% to 15%; the other disintegrant is The weight percentage in the pharmaceutical composition is 0% to 20%, preferably 5% to 15%, preferably 0% to 15%, preferably 0% to 10%, preferably 5% to 10%, preferably 10% ⁇ 20%;
  • the glidant is colloidal silica.
  • the weight percentage of the hydrogenated vegetable oil in the pharmaceutical composition is 0.5% to 4%, preferably 0.5% to 3.5%, and further preferably 1% to 1%. 3%, more preferably 1% to 2%.
  • the weight percentage of the glidant in the pharmaceutical composition is 3% to 8%; or 3% to 7%; or 3% to 6%; or 3% to 5.5%; or 3% to 5%; or 3.5% to 7%; or 4% to 7%; or 4.5% to 7%; or 5% to 7%; or 4% to 7%; or 4% to 6%.
  • the non-ionic filler contains microcrystalline cellulose, optionally further containing one of starch, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose, or variety;
  • the non-ionic filler comprises pregelatinized starch, optionally further comprising one or more of microcrystalline cellulose, starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose. kind;
  • the non-ionic filler includes lactose, optionally further including one or more of microcrystalline cellulose, pregelatinized starch, starch, mannitol, xylitol, dextrin, powdered sugar or sucrose. kind;
  • the nonionic filler includes mannitol, optionally, further including one or more of microcrystalline cellulose, pregelatinized starch, lactose, starch, xylitol, dextrin, powdered sugar or sucrose. kind.
  • the nonionic filler includes one or more of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; further preferably, the nonionic filler is selected from microcrystalline cellulose. , one of pregelatinized starch, mannitol or lactose, or selected from two
  • the combination of nonionic fillers includes the combination of microcrystalline cellulose and starch, the combination of microcrystalline cellulose and pregelatinized starch, the combination of microcrystalline cellulose and lactose, the combination of microcrystalline cellulose and mannitol, and the combination of pregelatinized starch and microcrystalline cellulose.
  • the weight ratio of the two nonionic fillers is 1:10 to 10:1; or 1:9 to 9:1; Or 1:8 ⁇ 8:1; 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 weight ratio of the non-ionic filler and the ionic filler is 1000 ⁇ 1:1; or 900 ⁇ 1:1; 800 ⁇ 1: 1; or 700 ⁇ 1:1; or 600 ⁇ 1:1; or 500 ⁇ 1:1; or 300 ⁇ 1:1, or 200 ⁇ 1:1; or 100 ⁇ 1:1; or 50 ⁇ 1:1 ; Or 20 ⁇ 1:1; Or 10 ⁇ 1:1.
  • the pharmaceutical composition includes, by total weight thereof, the following components:
  • Active ingredients 0.5% to 80%; or 1% to 75%; or 5% to 70%; or 5% to 65%; or 5% to 60%; or 5% to 55%; or 5% to 50% ;
  • Filler 10% to 85%; or 10% to 80%; or 10% to 75%;
  • Disintegrant 5% to 35%; or 5% to 30%; or 5% to 20%; or 6% to 25%;
  • Lubricant 1% to 6%; or 1% to 5%; or 1% to 4%; or 1% to 3.5%; or 1% to 3%;
  • Glidant 3% to 8%; or 3% to 7%; or 3% to 6%; or 3% to 5.5%; or 3% to 5%;
  • the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the pharmaceutical composition includes, by total weight thereof, the following components:
  • Active ingredients 10% to 70%; or 15% to 70%; or 10% to 55%; or 10% to 50%; or 15% to 55%; or 15% to 50%; or 15% to 45% ;
  • Disintegrant 5% to 35%; or 5% to 30%; or 5% to 20%; or 7% to 20%; or 7% to 30%; or 7% to 25%;
  • Lubricant 1% to 6%; or 1% to 5%; or 1.5% to 5%; or 1% to 4%; or 1.5% to 4%; or 1% to 3.5%; or 1.5% to 3.5% ; Or 1% ⁇ 3%; Or 1.5% ⁇ 3%; Or 1% ⁇ 2%;
  • Glidant 3% to 8%; or 3% to 7%; or 3% to 6%; or 3% to 5.5%; or 3% to 5%; or 3.5% to 6%; or 3.5% to 5.5 %; or 3.5% to 5%; or 4% to 6%; or 4.5% to 6%; or 5% to 6%;
  • the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the pharmaceutical composition includes, by total weight thereof, the following components:
  • Active ingredients 16% to 68%; or 16% to 60%; or 20% to 55%; or 20% to 50%; or 20% to 45%; or 20% to 40%;
  • Filler 15% to 68%; or 17% to 68%; or 15% to 60%; or 15% to 55%; or 17% to 50%;
  • Disintegrant 7% to 20%; or 8% to 20%; or 7% to 18%; or 8% to 18%; or 8% to 15%;
  • Lubricant 1% to 4%; or 1.5% to 4%; or 1% to 3.5%; or 1.5% to 3.5%; or 1% to 3%; or 1.5% to 3%; or 1% to 2% ;
  • Glidant 3% to 8%; or 3% to 7%; or 3% to 6%; or 3% to 5.5%; or 3% to 5%; or 3.5% to 6%; or 3.5% to 5.5 %; or 3.5% to 5%; or 4% to 6%; or 4.5% to 6%; or 5% to 6%;
  • the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 5% to 70% active ingredient, 10% to 85% filler, 5% to 35% disintegrant, 1% to 4% lubricant, 3% to 8% glidant; the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 10% to 70% active ingredient, 10% to 70% filler, 7% to 30% disintegrant, 1% to 3.5% lubricant, 3% to 7% glidant; the active ingredient, filler, disintegrant, lubricant and glidant as defined previously.
  • the pharmaceutical composition includes the following components by total weight: 15% to 70% active ingredient, 15% to 70% filler, 7% to 25% disintegrant, 1% to 3.5% lubricant, 3% to 7% glidant; the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 15% to 70% active ingredient, 15% to 70% filler, 8% to 20% disintegrant, 1% to 3% lubricant, 3% to 7% glidant; the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above. In some embodiments, the pharmaceutical composition includes the following components by total weight: 16% to 68% active ingredient, 17% to 68% filler, 8% to 20% disintegrant, 1% to 3% lubricant, 3% to 7% glidant; the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 16% to 68% active ingredient, 17% to 68% filler, 8% to 15% disintegrant, 1% to 3% lubricant, 3% to 7% glidant; the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 15% to 50% active ingredient, 30% to 65% filler, 8% to 15% disintegrant, 1% to 3% lubricant, 3% to 7% glidant.
  • the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 15% to 45% active ingredient, 30% to 65% filler, 8% to 15% disintegrant, 1% to 3% lubricant, 3% to 7% glidant.
  • the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 15% to 45% active ingredient, 30% to 65% filler, 8% to 15% disintegrant, 1% to 3% lubricant, 3.5% to 5% glidant.
  • the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the filler includes a non-ionic filler, optionally, further comprising an ionic filler;
  • the disintegrant is a non-ionic disintegrant; preferably, the non-ionic disintegrant contains cross-linked povidone;
  • the lubricant includes a non-ionic lubricant, and optionally, further includes an ionic lubricant;
  • the glidant is colloidal silica
  • the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably 0% to 0.5%, preferably 0% to 0.5%. ⁇ 0.5%; preferably, when the weight percentage of active ingredients in the pharmaceutical composition is ⁇ 40% (for example, 40% to 70%, 40% to 68%), the ionic lubricant is present in the pharmaceutical composition.
  • the weight percentage in the composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably ⁇ 0.5%; preferably, the nonionic lubricant contains stearic acid; preferably Land, the ionic lubricant contains magnesium stearate;
  • nonionic disintegrant nonionic lubricant, ionic lubricant, nonionic filler and ionic filler are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 15% to 70% active ingredient, 15% to 70% filler, 8% to 20% disintegrant, 1% to 3% lubricant, 3% to 7% glidant;
  • the filler includes a non-ionic filler, the non-ionic filler includes one or more of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; preferably, the non-ionic filler
  • the filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; or is selected from a combination of two non-ionic fillers, including a combination of microcrystalline cellulose and starch, microcrystalline cellulose and Combination of pregelatinized starch, combination of microcrystalline cellulose and lactose, combination of microcrystalline cellulose and mannitol, combination of pregelatinized starch and mannitol, or pregelatinization Combination of starch and lactose;
  • the disintegrant is a non-ionic disintegrant; preferably, the non-ionic disintegrant contains cross-linked povidone;
  • the lubricant includes a nonionic lubricant, optionally, further including an ionic lubricant; preferably, the nonionic lubricant includes stearic acid; preferably, the ionic lubricant includes stearic acid magnesium;
  • the glidant is colloidal silica
  • the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably 0% to 0.5%, preferably 0% to 0.5%. ⁇ 0.5%; preferably, when the weight percentage of active ingredients in the pharmaceutical composition is ⁇ 40% (for example, 40% to 70%, 40% to 68%), the ionic lubricant is present in the pharmaceutical composition.
  • the weight percentage in the composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably ⁇ 0.5%;
  • the pharmaceutical composition includes the following components by total weight: 16% to 68% active ingredient, 17% to 68% filler, 8% to 20% disintegrant, 1% to 3% lubricant, 3% to 7% glidant;
  • the filler includes a non-ionic filler, optionally, further comprising an ionic filler;
  • the disintegrant is a non-ionic disintegrant; preferably, the non-ionic disintegrant contains cross-linked povidone;
  • the lubricant includes a nonionic lubricant, optionally, further including an ionic lubricant; preferably, the nonionic lubricant includes stearic acid; preferably, the ionic lubricant includes stearic acid magnesium;
  • the glidant is colloidal silica
  • the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably 0% to 0.5%, preferably 0% to 0.5%. ⁇ 0.5%; preferably, when the weight percentage of active ingredients in the pharmaceutical composition is ⁇ 40% (for example, 40% to 70%, 40% to 68%), the ionic lubricant is present in the pharmaceutical composition.
  • the weight percentage in the composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably ⁇ 0.5%;
  • nonionic disintegrant nonionic lubricant, ionic lubricant, nonionic filler and ionic filler are as defined above.
  • the filler includes a non-ionic filler, the non-ionic filler includes one or more of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; preferably, the non-ionic filler
  • the filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; or is selected from a combination of two non-ionic fillers, including a combination of microcrystalline cellulose and starch, microcrystalline cellulose and A combination of pregelatinized starch, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose;
  • the disintegrant is a non-ionic disintegrant, and the non-ionic disintegrant includes crospovidone;
  • the glidant is colloidal silica
  • the coated tablet includes a tablet core and a coating material, wherein the tablet core includes the aforementioned pharmaceutical composition.
  • the “coating material” described in this application can also be called “coating powder”, “coating agent” or “coating premix”. It is a mixture of various pharmaceutical excipients. Its main function is to color, Mask odor, protect from light, extend shelf life, improve appearance, etc.
  • the "film-coated tablet” described in this application can also be called “film-coated tablet”, which refers to a tablet core (which is made from the pharmaceutical composition of this application through tableting) and is coated with a film (coat). tablet.
  • Film coating materials include one or more of film-forming materials (or film-forming agents, polymer materials), plasticizers, porogens, colorants (or lakes), opacifiers and certain solid materials.
  • the film-forming material can be selected from polyvinyl alcohol polyethylene glycol copolymer, polyvinyl alcohol, hypromellose, methyl cellulose, hydroxyethyl cellulose, acrylic resin, ethyl cellulose, cellulose acetate, One or more of cellulose acetate phthalate, polyvinyl alcohol phthalate, cellulose acetate trimellitate, hypromellose phthalate, etc.; the plasticizer can be selected from glycerin, propylene glycol, polyethylene glycol, etc.
  • the weight gain of the film coating accounts for 1% to 5% of the weight of the tablet core, preferably 1.5% to 4%, more preferably 1.5% to 3%, and more preferably 2% to 3%.
  • the coating solvent is selected from water and ethanol, preferably water, which can be removed during drying without remaining in the final product.
  • Series coating powder models include: 321A620034-CN ⁇ 321A630026-CN ⁇ 321A610052-CN etc.
  • the present application provides a pharmaceutical composition suitable for oral administration, which contains a compound represented by Formula 2 as an active ingredient, a filler, a disintegrant, a lubricant and a glidant, wherein the lubricant It is an ionic lubricant, the disintegrant is a nonionic disintegrant, the filler includes a nonionic filler, the glidant is a nonionic glidant, and the nonionic filler , nonionic glidant, ionic lubricant and nonionic disintegrant are defined as described in the first aspect and/or the second aspect above.
  • a pharmaceutical composition suitable for oral administration which contains a compound represented by Formula 2 as an active ingredient, a filler, a disintegrant, a lubricant and a glidant, wherein the lubricant It is an ionic lubricant, the disintegrant is a nonionic disintegrant, the filler includes a nonionic filler, the
  • the compound represented by Formula 2 is as described in the first aspect above.
  • the ionic lubricant is selected from the group consisting of magnesium stearate, calcium stearate, sodium benzoate, sodium lauryl sulfate, zinc stearate, sodium stearyl fumarate, magnesium stearyl fumarate , one or more of magnesium lauryl sulfate, sodium lauryl sulfate or magnesium lauryl sulfate; preferably magnesium stearate or sodium stearyl fumarate; further preferably magnesium stearate.
  • the nonionic disintegrant is selected from dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low-substituted hydroxypropylcellulose, or crospovidone One or more; preferably crospovidone and/or low-substituted hydroxypropylcellulose.
  • the ionic lubricant includes magnesium stearate and the nonionic disintegrant includes crospovidone or low One or two types of hydroxypropylcellulose.
  • the ionic lubricant is magnesium stearate and the nonionic disintegrant is selected from crospovidone or a combination of crospovidone and low-substituted hydroxypropylcellulose.
  • the weight percentage of the active ingredient in the pharmaceutical composition is ⁇ 40%, preferably ⁇ 35%; preferably ⁇ 34%, such as 15% to 38%, 15% to 37%, 15% to 36% , 15% to 35%, 15% to 34%, 16% to 35%, 18% to 35%, 16% to 34%, 18% to 34%, 20% to 34%, 20% to 35%, 20 % ⁇ 33.5%.
  • the weight percentage of the ionic lubricant in the pharmaceutical composition is 1% to 3%, preferably 1% to 2.5%, preferably 1% to 2%, preferably 1% to 1%. 1.5%.
  • the weight percentage of the nonionic disintegrant in the pharmaceutical composition is 8% to 40%; preferably 10% to 40%; preferably 10% to 35%; preferably 10% % ⁇ 30%; preferably 15% ⁇ 40%; preferably 15% ⁇ 30%; preferably 20% ⁇ 30%; preferably 20% ⁇ 40%; preferably 25% ⁇ 40%; preferably 30% ⁇ 40%.
  • the filler includes a nonionic filler selected from the group consisting of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, One or more of powdered sugar or sucrose; preferably, the non-ionic filler contains one or more of microcrystalline cellulose, lactose, mannitol or pregelatinized starch; further preferably, the The nonionic filler is selected from one of microcrystalline cellulose, lactose, mannitol, starch or pregelatinized starch; or is selected from a combination of two nonionic fillers, including microcrystalline cellulose and starch.
  • a nonionic filler selected from the group consisting of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, One or more of powdered sugar or sucrose; preferably, the non-ionic filler contains one or more of micro
  • the filler is a non-ionic filler; preferably, the non-ionic filler includes one or more of microcrystalline cellulose, lactose, mannitol or pregelatinized starch; Further preferably, the non-ionic filler contains microcrystalline cellulose, optionally further containing one of starch, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose. or more;
  • the non-ionic filler comprises pregelatinized starch, optionally further comprising one or more of microcrystalline cellulose, starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose. kind;
  • the non-ionic filler includes lactose, optionally further including one or more of microcrystalline cellulose, pregelatinized starch, starch, mannitol, xylitol, dextrin, powdered sugar or sucrose. kind;
  • the weight percentage of the active ingredient in the pharmaceutical composition is 5% to 45%; preferably 5% to 40%; preferably 5% to 35%; preferably 5% to 30% ; Preferably 10% to 40%; Preferably 10% to 35%; Preferably 15% to 35%; Preferably 10% to 30%; Preferably 10% to 27%; Preferably 10% to 25%; Preferably 10% to 20%; preferably 10% to 24%; preferably 10% to 23%; preferably 10% to 22%; preferably 10% to 21%; preferably 15% to 25%; preferably 15 % ⁇ 20%; preferably 20% ⁇ 35%; preferably 20% ⁇ 30%; preferably 15% ⁇ 38%, preferably 15% ⁇ 37%, preferably 15% ⁇ 36%, preferably 15% ⁇ 35%, preferably 15% to 34%, preferably 16% to 35%, preferably 18% to 35%, preferably 16% to 34%, preferably 18% to 34%, preferably 20% to 34% , preferably 20% to 35%, preferably 20% to 33.5%.
  • the weight percentage of the nonionic filler in the pharmaceutical composition is 25% to 70%; preferably 28% to 60%; preferably 28% to 55%; preferably 28% % ⁇ 50%; preferably 30% ⁇ 60%; preferably 35% ⁇ 55%; preferably 38% to 55%; preferably 25% to 55%; preferably 30% to 70%; preferably 35% to 70%; preferably 40% to 70%; preferably 40% to 65%; preferably 40% ⁇ 60%; Preferably 40% ⁇ 55%; Preferably 40% ⁇ 50%; Preferably 35% ⁇ 45%; Preferably 30% ⁇ 45%; Preferably 30% ⁇ 44%; Preferably 35% ⁇ 50 %.
  • the glidant is a nonionic glidant; preferably, the nonionic glidant is selected from colloidal silica.
  • the weight percentage of the colloidal silica in the pharmaceutical composition is: 0% to 8%; or 0% to 7%; or 0.5% to 7%; or 1% to 7%; or 1.5% to 7%; or 2% to 7%; or 2.5% to 7%; or 3% to 7%; or 3% to 6%; or 3% to 5.5%; or 3% to 5%.
  • the pharmaceutical composition includes the following components by total weight: 10% to 35% active ingredient, 30% to 65% filler, 20% to 40% disintegrant, 1% to 3% lubricant, 0.5% to 5% glidant; the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 10% to 35% active ingredient, 30% to 60% filler, 20% to 40% disintegrant, 1% to 2% lubricant, 3% to 5% glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 10% to 35% active ingredient, 30% to 55% filler, 20% to 40% disintegrant, 1% to 1.5% lubricant, 3% to 5% glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 15% to 35% active ingredient, 30% to 50% filler, 30% to 40% disintegrant, 1% to 1.5% lubricant, 3% to 5% glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 18% to 35% active ingredient, 30% to 50% filler, 20% to 40% disintegrant, 1% to 3% lubricant, 3% to 7% glidant; the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 20% to 35% active ingredient, 30% to 45% filler, 20% to 40% disintegrant, 1% to 3% lubricant, 3% to 7% glidant; the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 20% to 34% active ingredient, 30% to 45% filler, 20% to 40% disintegrant, 1% to 3% lubricant, 3% to 7% glidant; the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 20% to 35% active ingredient, 30% to 45% filler, 20% to 40% disintegrant, 1% to 2% lubricant, 3% to 7% glidant; the active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 10% to 30% active ingredient, 30% to 60% filler, 20% to 40% disintegrant, 1% to 1.5% lubricant, 3% to 5% glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 10% to 35% active ingredient, 28% to 50% filler, 20% to 40% disintegrant, 1% to 1.5% lubricant, 3% to 5% glidant; the active ingredient, filler, disintegrant, lubricant and glidant are as defined above.
  • the pharmaceutical composition includes the following components by total weight: 10% to 35% active ingredient, 30% to 50% filler, 20% to 40% disintegrant, 1% to 2% lubricant, 3% to 5% glidant;
  • the filler includes a non-ionic filler, the non-ionic filler includes one or more of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; preferably, the non-ionic filler
  • the agent is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose. or selected from a combination of two non-ionic fillers, including a combination of microcrystalline cellulose and starch, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and lactose, microcrystalline cellulose Combination with mannitol, combination of pregelatinized starch with mannitol, or combination of pregelatinized starch with lactose;
  • the disintegrant is a non-ionic disintegrant; preferably, the non-ionic disintegrant includes crospovidone, optionally; further including low-substituted hydroxypropylcellulose;
  • the lubricant is magnesium stearate
  • the glidant is a nonionic glidant; preferably, the nonionic glidant is selected from colloidal silica,
  • the nonionic disintegrant is selected from crospovidone or a combination of crospovidone and low-substituted hydroxypropylcellulose.
  • the pharmaceutical composition includes the following components by total weight: 10% to 35% active ingredient, 30% to 55% filler, 20% to 40% disintegrant, 1% to 1.5% lubricant, 3% to 5% glidant;
  • the filler includes a non-ionic filler, the non-ionic filler includes one or more of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; preferably, the non-ionic filler
  • the filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; or is selected from a combination of two non-ionic fillers, including a combination of microcrystalline cellulose and starch, microcrystalline cellulose and A combination of pregelatinized starch, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose;
  • the disintegrant is a non-ionic disintegrant; preferably, the non-ionic disintegrant includes crospovidone, optionally; further including low-substituted hydroxypropylcellulose;
  • the lubricant is magnesium stearate
  • the glidant is a nonionic glidant; preferably, the nonionic glidant is selected from colloidal silica,
  • nonionic disintegrant and the nonionic glidant are the same as in the second aspect above.
  • the nonionic disintegrant is selected from crospovidone or a combination of crospovidone and low-substituted hydroxypropylcellulose.
  • the pharmaceutical composition includes the following components by total weight: 15% to 35% active ingredient, 30% to 50% filler, 30% to 40% disintegrant, 1% to 1.5% lubricant, 3% to 5% glidant;
  • the filler includes a non-ionic filler, the non-ionic filler includes one or more of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; preferably, the non-ionic filler
  • the filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; or is selected from a combination of two non-ionic fillers, including a combination of microcrystalline cellulose and starch, microcrystalline cellulose and A combination of pregelatinized starch, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose;
  • the disintegrant is a non-ionic disintegrant; preferably, the non-ionic disintegrant includes crospovidone, optionally; further including low-substituted hydroxypropylcellulose;
  • the glidant is a nonionic glidant; preferably, the nonionic glidant is selected from colloidal silica,
  • nonionic disintegrant and the nonionic glidant are the same as in the second aspect above.
  • the pharmaceutical composition includes the following components by total weight: 20% to 35% active ingredient, 30% to 45% filler, 20% to 40% disintegrant, 1% to 3% lubricant, 3% to 5% glidant;
  • the filler includes a non-ionic filler, the non-ionic filler includes one or more of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; preferably, the non-ionic filler
  • the filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; or is selected from a combination of two non-ionic fillers, including a combination of microcrystalline cellulose and starch, microcrystalline cellulose and Combination of pregelatinized starch, combination of microcrystalline cellulose and lactose, combination of microcrystalline cellulose and mannitol, combination of pregelatinized starch and mannitol, or pregelatinization A combination of starch and lactose; preferably, the non-ionic filler is microcrystalline cellulose;
  • the disintegrant is a non-ionic disintegrant; preferably, the non-ionic disintegrant includes crospovidone, optionally; further including low-substituted hydroxypropylcellulose;
  • the lubricant is magnesium stearate or sodium stearyl fumarate
  • the glidant is a nonionic glidant; preferably, the nonionic glidant is selected from colloidal silica,
  • nonionic disintegrant and the nonionic glidant are the same as in the second aspect above.
  • the pharmaceutical composition includes the following components by total weight: 20% to 34% active ingredient, 30% to 45% filler, 20% to 40% disintegrant, 1% to 2% lubricant, 3% to 5% glidant;
  • the filler includes a non-ionic filler, the non-ionic filler includes one or more of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; preferably, the non-ionic filler
  • the filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose; or is selected from a combination of two non-ionic fillers, including a combination of microcrystalline cellulose and starch, microcrystalline cellulose and A combination of pregelatinized starch, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose; preferably, the The non-ionic filler is microcrystalline cellulose;
  • the disintegrant is a non-ionic disintegrant; preferably, the non-ionic disintegrant includes crospovidone, optionally; further including low-substituted hydroxypropylcellulose;
  • the lubricant is magnesium stearate or sodium stearyl fumarate
  • the glidant is a nonionic glidant; preferably, the nonionic glidant is selected from colloidal silica,
  • nonionic disintegrant and the nonionic glidant are the same as in the second aspect above.
  • the pharmaceutical composition is made into an oral preparation; preferably, the oral preparation is an oral solid preparation; further preferably, the oral solid preparation is selected from the group consisting of capsules, tablets, powders and fine granules; Capsules and tablets are further preferred; tablets are further preferred; and the tablets are coated tablets.
  • the coated tablet includes a tablet core and a coating material, wherein the tablet core includes the aforementioned pharmaceutical composition, and the coating material is as defined in the second aspect above.
  • the coating material includes a film-forming material, and the film-forming material includes polyvinyl alcohol polyethylene glycol copolymer; preferably, the film-forming material is selected from polyvinyl alcohol polyethylene glycol. copolymer, or a combination of polyvinyl alcohol polyethylene glycol copolymer and polyvinyl alcohol.
  • the present application provides a pharmaceutical composition suitable for oral administration, which contains a compound represented by Formula 2 as an active ingredient, a filler and a disintegrant, optionally further comprising a glidant and/or lubricant. agent, wherein the disintegrant is a non-ionic disintegrant, and the filler, glidant and non-ionic disintegrant are as defined in the first, second or third aspect above.
  • the compound represented by Formula 2 is as described in the first aspect above.
  • the weight percentage of the nonionic lubricant in the pharmaceutical composition is 1% to 6%, preferably 1% to 6%. 5%, preferably 1% to 4%, more preferably 1% to 3.5%, even more preferably 1% to 3%, even more preferably 1% to 2%.
  • the weight percentage of the nonionic lubricant in the pharmaceutical composition is 1% to 4%. , preferably 1% to 3.5%, more preferably 1% to 3%, even more preferably 1% to 2%; and,
  • the weight percentage of the active ingredient in the pharmaceutical composition is ⁇ 40% (for example, 40% to 70%, 40% to 68%), the proportion of the ionic lubricant in the pharmaceutical composition
  • the weight percentage is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably ⁇ 0.5%;
  • the weight percentage of the active ingredient in the pharmaceutical composition is less than 40% (for example, 15% ⁇ active ingredient weight percentage ⁇ 40%, 16% ⁇ active ingredient weight percentage ⁇ 40%, 16% to 35%, 16% to 34%), the weight percentage of the ionic lubricant in the pharmaceutical composition is less than or equal to 2%, preferably Less than or equal to 1.5%, preferably less than or equal to 1%, preferably less than or equal to 0.8%, more preferably less than or equal to 0.7%, further preferably less than or equal to 0.6%, still more preferably less than or equal to 0.5%.
  • the weight percentage of the active ingredient in the pharmaceutical composition is ⁇ 40% (preferably ⁇ 35%; preferably ⁇ 34%, for example, 15% to 15%). 35%, 15% to 34%, 20% to 34%, 20% to 35%, 20% to 33.5%), the weight percentage of the ionic lubricant in the pharmaceutical composition is 1% to 3% ; Preferably 1% to 2.5%, preferably 1% to 2%, preferably 1% to 1.5%; Preferably, the ionic lubricant is magnesium stearate or sodium stearyl fumarate; further preferably Magnesium stearate.
  • the lubricant includes a nonionic lubricant, optionally further comprising an ionic lubricant; preferably, the lubricant is a nonionic lubricant; the nonionic lubricant and
  • the definition of ionic lubricant is as described in the second aspect above.
  • the weight percentage of the nonionic lubricant in the pharmaceutical composition is 0% to 3%, preferably 0% to 2%, preferably 0% to 1%, preferably 0.5% to 2.5%. , further preferably 1% to 2%; the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably 0% to 0.5%, preferably ⁇ 0.5%.
  • the lubricant comprises stearic acid, optionally, further comprising another lubricant selected from the group consisting of magnesium stearate, calcium stearate, palmitic acid, palmitic acid Glyceryl stearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium stearyl fumarate, magnesium lauryl sulfate , sodium lauryl sulfate, magnesium lauryl sulfate or polyethylene glycols; wherein the weight percentage of the stearic acid in the pharmaceutical composition is 1% to 4%, preferably 1% to 4%.
  • the lubricant is selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate , hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate or polyethylene glycols one or more of them.
  • the weight percentage of the lubricant in the pharmaceutical composition is 0.1% to 3%; preferably 0.1% to 2%; preferably 0.1% to 1.5%; preferably 0.1% to 1%.
  • the filler includes a non-ionic filler, optionally, further comprising an ionic filler; preferably, the filler is a non-ionic filler; the non-ionic filler and
  • ionic filler is as described in the second aspect above.
  • the weight percentage of the active ingredient is 0.5% to 80%; or 1% to 75%; or 5% to 70%; Or 10% to 70%; Or 15% to 70%; Or 16% to 68%; Or 16% to 67%; Or 20% to 70%; Or 20% to 67%; Or 5% to 65%; Or 5% to 60%; or 5% to 55%; or 5% to 50%; or 10% to 55%; or 10% to 50%; or 15% to 55%; or 15% to 50%; or 15 % ⁇ 45%; or 20% ⁇ 50%; or 20% ⁇ 45%; or 20% ⁇ 40%.
  • the non-ionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose.
  • the nonionic filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose, or the nonionic filler is a combination of two nonionic fillers , including a combination of microcrystalline cellulose and starch, or a combination of microcrystalline cellulose and pregelatinized starch, or a combination of microcrystalline cellulose and lactose, or a combination of microcrystalline cellulose and mannitol, or pregelatinized starch The combination with mannitol, or the combination of pregelatinized starch and lactose, or the combination of microcrystalline cellulose and dextrin, or the combination of microcrystalline cellulose and powdered sugar, or the combination of microcrystalline cellulose and sucrose; further preferred
  • the nonionic filler is selected from one of microcrystalline cellulose, pregelatinized starch, mannitol or lactose, or a combination of microcrystalline cellulose and starch, or microcrystalline cellulose and pregelatin
  • the weight percentage of the filler in the pharmaceutical composition is: 10% to 85%; or 10% to 80%; Or 15% to 75%; or 17% to 68%; or 15% to 70%; or 15% to 65%; or 20% to 65%; or 30% to 65%; or 30% to 60%; or 30% to 55%; or 30% to 50%; or 35% to 50%; or 40% to 55%.
  • the weight percentage of the disintegrant in the pharmaceutical composition is: 5% to 35%; or 8% to 40%; or 8% to 35%; or 8% to 30%; Or 10% to 40%; or 10% to 35%; or 10% to 30%; or 15% to 40%; or 15% to 30%; or 20% to 30%; or 20% to 40%; or 25% to 40%; or 30% to 40%; or 5% to 30%; or 5% to 25%; or 6% to 25%; or 7% to 20%; or 8% to 20%; or 8 % ⁇ 18%; or 8% ⁇ 10%; or 8% ⁇ 15%; or 10% ⁇ 15%.
  • the lubricant is selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate , hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate or polyethylene glycols One or more of them; preferably, the lubricant contains stearic acid; preferably, the lubricant is stearic acid.
  • the weight percentage of the lubricant in the pharmaceutical composition is: 0% to 6%; or 0% to 5%; or 0% to 4%; or 0% to 3.5%; or 0% to 3%; or 0% to 2.5%; or 0% to 2%; or 0% to 1.5%; or 0% to 1%.
  • the weight percentage of the lubricant in the pharmaceutical composition is: 1% to 6%; or 1% to 5%; or 1.5% to 5%; or 1% to 4%; or 1.5% to 4%; or 1% to 3.5%; or 1.5% to 3.5%; or 1% to 3%; or 1% to 2%; or 1.5% to 3%; or 2% to 3.5%.
  • the glidant is a nonionic glidant; preferably, the nonionic glidant is selected from colloidal silica.
  • the weight percentage of the colloidal silica in the pharmaceutical composition is: 0% to 8%; or 0% to 7%; or 0% to 6%; or 0% to 5.5%; or 0% to 5%; or 0% to 4%; or 0% to 3%; or 0% to 2%; or 0% to 1.5%; or 0% to 1%; or 0% to 0.5%.
  • the weight percentage of the glidant in the pharmaceutical composition is: 0% to 8%; or 0% to 7%; or 0% to 6%; or 0% to 5.5%; or 0 % ⁇ 5%; or 0% ⁇ 4%; or 0% ⁇ 3%; or 0% ⁇ 2%; or 0% ⁇ 1.5%; or 0% ⁇ 1%; or 0% ⁇ 0.5%; or,
  • the weight percentage of the glidant in the pharmaceutical composition is 3% to 8%; or 3% to 7%; or 3% to 6%; or 3% to 5.5%; or 3% to 5%; or 3.5 % to 7%; or 4% to 7%; or 4.5% to 7%; or 5% to 7%; or 4% to 7%; or 4% to 6%.
  • the pharmaceutical composition includes the following components by total weight: 10% to 70% active ingredient, 15% to 80% filler, 8% to 30% disintegrant, 0% to 3% lubricant, 0% ⁇ 6% glidant.
  • the pharmaceutical composition includes the following components by total weight: 15% to 70% active ingredient, 15% to 75% filler, 8% to 20% disintegrant, 0% to 3% lubricant, 0% to 5% glidant.
  • the pharmaceutical composition includes the following components by total weight: 16% to 68% active ingredient, 17% to 75% filler, 8% to 20% disintegrant, 0% to 2% lubricant, 0% to 5% glidant.
  • the pharmaceutical composition includes the following components by total weight: 16% to 68% active ingredient, 17% to 75% filler, 8% to 15% disintegrant, 0% to 2% lubricant, 0% ⁇ 5% glidant;
  • the filler includes a non-ionic filler, optionally, further comprising an ionic filler;
  • the disintegrant is a non-ionic disintegrant; preferably, the non-ionic disintegrant contains cross-linked povidone;
  • the lubricant includes a nonionic lubricant, optionally, further comprising an ionic lubricant; preferably, the nonionic lubricant includes stearic acid, and the ionic lubricant includes magnesium stearate or hard Sodium lipofumarate, further preferably contains magnesium stearate;
  • the glidant is colloidal silica
  • the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably 0% to 0.5%, preferably 0% to 0.5%. ⁇ 0.5%;
  • nonionic filler ionic filler, nonionic disintegrant, nonionic lubricant or ionic lubricant is as defined above (second aspect).
  • the nonionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose.
  • the non-ionic filler contains microcrystalline cellulose, or one or more of pregelatinized starch, mannitol or lactose; preferably, the non-ionic filler is selected from microcrystalline cellulose , or one of pregelatinized starch, mannitol or lactose; or a combination of two non-ionic fillers, including a combination of microcrystalline cellulose and starch, a combination of microcrystalline cellulose and pregelatinized starch , a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose; preferably, the nonionic filler Selected from microcrystalline cellulose.
  • the filler is a non-ionic filler.
  • the pharmaceutical composition includes the following components by total weight: 16% to 68% active ingredient, 17% to 75% filler, 8% to 15% disintegrant, 0% to 2% lubricant, 0% ⁇ 5% glidant;
  • the filler includes a non-ionic filler, optionally, further comprising an ionic filler;
  • the disintegrant is a non-ionic disintegrant; preferably, the non-ionic disintegrant contains cross-linked povidone;
  • the glidant is colloidal silica
  • nonionic filler ionic filler
  • nonionic disintegrant ionic filler, and nonionic disintegrant
  • the nonionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose.
  • the non-ionic filler contains microcrystalline cellulose, or one or more of pregelatinized starch, mannitol or lactose; preferably, the non-ionic filler is selected from microcrystalline cellulose , or one of pregelatinized starch, mannitol or lactose; or a combination of two non-ionic fillers, including a combination of microcrystalline cellulose and starch, a combination of microcrystalline cellulose and pregelatinized starch , a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and mannitol, a combination of pregelatinized starch and mannitol, or a combination of pregelatinized starch and lactose; preferably, the nonionic filler It is microcrystalline cellulose.
  • the filler is a non-ionic filler.
  • the lubricant is selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitostearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate , hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate or polyethylene glycols
  • the lubricant contains stearic acid.
  • the pharmaceutical composition includes the following components by total weight: 15% to 70% active ingredient, 15% to 75% filler, 8% to 30% disintegrant, 0% to 3% lubricant, 0% ⁇ 6% glidant;
  • the filler includes a nonionic filler, optionally, further comprising an ionic filler;
  • the nonionic filler is selected from starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylose One or more of alcohol, dextrin, powdered sugar or sucrose;
  • the ionic filler is selected from one or more of calcium sulfate, calcium hydrogen phosphate or calcium phosphate; preferably, the non-ionic filler Fillers contain microcrystalline cellulose;
  • the disintegrant is selected from non-ionic disintegrants; preferably, the non-ionic disintegrant includes crospovidone;
  • the lubricant includes stearic acid, optionally, further comprising another lubricant selected from the group consisting of magnesium stearate, calcium stearate, palmitic acid, and glyceryl palmitate stearate.
  • Glyceryl behenate sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium stearyl fumarate, magnesium lauryl sulfate, lauryl sulfate
  • the glidant is colloidal silica
  • the weight percentage of the other lubricant in the pharmaceutical composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably 0% to 0.5%; preferably is ⁇ 0.5%.
  • the pharmaceutical composition includes the following components by total weight: 15% to 70% active ingredient, 15% to 75% filler, 8% to 20% disintegrant, 0% to 3% lubricant, 0% to 5% glidant;
  • the filler is a nonionic filler, and the nonionic filler includes microcrystalline cellulose, optionally further including starch, pregelatinized starch, mannitol, lactose, xylitol, dextrin, sugar One or more of powder or sucrose; preferably, the non-ionic filler is microcrystalline cellulose;
  • the disintegrant is a non-ionic disintegrant, the non-ionic disintegrant includes crospovidone, optionally, further includes another non-ionic disintegrant, the other non-ionic disintegrant
  • the ionic disintegrant is selected from dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch or low-substituted hydroxypropylcellulose; preferably, the nonionic disintegrant is cross-linked poly Vitone;
  • the lubricant includes stearic acid, optionally, further comprising another lubricant selected from the group consisting of magnesium stearate, calcium stearate, palmitic acid, and glyceryl palmitate stearate.
  • Glyceryl behenate sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, zinc stearate, sodium stearyl fumarate, magnesium stearyl fumarate, magnesium lauryl sulfate, lauryl sulfate
  • the lubricant is stearic acid;
  • the glidant is colloidal silica
  • the weight percentage of the other lubricant in the pharmaceutical composition is less than 1%, preferably ⁇ 0.8%, preferably ⁇ 0.7%, preferably ⁇ 0.6%, preferably 0% to 0.5%, preferably is ⁇ 0.5%.
  • each preparation unit of the oral preparation or oral solid preparation of the first to fourth aspects may contain 1-500 mg of active ingredient, or 10-450 mg, or 25-400 mg, or 50-350 mg. , or 100-300mg, or 150-200mg, or 25-200mg; for example, a single-dose form of the drug contains active ingredients 5mg, 10mg, 20mg, 25mg, 30mg, 50mg, 60mg, 100mg, 150mg, 200mg, 250mg, 300mg, 400mg, 500mg, etc.; wherein, the active ingredient is in the form of the compound represented by Formula 2, that is, the dihydrochloride salt.
  • the dosage is calculated as the compound represented by Formula 2; further preferably, the dosage is calculated as the crystalline form (anhydrous and solvent-free form) of the compound represented by Formula 2; even further preferably, the dosage is calculated as Formula 2
  • the crystal form I of the compound shown in 2 is calculated.
  • the oral preparations, oral dosage forms or oral solid preparations of the first to fourth aspects contain a therapeutically effective amount of the compound represented by Formula 2, and the dosage is: 25 mg to 900 mg per administration;
  • each administration is 200 mg-800 mg; further preferably, each administration is 300 mg-700 mg; further preferably, each administration is 300 mg-600 mg; further preferably, each administration is 400 mg-600 mg; further preferably, each administration is 400 mg-600 mg.
  • exemplary dosages include 25mg, 50mg, 100mg, 200mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg per administration or 900mg.
  • the dosage is based on the compound represented by Formula 2.
  • the dosage is calculated as the compound represented by Formula 2; further preferably, the dosage is calculated as the crystalline form (anhydrous and solvent-free form) of the compound represented by Formula 2; further preferably, the dosage is calculated as the compound represented by Formula 2.
  • the dosage is based on the crystal form I of the compound represented by Formula 2.
  • the daily dosage frequency of the oral preparation or oral solid preparation of the first to fourth aspects is: once a day, twice a day, three times a day or four times a day. times; preferably once a day.
  • the oral preparations or oral solid preparations of the first to fourth aspects contain a therapeutically effective amount of the compound represented by Formula 2, and the daily dosage is 25 mg-900 mg; preferably 200 mg-800 mg; It is further preferably 300mg-700mg; further preferably 300mg-600mg; further preferably 400mg-600mg; further preferably 450mg-600mg; exemplary daily dosages include daily administration of 25mg, 50mg, 100mg, 200mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg or 900mg.
  • the dosage is based on the anhydrous form of Compound 2.
  • the dosage is calculated as the compound represented by Formula 2; further preferably, the dosage is calculated as the crystalline form (anhydrous and solvent-free form) of the compound represented by Formula 2; further preferably, the dosage is calculated as the compound represented by Formula 2.
  • the dosage is based on the crystal form I of the compound represented by Formula 2.
  • the oral preparations or oral solid preparations of the first to fourth aspects contain a therapeutically effective amount of the compound represented by Formula 2, and the dosage and dosage frequency are: once a day, each time
  • the drug is 25 mg-900 mg; preferably, it is administered once a day, and 200 mg-800 mg is administered each time; further preferably, it is administered once a day, and 300 mg-700 mg is administered each time; further preferably, it is administered once a day, and each administration is 300 mg-700 mg.
  • the drug is 300 mg-600 mg; further preferably, it is administered once a day, and 400 mg-600 mg is administered each time; further preferably, it is administered once a day, and 450 mg-600 mg is administered each time; exemplary dosage and frequency include, every day Dosing once, 25mg, 50mg, 100mg, 200mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg or 900mg. The dosage is based on Compound 2.
  • the dosage is calculated as the compound represented by Formula 2; further preferably, the dosage is calculated as the crystalline form (anhydrous and solvent-free form) of the compound represented by Formula 2; further preferably, the dosage is calculated as the compound represented by Formula 2.
  • the dosage is based on the crystal form I of the compound represented by Formula 2.
  • the oral preparations or oral solid preparations of the first to fourth aspects contain a therapeutically effective amount of the compound represented by Formula 2, and the dosage frequency is: once a day for 21 days, Stop taking the drug for 7 days, and every 28 days constitutes a cycle.
  • the oral formulation or oral solid formulation may be administered in a single dose or in divided doses; preferably, in a single dose.
  • the compound represented by Formula 2 is in crystalline form; further preferably, the crystalline form of the compound represented by Formula 2 is Form I.
  • this application provides the pharmaceutical compositions of the aforementioned first to fourth aspects, the oral preparations or oral solid preparations of the aforementioned first to fourth aspects for inhibiting RET, FGFR, VEGFR, FLT, EGFR kinase or The use of one or more activities in their mutants.
  • the present application provides the use of the pharmaceutical compositions of the first to fourth aspects, the oral preparations or oral solid preparations of the first to fourth aspects for preparing medicines.
  • the medicament is used to treat or prevent a disease mediated by a protein kinase selected from one or more of: RET, FGFR, VEGFR, FLT, EGFR or mutants thereof.
  • a protein kinase selected from one or more of: RET, FGFR, VEGFR, FLT, EGFR or mutants thereof.
  • the present application provides the pharmaceutical compositions of the first to fourth aspects, the oral preparations or oral solid preparations of the first to fourth aspects, for treating protein kinase-mediated diseases, and the protein
  • the kinase is selected from one or more of RET, FGFR, VEGFR, FLT, EGFR or their mutants.
  • the present application provides a method for treating protein kinase-mediated diseases, including: using the pharmaceutical compositions of the first to fourth aspects and the oral preparations of the first to fourth aspects to a subject in need thereof.
  • the protein kinase is selected from one or more of: RET, FGFR, VEGFR, FLT, EGFR or their mutants.
  • the diseases in the aforementioned sixth, seventh, and eighth aspects are cell proliferative diseases.
  • the cell proliferative disease is tumor or cancer.
  • the tumor includes thyroid cancer, biliary tract cancer, epidermoid cancer, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, renal cancer, liver cancer, lung cancer or ovarian cancer.
  • the thyroid cancer is medullary thyroid cancer
  • the lung cancer is non-small cell lung cancer
  • the biliary tract cancer is intrahepatic cholangiocarcinoma.
  • the non-small cell lung cancer is RET fusion non-small cell lung cancer.
  • the present application provides a kit, comprising the pharmaceutical compositions of the first to fourth aspects, the oral preparations or oral solid preparations of the first to fourth aspects.
  • the kit includes one or more containers, which contain the pharmaceutical compositions of the first to fourth aspects, the oral preparations or oral solids of the first to fourth aspects. preparation.
  • the kit includes the pharmaceutical compositions of the first to fourth aspects, the oral preparations or oral solid preparations of the first to fourth aspects.
  • this application provides a method for preparing the pharmaceutical composition of the aforementioned first to fourth aspects, which includes: (1) Weighing: weigh the active ingredients and excipients according to the prescription amount; (2) Mixing: Mix active ingredients and excipients in a mixing container.
  • the pharmaceutical composition is made into tablets, and the preparation method includes: (1) weighing the active ingredient and excipient according to the prescription amount; (2) adding the active ingredient and excipient 1 to the mixture Mix in a container to produce a premix; (3) granulate; (4) mix: mix the granules prepared in step (3) and excipient 2; (5) compress into tablets.
  • the granulation is dry granulation.
  • excipient 1 contains fillers and glidants
  • excipient 2 contains disintegrants and lubricants, optionally further containing fillers and/or glidants.
  • the pharmaceutical composition is made into capsules, and the preparation method includes: (1) weighing the active ingredients and excipients according to the prescription amount; (2) adding the active ingredients and excipient 1 to the mixing container Mix in step (3) to produce a premix; (3) Granulation; (4) Total mixing: Mix the granules prepared in step (3) and excipient 2; (5) Fill capsules.
  • the granulation is selected from direct compression granulation or dry granulation.
  • excipient 1 contains fillers and glidants
  • excipient 2 contains disintegrants and lubricants, optionally further containing fillers and/or glidants.
  • Oral preparation or “oral dosage form” as used herein refers to pharmaceutical preparations for oral administration.
  • Oral solid preparation refers to a solid pharmaceutical preparation for oral administration.
  • the administration subject 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 2 and an excipient
  • a pharmaceutical composition comprising as an active ingredient a compound represented by Formula 2 and excipient composition
  • Optional means that the subsequently described event, environment or situation may but need not occur, including the occasions when the event, environment or situation does or does not occur.
  • further comprising an ionic filler means that the ionic filler may but does not have to be present, and this description includes the case where the pharmaceutical composition contains the ionic filler and the case where it does not contain the ionic filler.
  • the dosage of the compound shown in formula 2 in the prescription can be appropriately adjusted, or the ratio (mass ratio) to the excipient can be adjusted to obtain compounds containing different specifications or different drug weights.
  • Pharmaceutical compositions or oral formulations which also fall within the scope of this application.
  • the "2 ⁇ ", “2 ⁇ angle” or “2 ⁇ angle” mentioned in this application refers to the diffraction angle in degrees or degrees.
  • the error range of 2 ⁇ can be ⁇ 0.5°, ⁇ 0.4°, ⁇ 0.3 °, ⁇ 0.2°, or ⁇ 0.1°; in some embodiments of the present application, the error range for 2 ⁇ is ⁇ 0.2°.
  • substantially as shown in the drawings means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96% of the X-ray powder diffraction pattern %, or at least 97%, or at least 98%, or at least 99% of the peaks are shown in its plot. Furthermore, when the content of a certain crystal form in the product gradually decreases, some of its powder X-ray diffraction patterns belong to this crystal form. The number of diffraction peaks may be reduced due to the detection sensitivity of the instrument.
  • characteristic diffraction peak refers to the diffraction peak that can be used to represent the crystal form in the X-ray powder diffraction pattern, which is related to the peak position, peak shape and relative peak intensity of the diffraction peak, for example, small angle peak, peak
  • the shape is sharp, and the relative peak intensity is at least 3% or more, or at least 5% or more, or at least 10% or more, or at least 20% or more, or at least 30% or more, or at least 40% or more, or at least 50% or more, or at least More than 60%, or at least more than 70%, or at least more than 75% of the diffraction peaks.
  • crystalline form refers to the compound represented by Formula 2 in crystalline form, including the anhydrous and solvent-free form, hydrate form and solvate form of the compound represented by Formula 2.
  • solvate refers to an association formed by stoichiometric or non-stoichiometric ratios of solvent molecules and the compound represented by Formula 2 of the present application, including simultaneously containing water molecules and one or more Associations of other solvent molecules, and associations containing only one or more other solvent molecules.
  • water-free and solvent-free form means that it does not contain water molecules or solvent molecules, or water molecules or solvent molecules coexist with the compound represented by Formula 2 in a non-intermolecular force combination, such as adsorption.
  • compositions and/or oral preparation in this application achieves one or more of the following beneficial technical effects:
  • Test conditions wavelength 252nm; column temperature 40 ⁇ 5°C.
  • Detection medium purified water, pH2.0 phosphoric acid-disodium hydrogen phosphate buffer
  • Preparation of the reference solution Take an appropriate amount of the reference standard of the compound of formula 1, weigh it accurately, add solvent to completely dissolve it, and dilute it to make a 100 ⁇ g/mL solution. Precisely measure 10 uL, and use HPLC to measure the content of compound 1 in the reference solution. .
  • Light tube type Cu target, ceramic X-ray tube
  • Test method Weigh the sample (about 3mg), place it in an aluminum oxide crucible for testing, and heat the sample from 20°C to 340°C.
  • test solution Take an appropriate amount of the test product, weigh it accurately, dissolve it with eluent (12.5 mmol/L sodium hydroxide solution) and quantitatively dilute it into a solution containing approximately 0.5 mg of the test product per 1 mL, and shake well , as the test solution.
  • eluent 12.5 mmol/L sodium hydroxide solution
  • Preparation of reference solution Take an appropriate amount of sodium chloride (equivalent to 18mg of chloride ions), weigh it accurately, place it in a 250mL volumetric flask, dissolve it with eluent and dilute to volume, shake well, and use it as the reference solution.
  • Determination method Precisely measure 10 ⁇ L each of the reference solution and the test solution, inject them into the ion chromatograph respectively, record the chromatogram, and calculate the chloride ion content based on the peak area according to the external standard method.
  • Measurement conditions Use DMSO-d6 as the solvent and conduct the test at room temperature ( ⁇ 25°C).
  • biosolvent media SGF, FeSSIF and FaSSIF
  • Test method Add the sample to be tested into the biological solvent medium to prepare a solution or suspension with a target concentration of 10 mg/mL. The resulting solution or suspension was continuously shaken at 37°C at a rotation speed of 200 rpm. The suspension was filtered at 0.5 hours and the compound concentration in the filtrate was determined using HPLC.
  • Dissolution medium 1000ml water
  • Compound 1 was prepared using the method in CN106660970B (Example 22).
  • the obtained hydrochloride sample was subjected to X-ray powder diffraction. It showed good crystallinity and was named Form I of the dihydrochloride. Its XRPD characterization spectrum is shown in Figure 1, and the diffraction peak data is shown in Table 3. Take the sample for DSC-TGA testing. There are two endothermic peaks. Endothermic Peak 1: There is an endothermic peak starting at 219.1°C and reaching a peak near 231.0°C. Endothermic Peak 2: There is an endothermic peak starting at 235.1°C. The starting point reaches a peak value near 284.2°C, and decomposition occurs at around 205°C. The PLM image shows that the crystalline particles are in regular shape.
  • solid oral dosage forms require the solubility of the drug in water to be greater than 0.1g/L, and solution preparations such as injections or oral liquids require the solubility of the drug to be above 10g/L. More importantly, the solubility of the drug is Solubility should meet clinically required dose concentrations.
  • the dihydrochloride in Preparation Example 2 can be considered for the preparation of solid oral dosage forms, and can further be considered for the preparation of solution preparations such as injections or oral liquids.
  • Test example 3 Stability test
  • the dihydrochloride of compound 1 obtained in Preparation Example 2 can maintain chemical stability and crystal form stability, and complies with the storage requirements as raw materials.
  • the dihydrochloride of compound 1 obtained in Preparation Example 2 can maintain chemical stability and crystal form stability after being placed under 40°C/75% RH (open) conditions for 7 days. Therefore, the sample obtained in Preparation Example 2 has better Thermal stability complies with the storage requirements for raw materials.
  • the specific method is: 1) Weighing or preparing materials: weigh the active ingredient (API) compound 2 according to the prescription amount and corresponding fillers, disintegrants, glidants and lubricants; 2) Premixing: Add the active ingredients, fillers, and glidants into the mixing container and premix to obtain premixed powder; 3) Granulation : Use premixed powder for dry granulation; 4) Mixing: Mix the granules obtained by dry granulation with disintegrant and lubricant to obtain a total mixed powder; 5) Tablet compression: Compact the total mixed powder into tablets machine for tableting.
  • API active ingredient
  • the tableting process was smooth and non-sticky.
  • the prepared tablet core had qualified content and rapid dissolution, and the prescription was qualified.
  • Example 2 Tablets of compound 2 (adjusting the composition and/or weight ratio of the lubricant)
  • Example 1 adjust the amount or composition of the lubricant to obtain tablets of Examples 2-1 to 2-6.
  • the tableting process was smooth and non-sticky.
  • the prepared tablet core had qualified content and rapid dissolution. It met the preparation requirements and the prescription was qualified.
  • the tableting process was smooth and non-sticky.
  • the prepared tablet core had qualified content and rapid dissolution. It met the preparation requirements and the prescription was qualified.
  • Example 3 Tablets of compound 2 (investigation of ionic lubricants)
  • Example 3-1 using magnesium stearate as a lubricant and adjusting the amount of magnesium stearate, Example 3-1, Example 3-2 and Example 3-3 were obtained.
  • Example 3-3 results: The prescriptions of Example 3-1 and Example 3-2 were unqualified and the dissolution was slow; the dosage of magnesium stearate was further reduced to obtain Example 3-3. Although the dissolution rate met the requirements, sticking occurred during the tableting process. Phenomenon, the prescription of Example 3-3 is unqualified.
  • Example 3-1 Referring to the preparation method of Example 1, based on the prescription of Example 3-1, an attempt was made to adjust the disintegrant to obtain Example 3-4, Example 3-5 and Example 3-6.
  • Example 3-7 and 3-8 were obtained.
  • Example 1 Based on the prescription of Example 1, sodium stearyl fumarate was used as a lubricant, but the dosage remained unchanged. The resulting prescription (Examples 3-7) showed obvious sticking phenomenon during the tableting process. The prescription Unqualified; further increase the dosage ratio of sodium stearyl fumarate, and the resulting prescription (Example 3-8) still exhibits sticking phenomenon during the tableting process, and the prescription is unqualified.
  • Example 3-9 Referring to the prescription of Example 3-6 and the preparation method of Example 1, changing the type of lubricant, Example 3-9 was obtained.
  • Example 4-1 Refer to the preparation method of Example 1, reduce the amount of lubricant, and obtain Example 4-1. Further, on the basis of Example 4-1, adjust the amount of glidant to obtain Example 4-2 and Example 4- 3.
  • Example 4-1 The amount of lubricant was reduced to 1% (Example 4-1), the tableting process was smooth, the content and dissolution were in compliance with the requirements, and the prescription was qualified; on the basis of Example 4-1, the proportion of glidant was reduced to 3%, Example 4-2 was obtained.
  • the tableting process was smooth, the content and dissolution were in compliance with the requirements, and the prescription was qualified; the glidant was increased to 7%, and Example 4-3 was obtained.
  • the tableting process of the obtained prescription was smooth, and the content and The dissolution meets the requirements and the prescription is qualified.
  • Example 5-1 Based on the prescription of Example 1, the dosage of disintegrant was reduced (Example 5-1) or the dosage of disintegrant was increased (Example 5-2).
  • the tableting process of the obtained prescription was smooth, and the content and dissolution were in compliance with the requirements. , all prescriptions are qualified. Furthermore, a combination of two disintegrants was used (Example 5-3), and the resulting prescription was qualified.
  • Example 5-4 Referring to the preparation method of Example 1, changing the type of disintegrant, Example 5-4 and Example 5-5 were obtained.
  • Example 5-3 Referring to the prescription of Example 5-3 and the preparation method of Example 1, adjust the dosage of the disintegrant to obtain Examples 5-6 and 5-7.
  • Example 6-1 Referring to the prescription and preparation method of Example 1, using a single filler and adjusting the type of filler, Example 6-1, Example 6-2 and Example 6-3 were obtained.
  • microcrystalline cellulose was replaced with lactose (Example 6-1), pregelatinized starch (Example 6-2) or mannitol (Example 6-3), and the resulting prescription pressure
  • lactose Example 6-1
  • pregelatinized starch Example 6-2
  • mannitol Example 6-3
  • Example 7-1 a combination of two fillers was used to obtain Example 7-1, Example 7-2 and Example 7-3.
  • Results A single filler (microcrystalline cellulose) was replaced with a combination of two fillers.
  • the tableting process of the obtained prescription was smooth, the content and dissolution were both qualified, and the prescription was qualified.
  • Example 8-1 the dosage of the active ingredient (API) was adjusted to obtain Example 8-1, Example 8-2 and Example 8-3.
  • Example 9-1 Example 9-2, Example 9-3 and Example 9-4.
  • Example 10-2 On the basis of the prescription of Example 10-1, when no lubricant is used (Example 10-2), the obtained prescription is qualified; on the basis of the prescription of Example 10-2, when the proportion of glidant is further reduced (implementation Example 10-3), the obtained prescription is also qualified; on the basis of the prescription of Example 10-3, no glidant is added (Example 10-4), the obtained prescription is qualified.
  • Example 10-1 Referring to the prescriptions of Example 10-1, Example 10-2 and Example 10-4 and the preparation method of Example 10-1, change the active ingredient The dosage was used to obtain Example 11-1 to Example 11-9 respectively.
  • Test Example 6 Compatibility test of active ingredients and excipients
  • the oral preparations obtained in each example were packaged in aluminum-aluminum blister packs, and stability tests were conducted (30°C ⁇ 2°C/65% RH ⁇ 5% RH).
  • the stability results of the exemplary embodiments are shown in the table below.

Abstract

本发明涉及多靶点蛋白激酶抑制剂的药物组合物及其用途及制备方法。所述药物组合物包含作为活性成分的式2所示化合物和赋形剂。该药物组合物可用于制备药物，特别是治疗蛋白激酶介导的疾病的药物，由药物组合物制成的口服制剂的各项指标均符合制剂标准且稳定性良好，适合于规模化生产。

Description

多靶点蛋白激酶抑制剂的药物组合物及其用途和制备方法 技术领域
本发明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用途和制备方法。
背景技术
蛋白酪氨酸激酶(Protein tyrosine kinases,PTKs)作为蛋白激酶家族中非常重要的一员，PTKs将三磷酸腺苷上的γ-磷酸基转移到底物的蛋白酪氨酸残基上，通过将酚羟基磷酸化来完成细胞间的信息传递，在细胞发育、调节和肿瘤细胞的分化、迁移、凋亡等过程中起着至关重要的作用。若PTKs在调节过程中失控将会影响其下游信号通路的正确激活，进而引起细胞增殖调节功能紊乱而引发许多疾病，如酪氨酸激酶活性过高使受体磷酸化进而激活下游信号，导致细胞过度转化、增殖、对抗细胞凋亡、促进细胞生存进而形成恶性肿瘤。
表皮生长因子受体(Epidermal Growth Factor Receptor,EGFR)、成纤维生长因子受体(Fibroblast Growth Factor Receptors,FGFRs)、血小板源生长因子受体(Platelet-derived Growth Factor Receptor,PDGFR)、RET(Rearranged during Transfection)原癌基因编码的RET蛋白等就是PTKs的重要成员，是肿瘤治疗的重要靶标。
EGFR包括EGFR(ErbB-1)、2型人表皮生长因子受体HER-2(ErbB-2)、3型人表皮生长因子受体HER3(ErbB-3)及4型人表皮生长因子受体HER4(ErbB-4)，其中，EGFR和HER-2是EGFR家族成员中与肿瘤关系最为密切的靶点。研究表明，EGFR在多种肿瘤如肺癌、胃癌、表皮样癌、肾癌、卵巢癌等中表现出过度表达、基因突变或基因融合。
FGFR主要包括FGFR1/2/3/4四种亚型，它们通过基因扩增、突变、融合或配体诱导等方式过度表达或过度激活，对肿瘤细胞增殖、侵袭和迁移及肿瘤血管的生成具有重要作用。研究发现，FGFRs在多种肿瘤如肺癌、胃癌、胆道癌(例如，肝内胆管癌)、结直肠癌、肝癌等中均表现出突变、过度表达或过度激活。
RET的正常生理功能包含肾发育、神经***的发育、***干细胞的维持更新、髓单核细胞分化、淋巴组织的形成等，在人肠神经节细胞、神经母细胞瘤、嗜铬细胞瘤、甲状腺髓样癌、甲状腺C细胞和黑色素瘤等细胞中表达。近年来，通过对RET深入研究，发现在肿瘤中RET的过度激活对多种肿瘤的增殖、存活、侵袭、转移及肿瘤炎症等均有显著促进作用，RET在甲状腺癌(例如，甲状腺髓样癌、***状甲状腺癌)、肺癌(例如，非小细胞肺癌)、结直肠癌、胰腺癌、黑色素瘤等中均表现出过度表达。
肿瘤常与多条信号转导通路、多个靶点调节失衡相关，单靶点药物***不一定能达到预期治疗效果，且其应用也受限于药物毒副作用和耐药性，因此，多靶点药物成为新的药物研究方向。相比单靶点药物，多靶点药物可以作用于肿瘤相关的多个靶点，即使其针对单一靶点的活性相比于单靶点药物可能有所降低，但可能受益于多靶点调节所产生的协同作用，使总效应可能大于单个效应的总和，从而获得更好的疗效和产生更小的不良反应。
CN106660970B公开了如式1所示的化合物(实施例22)，其是一种具有抑制RET、KDR、EGFR、FGFR1、FLT-1等蛋白酪氨酸激酶活性的多靶点抑制剂。
发明内容
目前尚未有化合物1及其药学上可接受的盐的药物组合物的相关研究报道。
发明人在化合物1的基础上，进一步发现了成药性较化合物1更好的化合物1的二盐酸盐(如式2所示)，所述二盐酸盐不仅溶解性能显著优于化合物1，而且综合指标考察，该二盐酸盐比化合物1的其他盐型更适合用于制备药物，并可根据临床用药需要，制成多种药物剂型。相应的研究和筛选过程已记载在PCT/CN2021/120328专利申请中，该申请的全部内容作为整体被引入本申请。
本申请所要解决的技术问题是提供一种符合制剂要求且满足口服给药需要的、包含作为活性成分的式2所示化合物的药物组合物。
【技术方案】
在探索合乎需要的包含式2所示化合物的药物组合物和/或口服制剂的持续研究过程中，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。
第一方面，本申请提供了一种适于口服的药物组合物，其包含：作为活性成分的式2所示化合物和赋形剂，
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填充剂(或称稀释剂)、崩解剂、润滑辅料(润滑剂、助流剂、抗粘着剂)、粘合剂、稳定剂、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(包含增塑剂、遮光剂、色素等)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。所述赋形剂也可分为离子型赋形剂和非离子型赋形剂，所述的“非离子型赋形剂”，是指不含金属离子的赋形剂，例如，非离子型赋形剂包括非离子型填 充剂、非离子型润滑剂、非离子型崩解剂、非离子型助流剂等；其中，例如非离子型填充剂包括微晶纤维素、预胶化淀粉、乳糖、甘露醇、淀粉等，非离子型润滑剂包括硬脂酸、氢化植物油等，非离子型崩解剂包括交联聚维酮、低取代羟丙纤维素等，非离子型助流剂包括胶态二氧化硅；所述的“离子型赋形剂”，是指包含金属离子的赋形剂，离子型赋形剂包括离子型填充剂、离子型润滑剂、离子型崩解剂等，其中，例如离子型填充剂包括磷酸氢钙、碳酸钙等，离子型润滑剂包括硬脂酸镁、硬脂富马酸钠、硬脂酸钙、硬脂酸锌等。
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。
在一些实施方案中，所述药物组合物制成口服制剂。优选地，所述口服制剂为口服固体制剂。
在一些实施方案中，根据中国药典2020年版四部中记载的桨法，在用水作为试验介质且桨速度为50rpm的条件下，所述药物组合物或口服制剂在溶出试验中溶解85％的时间不超过60分钟。
在一些实施方案中，所述药物组合物或口服制剂在溶出试验中溶解85％的时间不超过55分钟；优选为50分钟；更优选为45分钟。
在一些实施方案中，所述药物组合物或口服制剂经过含量测定，活性成分的含量为100％±10％；优选为100％±5％；更优选为100％±3％。
在一些实施方案中，所述赋形剂包含崩解剂，所述崩解剂为非离子型崩解剂。优选地，所述赋形剂进一步包含非离子型赋形剂，任选地，进一步包含离子型赋形剂。
在一些实施方案中，所述赋形剂包含崩解剂和填充剂，所述崩解剂为非离子型崩解剂，任选地，所述赋形剂进一步包含助流剂和/或润滑剂。
在一些实施方案中，所述非离子型崩解剂包含干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉、低取代羟丙纤维素或交联聚维酮中的一种或多种；优选地，所述非离子型崩解剂包含交联聚维酮，任选地，进一步包含另一种非离子型崩解剂，所述另一种非离子型崩解剂选自干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉或低取代羟丙纤维素。
优选地，所述崩解剂在所述药物组合物中的重量百分比为5％～40％；优选为7％～40％；优选为8％～35％；进一步优选为8％～40％；进一步优选为10％～40％；进一步优选为8％～30％；进一步优选为8％～25％；进一步优选为8％～20％；进一步优选为8％～15％；进一步优选为10％～15％。
在一些实施方案中，所述赋形剂包含非离子型崩解剂和非离子型填充剂，任选地，进一步包含非离子型助流剂、离子型填充剂和/或离子型润滑剂。
在一些实施方案中，所述赋形剂包含非离子型崩解剂和非离子型填充剂，任选地，进一步包含非离子型润滑剂、非离子型助流剂、离子型填充剂和/或离子型润滑剂。
在一些实施方案中，所述赋形剂包含非离子型崩解剂、非离子型填充剂和非离子型助流剂，任选地，进一步包含非离子型润滑剂、离子型填充剂和/或离子型润滑剂。
在一些实施方案中，所述式2所示化合物为结晶形式。
在一些实施方案中，所述式2所示化合物的结晶形式(晶型I)，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰(±0.2°)：12.4、18.8、20.3、24.6。
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰(±0.2°)：9.8、12.4、18.8、20.3、24.6。
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰(±0.2°)：8.1、9.8、12.4、18.8、20.3、24.6、29.9。
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰(±0.2°)：8.1、9.8、12.4、18.8、19.3、20.3、24.6、28.6、29.9。
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰(±0.2°)：8.1、9.8、12.4、16.1、18.8、19.3、20.3、24.6、28.6、29.9、30.9。
或者，使用Cu-Kα辐射，具有基本上如图1或图2所示的X-射线粉末衍射图谱。
在一些实施方案中，式2所示化合物的结晶形式(晶型I)，其DSC曲线在231.0±5℃和284.2±5℃处分别有吸热峰。
在一些实施方案中，式2所示化合物的结晶形式(晶型I)，其TGA曲线在205.6±5℃处开始发生分解。
在一些实施方案中，在所述药物组合物中，所述活性成分(式2所示化合物)，其重量百分比为0.5％～80％；或者1％～75％；或者5％～70％；或者10％～70％；或者15％～70％；或者16％～68％；或者16％～67％；或者20％～70％；或者20％～67％；或者5％～65％；或者5％～60％；或者5％～55％；或者5％～50％；或者10％～55％；或者10％～50％；或者15％～55％；或者15％～50％；或者15％～45％；或者20％～50％；或者20％～45％；或者20％～40％。
在一些实施方案中，在所述药物组合物中，所述非离子型崩解剂在所述药物组合物中的重量百分比为8％～40％；优选为8％～30％；优选为10％～40％；优选为10％～35％；优选为10％～30％；优选为15％～40％；优选为15％～30％；优选为20％～30％；优选为20％～40％；优选为25％～40％；优选为30％～40％。
在一些实施方案中，在所述药物组合物中，所述填充剂在所述药物组合物中的重量百分比为：10％～85％；或10％～80％；或15％～75％；或17％～68％；或15％～70％；或15％～65％；或20％～65％；或30％～65％；或30％～60％；或30％～55％；或30％～50％；或35％～50％；或40％～55％。
在一些实施方案中，在所述药物组合物中，润滑剂在所述药物组合物中的重量百分比为：0％～6％；或0％～5％；或0％～4％；或0％～3.5％；或0％～3％；或0％～2.5％；或0％～2％；或0％～1.5％；或0％～1％；或者，
润滑剂在所述药物组合物中的重量百分比为：1％～6％；或1％～5％；或1.5％～5％；或1％～4％；或1.5％～4％；或1％～3.5％；或1.5％～3.5％；或1％～3％；或1％～2％；或1.5％～3％；或2％～3.5％。
在一些实施方案中，在所述药物组合物中，
在一些实施方案中，所述药物组合物包含润滑剂，并且其中所述润滑剂为非离子型润滑剂，其中，所述非离子型润滑剂在所述药物组合物中的重量百分比为1％～6％，优选为1％～5％，优选为1％～4％，进一步优选为1％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％。
在一些实施方案中，所述药物组合物包含润滑剂，并且其中所述润滑剂同时包含非离子型润滑剂和离子型润滑剂，其中，所述非离子型润滑剂在所述药物组合物中的重量百分比为1％～4％，优选为1％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％；并且
(i)所述活性成分在所述药物组合物中的重量百分比≥40％(例如，40％～70％，40％～68％)，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为≤0.5％；或者
(ii)所述活性成分在所述药物组合物中的重量百分比小于40％(例如，15％≤活性成分重量百分比 ＜40％，16％≤活性成分重量百分比＜40％，16％～35％，16％～34％)，所述离子型润滑剂在药物组合物中的重量百分比≤2％，优选为≤1.5％，优选为≤1％，优选为≤0.8％，进一步优选为≤0.7％，进一步优选为≤0.6％，更进一步优选为≤0.5％。
在一些实施方案中，所述药物组合物包含润滑剂，并且其中所述润滑剂为离子型润滑剂，所述活性成分在所述药物组合物中的重量百分比＜40％(优选≤35％；优选≤34％，例如15％～35％，15％～34％，20％～34％，20％～35％，20％～33.5％)，所述离子型润滑剂在所述药物组合物中的重量百分比为1％～3％；优选为1％～2.5％，优选为1％～2％，优选为1％～1.5％。
在一些实施方案中，助流剂在所述药物组合物中的重量百分比为：0％～8％；或0％～7％；或0％～6％；或0％～5.5％；或0％～5％；或0％～4％；或0％～3％；或0％～2％；或0％～1.5％；或0％～1％；或0％～0.5％；或者，
助流剂在所述药物组合物中的重量百分比为3％～8％；或3％～7％；或3％～6％；或3％～5.5％；或3％～5％；或3.5％～7％；或4％～7％；或4.5％～7％；或5％～7％；或4％～7％；或4％～6％。
在一些实施方案中，所述非离子型崩解剂选自干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉、低取代羟丙纤维素或交联聚维酮中的一种或多种；
优选地，所述非离子型崩解剂选自干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉、低取代羟丙纤维素或交联聚维酮中的一种，或者交联聚维酮与干淀粉、微晶纤维素、聚乙烯吡咯烷酮、玉米淀粉、预胶化淀粉或低取代羟丙纤维素中的一种或多种的组合；
更优选地，所述非离子型崩解剂选自交联聚维酮、交联聚维酮和低取代羟丙纤维素的组合。
在一些实施方案中，所述填充剂包含非离子型填充剂，任选地，进一步包含离子型填充剂；
优选地，所述非离子型填充剂选自淀粉、微晶纤维素、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
进一步优选地，所述非离子型填充剂选自微晶纤维素、或预胶化淀粉、甘露醇或乳糖中的一种；或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合、或微晶纤维素与糊精的组合、或微晶纤维素与糖粉的组合、或微晶纤维素与蔗糖的组合。
在一些实施方案中，所述药物组合物包含润滑剂，当所述润滑剂包含非离子型润滑剂时，所述非离子型润滑剂选自硬脂酸、棕榈酸、棕榈酸硬脂酸甘油酯、山嵛酸甘油酯、氢化植物油、滑石粉或聚乙二醇类中的一种或多种；优选为硬脂酸；和/或
当所述润滑剂包含离子型润滑剂时，所述离子型润滑剂选自硬脂酸镁、硬脂酸钙、苯甲酸钠、月桂基硫酸钠、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、月桂醇硫酸镁、十二烷基硫酸钠或十二烷基硫酸镁中的一种或多种；优选为硬脂酸镁或硬脂富马酸钠；更优选为硬脂酸镁。
在一些实施方案中，所述药物组合物包含助流剂，并且其中所述助流剂为非离子型助流剂；优选地，所述非离子型助流剂选自胶态二氧化硅。
在一些实施方案中，所述赋形剂包含填充剂、崩解剂、润滑剂和助流剂，其中，所述崩解剂为非离子型崩解剂，所述润滑剂包含非离子型润滑剂，任选地，进一步包含离子型润滑剂。
在一些实施方案中，所述赋形剂包含填充剂、崩解剂、润滑剂和助流剂，其中，所述崩解剂为非离子型崩解剂，所述润滑剂为离子型润滑剂，所述填充剂包含非离子型填充剂，所述助流剂为非离子型助流剂。
第二方面，本申请提供了适于口服的药物组合物，其包含作为活性成分的如式2所示化合物、填充 剂、崩解剂、润滑剂和助流剂，其中，所述崩解剂为非离子型崩解剂，
在一些实施方案中，所述式2所示化合物的定义如前文第一方面所述。
在一些实施方案中，当所述润滑剂为非离子型润滑剂时，其中，所述非离子型润滑剂在所述药物组合物中的重量百分比为1％～6％，优选为1％～5％，优选为1％～4％，进一步优选为1％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％。
在一些实施方案中，当所述润滑剂同时包含非离子型润滑剂和离子型润滑剂时，其中，所述非离子型润滑剂在所述药物组合物中的重量百分比为1％～4％，优选为1％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％；当活性成分在所述药物组合物中的重量百分比≥40％时(例如，40％～70％，40％～68％)，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为≤0.5％。
在一些实施方案中，所述润滑剂包含非离子型润滑剂，任选地，进一步包含离子型润滑剂；优选地，当包含离子型润滑剂，且活性成分在所述药物组合物中的重量百分比≥40％时(例如，40％～70％，40％～68％)，所述离子型润滑剂在药物组合物中的重量百分比小于1％，优选为≤0.8％，进一步优选为≤0.7％，进一步优选为≤0.6％，更进一步优选为≤0.5％。
在一些实施方案中，所述润滑剂包含非离子型润滑剂，任选地，进一步包含离子型润滑剂；优选地，当包含离子型润滑剂，且活性成分在所述药物组合物中的重量百分比＜40％时(例如，15％≤活性成分重量百分比＜40％，16％≤活性成分重量百分比＜40％，16％～35％，16％～34％)，所述离子型润滑剂在药物组合物中的重量百分比≤2％，优选为≤1.5％，优选为≤1％，优选为≤0.8％，进一步优选为≤0.7％，进一步优选为≤0.6％，更进一步优选为≤0.5％。
在一些实施方案中，所述润滑剂包含非离子型润滑剂，任选地，进一步包含离子型润滑剂；优选地，当包含离子型润滑剂时，所述离子型润滑剂在药物组合物中的重量百分比小于1％，进一步优选为≤0.8％，进一步优选为≤0.7％，进一步优选为≤0.6％，更进一步优选为≤0.5％，更进一步优选为0％～0.5％。
在一些实施方案中，所述填充剂包含非离子型填充剂，任选地，进一步包含离子型填充剂；优选地，所述填充剂为非离子型填充剂。
在一些实施方案中，所述非离子型填充剂包含微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种或多种。
在一些实施方案中，所述非离子型填充剂包含微晶纤维素，任选地，进一步包含淀粉、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含预胶化淀粉，任选地，进一步包含微晶纤维素、淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含乳糖，任选地，进一步包含微晶纤维素、预胶化淀粉、淀粉、甘露醇、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含甘露醇，任选地，进一步包含微晶纤维素、预胶化淀粉、乳糖、淀粉、木糖醇、糊精、糖粉或蔗糖中的一种或多种。
在一些实施方案中，所述非离子型填充剂选自淀粉、微晶纤维素、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种，或者所述非离子型填充剂为两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、或微晶纤维素与预胶化淀粉的组合、或微晶纤维素与乳糖的组合、或微晶纤维素与甘露醇的组合、或预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合、或微晶纤维素与糊精的组合、或微晶纤维素与糖粉的组合、或微晶纤维素与蔗糖的组合；进一步优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种，或微晶纤维素与淀粉的组合、或微晶纤维素与预胶化淀粉的组合、或微晶纤维素与乳糖的组合、或微晶纤维素与甘露醇的组合、或预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合。
在一些实施方案中，当所用非离子型填充剂为两种非离子型填充剂的组合时，所述两种非离子型填充剂的组合中，两种填充剂的重量比为1:10～10:1；或者1:9～9:1；或者1:8～8:1；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。
在一些实施方案中，所述离子型填充剂选自硫酸钙、磷酸氢钙或磷酸钙中的一种或多种。
在一些实施方案中，所述离子型填充剂在所述药物组合物中的重量百分比为：0％～20％；或0％～15％；或0％～10％；或0％～9％；或0％～8％；或0％～7％；或0％～6％；或0％～5％；或0％～4％；或0％～3％。
在一些实施方案中，当所用填充剂包含离子型填充剂时，所述非离子型填充剂和离子型填充剂的重量比为1000～1：1；或者900～1：1；800～1：1；或者700～1：1；或者600～1:1；或者500～1:1；或者300～1:1，或者200～1:1；或者100～1:1；或者50～1:1；或者20～1:1；或者10～1:1。
在一些实施方案中，所述填充剂在所述药物组合物中的重量百分比为：10％～85％；或10％～80％；或15％～75％；或17％～68％；或15％～70％；或15％～65％；或20％～65％；或30％～65％；或30％～60％；或30％～55％；或30％～50％；或35％～50％；或40％～55％。
在一些实施方案中，所述非离子型崩解剂包含交联聚维酮，任选地，进一步包含另一种非离子型崩解剂，所述另一种非离子型崩解剂选自干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉或低取代羟丙纤维素。优选地，所述交联聚维酮在所述药物组合物中的重量百分比为5％～20％，进一步优选为5％～18％；进一步优选为7％～18％，进一步优选为8％～15％，进一步优选为5％～15％，进一步优选为10％～15％。所述另一种非离子型崩解剂在所述药物组合物中的重量百分比为0％～20％，优选为5％～20％，优选为5％～10％，优选为0％～10％，优选为10％～20％。
在一些实施方案中，所述非离子型崩解剂选自干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉、低取代羟丙纤维素或交联聚维酮中的一种或多种；优选地，所述非离子型崩解剂选自干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉、低取代羟丙纤维素或交联聚维酮中的一种，或者交联聚维酮与干淀粉、微晶纤维素、聚乙烯吡咯烷酮、玉米淀粉、预胶化淀粉或低取代羟丙纤维素中的一种或多种的组合；优选为交联聚维酮、交联聚维酮和低取代羟丙纤维素的组合。
优选地，所述交联聚维酮在所述药物组合物中的重量百分比为5％～20％；进一步优选为7％～18％；进一步优选为8％～15％；进一步优选为5％～15％；进一步优选为10％～15％。
在一些实施方案中，所述崩解剂在所述药物组合物中的重量百分比为：5％～35％；或5％～30％；或5％～25％；或6％～25％；或7％～20％；或5％～20％；或8％～20％；或8％～18％；或8％～15％；或10％～15％。
在一些实施方案中，所述润滑剂包含非离子型润滑剂，任选地，进一步包含离子型润滑剂。
在一些实施方案中，所述非离子型润滑剂选自硬脂酸、棕榈酸、棕榈酸硬脂酸甘油酯、山嵛酸甘油酯、氢化植物油、滑石粉或聚乙二醇类中的一种或多种；优选为硬脂酸。
在一些实施方案中，所述非离子型润滑剂包含硬脂酸，任选地，进一步包含棕榈酸、棕榈酸硬脂酸 甘油酯、氢化植物油、滑石粉、山嵛酸甘油酯或聚乙二醇类中的一种或多种。
在一些实施方案中，所述离子型润滑剂选自硬脂酸镁、硬脂酸钙、苯甲酸钠、月桂基硫酸钠、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、月桂醇硫酸镁、十二烷基硫酸钠或十二烷基硫酸镁中的一种或多种；优选为硬脂酸镁或硬脂富马酸钠；更优选为硬脂酸镁。
在一些实施方案中，所述润滑剂包含硬脂酸，任选地，进一步包含另一种润滑剂(即硬脂酸与另一种润滑剂的组合)，所述另一种润滑剂选自硬脂酸镁、硬脂酸钙、棕榈酸、棕榈酸硬脂酸甘油酯、山嵛酸甘油酯、苯甲酸钠、月桂基硫酸钠、氢化植物油、滑石粉、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、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。优选地，所述另一种润滑剂为硬脂酸镁、硬脂富马酸钠或氢化植物油；更优选为硬脂酸镁。
在一些优选的实施方案中，所述润滑剂选自硬脂酸、硬脂酸与硬脂酸镁的组合、硬脂酸与硬脂富马酸钠的组合、或硬脂酸与氢化植物油的组合；更优选为硬脂酸、或硬脂酸与硬脂酸镁的组合。
在一些优选的实施方案中，所述硬脂酸在所述药物组合物中的重量百分比为1％～4％；进一步优选为1％～3.5％；进一步优选为1％～3％；进一步优选为1％～2％。优选地，当所述另一种润滑剂为离子型润滑剂(例如，硬脂酸镁、硬脂酸钙、苯甲酸钠、月桂基硫酸钠、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、月桂醇硫酸镁、十二烷基硫酸钠或十二烷基硫酸镁；优选为硬脂酸镁或硬脂富马酸钠)，且活性成分在所述药物组合物中的重量百分比≥40％时(例如40％～70％，40％～68％)，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为≤0.5％。
在一些优选的实施方案中，所述硬脂酸在所述药物组合物中的重量百分比为1％～4％；进一步优选为1％～3.5％；进一步优选为1％～3％；进一步优选为1％～2％。优选地，当所述另一种润滑剂为离子型润滑剂(例如，硬脂酸镁、硬脂酸钙、苯甲酸钠、月桂基硫酸钠、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、月桂醇硫酸镁、十二烷基硫酸钠或十二烷基硫酸镁；优选为硬脂酸镁或硬脂富马酸钠)，且活性成分在所述药物组合物中的重量百分比＜40％时(例如，15％≤活性成分重量百分比＜40％，16％≤活性成分重量百分比＜40％，16％～35％，16％～34％)，所述离子型润滑剂在所述药物组合物中的重量百分比≤2％，优选为≤1.5％，优选为≤1％，优选为≤0.8％，进一步优选为≤0.7％，进一步优选为≤0.6％，更进一步优选为≤0.5％。
在一些优选的实施方案中，所述硬脂酸在所述药物组合物中的重量百分比为1％～4％；进一步优选为1％～3.5％；进一步优选为1％～3％；进一步优选为1％～2％。优选地，当所述另一种润滑剂为非离子型润滑剂(例如，棕榈酸、棕榈酸硬脂酸甘油酯、山嵛酸甘油酯、氢化植物油、滑石粉或聚乙二醇类，优选为氢化植物油)时，所述非离子型润滑剂在药物组合物中的重量百分比≤4％；优选为≤3.5％；优选为≤3％；优选为≤2.5％；优选为≤2％；优选为≤1.5％；优选为≤1％；优选为≤0.5％。
在一些优选的实施方案中，所述硬脂酸在所述药物组合物中的重量百分比为1％～4％；进一步优选为1％～3.5％；进一步优选为1％～3％；进一步优选为1％～2％。优选地，所述另一种润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％，优选为≤0.5％。
在一些实施方案中，所述硬脂酸与另一种润滑剂的组合中，硬脂酸与另一种润滑剂的重量比为1～3：3～1；优选为1～2：2～1；优选为2～10：1；优选为2～5：1；优选为2～3：1；优选为2：1、1：2、1：1；优选为2：1。
在一些实施方案中，所述润滑剂在所述药物组合物中的重量百分比为：1％～6％；或1％～5％；或1.5％～5％；或1％～4％；或1.5％～4％；或1％～3.5％；或1.5％～3.5％；或1％～3％；或1％～2％；或1.5％～3％；或2％～3.5％。
在一些实施方案中，所述助流剂为非离子型助流剂；优选地，所述助流剂在所述药物组合物中的重量百分比为3％～8％；或3％～7％；或3％～6％；或3％～5.5％；或3％～5％；或3.5％～7％；或4％～7％；或4.5％～7％；或5％～7％；或4％～7％；或4％～6％。
在一些实施方案中，所述助流剂为非离子型助流剂；优选地，所述非离子型助流剂选自胶态二氧化硅。优选地，所述胶态二氧化硅在所述药物组合物中的重量百分比为：3％～8％；或3％～7％；或3％～6％；或3％～5.5％；或3％～5％；或3.5％～7％；或4％～7％；或4.5％～7％；或5％～7％；或4％～7％；或4％～6％。
在一些实施方案中，在所述药物组合物中，所述填充剂包含非离子型填充剂；所述崩解剂为非离子型崩解剂；所述助流剂为非离子型助流剂；所述润滑剂包含非离子型润滑剂，任选地，进一步包含离子型润滑剂；
所述非离子型填充剂、非离子型崩解剂、非离子型润滑剂、离子型润滑剂及非离子型助流剂定义如前所述。
优选地，所述非离子型润滑剂在所述药物组合物中的重量百分比为1％～4％，优选为1％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％；离子型润滑剂在所述药物组合物中的重量百分比不高于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％，优选为≤0.5％。
在一些实施方案中，在所述药物组合物中，
所述填充剂包含非离子型填充剂，任选地，进一步包含离子型填充剂；
所述润滑剂包含硬脂酸，任选地，进一步包含另一种润滑剂，所述另一种润滑剂选自硬脂酸镁、硬脂酸钙、棕榈酸、棕榈酸硬脂酸甘油酯、山嵛酸甘油酯、苯甲酸钠、月桂基硫酸钠、氢化植物油、滑石粉、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、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；其中，所述硬脂酸在所述药物组合物中的重量百分比为1％～4％，优选为1％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％；所述另一种润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％，优选为≤0.5％；优选地，当所述另一种润滑剂为离子型润滑剂时，且活性成分在所述药物组合物中的重量百分比为≥40％时(例如40％～70％，40％～68％)，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为≤0.5％；
所述崩解剂为非离子型崩解剂，所述非离子型崩解剂选自干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉、低取代羟丙纤维素或交联聚维酮中的一种，或者交联聚维酮与干淀粉、微晶纤维素、玉米淀粉、粉状纤维素、预胶化淀粉或低取代羟丙纤维素中的一种或多种的组合；其中，所述崩解剂在所述药物组合物中的重量百分比为5％～35％，优选为7％～30％，优选为8％～30％，优选为8％～20％，优选为8％～18％，优选为8％～15％，优选为10％～30％，优选为10％～20％，优选为10％～15％；
所述助流剂为胶态二氧化硅；
所述非离子型填充剂或所述离子型填充剂定义如前所述。
优选地，所述助流剂在所述药物组合物中的重量百分比为3％～8％；或3％～7％；或3％～6％；或3％～5.5％；或3％～5％；或3.5％～7％；或4％～7％；或4.5％～7％；或5％～7％；或4％～7％；或4％～6％。
优选地，所述非离子型填充剂包含微晶纤维素，任选地，进一步包含淀粉、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含预胶化淀粉，任选地，进一步包含微晶纤维素、淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含乳糖，任选地，进一步包含微晶纤维素、预胶化淀粉、淀粉、甘露醇、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含甘露醇，任选地，进一步包含微晶纤维素、预胶化淀粉、乳糖、淀粉、木糖醇、糊精、糖粉或蔗糖中的一种或多种。
优选地，所述非离子型填充剂包含微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种或多种；进一步优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种，或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合。
优选地，当所用非离子型填充剂为两种非离子型填充剂的组合时，两种非离子型填充剂的重量比为1:10～10:1；或者1:9～9:1；或者1:8～8:1；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。
优选地，当所用填充剂包含离子型填充剂时，所述非离子型填充剂和离子型填充剂的重量比为1000～1:1；或者900～1:1；800～1:1；或者700～1:1；或者600～1:1；或者500～1:1；或者300～1:1，或者200～1:1；或者100～1:1；或者50～1:1；或者20～1:1；或者10～1:1。
在一些实施方案中，在所述药物组合物中，
所述填充剂包含非离子型填充剂，任选地，进一步包含离子型填充剂；
所述润滑剂选自硬脂酸、硬脂酸和硬脂酸镁的组合、硬脂酸和硬脂酸钙的组合、或硬脂酸和硬脂酸锌的组合、或硬脂酸和硬脂富马酸钠的组合、或硬脂酸和氢化植物油的组合；其中，所述硬脂酸在所述药物组合物中的重量百分比为1％～4％，优选为1％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％；所述硬脂酸镁、硬脂酸钙、硬脂富马酸钠或硬脂酸锌在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％，优选为≤0.5％；优选地，当活性成分在所述药物组合物中的重量百分比为≥40％时(例如40％～70％，40％～68％)，所述硬脂酸镁、硬脂酸钙、硬脂富马酸钠或硬脂酸锌在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为≤0.5％；
所述崩解剂选自干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉、低取代羟丙纤维素或交联聚维酮中的一种，或者交联聚维酮与干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉或低取代羟丙纤维素中的一种或多种的组合；其中，所述崩解剂在所述药物组合物中的重量百分比为5％～35％，优选为7％～30％，优选为8％～30％，优选为8％～20％，优选为8％～18％，优选为8％～15％，优选为10％～30％，优选为10％～20％，优选为10％～15％；
所述助流剂为胶态二氧化硅。
优选地，所述硬脂酸和氢化植物油的组合中，所述氢化植物油在所述药物组合物中的重量百分比为0.5％～4％，优选为0.5％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％。
优选地，所述助流剂在所述药物组合物中的重量百分比为3％～8％；或3％～7％；或3％～6％；或3％～5.5％；或3％～5％；或3.5％～7％；或4％～7％；或4.5％～7％；或5％～7％；或4％～7％；或4％～6％。
优选地，所述非离子型填充剂包含微晶纤维素，任选地，进一步包含淀粉、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含预胶化淀粉，任选地，进一步包含微晶纤维素、淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含乳糖，任选地，进一步包含微晶纤维素、预胶化淀粉、淀粉、甘露醇、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含甘露醇，任选地，进一步包含微晶纤维素、预胶化淀粉、乳糖、淀粉、木糖醇、糊精、糖粉或蔗糖中的一种或多种。
优选地，所述非离子型填充剂包含微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种或多种；进一步优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种，或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合。
优选地，当所用非离子型填充剂为两种非离子型填充剂的组合时，两种非离子型填充剂的重量比为1:10～10:1；或者1:9～9:1；或者1:8～8:1；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。
在一些实施方案中，当所用填充剂包含离子型填充剂时，所述非离子型填充剂和离子型填充剂的重量比为1000～1:1；或者900～1：1；800～1:1；或者700～1:1；或者600～1:1；或者500～1:1；或者300～1:1，或者200～1:1；或者100～1:1；或者50～1:1；或者20～1:1；或者10～1:1。
在一些实施方案中，在所述药物组合物中，
所述填充剂包含非离子型填充剂，任选地，进一步包含离子型填充剂；
所述润滑剂包含硬脂酸，任选地，进一步包含另一种润滑剂，所述另一种润滑剂选自硬脂酸镁、硬脂酸钙、棕榈酸、棕榈酸硬脂酸甘油酯、山嵛酸甘油酯、苯甲酸钠、月桂基硫酸钠、氢化植物油、滑石粉、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、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；其中，所述硬脂酸在所述药物组合物中的重量百分比为1％～4％，优选为1％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％；所述另一种润滑剂在所述药物组合物中的重量百分比为小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％，优选为≤0.5％；优选地，当所述另一种润滑剂为离子型润滑剂(例如，硬脂酸镁、硬脂酸钙、苯甲酸钠、月桂基硫酸钠、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、月桂醇硫酸镁、十二烷基硫酸钠或十二烷基硫酸镁)时，且活性成分在所述药物组合物中的重量百分比为≥40％时(例如40％～70％，40％～68％)，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为≤0.5％；
所述崩解剂为非离子型崩解剂，所述非离子型崩解剂包含交联聚维酮，任选地，进一步包含另一种崩解剂，所述另一种崩解剂选自干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉或低取代羟丙纤维素；其中，所述交联聚维酮在所述药物组合物中的重量百分比为5％～20％，进一步优选为5％～15％；进一步优选为7％～15％；进一步优选为8％～15％；进一步优选为10％～15％；所述另一种崩解剂在所述药物组合物中的重量百分比为0％～20％，优选为5％～15％，优选为0％～15％，优选为0％～10％，优选为5％～10％，优选为10％～20％；
所述助流剂为胶态二氧化硅。
优选地，所述助流剂在所述药物组合物中的重量百分比为3％～8％；或3％～7％；或3％～6％；或3％～5.5％；或3％～5％；或3.5％～7％；或4％～7％；或4.5％～7％；或5％～7％；或4％～7％；或4％～6％。
优选地，所述非离子型填充剂包含微晶纤维素，任选地，进一步包含淀粉、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含预胶化淀粉，任选地，进一步包含微晶纤维素、淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含乳糖，任选地，进一步包含微晶纤维素、预胶化淀粉、淀粉、甘露醇、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含甘露醇，任选地，进一步包含微晶纤维素、预胶化淀粉、乳糖、淀粉、木糖醇、糊精、糖粉或蔗糖中的一种或多种。
优选地，所述非离子型填充剂包含微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种或多种；进一 步优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种，或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合。
优选地，当所用非离子型填充剂为两种非离子型填充剂的组合时，两种非离子型填充剂的重量比为1:10～10:1；或者1:9～9:1；或者1:8～8:1；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。
在一些实施方案中，当所用填充剂包含离子型填充剂时，所述非离子型填充剂和离子型填充剂的重量比为1000～1:1；或者900～1:1；800～1:1；或者700～1:1；或者600～1:1；或者500～1:1；或者300～1:1，或者200～1:1；或者100～1:1；或者50～1:1；或者20～1:1；或者10～1:1。
在一些实施方案中，在前述药物组合物中，
所述填充剂包含非离子型填充剂，任选地，进一步包含离子型填充剂；
所述润滑剂选自硬脂酸、硬脂酸和硬脂酸镁的组合、硬脂酸和硬脂酸钙的组合、或硬脂酸和硬脂酸锌的组合、或硬脂酸和硬脂富马酸钠的组合、或硬脂酸和氢化植物油的组合；其中，所述硬脂酸在所述药物组合物中的重量百分比为1％～4％，优选为1％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％；所述硬脂酸镁、硬脂酸钙、硬脂富马酸钠或硬脂酸锌在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％，优选为≤0.5％；优选地，当活性成分在所述药物组合物中的重量百分比为≥40％时(例如40％～70％，40％～68％)，所述硬脂酸镁、硬脂酸钙、硬脂富马酸钠或硬脂酸锌在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为≤0.5％；
所述崩解剂为非离子型崩解剂，所述非离子型崩解剂包含交联聚维酮，任选地，进一步包含另一种崩解剂，所述另一种崩解剂选自干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉或低取代羟丙纤维素；其中，所述交联聚维酮在所述药物组合物中的重量百分比为5％～20％，进一步优选为5％～15％；进一步优选为7％～15％；进一步优选为8％～15％；进一步优选为10％～15％；所述另一种崩解剂在所述药物组合物中的重量百分比为0％～20％，优选为5％～15％，优选为0％～15％，优选为0％～10％，优选为5％～10％，优选为10％～20％；
所述助流剂为胶态二氧化硅。
优选地，所述硬脂酸和氢化植物油的组合中，所述氢化植物油在所述药物组合物中的重量百分比为0.5％～4％，优选为0.5％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％。
优选地，所述助流剂在所述药物组合物中的重量百分比为3％～8％；或3％～7％；或3％～6％；或3％～5.5％；或3％～5％；或3.5％～7％；或4％～7％；或4.5％～7％；或5％～7％；或4％～7％；或4％～6％。
优选地，所述非离子型填充剂包含微晶纤维素，任选地，进一步包含淀粉、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含预胶化淀粉，任选地，进一步包含微晶纤维素、淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含乳糖，任选地，进一步包含微晶纤维素、预胶化淀粉、淀粉、甘露醇、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含甘露醇，任选地，进一步包含微晶纤维素、预胶化淀粉、乳糖、淀粉、木糖醇、糊精、糖粉或蔗糖中的一种或多种。
优选地，所述非离子型填充剂包含微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种或多种；进一步优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种，或者选自两种 非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合。
优选地，当所用非离子型填充剂为两种非离子型填充剂的组合时，两种非离子型填充剂的重量比为1:10～10:1；或者1:9～9:1；或者1:8～8:1；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。
在一些实施方案中，当所用填充剂包含离子型填充剂时，所述非离子型填充剂和离子型填充剂的重量比为1000～1:1；或者900～1:1；800～1:1；或者700～1:1；或者600～1:1；或者500～1:1；或者300～1:1，或者200～1:1；或者100～1:1；或者50～1:1；或者20～1:1；或者10～1:1。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：
活性成分：0.5％～80％；或者1％～75％；或者5％～70％；或者5％～65％；或者5％～60％；或者5％～55％；或者5％～50％；
填充剂：10％～85％；或10％～80％；或10％～75％；
崩解剂：5％～35％；或5％～30％；或5％～20％；或6％～25％；
润滑剂：1％～6％；或1％～5％；或1％～4％；或1％～3.5％；或1％～3％；
助流剂：3％～8％；或3％～7％；或3％～6％；或3％～5.5％；或3％～5％；
所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：
活性成分：10％～70％；或者15％～70％；或者10％～55％；或者10％～50％；或者15％～55％；或者15％～50％；或者15％～45％；
填充剂：15％～70％；或15％～65％；或15％～60％；
崩解剂：5％～35％；或5％～30％；或5％～20％；或7％～20％；或7％～30％；或7％～25％；
润滑剂：1％～6％；或1％～5％；或1.5％～5％；或1％～4％；或1.5％～4％；或1％～3.5％；或1.5％～3.5％；或1％～3％；或1.5％～3％；或1％～2％；
助流剂：3％～8％；或3％～7％；或3％～6％；或3％～5.5％；或3％～5％；或3.5％～6％；或3.5％～5.5％；或3.5％～5％；或4％～6％；或4.5％～6％；或5％～6％；
所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：
活性成分：16％～68％；或者16％～60％；或者20％～55％；或者20％～50％；或者20％～45％；或者20％～40％；
填充剂：15％～68％；或17％～68％；或15％～60％；或15％～55％；或17％～50％；
崩解剂：7％～20％；或8％～20％；或7％～18％；或8％～18％；或8％～15％；
润滑剂：1％～4％；或1.5％～4％；或1％～3.5％；或1.5％～3.5％；或1％～3％；或1.5％～3％；或1％～2％；
助流剂：3％～8％；或3％～7％；或3％～6％；或3％～5.5％；或3％～5％；或3.5％～6％；或3.5％～5.5％；或3.5％～5％；或4％～6％；或4.5％～6％；或5％～6％；
所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：5％～70％活性成分、10％～85％填充剂、5％～35％崩解剂、1％～4％润滑剂、3％～8％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：10％～70％活性成分、10％～70％填充剂、7％～30％崩解剂、1％～3.5％润滑剂、3％～7％助流剂；所述活性成分、填充剂、崩解剂、润滑剂 和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：15％～70％活性成分、15％～70％填充剂、7％～25％崩解剂、1％～3.5％润滑剂、3％～7％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：15％～70％活性成分、15％～70％填充剂、8％～20％崩解剂、1％～3％润滑剂、3％～7％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：16％～68％活性成分、17％～68％填充剂、8％～20％崩解剂、1％～3％润滑剂、3％～7％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：16％～68％活性成分、17％～68％填充剂、8％～15％崩解剂、1％～3％润滑剂、3％～7％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：15％～50％活性成分、30％～65％填充剂、8％～15％崩解剂、1％～3％润滑剂、3％～7％助流剂所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：15％～45％活性成分、30％～65％填充剂、8％～15％崩解剂、1％～3％润滑剂、3％～7％助流剂所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：15％～45％活性成分、30％～65％填充剂、8％～15％崩解剂、1％～3％润滑剂、3.5％～5％助流剂所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：15％～70％活性成分、15％～70％填充剂、8％～30％崩解剂、1％～3％润滑剂、3％～7％助流剂；
所述填充剂包含非离子型填充剂，任选地，进一步包含离子型填充剂；
所述崩解剂为非离子型崩解剂；优选地，所述非离子型崩解剂包含交联聚维酮；
所述润滑剂包含非离子型润滑剂，任选地，进一步包含离子型润滑剂；
所述助流剂为胶态二氧化硅；
其中，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％，优选为≤0.5％；优选地，当活性成分在所述药物组合物中的重量百分比为≥40％时(例如40％～70％，40％～68％)，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为≤0.5％；优选地，所述非离子型润滑剂包含硬脂酸；优选地，所述离子型润滑剂包含硬脂酸镁；
所述非离子型崩解剂、非离子型润滑剂、离子型润滑剂、非离子型填充剂和离子型填充剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：15％～70％活性成分、15％～70％填充剂、8％～20％崩解剂、1％～3％润滑剂、3％～7％助流剂；
所述填充剂包含非离子型填充剂，所述非离子型填充剂包含微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种或多种；优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种；或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化 淀粉与乳糖的组合；
所述崩解剂为非离子型崩解剂；优选地，所述非离子型崩解剂包含交联聚维酮；
所述润滑剂包含非离子型润滑剂，任选地，进一步包含离子型润滑剂；优选地，所述非离子型润滑剂包含硬脂酸；优选地，所述离子型润滑剂包含硬脂酸镁；
所述助流剂为胶态二氧化硅；
其中，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％，优选为≤0.5％；优选地，当活性成分在所述药物组合物中的重量百分比为≥40％时(例如40％～70％，40％～68％)，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为≤0.5％；
所述非离子型崩解剂、非离子型润滑剂、离子型润滑剂和非离子型填充剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：16％～68％活性成分、17％～68％填充剂、8％～20％崩解剂、1％～3％润滑剂、3％～7％助流剂；
所述填充剂包含非离子型填充剂，任选地，进一步包含离子型填充剂；
所述崩解剂为非离子型崩解剂；优选地，所述非离子型崩解剂包含交联聚维酮；
所述润滑剂包含非离子型润滑剂，任选地，进一步包含离子型润滑剂；优选地，所述非离子型润滑剂包含硬脂酸；优选地，所述离子型润滑剂包含硬脂酸镁；
所述助流剂为胶态二氧化硅；
其中，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％，优选为≤0.5％；优选地，当活性成分在所述药物组合物中的重量百分比为≥40％时(例如40％～70％，40％～68％)，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为≤0.5％；
所述非离子型崩解剂、非离子型润滑剂、离子型润滑剂、非离子型填充剂和离子型填充剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计：16％～68％活性成分、17％～68％填充剂、8％～15％崩解剂、1％～3％润滑剂、3％～7％助流剂；
所述填充剂包含非离子型填充剂，所述非离子型填充剂包含微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种或多种；优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种；或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合；
所述崩解剂为非离子型崩解剂，所述非离子型崩解剂包含交联聚维酮；
所述润滑剂包含非离子型润滑剂，任选地，进一步包含离子型润滑剂；优选地，所述非离子型润滑剂包含硬脂酸，所述离子型润滑剂包含硬脂酸镁；
所述助流剂为胶态二氧化硅；
其中，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％，优选为≤0.5％；优选地，当活性成分在所述药物组合物中的重量百分比为≥40％时(例如40％～70％，40％～68％)，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为≤0.5％；
所述非离子型崩解剂、非离子型润滑剂、离子型润滑剂和非离子型填充剂定义如前所述。
在一些实施方案中，如第一方面或第二方面所述的药物组合物制成口服制剂；优选地，所述口服制 剂为口服固体制剂；进一步优选地，所述口服固体制剂选自胶囊、片剂、散剂和细粒剂；进一步优选为胶囊和片剂；更进一步优选为片剂；更进一步优选地，所述片剂为包衣片剂；更进一步优选地，所述包衣片剂为薄膜包衣片剂。
在一些实施方案中，所述包衣片剂包含片芯和包衣材料，其中，所述片芯包含前述药物组合物。
本申请所述的“包衣材料”，也可以称为“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”也可称为“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。薄膜包衣材料包含成膜材料(或称成膜剂、高分子材料)、增塑剂、致孔剂、着色剂(或称色淀)、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。其中成膜材料可选自聚乙烯醇聚乙二醇共聚物、聚乙烯醇、羟丙甲纤维素、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和羟丙甲纤维素酞酸酯等中的一种或多种；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、辛酸葵酸单双甘油酯等；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红氧化铁、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，例如系列包衣粉、系列包衣粉、系列包衣粉、系列包衣粉、系列包衣粉等，也可自行配置。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，优选为胃溶性包衣材料。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％，更优选为2％～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，系列包衣粉型号有： 321A620034-CN、321A630026-CN、321A610052-CN等。
在一些实施方案中，所述包衣材料中包含成膜材料，所述成膜材料包含聚乙烯醇聚乙二醇共聚物；优选地，所述成膜材料选自聚乙烯醇聚乙二醇共聚物、或聚乙烯醇聚乙二醇共聚物和聚乙烯醇的组合。
第三方面，本申请提供了一种适于口服的药物组合物，其包含作为活性成分的式2所示化合物、填充剂、崩解剂、润滑剂和助流剂，其中，所述润滑剂为离子型润滑剂，所述崩解剂为非离子型崩解剂，所述填充剂包含非离子型填充剂，所述助流剂为非离子型助流剂，所述非离子型填充剂、非离子型助流剂、离子型润滑剂和非离子型崩解剂定义如前文第一方面和/或第二方面所述。
在一些实施方案中，所述式2所示化合物如前文第一方面所述。
在一些实施方案中，所述活性成分在所述药物组合物中的重量百分比＜40％(优选≤35％；优选≤34％，例如15％～35％，15％～34％，20％～34％，20％～35％，20％～33.5％)，所述离子型润滑剂在所述药物组合物中的重量百分比为1％～3％，优选为1％～2.5％，优选为1％～2％，优选为1％～1.5％；优选地，所述离子型润滑剂为硬脂酸镁或硬脂富马酸钠；进一步优选为硬脂酸镁。
在一些实施方案中，所述离子型润滑剂选自硬脂酸镁、硬脂酸钙、苯甲酸钠、月桂基硫酸钠、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、月桂醇硫酸镁、十二烷基硫酸钠或十二烷基硫酸镁中的一种或多种；优选为硬脂酸镁或硬脂富马酸钠；进一步优选为硬脂酸镁。
在一些实施方案中，所述非离子型崩解剂选自干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉、低取代羟丙纤维素或交联聚维酮中的一种或多种；优选为交联聚维酮和/或低取代羟丙纤维素。
在一些实施方案中，所述离子型润滑剂包含硬脂酸镁，所述非离子型崩解剂包含交联聚维酮或低取 代羟丙纤维素中一种或两种。
在一些实施方案中，所述离子型润滑剂为硬脂酸镁，所述非离子型崩解剂选自交联聚维酮或交联聚维酮和低取代羟丙纤维素的组合。
在一些实施方案中，所述活性成分在药物组合物中的重量百分比＜40％，优选≤35％；优选≤34％，例如15％～38％，15％～37％，15％～36％，15％～35％，15％～34％，16％～35％，18％～35％，16％～34％，18％～34％，20％～34％，20％～35％，20％～33.5％。
在一些实施方案中，所述离子型润滑剂在所述药物组合物中的重量百分比为1％～3％,优选为1％～2.5％，优选为1％～2％，优选为1％～1.5％。
在一些实施方案中，所述活性成分在药物组合物中的重量百分比＜40％，优选≤35％；优选≤34％，例如15％～38％，15％～37％，15％～36％，15％～35％，15％～34％，16％～35％，18％～35％，16％～34％，18％～34％，20％～34％，20％～35％，20％～33.5％；所述离子型润滑剂在所述药物组合物中的重量百分比为1％～3％，优选为1％～2.5％，优选为1％～2％，优选为1％～1.5％。
在一些实施方案中，所述非离子型崩解剂在所述药物组合物中的重量百分比为8％～40％；优选为10％～40％；优选为10％～35％；优选为10％～30％；优选为15％～40％；优选为15％～30％；优选为20％～30％；优选为20％～40％；优选为25％～40％；优选为30％～40％。
在一些实施方案中，所述填充剂包含非离子型填充剂，所述非离子型填充剂选自淀粉、微晶纤维素、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；优选地，所述非离子型填充剂包含微晶纤维素、乳糖、甘露醇或预胶化淀粉中的一种或多种；进一步优选地，所述非离子型填充剂选自微晶纤维素、乳糖、甘露醇、淀粉或预胶化淀粉中的一种；或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合；优选地，所述非离子型填充剂选自微晶纤维素。
在一些实施方案中，所述填充剂为非离子型填充剂；优选地，所述非离子型填充剂包含微晶纤维素、乳糖、甘露醇或预胶化淀粉中的一种或多种；进一步优选地，所述非离子型填充剂包含微晶纤维素，任选地，进一步包含淀粉、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含预胶化淀粉，任选地，进一步包含微晶纤维素、淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含乳糖，任选地，进一步包含微晶纤维素、预胶化淀粉、淀粉、甘露醇、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
或者，所述非离子型填充剂包含甘露醇，任选地，进一步包含微晶纤维素、预胶化淀粉、乳糖、淀粉、木糖醇、糊精、糖粉或蔗糖中的一种或多种。
在一些实施方案中，所述活性成分在所述药物组合物中的重量百分比为5％～45％；优选为5％～40％；优选为5％～35％；优选为5％～30％；优选为10％～40％；优选为10％～35％；优选为15％～35％；优选为10％～30％；优选为10％～27％；优选为10％～25％；优选为10％～20％；优选为10％～24％；优选为10％～23％；优选为10％～22％；优选为10％～21％；优选为15％～25％；优选为15％～20％；优选为20％～35％；优选为20％～30％；优选为15％～38％，优选为15％～37％，优选为15％～36％，优选为15％～35％，优选为15％～34％，优选为16％～35％，优选为18％～35％，优选为16％～34％，优选为18％～34％，优选为20％～34％，优选为20％～35％，优选为20％～33.5％。
在一些实施方案中，所述非离子型填充剂在在所述药物组合物中的重量百分比为25％～70％；优选为28％～60％；优选为28％～55％；优选为28％～50％；优选为30％～60％；优选为35％～55％；优选为 38％～55％；优选为25％～55％；优选为30％～70％；优选为35％～70％；优选为40％～70％；优选为40％～65％；优选为40％～60％；优选为40％～55％；优选为40％～50％；优选为35％～45％；优选为30％～45％；优选为30％～44％；优选为35％～50％。
在一些实施方案中，所述助流剂为非离子型助流剂；优选地，所述非离子型助流剂选自胶态二氧化硅。优选地，所述胶态二氧化硅在所述药物组合物中的重量百分比为：0％～8％；或0％～7％；或0.5％～7％；或1％～7％；或1.5％～7％；或2％～7％；或2.5％～7％；或3％～7％；或3％～6％；或3％～5.5％；或3％～5％。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：10％～35％活性成分、30％～65％填充剂、20％～40％崩解剂、1％～3％润滑剂、0.5％～5％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：10％～35％活性成分、30％～60％填充剂、20％～40％崩解剂、1％～2％润滑剂、3％～5％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：10％～35％活性成分、30％～55％填充剂、20％～40％崩解剂、1％～1.5％润滑剂、3％～5％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：15％～35％活性成分、30％～50％填充剂、30％～40％崩解剂、1％～1.5％润滑剂、3％～5％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：18％～35％活性成分、30％～50％填充剂、20％～40％崩解剂、1％～3％润滑剂、3％～7％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：20％～35％活性成分、30％～45％填充剂、20％～40％崩解剂、1％～3％润滑剂、3％～7％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：20％～34％活性成分、30％～45％填充剂、20％～40％崩解剂、1％～3％润滑剂、3％～7％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：20％～35％活性成分、30％～45％填充剂、20％～40％崩解剂、1％～2％润滑剂、3％～7％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：10％～30％活性成分、30％～60％填充剂、20％～40％崩解剂、1％～1.5％润滑剂、3％～5％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：10％～35％活性成分、28％～50％填充剂、20％～40％崩解剂、1％～1.5％润滑剂、3％～5％助流剂；所述活性成分、填充剂、崩解剂、润滑剂和助流剂定义如前所述。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：10％～35％活性成分、30％～50％填充剂、20％～40％崩解剂、1％～2％润滑剂、3％～5％助流剂；
所述填充剂包含非离子型填充剂，所述非离子型填充剂包含微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种或多种；优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一 种；或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合；
所述崩解剂为非离子型崩解剂；优选地，所述非离子型崩解剂包含交联聚维酮，任选地；进一步包含低取代羟丙纤维素；
所述润滑剂为硬脂酸镁；
所述助流剂为非离子型助流剂；优选地，所述非离子型助流剂选自胶态二氧化硅，
其中，所述非离子型崩解剂和所述非离子型助流剂定义同前文第二方面。
优选地，所述非离子型崩解剂选自交联聚维酮或交联聚维酮和低取代羟丙纤维素的组合。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：10％～35％活性成分、30％～55％填充剂、20％～40％崩解剂、1％～1.5％润滑剂、3％～5％助流剂；
所述填充剂包含非离子型填充剂，所述非离子型填充剂包含微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种或多种；优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种；或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合；
所述崩解剂为非离子型崩解剂；优选地，所述非离子型崩解剂包含交联聚维酮，任选地；进一步包含低取代羟丙纤维素；
所述润滑剂为硬脂酸镁；
所述助流剂为非离子型助流剂；优选地，所述非离子型助流剂选自胶态二氧化硅，
其中，所述非离子型崩解剂和所述非离子型助流剂定义同前文第二方面。
优选地，所述非离子型崩解剂选自交联聚维酮或交联聚维酮和低取代羟丙纤维素的组合。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：15％～35％活性成分、30％～50％填充剂、30％～40％崩解剂、1％～1.5％润滑剂、3％～5％助流剂；
所述填充剂包含非离子型填充剂，所述非离子型填充剂包含微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种或多种；优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种；或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合；
所述崩解剂为非离子型崩解剂；优选地，所述非离子型崩解剂包含交联聚维酮，任选地；进一步包含低取代羟丙纤维素；
所述润滑剂为硬脂酸镁；
所述助流剂为非离子型助流剂；优选地，所述非离子型助流剂选自胶态二氧化硅，
其中，所述非离子型崩解剂和所述非离子型助流剂定义同前文第二方面。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：20％～35％活性成分、30％～45％填充剂、20％～40％崩解剂、1％～3％润滑剂、3％～5％助流剂；
所述填充剂包含非离子型填充剂，所述非离子型填充剂包含微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种或多种；优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种；或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化 淀粉与乳糖的组合；优选地，所述非离子型填充剂为微晶纤维素；
所述崩解剂为非离子型崩解剂；优选地，所述非离子型崩解剂包含交联聚维酮，任选地；进一步包含低取代羟丙纤维素；
所述润滑剂为硬脂酸镁或硬脂富马酸钠；
所述助流剂为非离子型助流剂；优选地，所述非离子型助流剂选自胶态二氧化硅，
其中，所述非离子型崩解剂和所述非离子型助流剂定义同前文第二方面。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：20％～34％活性成分、30％～45％填充剂、20％～40％崩解剂、1％～2％润滑剂、3％～5％助流剂；
所述填充剂包含非离子型填充剂，所述非离子型填充剂包含微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种或多种；优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种；或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合；优选地，所述非离子型填充剂为微晶纤维素；
所述崩解剂为非离子型崩解剂；优选地，所述非离子型崩解剂包含交联聚维酮，任选地；进一步包含低取代羟丙纤维素；
所述润滑剂为硬脂酸镁或硬脂富马酸钠；
所述助流剂为非离子型助流剂；优选地，所述非离子型助流剂选自胶态二氧化硅，
其中，所述非离子型崩解剂和所述非离子型助流剂定义同前文第二方面。
在一些实施方案中，所述药物组合物制成口服制剂；优选地，所述口服制剂为口服固体制剂；进一步优选地，所述口服固体制剂选自胶囊、片剂、散剂和细粒剂；进一步优选为胶囊和片剂；更进一步优选为片剂；更进一步优选地，所述片剂为包衣片剂。
在一些实施方案中，所述包衣片剂包含片芯和包衣材料，其中，所述片芯包含前述药物组合物，所述包衣材料定义同前文第二方面。
在一些实施方案中，所述包衣材料中包含成膜材料，所述成膜材料包含聚乙烯醇聚乙二醇共聚物；优选地，所述成膜材料选自聚乙烯醇聚乙二醇共聚物、或聚乙烯醇聚乙二醇共聚物和聚乙烯醇的组合。
第四方面，本申请提供了一种适于口服的药物组合物，其包含作为活性成分的式2所示化合物、填充剂和崩解剂，任选地，进一步包含助流剂和/或润滑剂，其中，所述崩解剂为非离子型崩解剂，所述填充剂、助流剂和非离子型崩解剂的定义如前文第一方面、第二方面或第三方面所述。
在一些实施方案中，所述式2所示化合物如前文第一方面所述。
在一些实施方案中，当所述润滑剂为非离子型润滑剂时，其中，所述非离子型润滑剂在所述药物组合物中的重量百分比为1％～6％，优选为1％～5％，优选为1％～4％，进一步优选为1％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％。
在一些实施方案中，当所述润滑剂同时包含非离子型润滑剂和离子型润滑剂时，其中，所述非离子型润滑剂在所述药物组合物中的重量百分比为1％～4％，优选为1％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％；并且，
(i)当活性成分在所述药物组合物中的重量百分比≥40％时(例如，40％～70％，40％～68％)，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为≤0.5％；
(ii)所述活性成分在所述药物组合物中的重量百分比小于40％(例如，15％≤活性成分重量百分比 ＜40％，16％≤活性成分重量百分比＜40％，16％～35％，16％～34％)，所述离子型润滑剂在药物组合物中的重量百分比小于或等于2％，优选为小于或等于1.5％，优选为小于或等于1％，优选为小于或等于0.8％，进一步优选为小于或等于0.7％，进一步优选为小于或等于0.6％，更进一步优选为小于或等于0.5％。
在一些实施方案中，当所述润滑剂为离子型润滑剂时，所述活性成分在所述药物组合物中的重量百分比＜40％(优选≤35％；优选≤34％，例如15％～35％，15％～34％，20％～34％，20％～35％，20％～33.5％)，所述离子型润滑剂在所述药物组合物中的重量百分比为1％～3％；优选为1％～2.5％，优选为1％～2％，优选为1％～1.5％；优选地，所述离子型润滑剂为硬脂酸镁或硬脂富马酸钠；进一步优选为硬脂酸镁。
在一些实施方案中，所述润滑剂包含非离子型润滑剂，任选地，进一步包含离子型润滑剂；优选地，所述润滑剂为非离子型润滑剂；所述非离子型润滑剂和离子型润滑剂的定义如前文第二方面所述。
优选地，所述非离子型润滑剂在所述药物组合物中的重量百分比为0％～3％，优选为0％～2％，优选为0％～1％，优选为0.5％～2.5％，进一步优选为1％～2％；所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％，优选为≤0.5％。
在一些实施方案中，所述润滑剂包含硬脂酸，任选地，进一步包含另一种润滑剂，所述另一种润滑剂选自硬脂酸镁、硬脂酸钙、棕榈酸、棕榈酸硬脂酸甘油酯、山嵛酸甘油酯、苯甲酸钠、月桂基硫酸钠、氢化植物油、滑石粉、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、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；其中，所述硬脂酸在所述药物组合物中的重量百分比为1％～4％，优选为1％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％；所述另一种润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％，优选为≤0.5％。
在一些实施方案中，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、山嵛酸甘油酯、苯甲酸钠、月桂基硫酸钠、氢化植物油、滑石粉、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、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。优选地，所述润滑剂在所述药物组合物中的重量百分比为0.1％～3％；优选为0.1％～2％；优选为0.1％～1.5％；优选为0.1％～1％。
在一些实施方案中，所述填充剂包含非离子型填充剂，任选地，进一步包含离子型填充剂；优选地，所述填充剂为非离子型填充剂；所述非离子型填充剂和离子型填充剂的定义如前文第二方面所述。
在一些实施方案中，在所述药物组合物中，所述活性成分(式2所示化合物)，其重量百分比为0.5％～80％；或者1％～75％；或者5％～70％；或者10％～70％；或者15％～70％；或者16％～68％；或者16％～67％；或者20％～70％；或者20％～67％；或者5％～65％；或者5％～60％；或者5％～55％；或者5％～50％；或者10％～55％；或者10％～50％；或者15％～55％；或者15％～50％；或者15％～45％；或者20％～50％；或者20％～45％；或者20％～40％。
在一些实施方案中，所述非离子型填充剂选自淀粉、微晶纤维素、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种，或者所述非离子型填充剂为两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、或微晶纤维素与预胶化淀粉的组合、或微晶纤维素与乳糖的组合、或微晶纤维素与甘露醇的组合、或预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合、或微晶纤维素与糊精的组合、或微晶纤维素与糖粉的组合、或微晶纤维素与蔗糖的组合；进一步优选地，所述非离子型填充剂选自微晶纤维素、预胶化淀粉、甘露醇或乳糖中的一种，或微晶纤维素与淀粉的组合、或微晶纤维素与预胶化淀粉的组合、或微晶纤维素与乳糖的组合、或微晶纤维素与甘露醇的组合、或预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合。优选地，所述非离子型填充剂为微晶纤维素。
在一些实施方案中，所述填充剂在所述药物组合物中的重量百分比为：10％～85％；或10％～80％； 或15％～75％；或17％～68％；或15％～70％；或15％～65％；或20％～65％；或30％～65％；或30％～60％；或30％～55％；或30％～50％；或35％～50％；或40％～55％。
在一些实施方案中，所述非离子型崩解剂包含交联聚维酮；优选地，所述非离子型崩解剂为交联聚维酮。
在一些实施方案中，所述崩解剂在所述药物组合物中的重量百分比为：5％～35％；或8％～40％；或8％～35％；或8％～30％；或10％～40％；或10％～35％；或10％～30％；或15％～40％；或15％～30％；或20％～30％；或20％～40％；或25％～40％；或30％～40％；或5％～30％；或5％～25％；或6％～25％；或7％～20％；或8％～20％；或8％～18％；或8％～10％；或8％～15％；或10％～15％。
在一些实施方案中，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、山嵛酸甘油酯、苯甲酸钠、月桂基硫酸钠、氢化植物油、滑石粉、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、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；优选地，所述润滑剂包含硬脂酸；优选地，所述润滑剂为硬脂酸。
在一些实施方案中，所述润滑剂在所述药物组合物中的重量百分比为：0％～6％；或0％～5％；或0％～4％；或0％～3.5％；或0％～3％；或0％～2.5％；或0％～2％；或0％～1.5％；或0％～1％。
在一些实施方案中，所述润滑剂在所述药物组合物中的重量百分比为：1％～6％；或1％～5％；或1.5％～5％；或1％～4％；或1.5％～4％；或1％～3.5％；或1.5％～3.5％；或1％～3％；或1％～2％；或1.5％～3％；或2％～3.5％。
在一些实施方案中，所述助流剂为非离子型助流剂；优选地，所述非离子型助流剂选自胶态二氧化硅。优选地，所述胶态二氧化硅在所述药物组合物中的重量百分比为：0％～8％；或0％～7％；或0％～6％；或0％～5.5％；或0％～5％；或0％～4％；或0％～3％；或0％～2％；或0％～1.5％；或0％～1％；或0％～0.5％。
在一些实施方案中，助流剂在所述药物组合物中的重量百分比为：0％～8％；或0％～7％；或0％～6％；或0％～5.5％；或0％～5％；或0％～4％；或0％～3％；或0％～2％；或0％～1.5％；或0％～1％；或0％～0.5％；或者，
助流剂在所述药物组合物中的重量百分比为3％～8％；或3％～7％；或3％～6％；或3％～5.5％；或3％～5％；或3.5％～7％；或4％～7％；或4.5％～7％；或5％～7％；或4％～7％；或4％～6％。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：10％～70％活性成分、15％～80％填充剂、8％～30％崩解剂、0％～3％润滑剂、0％～6％助流剂。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：15％～70％活性成分、15％～75％填充剂、8％～20％崩解剂、0％～3％润滑剂、0％～5％助流剂。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：16％～68％活性成分、17％～75％填充剂、8％～20％崩解剂、0％～2％润滑剂、0％～5％助流剂。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：16％～68％活性成分、17％～75％填充剂、8％～15％崩解剂、0％～2％润滑剂、0％～5％助流剂；
所述填充剂包含非离子型填充剂，任选地，进一步包含离子型填充剂；
所述崩解剂为非离子型崩解剂；优选地，所述非离子型崩解剂包含交联聚维酮；
所述润滑剂包含非离子型润滑剂，任选地，进一步包含离子型润滑剂；优选地，所述非离子型润滑剂包含硬脂酸，所述离子型润滑剂包含硬脂酸镁或硬脂富马酸钠，进一步优选为包含硬脂酸镁；
所述助流剂为胶态二氧化硅；
其中，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％，优选为≤0.5％；
所述非离子型填充剂、离子型填充剂、非离子型崩解剂、非离子型润滑剂或离子型润滑剂定义如前(第二方面)所述。
优选地，所述非离子型填充剂选自淀粉、微晶纤维素、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种。
优选地，所述非离子型填充剂包含微晶纤维素、或预胶化淀粉、甘露醇或乳糖中的一种或多种；优选地，所述非离子型填充剂选自微晶纤维素、或预胶化淀粉、甘露醇或乳糖中的一种；或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合；优选地，所述非离子型填充剂选自微晶纤维素。
优选地，所述填充剂为非离子型填充剂。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：16％～68％活性成分、17％～75％填充剂、8％～15％崩解剂、0％～2％润滑剂、0％～5％助流剂；
所述填充剂包含非离子型填充剂，任选地，进一步包含离子型填充剂；
所述崩解剂为非离子型崩解剂；优选地，所述非离子型崩解剂包含交联聚维酮；
所述助流剂为胶态二氧化硅；
所述非离子型填充剂、离子型填充剂、非离子型崩解剂定义如前文第二方面所述。
优选地，所述非离子型填充剂选自淀粉、微晶纤维素、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种。
优选地，所述非离子型填充剂包含微晶纤维素、或预胶化淀粉、甘露醇或乳糖中的一种或多种；优选地，所述非离子型填充剂选自微晶纤维素、或预胶化淀粉、甘露醇或乳糖中的一种；或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合；优选地，所述非离子型填充剂为微晶纤维素。
优选地，所述填充剂为非离子型填充剂。
在一些实施方案中，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、山嵛酸甘油酯、苯甲酸钠、月桂基硫酸钠、氢化植物油、滑石粉、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、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；优选地，所述润滑剂包含硬脂酸。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：15％～70％活性成分、15％～75％填充剂、8％～30％崩解剂、0％～3％润滑剂、0％～6％助流剂；
所述填充剂包含非离子型填充剂，任选地，进一步包含离子型填充剂；所述非离子型填充剂选自淀粉、微晶纤维素、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；所述离子型填充剂选自硫酸钙、磷酸氢钙或磷酸钙中的一种或多种；优选地，所述非离子型填充剂包含微晶纤维素；
所述崩解剂选自非离子型崩解剂；优选地，所述非离子型崩解剂包含交联聚维酮；
所述润滑剂包含硬脂酸，任选地，进一步包含另一种润滑剂，所述另一种润滑剂选自硬脂酸镁、硬脂酸钙、棕榈酸、棕榈酸硬脂酸甘油酯、山嵛酸甘油酯、苯甲酸钠、月桂基硫酸钠、氢化植物油、滑石粉、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、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；
所述助流剂为胶态二氧化硅；
其中，所述另一种润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％；优选为≤0.5％。
在一些实施方案中，所述药物组合物包含按其总重量计的以下组分：15％～70％活性成分、15％～75％填充剂、8％～20％崩解剂、0％～3％润滑剂、0％～5％助流剂；
所述填充剂为非离子型填充剂，所述非离子型填充剂包含微晶纤维素，任选地，进一步包含淀粉、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；优选地，所述非离子型填充剂为微晶纤维素；
所述崩解剂为非离子型崩解剂，所述非离子型崩解剂包含交联聚维酮，任选地，进一步包含另一种非离子型崩解剂，所述另一种非离子型崩解剂选自干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉或低取代羟丙纤维素；优选地，所述非离子型崩解剂为交联聚维酮；
所述润滑剂包含硬脂酸，任选地，进一步包含另一种润滑剂，所述另一种润滑剂选自硬脂酸镁、硬脂酸钙、棕榈酸、棕榈酸硬脂酸甘油酯、山嵛酸甘油酯、苯甲酸钠、月桂基硫酸钠、氢化植物油、滑石粉、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、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；优选地，所述润滑剂为硬脂酸；
所述助流剂为胶态二氧化硅；
其中，所述另一种润滑剂在所述药物组合物中的重量百分比小于1％，优选为≤0.8％，优选为≤0.7％，优选为≤0.6％，优选为0％～0.5％，优选为≤0.5％。
在一些实施方案中，所述药物组合物制成口服制剂，优选地，所述口服制剂为口服固体制剂；优选地，所述口服固体制剂为片剂或胶囊；优选地，所述口服固体制剂为胶囊。
在一些实施方案中，前述第一方面至第四方面的口服制剂或口服固体制剂的每个制剂单位中可含有1-500mg的活性成分，或10～450mg，或25-400mg，或50-350mg，或100-300mg，或150-200mg，或25～200mg；例如单剂量形式的药物中包含活性成分5mg、10mg、20mg、25mg、30mg、50mg、60mg、100mg、150mg、200mg、250mg、300mg、400mg、500mg等；其中，所述活性成分以式2所示化合物，即二盐酸盐的形式计。优选地，所述剂量以式2所示化合物计；进一步优选地，所述剂量以式2所示化合物的结晶形式(无水且无溶剂形式)计；更进一步优选地，所述剂量以式2所示化合物的晶型I计。
在一些实施方案中，前述第一方面至第四方面的口服制剂、口服剂型或口服固体制剂中含有治疗有效量的式2所示化合物，其给药剂量为：每次给药25mg-900mg；优选地，每次给药200mg-800mg；进一步优选地，每次给药300mg-700mg；进一步优选地，每次给药300mg-600mg；进一步优选地，每次给药400mg-600mg；进一步优选地，每次给药450mg-600mg；示例性的给药剂量包括，每次给药25mg、50mg、100mg、200mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg或900mg。所述给药剂量以式2所示化合物计。优选地，所述给药剂量以式2所示化合物计；进一步优选地，所述给药剂量以式2所示化合物的结晶形式(无水且无溶剂形式)计；更进一步优选地，所述给药剂量以式2所示化合物的晶型I计。
在一些实施方案中，前述第一方面至第四方面的口服制剂或口服固体制剂的每日给药剂量频率为：每天给药一次、每天给药两次、每天给药三次或每天给药四次；优选为每天给药一次。
在一些实施方案中，前述第一方面至第四方面的口服制剂或口服固体制剂中含有治疗有效量的式2所示化合物，其每日给药剂量为25mg-900mg；优选为200mg-800mg；进一步优选为300mg-700mg；进一步优选为300mg-600mg；进一步优选为400mg-600mg；进一步优选为450mg-600mg；示例性的每日给药剂量包括，每日给药25mg、50mg、100mg、200mg、300mg、350mg、400mg、450mg、500mg、 550mg、600mg、650mg、700mg、750mg、800mg或900mg。所述剂量以无水形式的化合物2计。优选地，所述给药剂量以式2所示化合物计；进一步优选地，所述给药剂量以式2所示化合物的结晶形式(无水且无溶剂形式)计；更进一步优选地，所述给药剂量以式2所示化合物的晶型I计。
在一些实施方案中，前述第一方面至第四方面的口服制剂或口服固体制剂中含有治疗有效量的式2所示化合物，其给药剂量和剂量频率为：每天给药一次，每次给药25mg-900mg；优选地，每天给药一次，每次给药200mg-800mg；进一步优选地，每天给药一次，每次给药300mg-700mg；进一步优选地，每天给药一次，每次给药300mg-600mg；进一步优选地，每天给药一次，每次给药400mg-600mg；进一步优选地，每天给药一次，每次给药450mg-600mg；示例性的给药剂量和频率包括，每天给药一次，每次给药25mg、50mg、100mg、200mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg或900mg。所述剂量以化合物2计。优选地，所述给药剂量以式2所示化合物计；进一步优选地，所述给药剂量以式2所示化合物的结晶形式(无水且无溶剂形式)计；更进一步优选地，所述给药剂量以式2所示化合物的晶型I计。
在一些实施方案中，前述第一方面至第四方面的口服制剂或口服固体制剂中含有治疗有效量的式2所示化合物，其给药剂量频率为：每天给药一次，给药21天，停药7天，每28天为一周期。在一些实施方案中，所述口服制剂或口服固体制剂可以单剂量施用或分剂量施用；优选地，以单剂量施用。优选地，所述式2所示化合物为结晶形式；进一步优选地，所述式2所示化合物的结晶形式为晶型I。
第五方面，本申请提供了前述第一方面至第四方面的药物组合物、前述第一方面至第四方面的口服制剂或口服固体制剂用于抑制RET、FGFR、VEGFR、FLT、EGFR激酶或它们的突变体中一种或多种活性的用途。
第六方面，本申请提供了前述第一方面至第四方面的药物组合物、前述第一方面至第四方面的口服制剂或口服固体制剂用于制备药物的用途。
在一些实施方案中，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：RET、FGFR、VEGFR、FLT、EGFR或它们的突变体中一种或多种。
第七方面，本申请提供了前述第一方面至第四方面的药物组合物、前述第一方面至第四方面的口服制剂或口服固体制剂，用于治疗蛋白激酶介导的疾病，所述蛋白激酶选自：RET、FGFR、VEGFR、FLT、EGFR或它们的突变体中一种或多种。
第八方面，本申请提供了治疗蛋白激酶介导的疾病的方法，包括：向需要其的对象使用前述第一方面至第四方面的药物组合物、前述第一方面至第四方面的口服制剂或口服固体制剂，所述蛋白激酶选自：RET、FGFR、VEGFR、FLT、EGFR或它们的突变体中一种或多种。
在一些实施方案中，前述第六方面、第七方面、第八方面中的疾病为细胞增殖性疾病。优选地，所述细胞增殖性疾病为肿瘤或癌症。优选地，所述肿瘤包括甲状腺癌、胆道癌、表皮样癌、黑色素瘤、结直肠癌、胃癌、食管癌、胰腺癌、肾癌、肝癌、肺癌或卵巢癌。优选地，所述甲状腺癌为甲状腺髓样癌，所述肺癌为非小细胞肺癌，所述胆道癌为肝内胆管癌。优选地，所述非小细胞肺癌为RET融合型非小细胞肺癌。
第九方面，本申请提供了一种试剂盒，包含前述第一方面至第四方面的药物组合物、前述第一方面至第四方面的口服制剂或口服固体制剂。
在一个实施方案中，所述试剂盒包括一种或多种容器，所述容器中包含前述第一方面至第四方面的药物组合物、前述第一方面至第四方面的口服制剂或口服固体制剂。
在一个实施方案中，所述试剂盒，包含前述第一方面至第四方面的药物组合物、前述第一方面至第四方面的口服制剂或口服固体制剂。
第十方面，本申请提供了前述第一方面至第四方面的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。
在一些实施方案中，所述药物组合物制成片剂，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1加入混合容器中进行混合产生预混物；(3)制粒；(4)总混：将步骤(3)制备得到的颗粒与赋形剂2进行总混；(5)压片。
优选地，所述制粒为干法制粒。
优选地，赋形剂1包含填充剂和助流剂，赋形剂2包含崩解剂和润滑剂，任选地，进一步包含填充剂和/或助流剂。
在一些实施方案中，所述药物组合物制成胶囊，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1加入混合容器中进行混合产生预混物；(3)制粒；(4)总混：将步骤(3)制备得到的颗粒与赋形剂2进行总混；(5)灌装胶囊。
优选地，所述制粒选自直压制粒或干法制粒。
优选地，赋形剂1包含填充剂和助流剂，赋形剂2包含崩解剂和润滑剂，任选地，进一步包含填充剂和/或助流剂。
【定义和说明】
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
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”或“口服剂型”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。
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2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2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。
本申请所述的“任选”、“任选的”或“任选地”意味着随后所描述的事件、环境或情况可以但不必发生，包括该事件、环境或情况发生或不发生的场合。例如，“任选地，进一步包含离子型填充剂”意味着离子型填充剂可以但不必须存在，该说明包括药物组合物包含离子型填充剂的情形和不包含离子型填充剂的情形。
在本申请的范围中，可对如式2所示的化合物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。
如无特别说明，本申请所述的“2θ”、“2θ角”或“2θ角度”是指衍射角，单位为°或度，2θ的误差范围可以为±0.5°、±0.4°、±0.3°、±0.2°或±0.1°；在本申请的一些实施方案中，2θ的误差范围为±0.2°。
术语“基本上如图所示”是指X-射线粉末衍射图谱中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少96％，或至少97％，或至少98％，或至少99％的峰显示在其图中。进一步地，当产品中某种晶型的含量逐渐降低时，其粉末X-射线衍射图谱中的一些归属于该晶 型的衍射峰可能会由于仪器的检测灵敏度的因素而变少。
术语“特征衍射峰”是指在X-射线粉末衍射图谱中，可用于代表该晶型的衍射峰，其与衍射峰的峰位置、峰形和相对峰强度有关，例如，小角度峰，峰形尖锐，且相对峰强度至少3％以上，或至少5％以上，或至少10％以上，或至少20％以上，或至少30％以上，或至少40％以上，或至少50％以上，或至少60％以上，或至少70％以上，或至少75％以上的衍射峰。
本申请提及的“结晶形式”是指呈结晶形态的式2所示化合物，包括式2所示化合物的无水且无溶剂形式、水合物形式和溶剂合物形式。
术语“溶剂化物”或“溶剂合物”是指化学计量比或非化学计量比的溶剂分子与本申请的式2所示化合物所形成的缔合物，包括同时含有水分子和一种或多种其它溶剂分子的缔合物，及仅含一种或多种其它溶剂分子的缔合物。
术语“水合物”是指化学计量比或非化学计量比的水分子与本申请的式2所示化合物所形成的缔合物。
所述“无水且无溶剂形式”是指不含水分子或溶剂分子，或者水分子或溶剂分子以非分子间力结合的方式与式2所示化合物共存，例如吸附的方式。
【技术效果】
本申请中的药物组合物和/或口服制剂取得以下一种或多种有益的技术效果：
(1)具有良好的溶出效果；(2)具有合格的活性成分含量；(3)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；(4)具有良好的稳定性。
附图说明
图1示出了制备例2所得化合物1的二盐酸盐的晶型I的XRPD谱图；
图2示出了测试例3中制备例2所得化合物1的二盐酸盐的晶型I在长期稳定性测试后的XRPD谱图。
具体实施方式
下文将结合具体制备例和实施例对本申请的技术方案做更进一步的详细说明。下列制备例和实施例仅为示例性地说明和解释本申请，而不应被解释为对本申请保护范围的限制。本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本申请的保护范围。除非另有说明，以下制备例和实施例中使用的原料、试剂(例如，有机溶剂、无机溶剂、缓冲液、赋形剂等)均为市售商品，或者可以通过已知方法或试剂说明书制备或配制。
以下制备例中，分析检测条件如下：
1、含量或有关物质测试
检测仪器：Agilent 1260(LC1260-3-DAD)高效液相色谱仪
柱子：C18 4.6×250mm,5μm
测试条件：波长252nm；柱温40±5℃。
2、溶解度(水及pH2·0缓冲液)
检测仪器：Agilent 1260高效液相色谱仪
检测介质：纯化水、pH2.0磷酸-磷酸氢二钠缓冲液
对照品溶液制备：取式1化合物对照品适量，精密称定，加溶剂使其完全溶解，并稀释制成100μg/mL的溶液，精密量取10uL，使用HPLC测定对照品溶液中化合物1的含量。
3、X-射线粉末衍射(X-RayPowderDiffraction，XRPD)
检测仪器：Bruker D2PHASER型粉末X-射线衍射仪
测试条件：
光管类型：Cu靶，陶瓷X光管；
X-射线波长：CuKα，1.5406；
电压电流：30kV，10mA；
扫描范围：3～40°2θ；
扫描总时间：40min；
扫描速度：0.5秒/步；
样品用量：3mg
采集软件：Diffrac Plus XRD Commander
分析软件：MDI Jade 6.0。
4差示扫描量热-热重分析(DimrentialScanningCalorimetry-ThermogravimetricAnalysis，DSC-TGA)
检测仪器：NETZSCH STA449F3同步热分析仪
测试方法：称取样品(约3mg)，置于三氧化二铝坩埚内进行测试，在20mL/min干燥氮气(保护气体)的条件下，以10K/min的升温速率，加热样品从20℃至340℃。
仪器控制软件：NETZSCH-proteus
分析软件：Proteus Analysis。
5、氯化物
检测仪器：戴安ICS-900离子色谱仪
柱子：Dionex Ion Pac AS11-HC阴离子色谱柱(规格：4×250mm)
实验操作：
供试品溶液制备：取供试品适量，精密称定，用淋洗液(12.5mmol/L氢氧化钠溶液)溶解并定量稀释成每1mL中约含供试品0.5mg的溶液，摇匀，作为供试品溶液。
对照品溶液制备：取氯化钠适量(相当于氯离子18mg)，精密称定，置250mL量瓶中，用淋洗液溶解并定容，摇匀，作为对照品溶液。
测定法：精密量取对照品溶液和供试品溶液各10μL，分别注入离子色谱仪，记录色谱图，按外标法以峰面积计算氯离子含量。
6、核磁氢谱
仪器型号：Bruker Advance 600型核磁共振谱仪
测定条件：以DMSO-d6为溶剂，在室温下(～25℃)进行测试。
7、生物溶媒中溶解度测定
用于溶解度测定的生物溶媒介质(SGF，FeSSIF和FaSSIF)的配制过程见下表1：
表1

测试方法：将待测样品加入到生物溶媒介质中，配制成目标浓度为10mg/mL的溶液或混悬液。所得溶液或混悬液在37℃条件下以200rpm的转速持续振摇。在0.5小时将混悬液过滤，使用HPLC测定滤液中的化合物浓度。
8、溶出度测定
溶出介质：1000ml水
溶出方法：中国药典2020年版四部0931第二法桨法
转速：50rpm
制备例1:化合物1的制备
使用CN106660970B中的方法(实施例22)制备化合物1。
制备例2:化合物1的二盐酸盐的制备
称取制备例1所得的化合物1(10g，21.58mmol)于茄型瓶中，加入甲醇溶剂(110mL)，升温至55±5℃，搅拌至溶清，滴加盐酸(3.7mL，44.4mmol)，搅拌20分钟，缓慢加入200mL乙酸乙酯，降温至5±5℃，搅拌2±1h，抽滤，滤饼用乙酸乙酯(20mL)洗涤，得白色的化合物1的二盐酸盐(11g)，收率94.8％。
1H-NMR(600MHz,DMSO-d6)δ:15.41(s,1H),11.78(s,1H),10.44(s,1H),8.80(s,1H),8.42(s,1H),7.78(dd,J＝9.6Hz，J＝2.4Hz,1H),7.58-7.52(m,2H),7.47(s,1H),4.24(t,J＝6Hz,2H),4.03(s,3H),3.15-3.14(m,2H),2.76-2.75(m,6H),1.90-1.88(m,4H).
通过离子色谱法测定氯离子含量，计算该盐酸盐的化学计量比(见下表2)，可以推断得到该盐酸盐的碱/酸比为1:2。
表2
取所得盐酸盐样品进行X-射线粉末衍射，其呈现良好的结晶性，命名为二盐酸盐的晶型I，其XRPD表征谱图如图1所示，衍射峰数据如表3。取样品进行DSC-TGA测试，有两个吸热峰，吸热峰1：在219.1℃有一吸热峰起始点，在231.0℃附近达到峰值；吸热峰2：在235.1℃有一吸热峰起始点，在284.2℃附近达到峰值，在205℃左右发生分解。PLM图显示其结晶颗粒为规则形态。
表3.制备例2所得二盐酸盐的晶型I的XRPD衍射峰数据表
测试例1:溶解度测试
取制备例2样品，在水中及pH2.0缓冲液中进行溶解度测试，测试结果如下表4所示：
表4.溶解度结果
结果：制备例2的样品在水及pH2.0缓冲液中均具有高溶解度，虽然在酸性条件下，制备例2的溶解度相比其在水中的溶解度有所降低，但依然具有>10mg/mL的溶解度，符合制剂要求。
根据药物剂型对原料药溶解度的一般要求，固体口服剂型要求药物的水中溶解度大于0.1g/L，注射剂或口服液等溶液制剂则要求药物的溶解度在10g/L以上，更重要的是，药物的溶解度应满足临床所需的剂量浓度。基于表4的溶解度结果，制备例2的二盐酸盐可考虑用于制备固体口服剂型，还可以进一步考虑用于制备注射剂或口服液等溶液制剂。
测试例2:生物溶媒中的溶解度测试
称取制备例2的样品(20mg)，加入不同的生物溶媒(2mL)，进行溶解度测试，结果见表5。
表5.样品在不同生物溶媒中的溶解度
结果：制备例2所得样品在不同的生物溶媒中，均能保持良好的溶解度，且溶解速度快。
测试例3:稳定性测试
取制备例2所得盐样品适量，在40±2℃、75％±5％RH条件下，聚乙烯膜封口放置5个月，进行试验，结果如下：
表6.样品的稳定性结果及晶型检测结果

表7.制备例2的晶体样品在稳定性测试后的XRPD数据表
制备例2所得化合物1的二盐酸盐的晶型I在稳定性测试后的XRPD谱图如图2所示。
结果：制备例2所得的化合物1的二盐酸盐能维持化学稳定和晶型稳定，符合作为原料药储存的规定。
测试例4:固体稳定性测试
取制备例2的二盐酸盐，分别放置于40℃/75％RH(开口)条件下7天，进行稳定性测试，结果见表8。
表8.稳定性结果及晶型检测结果
结果：在40℃/75％RH(开口)条件下放置7天，制备例2所得的化合物1的二盐酸盐能维持化学稳定和晶型稳定，因此，制备例2所得样品具有较好的热稳定性，符合作为原料药储存的规定。
测试例5:机械稳定性测试
取制备例2的二盐酸盐适量，进行机械研磨5分钟后进行X-射线粉末衍射，结果显示，晶型未发生变化。
实施例1·化合物2的片剂
表9.实施例1的处方(制成1000片)
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2以 及相应的填充剂、崩解剂、助流剂和润滑剂；2)预混合：将活性成分、填充剂、助流剂加入混合容器内，进行预混，得到预混粉；3)制粒：使用预混粉进行干法制粒；4)总混：将干法制粒得到的颗粒与崩解剂和润滑剂进行总混，得到总混粉；5)压片：将总混粉使用压片机进行压片。
结果:压片过程顺利，不黏冲，制备得到的片芯含量合格，且溶出快速，处方合格。
实施例2·化合物2的片剂(调整润滑剂的组成和/或重量比例)
参考实施例1的制备方法，调整润滑剂的用量或组成，得到实施例2-1至2-6的片剂。
表10.实施例2的处方(制成1000片)
结果:压片过程顺利，不黏冲，制备得到的片芯含量合格，且溶出快速，满足制剂要求，处方合格。
表10-1.实施例2的处方(制成1000片)
结果:压片过程顺利，不黏冲，制备得到的片芯含量合格，且溶出快速，满足制剂要求，处方合格。
实施例3·化合物2的片剂(离子型润滑剂的考察)
参考实施例1的制备方法，使用硬脂酸镁作为润滑剂，并调整硬脂酸镁的用量，得到实施例3-1、实施例3-2和实施例3-3。
表11.实施例3的处方(制成1000片)
结果:实施例3-1和实施例3-2的处方不合格，溶出缓慢；进一步降低硬脂酸镁的用量，得到实施例3-3，虽然溶出度符合要求，但压片过程出现黏冲现象，实施例3-3的处方不合格。
参考实施例1的制备方法，在实施例3-1的处方基础上，尝试调整崩解剂，得到实施例3-4、实施例3-5和实施例3-6。
表12.实施例3的处方(制成1000片)
结果:所得处方压片过程均顺利，不黏冲，制备得到的片芯含量符合要求，且溶出快速，处方均合格。由此可推知，在实施例3-2的处方基础上，参考实施例3-6的处方，调整崩解剂，亦可以得到合格的处方。
参考实施例1的制备方法，在实施例1的基础上，更改润滑剂的种类，得到实施例3-7和实施例3-8。
表13.实施例3-7和实施例3-8的处方(制成1000片)

结果:在实施例1处方的基础上，使用硬脂富马酸钠作为润滑剂，但用量保持不变，所得处方(实施例3-7)在压片过程中出现明显的黏冲现象，处方不合格；进一步提高硬脂富马酸钠的用量比例，所得处方(实施例3-8)在压片过程中仍出现黏冲现象，处方不合格。
参考实施例3-6的处方和实施例1的制备方法，更改润滑剂的种类，得到实施例3-9。
表13-1.实施例3-9的处方(制成1000片)
结果:所得处方合格。
实施例4·化合物2的片剂(调整助流剂的用量)
参考实施例1的制备方法，降低润滑剂的用量，得到实施例4-1，进一步在实施例4-1的基础上，调整助流剂的用量，得到实施例4-2和实施例4-3。
表14.实施例4的处方(制成1000片)
结果:将润滑剂用量降低到1％(实施例4-1)，压片过程顺利，含量和溶出均符合要求，处方合格；在实施例4-1基础上，将助流剂的比例降低到3％，得到实施例4-2，压片过程顺利，含量和溶出均符合要求，处方合格；将助流剂提升到7％，得到实施例4-3，所得处方压片过程顺利，含量和溶出均符合要求，处方合格。
实施例5·化合物2的片剂(崩解剂的考察)
参考实施例1的处方和制备方法，调整崩解剂的用量或崩解剂的组成，得到实施例5-1、实施例5-2和实施例5-3。
表15.实施例5的处方(制成1000片)
结果:在实施例1处方基础上，降低崩解剂用量(实施例5-1)或提高崩解剂用量(实施例5-2)，所得处方压片过程均顺利，含量和溶出均符合要求，处方均合格。进一步地，使用两种崩解剂的组合(实施例5-3)，所得处方合格。
参考实施例1的制备方法，更改崩解剂的种类，得到实施例5-4和实施例5-5。
表16.实施例5-4和实施例5-5的处方(制成1000片)
结果:使用交联羧甲基纤维素钠(实施例5-4)或羧甲淀粉钠(实施例5-5)等离子型崩解剂时，虽然压片过程顺利，但所得处方的活性成分(API)含量明显降低，处方不合格。
参考实施例5-3的处方和实施例1的制备方法，调整崩解剂的用量，得到实施例5-6和实施例5-7。
表15-1.实施例5的处方(制成1000片)

结果:在实施例5-3处方基础上，降低崩解剂用量，所得处方压片过程均顺利，含量和溶出均符合要求，处方均合格。
实施例6·化合物2的片剂(单一填充剂，种类调整)
参考实施例1的处方和制备方法，使用单一填充剂，调整填充剂的种类，得到实施例6-1、实施例6-2和实施例6-3。
表17.实施例6的处方(制成1000片)
结果:使用单一填充剂时，将微晶纤维素分别替换为乳糖(实施例6-1)、预胶化淀粉(实施例6-2)或甘露醇(实施例6-3)，所得处方压片过程均顺利，含量和溶出均合格，处方合格。
实施例7·化合物2的片剂(两种填充剂的组合)
参考实施例1的处方和制备方法，使用两种填充剂的组合，得到实施例7-1、实施例7-2和实施例7-3。
表18.实施例7的处方(制成1000片)

结果:将单一填充剂(微晶纤维素)分别替换为两种填充剂的组合，所得处方压片过程均顺利，含量和溶出均合格，处方合格。
实施例8·化合物2的片剂(调整活性成分的用量)
参考实施例1的制备方法和实施例2-3的处方，调整活性成分(API)的用量，得到实施例8-1、实施例8-2和实施例8-3。
表19.实施例8的处方(分别制成1000片)
结果:调整活性成分的用量，所得处方压片过程均顺利，含量和溶出均合格，处方均合格。
实施例9·化合物2的片剂(使用不同的包衣材料)
参考实施例1的制备方法和实施例2-3的处方，制备得到片芯，采用不同的包衣材料进行包衣，得到实施例9-1、实施例9-2、实施例9-3和实施例9-4。
表20.实施例9的包衣材料和结果(分别制成1000片)

结果:使用不同的包衣材料(或称为包衣粉)，包衣过程顺利，所得包衣片剂外观合格，且包衣速度快，包衣效率高，有利于降低生产成本。
实施例10·化合物2的胶囊
表21.实施例10-1的处方(制成1000粒)
制备:1)称量或备料：按照处方量称取活性成分(API)化合物2以及相应的填充剂、崩解剂、助流剂和润滑剂；2)预混合：将活性成分、填充剂、助流剂加入混合容器内，进行预混，得到预混粉；3)制粒：使用预混粉进行干法制粒；4)总混：将干法制粒得到的颗粒与崩解剂和润滑剂进行总混，得到总混粉；5)灌装胶囊：将总混粉灌装胶囊。
结果:含量合格，溶出快速，所得实施例10-1处方合格。
表22.实施例10-2、10-3和10-4的处方(制成1000粒)
结果:在实施例10-1的处方基础上，不使用润滑剂时(实施例10-2)，所得处方合格；在实施例10-2的处方基础上，进一步降低助流剂比例时(实施例10-3)，所得处方也合格；在实施例10-3的处方基础上，不添加助流剂(实施例10-4)，所得处方合格。
实施例11·化合物2的胶囊
参考实施例10-1、实施例10-2和实施例10-4的处方及实施例10-1的制备方法，改变活性成分的 用量，分别得到实施例11-1至实施例11-9。
表23.实施例11-1、11-2和11-3的处方(制成1000粒)
表24.实施例11-4、11-5和11-6的处方(制成1000粒)
表25.实施例11-7、11-8和11-9的处方(制成1000粒)
结果：表23、表24和表25中各实施例对应的处方，均合格。
测试例6:活性成分与辅料相容性试验
使用活性成分与不同的赋形剂进行相容性试验，在光照4500lx、高温60℃、高湿75％RH±5％RH和高湿92.5％RH±5％RH条件下分别检测有关物质含量，结果显示，活性成分(式2所示化合物)与检测的赋形剂(特别是非离子型赋形剂)相容性良好，有关物质无明显增长。
测试例7:加速稳定性试验
取各实施例所得口服制剂分别进行铝铝泡罩包装，并进行稳定性测试(加速条件，温度40℃±2℃，相对湿度75％±5％)，示例性实施例的稳定性结果如下表所示。
表26.加速(40℃)稳定性数据结果
表27.加速(40℃)稳定性数据结果
表27-1.加速(40℃)稳定性数据结果
结论:表26、表27和表27-1中的四个实施例所得口服制剂(片剂或胶囊)均具有稳定性良好的特点，有关物质无明显增长，水中溶出度维持稳定，含量符合要求。本申请中的其它合格处方亦均具有稳定性良好的特点，考察时间点的水中溶出度和含量均符合要求。
测试例8:长期稳定性试验
取各实施例所得口服制剂分别进行铝铝泡罩包装，并进行稳定性测试(30℃±2℃/65％RH±5％RH)，示例性实施例的稳定性结果如下表所示。
表28.稳定性数据结果
表29.稳定性数据结果
结论:表28和表29中的三个实施例所得口服制剂(片剂)均具有长期稳定性良好的特点，有关物质无明显增长，水中溶出度维持稳定，含量符合要求。本申请中的其它合格处方亦均具有稳定性良好的特点，考察时间点的水中溶出度和含量均符合要求。

Claims (18)

  1. 一种药物组合物，所述药物组合物适于口服，并且包含作为活性成分的式2所示化合物和赋形剂，
    其中，所述赋形剂包括崩解剂和填充剂，所述崩解剂为非离子型崩解剂，任选地，所述赋形剂进一步包含助流剂和/或润滑剂。
  2. 如权利要求1所述的药物组合物，其中，所述药物组合物制成为口服制剂形式；优选地，所述口服制剂为口服固体制剂；更优选地，所述口服固体制剂为片剂或胶囊剂。
  3. 如权利要求1或2所述的药物组合物，其中，所述口服制剂的每个制剂单位中包含活性成分1mg至500mg，或10至450mg，或25至400mg，或50至350mg，或100至300mg，或150至200mg，或25至200mg。
  4. 如权利要求1至3中任一项所述的药物组合物，其中，基于所述药物组合物的总重量，所述活性成分的含量以重量计为0.5％～80％；或者1％～75％；或者5％～70％；或者10％～70％；或者15％～70％；或者16％～68％；或者16％～67％；或者20％～70％；或者20％～67％；或者5％～65％；或者5％～60％；或者5％～55％；或者5％～50％；或者10％～55％；或者10％～50％；或者15％～55％；或者15％～50％；或者15％～45％；或者20％～50％；或者20％～45％；或者20％～40％。
  5. 如权利要求1至4中任一项所述的药物组合物，其中，所述非离子型崩解剂在所述药物组合物中的重量百分比为8％～40％；优选为8％～30％；优选为10％～40％；优选为10％～35％；优选为10％～30％；优选为15％～40％；优选为15％～30％；优选为20％～30％；优选为20％～40％；优选为25％～40％；优选为30％～40％。
  6. 如权利要求1至5中任一项所述的药物组合物，其中，所述填充剂在所述药物组合物中的重量百分比为：10％～85％；或10％～80％；或15％～75％；或17％～68％；或15％～70％；或15％～65％；或20％～65％；或30％～65％；或30％～60％；或30％～55％；或30％～50％；或35％～50％；或40％～55％。
  7. 如权利要求1至6中任一项所述的药物组合物，其中，润滑剂在所述药物组合物中的重量百分比为：0％～6％；或0％～5％；或0％～4％；或0％～3.5％；或0％～3％；或0％～2.5％；或0％～2％；或0％～1.5％；或0％～1％；或者，
    润滑剂在所述药物组合物中的重量百分比为：1％～6％；或1％～5％；或1.5％～5％；或1％～4％；或1.5％～4％；或1％～3.5％；或1.5％～3.5％；或1％～3％；或1％～2％；或1.5％～3％；或2％～3.5％。
  8. 如权利要求7所述的药物组合物，其中：
    (1)所述润滑剂为离子型润滑剂，所述活性成分在所述药物组合物中的重量百分比小于40％，所述离子型润滑剂在所述药物组合物中的重量百分比为1％～3％；优选为1％～2.5％，优选为1％～2％，优选为1％～1.5％；或者
    (2)所述润滑剂同时包含非离子型润滑剂和离子型润滑剂，所述非离子型润滑剂在所述药物组合物 中的重量百分比为1％～4％，优选为1％～3.5％，进一步优选为1％～3％，进一步优选为1％～2％；并且
    (i)所述活性成分在所述药物组合物中的重量百分比大于或等于40％，所述离子型润滑剂在所述药物组合物中的重量百分比小于1％，优选为小于或等于0.8％，优选为小于或等于0.7％，优选为小于或等于0.6％，优选为小于或等于0.5％；或者
    (ii)所述活性成分在所述药物组合物中的重量百分比小于40％，所述离子型润滑剂在药物组合物中的重量百分比小于或等于2％，优选为小于或等于1.5％，优选为小于或等于1％，优选为小于或等于0.8％，进一步优选为小于或等于0.7％，进一步优选为小于或等于0.6％，更进一步优选为小于或等于0.5％。
  9. 如权利要求1至8中任一项所述的药物组合物，其中，助流剂在所述药物组合物中的重量百分比为：0％～8％；或0％～7％；或0％～6％；或0％～5.5％；或0％～5％；或0％～4％；或0％～3％；或0％～2％；或0％～1.5％；或0％～1％；或0％～0.5％；或者，
    助流剂在所述药物组合物中的重量百分比为3％～8％；或3％～7％；或3％～6％；或3％～5.5％；或3％～5％；或3.5％～7％；或4％～7％；或4.5％～7％；或5％～7％；或4％～7％；或4％～6％。
  10. 如权利要求1至9中任一项所述的药物组合物，其中，所述非离子型崩解剂选自干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉、低取代羟丙纤维素或交联聚维酮中的一种或多种；
    优选地，所述非离子型崩解剂选自干淀粉、微晶纤维素、粉状纤维素、玉米淀粉、预胶化淀粉、低取代羟丙纤维素或交联聚维酮中的一种，或者交联聚维酮与干淀粉、微晶纤维素、聚乙烯吡咯烷酮、玉米淀粉、预胶化淀粉或低取代羟丙纤维素中的一种或多种的组合；
    更优选地，所述非离子型崩解剂选自交联聚维酮、交联聚维酮和低取代羟丙纤维素的组合。
  11. 如权利要求1至10中任一项所述的药物组合物，其中，所述填充剂包含非离子型填充剂，任选地，进一步包含离子型填充剂；
    优选地，所述非离子型填充剂选自淀粉、微晶纤维素、预胶化淀粉、甘露醇、乳糖、木糖醇、糊精、糖粉或蔗糖中的一种或多种；
    进一步优选地，所述非离子型填充剂选自微晶纤维素、或预胶化淀粉、甘露醇或乳糖中的一种；或者选自两种非离子型填充剂的组合，包括微晶纤维素与淀粉的组合、微晶纤维素与预胶化淀粉的组合、微晶纤维素与乳糖的组合、微晶纤维素与甘露醇的组合、预胶化淀粉与甘露醇的组合、或预胶化淀粉与乳糖的组合、或微晶纤维素与糊精的组合、或微晶纤维素与糖粉的组合、或微晶纤维素与蔗糖的组合。
  12. 如权利要求1至11中任一项所述的药物组合物，其中，所述药物组合物包含润滑剂，当所述润滑剂包含非离子型润滑剂时，所述非离子型润滑剂选自硬脂酸、棕榈酸、棕榈酸硬脂酸甘油酯、山嵛酸甘油酯、氢化植物油、滑石粉或聚乙二醇类中的一种或多种；优选为硬脂酸；和/或
    当所述润滑剂包含离子型润滑剂时，所述离子型润滑剂选自硬脂酸镁、硬脂酸钙、苯甲酸钠、月桂基硫酸钠、硬脂酸锌、硬脂富马酸钠、硬脂富马酸镁、月桂醇硫酸镁、十二烷基硫酸钠或十二烷基硫酸镁中的一种或多种；优选为硬脂酸镁或硬脂富马酸钠；更优选为硬脂酸镁。
  13. 如权利要求1至12中任一项所述的药物组合物，其中，所述药物组合物包含助流剂，并且其中所述助流剂为非离子型助流剂；优选地，所述非离子型助流剂选自胶态二氧化硅。
  14. 如权利要求1至13中任一项所述的药物组合物，所述赋形剂包含填充剂、崩解剂、润滑剂和助流剂，其中，所述崩解剂为非离子型崩解剂，所述润滑剂包含非离子型润滑剂，任选地，进一步包含离子型润滑剂。
  15. 如权利要求1至14中任一项所述的药物组合物，其中，所述赋形剂包含填充剂、崩解剂、润滑剂和助流剂，其中，所述崩解剂为非离子型崩解剂，所述润滑剂为离子型润滑剂，所述填充剂包含非 离子型填充剂，所述助流剂为非离子型助流剂。
  16. 权利要求1至15中任一项所述的药物组合物在制备药物中的应用。
  17. 如权利要求16所述的应用，其中，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：RET、FGFR、VEGFR、FLT、EGFR以及它们的突变体中一种或多种。
  18. 如权利要求17所述的应用，其中，所述疾病为细胞增殖性疾病；
    优选地，所述细胞增殖性疾病为肿瘤或癌症；
    更优选地，所述肿瘤包括甲状腺癌、胆道癌、表皮样癌、黑色素瘤、结直肠癌、胃癌、食管癌、胰腺癌、肾癌、肝癌、肺癌和卵巢癌；
    更优选地，所述甲状腺癌为甲状腺髓样癌，所述肺癌为非小细胞肺癌，所述胆道癌为肝内胆管癌；
    进一步优选地，所述非小细胞肺癌为RET融合型非小细胞肺癌。
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