WO2023186031A1

WO2023186031A1 - Pharmaceutical composition of multi-target protein kinase inhibitor, use thereof, and method for preparing same

Info

Publication number: WO2023186031A1
Application number: PCT/CN2023/085194
Authority: WO
Inventors: 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
Priority date: 2022-03-30
Filing date: 2023-03-30
Publication date: 2023-10-05
Also published as: CN117177756A

Abstract

The present invention relates to a pharmaceutical composition of a multi-target protein kinase inhibitor, use thereof, and a method for preparing same. The pharmaceutical composition comprises a compound represented by formula 2 as an active ingredient and an excipient. The pharmaceutical composition can be used for preparing a medicament, particularly a medicament for treating a protein kinase-mediated disease. An oral formulation prepared from the pharmaceutical composition meets the specifications of all parameters, and features good stability and suitability for large-scale production.

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Pharmaceutical compositions of multi-target protein kinase inhibitors and their uses and preparation methods

技术领域Technical field

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。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.

背景技术Background technique

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。Protein tyrosine kinases (PTKs) are a very important member of the protein kinase family. PTKs transfer the γ-phosphate group on adenosine triphosphate to the protein tyrosine residue of the substrate, phosphorylating the phenolic hydroxyl group To complete the transmission of information between cells, it plays a vital role in cell development, regulation, and the differentiation, migration, and apoptosis of tumor cells. 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. For example, 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.

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。Epidermal Growth Factor Receptor (EGFR), Fibroblast Growth Factor Receptors (FGFRs), Platelet-derived Growth Factor Receptor (PDGFR), RET (Rearranged during Transfection) proto-oncogene-encoded RET protein is an important member of PTKs and an important target for tumor treatment.

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。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。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.

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。The normal physiological functions of RET 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. In recent years, 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.

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。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. Compared with single-target drugs, 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。
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.

发明内容Contents of the invention

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。At present, there are no relevant research reports on pharmaceutical compositions of Compound 1 and its pharmaceutically acceptable salts.

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。
On the basis of Compound 1, the inventor further discovered the dihydrochloride of Compound 1 (shown in Formula 2) with better pharmaceutical properties than Compound 1. The dihydrochloride not only has significantly better solubility than Compound 1, but also Moreover, comprehensive index inspection shows that the dihydrochloride is more suitable for preparing drugs than other salt forms of compound 1, and can be made into a variety of pharmaceutical dosage forms according to clinical medication needs. The corresponding research and screening process has been documented in the PCT/CN2021/120328 patent application, the entire content of which is incorporated into this application as a whole.

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。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.

【技术方案】【Technical solutions】

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。In the process of continuous research to explore desirable pharmaceutical compositions and/or oral preparations containing the compound represented by Formula 2, the inventor of the present application has conducted rigorous screening experiments on the ingredients of the pharmaceutical composition, and has discovered specific drugs. The prescription composition of the composition can solve the above technical problems, thus completing this application.

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，
In a first aspect, 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,

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。The "excipients" mentioned in this application, 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. A general term for additional materials, generally pharmaceutically acceptable inert ingredients that have been reasonably evaluated in terms of safety. Examples of 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. For example, excipients can enhance the handling characteristics of pharmaceutical formulations, such as by increasing flowability and/or adhesion, allowing formulation preparation to meet process requirements. Furthermore, the "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. The "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.

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。"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.

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。"Disintegrant" as used in this application 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.

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。The "lubricating excipient" described in this application 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.

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。In some embodiments, the pharmaceutical composition is formulated for oral administration. Preferably, the oral preparation is an oral solid preparation.

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。In some embodiments, according to the paddle method recorded in Part 4 of the 2020 edition of the Chinese Pharmacopoeia, with water as the test medium and a paddle speed of 50 rpm, the pharmaceutical composition or oral preparation does not dissolve 85% of the time in the dissolution test. More than 60 minutes.

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。In some embodiments, 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.

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％。In some embodiments, 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%.

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。In some embodiments, the excipient includes a disintegrant, which is a nonionic disintegrant. Preferably, the excipients further comprise non-ionic excipients, optionally further comprising ionic excipients.

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。In some embodiments, 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.

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。In some embodiments, the nonionic disintegrant comprises dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low-substituted hydroxypropylcellulose, or crospovidone. One or more; preferably, 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.

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％。Preferably, 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%.

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。In some embodiments, the excipients comprise nonionic disintegrants and nonionic fillers, optionally further comprising nonionic glidants, ionic fillers and/or ionic lubricants.

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。In some embodiments, the excipients comprise nonionic disintegrants and nonionic fillers, optionally further comprising nonionic lubricants, nonionic glidants, ionic fillers and/or Or ionic lubricant.

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。In some embodiments, the excipients comprise nonionic disintegrants, nonionic fillers, and nonionic glidants, optionally further comprising nonionic lubricants, ionic fillers, and/or Or ionic lubricant.

在一些实施方案中，所述式2所示化合物为结晶形式。In some embodiments, the compound of Formula 2 is in crystalline form.

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。 In some embodiments, the crystalline form (form I) of the compound represented by formula 2 uses Cu-Kα radiation, and the powder X-ray diffraction pattern expressed in 2θ angle (°) has a characteristic diffraction peak at the following position ( ±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。Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks (±0.2°) at the following positions: 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。Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ angles (°) has characteristic diffraction peaks (±0.2°) at the following positions: 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。Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ 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.

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。Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern expressed in 2θ 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.

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。Alternatively, Cu-Kα radiation is used, with an X-ray powder diffraction pattern substantially as shown in Figure 1 or Figure 2.

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。In some embodiments, 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.

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。In some embodiments, the TGA curve of the crystalline form of the compound represented by Formula 2 (Form I) begins to decompose at 205.6±5°C.

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％。In some embodiments, in the pharmaceutical composition, the weight percentage of the active ingredient (compound represented by Formula 2) 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%.

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％。In some embodiments, in the pharmaceutical composition, 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%.

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％。In some embodiments, in the pharmaceutical composition, 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%.

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，In some embodiments, in the pharmaceutical composition, 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,

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％。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%.

在一些实施方案中，在所述药物组合物中，In some embodiments, in the pharmaceutical composition,

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％。In some embodiments, 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%.

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In some embodiments, 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%; and

(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(i) 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

(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％。(ii) 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%.

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％。In some embodiments, 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%.

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，In some embodiments, 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,

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％。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%.

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；In some embodiments, the nonionic disintegrant is selected from dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low-substituted hydroxypropylcellulose, or crospovidone one or more;

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；Preferably, 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;

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。More preferably, the non-ionic disintegrant is selected from crospovidone, a combination of crospovidone and low-substituted hydroxypropylcellulose.

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；In some embodiments, the filler comprises a non-ionic filler, optionally further comprising an ionic filler;

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；Preferably, the nonionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose;

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。Further preferably, 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.

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In some embodiments, 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. One or more of esters, glyceryl behenate, hydrogenated vegetable oil, talc or polyethylene glycols; preferably stearic acid; and/or

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。When the lubricant includes an ionic lubricant, 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.

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。In some embodiments, the pharmaceutical composition includes a glidant, and wherein the glidant is a nonionic glidant; preferably, the nonionic glidant is selected from colloidal silica.

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。In some embodiments, 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.

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。In some embodiments, 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.

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，
In a second aspect, 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,

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。In some embodiments, the compound represented by Formula 2 is as defined in the first aspect above.

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％。In some embodiments, when the lubricant is a nonionic lubricant, 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%.

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％。In some embodiments, when the lubricant includes both a nonionic lubricant and an ionic lubricant, 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%, further preferably 1% to 2%; when the weight percentage of the active ingredient in the pharmaceutical composition 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 ≤0.7%, preferably ≤0.6%, preferably ≤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％。In some embodiments, 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 When 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%.

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％。In some embodiments, 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 When the percentage is <40% (for example, 15% ≤ active ingredient weight percentage < 40%, 16% ≤ active ingredient weight percentage < 40%, 16% to 35%, 16% to 34%), 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% .

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％。In some embodiments, 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%.

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。In some embodiments, the filler comprises a non-ionic filler, optionally further comprising an ionic filler; preferably, the filler is a non-ionic filler.

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。In some embodiments, the nonionic filler includes one or more of microcrystalline cellulose, pregelatinized starch, mannitol, or lactose.

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；In some embodiments, the nonionic filler comprises microcrystalline cellulose, optionally further comprising starch, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar, or sucrose. one or more;

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；Alternatively, 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;

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；Alternatively, 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;

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。 Alternatively, 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.

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。In some embodiments, the non-ionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose. ; Preferably, 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 Preferably, 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 pregelatinized starch. The combination, or the combination of 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.

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。In some embodiments, when the nonionic filler used is a combination of two nonionic fillers, in the combination of the two nonionic fillers, 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.

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。In some embodiments, the ionic filler is selected from one or more of calcium sulfate, calcium hydrogen phosphate, or calcium phosphate.

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％。In some embodiments, the weight percentage of the ionic filler in the pharmaceutical composition is: 0% to 20%; or 0% to 15%; or 0% to 10%; or 0% to 9% ; Or 0% to 8%; Or 0% to 7%; Or 0% to 6%; Or 0% to 5%; Or 0% to 4%; Or 0% to 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。In some embodiments, when the filler used includes an ionic filler, 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.

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％。In some embodiments, 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%.

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％。In some embodiments, 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. Preferably, 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%.

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。In some embodiments, 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.

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％。Preferably, 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%.

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％。In some embodiments, 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%.

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。In some embodiments, the lubricant comprises a non-ionic lubricant, optionally further comprising an ionic lubricant.

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。In some embodiments, the nonionic lubricant is selected from the group consisting of stearic acid, palmitic acid, glyceryl palmitate stearate, glyceryl behenate, hydrogenated vegetable oil, talc, or polyethylene glycols. One or more; preferably stearic acid.

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。In some embodiments, the nonionic lubricant comprises stearic acid, optionally further comprising palmitic acid, palmitic acid stearic acid One or more of glyceryl esters, hydrogenated vegetable oil, talc, glyceryl behenate or polyethylene glycols.

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。In some embodiments, 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.

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。In some embodiments, 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. Preferably, the other lubricant is magnesium stearate, sodium stearyl fumarate or hydrogenated vegetable oil; more preferably, it is magnesium stearate.

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。In some preferred embodiments, 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.

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％。In some preferred embodiments, 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%. Preferably, when 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), and the active ingredient is in the pharmaceutical composition When 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%.

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％。In some preferred embodiments, 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%. Preferably, when 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), and the active ingredient is in the pharmaceutical composition When 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 The weight percentage of the agent 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 is ≤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％。In some preferred embodiments, 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%. Preferably, when the other lubricant is a non-ionic lubricant (for example, palmitic acid, glyceryl palmitate stearate, glyceryl behenate, hydrogenated vegetable oil, talc or polyethylene glycols, it is preferred When 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%.

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％。In some preferred embodiments, 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%. Preferably, 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%.

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。In some embodiments, in the combination of stearic acid and another lubricant, the weight ratio of stearic acid to another lubricant is 1-3:3-1; preferably 1-2:2- 1; preferably 2 to 10:1; preferably 2 to 5:1; preferably 2 to 3:1; preferably 2:1, 1:2, 1:1; preferably 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％。 In some embodiments, 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%.

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％。In some embodiments, 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%.

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％。In some embodiments, the glidant is a nonionic glidant; preferably, the nonionic glidant is selected from colloidal silica. Preferably, 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 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；In some embodiments, in the pharmaceutical composition, the filler 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;

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。The nonionic filler, nonionic disintegrant, nonionic lubricant, ionic lubricant and nonionic glidant are as defined above.

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％。Preferably, 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%.

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；The filler includes a non-ionic filler, optionally, further comprising an ionic filler;

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％；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%. ≤0.6%, preferably 0% to 0.5%, preferably ≤0.5%; preferably, when the other lubricant is an ionic lubricant, and the weight percentage of the active ingredient in the pharmaceutical composition is When ≥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 ≤0.7% , preferably ≤0.6%, preferably ≤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％；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%;

所述助流剂为胶态二氧化硅；The glidant is colloidal silica;

所述非离子型填充剂或所述离子型填充剂定义如前所述。The non-ionic filler or the ionic filler is as defined above.

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％。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%.

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；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 variety;

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； Alternatively, 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;

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。Alternatively, 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.

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。Preferably, 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.

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。Preferably, when the nonionic filler used is a combination of two nonionic fillers, 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.

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。Preferably, when the filler used includes an ionic filler, 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.

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％；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. A combination of sodium lipofumarate, or a combination of stearic acid and hydrogenated vegetable oil; wherein the weight percentage of the stearic acid in the pharmaceutical composition is 1% to 4%, preferably 1% to 3.5%, It is further preferably 1% to 3%, further preferably 1% to 2%; the weight of the magnesium stearate, calcium stearate, sodium stearyl fumarate or zinc stearate in the pharmaceutical composition 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 When 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 ≤0.6%, preferably ≤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％；The disintegrant is selected from one of dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, low-substituted hydroxypropylcellulose or cross-linked polyvinylpolypyrrolidone, or cross-linked polyvinyl alcohol. A combination of ketone and one or more of dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch or low-substituted hydroxypropylcellulose; wherein the disintegrant is in the drug The weight percentage in the composition is 5% to 35%, preferably 7% to 30%, preferably 8% to 30%, preferably 8% to 20%, preferably 8% to 18%, preferably 8% to 8%. 15%, preferably 10% to 30%, preferably 10% to 20%, preferably 10% to 15%;

所述助流剂为胶态二氧化硅。The glidant is colloidal silica.

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％。Preferably, in the combination of stearic acid and hydrogenated vegetable oil, 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%.

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。In some embodiments, when the filler used includes an ionic filler, 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.

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％；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 is ≤0.6%, preferably 0% to 0.5%, preferably ≤0.5%; preferably, when the other lubricant is an ionic lubricant (for example, magnesium stearate, calcium stearate, sodium benzoate , sodium lauryl sulfate, zinc stearate, sodium stearyl fumarate, magnesium stearyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate or magnesium lauryl sulfate) and the active ingredient is When the weight percentage in the pharmaceutical composition 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 It is ≤0.8%, preferably ≤0.7%, preferably ≤0.6%, preferably ≤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％；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%;

所述助流剂为胶态二氧化硅。The glidant is colloidal silica.

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。Preferably, 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.

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。In some embodiments, when the filler used includes an ionic filler, 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.

在一些实施方案中，在前述药物组合物中，In some embodiments, in the aforementioned pharmaceutical composition,

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％；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%;

所述助流剂为胶态二氧化硅。The glidant is colloidal silica.

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。Preferably, 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. A combination of gelatinized starch and mannitol, or a combination of pregelatinized starch and lactose.

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：In some embodiments, the pharmaceutical composition includes, by total weight thereof, the following components:

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％；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% ;

填充剂：10％～85％；或10％～80％；或10％～75％；Filler: 10% to 85%; or 10% to 80%; or 10% to 75%;

崩解剂：5％～35％；或5％～30％；或5％～20％；或6％～25％；Disintegrant: 5% to 35%; or 5% to 30%; or 5% to 20%; or 6% to 25%;

润滑剂：1％～6％；或1％～5％；或1％～4％；或1％～3.5％；或1％～3％；Lubricant: 1% to 6%; or 1% to 5%; or 1% to 4%; or 1% to 3.5%; or 1% to 3%;

助流剂：3％～8％；或3％～7％；或3％～6％；或3％～5.5％；或3％～5％；Glidant: 3% to 8%; or 3% to 7%; or 3% to 6%; or 3% to 5.5%; or 3% to 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。The active ingredients, fillers, disintegrants, lubricants and glidants are as defined above.

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％；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% ;

填充剂：15％～70％；或15％～65％；或15％～60％；Filler: 15% to 70%; or 15% to 65%; or 15% to 60%;

崩解剂：5％～35％；或5％～30％；或5％～20％；或7％～20％；或7％～30％；或7％～25％；Disintegrant: 5% to 35%; or 5% to 30%; or 5% to 20%; or 7% to 20%; or 7% to 30%; or 7% to 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％；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%;

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％；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%;

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％；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%;

填充剂：15％～68％；或17％～68％；或15％～60％；或15％～55％；或17％～50％；Filler: 15% to 68%; or 17% to 68%; or 15% to 60%; or 15% to 55%; or 17% to 50%;

崩解剂：7％～20％；或8％～20％；或7％～18％；或8％～18％；或8％～15％；Disintegrant: 7% to 20%; or 8% to 20%; or 7% to 18%; or 8% to 18%; or 8% to 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％；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% ;

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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；In some embodiments, the pharmaceutical composition includes the following components by total weight: 15% to 70% active ingredient, 15% to 70% filler, 8% to 30% disintegrant, 1% to 3% lubricant, 3% to 7% glidant;

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；The disintegrant is a non-ionic disintegrant; preferably, the non-ionic disintegrant contains cross-linked povidone;

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；The lubricant includes a non-ionic lubricant, and optionally, further includes an ionic lubricant;

所述助流剂为胶态二氧化硅；The glidant is colloidal silica;

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；Wherein, 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;

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。The nonionic disintegrant, nonionic lubricant, ionic lubricant, nonionic filler and ionic filler are as defined above.

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；In some embodiments, 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;

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；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;

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；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;

所述助流剂为胶态二氧化硅；The glidant is colloidal silica;

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％；Wherein, 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%;

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。The nonionic disintegrant, nonionic lubricant, ionic lubricant and nonionic filler are as defined above.

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；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;

所述助流剂为胶态二氧化硅；The glidant is colloidal silica;

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；In some embodiments, the pharmaceutical composition contains by total weight: 16% to 68% active ingredient, 17% to 68% filler, 8% to 15% disintegrant, 1% to 3% lubricant , 3% to 7% glidant;

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；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;

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；The disintegrant is a non-ionic disintegrant, and the non-ionic disintegrant includes crospovidone;

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；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;

所述助流剂为胶态二氧化硅；The glidant is colloidal silica;

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。In some embodiments, the pharmaceutical composition as described in the first or second aspect is formulated into an oral formulation; preferably, the oral formulation The dosage form is an oral solid preparation; further preferably, the oral solid preparation is selected from capsules, tablets, powders and fine granules; further preferably capsules and tablets; further preferably tablets; still further preferably, the The tablets are coated tablets; further preferably, the coated tablets are film-coated tablets.

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。In some embodiments, the coated tablet includes a tablet core and a coating material, wherein the tablet core includes the aforementioned pharmaceutical composition.

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。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. kind; further, the coating material can be dissolved in a solvent to form a coating liquid. 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. Ethylene glycol, glyceryl monoacetate, glyceryl triacetate, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, castor oil, silicone oil, corn oil, liquid paraffin, etc.; causing Pore agents (also known as release rate regulators) can be selected from sucrose, sodium chloride, surfactants, etc.; solid materials can be selected from talc, magnesium stearate, colloidal silica, caprylic acid monoglycerides and diglycerides etc.; the sunscreen agent includes titanium dioxide; conventional coloring agents in the field may also be used as appropriate. For example, the coloring agent is selected from red iron oxide, amaranth, carmine, tartrazine, soluble indigo, orange G, eosin, and martin. One or more of red, methylene blue, Sudan yellow or mercurochrome. The coating material can also directly use commercially available premixed coating powder, for example Series coating powder, Series coating powder, Series coating powder, Series coating powder, Series coating powder, etc., can also be configured by yourself. The coating material may be a gastric-soluble coating material or an enteric-soluble coating material, and is preferably a gastric-soluble coating material. 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. For example, Series coating powder models include: 321A620034-CN、 321A630026-CN、 321A610052-CN etc.

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。In some embodiments, 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.

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。In a third aspect, 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.

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。In some embodiments, the compound represented by Formula 2 is as described in the first aspect above.

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。In some embodiments, 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 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, it is magnesium stearate.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, the ionic lubricant includes magnesium stearate and the nonionic disintegrant includes crospovidone or low One or two types of hydroxypropylcellulose.

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。In some embodiments, the ionic lubricant is magnesium stearate and the nonionic disintegrant is selected from crospovidone or a combination of crospovidone and low-substituted hydroxypropylcellulose.

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％。In some embodiments, 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%.

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％。In some embodiments, 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%.

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％。In some embodiments, 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 % 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 %.

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％。In some embodiments, 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%.

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。In some embodiments, 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. Combinations, combinations of microcrystalline cellulose and pregelatinized starch, combinations of microcrystalline cellulose and lactose, combinations of microcrystalline cellulose and mannitol, combinations of pregelatinized starch and mannitol, or combinations of pregelatinized starch and lactose A combination of; preferably, the non-ionic filler is selected from microcrystalline cellulose.

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；In some embodiments, 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;

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％。In some embodiments, 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%.

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％。In some embodiments, 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 %.

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％。In some embodiments, the glidant is a nonionic glidant; preferably, the nonionic glidant is selected from colloidal silica. Preferably, 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%.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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；In some embodiments, 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;

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；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;

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；The disintegrant is a non-ionic disintegrant; preferably, the non-ionic disintegrant includes crospovidone, optionally; further including low-substituted hydroxypropylcellulose;

所述润滑剂为硬脂酸镁；The lubricant is magnesium stearate;

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，The glidant is a nonionic glidant; preferably, the nonionic glidant is selected from colloidal silica,

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。Wherein, the definitions of the nonionic disintegrant and the nonionic glidant are the same as in the second aspect above.

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。Preferably, the nonionic disintegrant is selected from crospovidone or a combination of crospovidone and low-substituted hydroxypropylcellulose.

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；In some embodiments, 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;

所述润滑剂为硬脂酸镁；The lubricant is magnesium stearate;

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；In some embodiments, 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;

所述润滑剂为硬脂酸镁；The lubricant is magnesium stearate;

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；In some embodiments, 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;

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；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;

所述润滑剂为硬脂酸镁或硬脂富马酸钠；The lubricant is magnesium stearate or sodium stearyl fumarate;

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；In some embodiments, 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;

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；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;

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In a fourth aspect, 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.

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，In some embodiments, when the lubricant includes both a nonionic lubricant and an ionic lubricant, 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,

(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％；(i) When 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%;

(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％。(ii) 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%.

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。In some embodiments, when the lubricant is an ionic lubricant, 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.

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。In some embodiments, 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.

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％。Preferably, 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%.

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％。In some embodiments, 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%. 3.5%, more preferably 1% to 3%, further preferably 1% to 2%; the weight percentage of the other lubricant in the pharmaceutical composition is less than 1%, preferably ≤0.8%, preferably ≤0.8%. ≤0.7%, preferably ≤0.6%, preferably 0% to 0.5%, preferably ≤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％。In some embodiments, 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 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%.

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。In some embodiments, 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 The definition of ionic filler is as described in the second aspect above.

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。In some embodiments, the non-ionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose. ; Preferably, 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 Preferably, 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 pregelatinized starch. The combination, or the combination of 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. Preferably, the non-ionic filler is microcrystalline cellulose.

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％。In some embodiments, 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%.

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。In some embodiments, the nonionic disintegrant comprises crospovidone; preferably, the nonionic disintegrant is crospovidone.

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％。In some embodiments, 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%.

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。In some embodiments, 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.

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％。In some embodiments, 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%.

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％。In some embodiments, 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%.

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％。In some embodiments, the glidant is a nonionic glidant; preferably, the nonionic glidant is selected from colloidal silica. Preferably, 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%.

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。In some embodiments, 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.

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。In some embodiments, 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.

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。In some embodiments, 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.

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；In some embodiments, 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;

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；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;

所述助流剂为胶态二氧化硅；The glidant is colloidal silica;

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％； Wherein, 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%;

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。The nonionic filler, ionic filler, nonionic disintegrant, nonionic lubricant or ionic lubricant is as defined above (second aspect).

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。Preferably, the nonionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose.

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。Preferably, 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.

优选地，所述填充剂为非离子型填充剂。Preferably, the filler is a non-ionic filler.

所述助流剂为胶态二氧化硅；The glidant is colloidal silica;

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。The definitions of the nonionic filler, ionic filler, and nonionic disintegrant are as described in the second aspect above.

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。Preferably, 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.

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。In some embodiments, 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; preferably, the lubricant contains stearic acid.

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；In some embodiments, 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;

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；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;

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；The disintegrant is selected from non-ionic disintegrants; preferably, the non-ionic disintegrant includes crospovidone;

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；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 One or more of sodium, magnesium lauryl sulfate or polyethylene glycols;

所述助流剂为胶态二氧化硅； The glidant is colloidal silica;

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％。Wherein, 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%.

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；In some embodiments, 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;

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；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;

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；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;

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；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 One or more of sodium, magnesium lauryl sulfate or polyethylene glycols; preferably, the lubricant is stearic acid;

所述助流剂为胶态二氧化硅；The glidant is colloidal silica;

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％。Wherein, 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%.

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。In some embodiments, the pharmaceutical composition is made into an oral preparation. Preferably, the oral preparation is an oral solid preparation; Preferably, the oral solid preparation is a tablet or capsule; Preferably, the oral solid preparation is for capsules.

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。In some embodiments, 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. Preferably, 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.

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。In some embodiments, 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; Preferably, 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. , 450mg-600mg per administration; 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. Preferably, 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.

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。In some embodiments, 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.

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。In some embodiments, 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. Preferably, 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.

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。In some embodiments, 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. Preferably, 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.

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。In some embodiments, 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. In some embodiments, the oral formulation or oral solid formulation may be administered in a single dose or in divided doses; preferably, in a single dose. Preferably, 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.

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。In the fifth aspect, 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.

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。In the sixth aspect, 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.

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。In some embodiments, 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.

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。In the seventh aspect, 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.

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。In an eighth aspect, 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. Or oral solid preparation, the protein kinase is selected from one or more of: RET, FGFR, VEGFR, FLT, EGFR or their mutants.

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。In some embodiments, the diseases in the aforementioned sixth, seventh, and eighth aspects are cell proliferative diseases. Preferably, the cell proliferative disease is tumor or cancer. Preferably, 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. Preferably, the thyroid cancer is medullary thyroid cancer, the lung cancer is non-small cell lung cancer, and the biliary tract cancer is intrahepatic cholangiocarcinoma. Preferably, the non-small cell lung cancer is RET fusion non-small cell lung cancer.

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。In a ninth aspect, 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.

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。In one embodiment, 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.

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。 In one embodiment, 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.

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。In a tenth aspect, 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.

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。In some embodiments, 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.

优选地，所述制粒为干法制粒。Preferably, the granulation is dry granulation.

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。Preferably, excipient 1 contains fillers and glidants, and excipient 2 contains disintegrants and lubricants, optionally further containing fillers and/or glidants.

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。In some embodiments, 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.

优选地，所述制粒选自直压制粒或干法制粒。Preferably, the granulation is selected from direct compression granulation or dry granulation.

【定义和说明】【Definition and Description】

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。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

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。Unless otherwise indicated, all percentages are given as weight % of the total weight of the pharmaceutical composition and its oral formulation.

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。"Oral preparation" or "oral dosage form" as used herein refers to pharmaceutical preparations for oral administration.

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。"Oral solid preparation" as used herein refers to a solid pharmaceutical preparation for oral administration.

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。In the embodiment of the present application, the administration subject may be a human or a non-human mammal, more preferably a human.

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。In the embodiments of this application, the terms "comprises," "includes," and "contains" generally indicate an open-ended meaning, but within their scope also include a closed case defined by "consisting of." For example, "a pharmaceutical composition comprising: as an active ingredient a compound represented by Formula 2 and an excipient" also includes "a pharmaceutical composition comprising as an active ingredient a compound represented by Formula 2 and excipient composition”.

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。Within the scope of this application, various options for any one feature may be combined with various options for other features to form many different embodiments. This application is intended to include all possible embodiments consisting of various options of all technical features.

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。"Optional", "optional" or "optionally" used in this application 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. . For example, "optionally, 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.

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。Within the scope of this application, 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.

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°。Unless otherwise specified, the "2θ", "2θ angle" or "2θ angle" mentioned in this application refers to the diffraction angle in degrees or degrees. The error range of 2θ can be ±0.5°, ±0.4°, ±0.3 °, ±0.2°, or ±0.1°; in some embodiments of the present application, the error range for 2θ is ±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。The term "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.

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。The term "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.

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。The "crystalline form" mentioned in this application 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.

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。The term "solvate" or "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.

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。The term "hydrate" refers to an association formed between stoichiometric or non-stoichiometric water molecules and the compound represented by Formula 2 of the present application.

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。The "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.

【技术效果】【Technical effect】

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：The pharmaceutical composition and/or oral preparation in this application achieves one or more of the following beneficial technical effects:

(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。(1) It has good dissolution effect; (2) It has qualified active ingredient content; (3) The preparation method is simple, the preparation process is smooth, and there are no strict requirements on the equipment and operating techniques used, making it more suitable for industrial production. ; (4) Has good stability.

附图说明Description of drawings

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；Figure 1 shows the XRPD spectrum of Form I of the dihydrochloride salt of Compound 1 obtained in Preparation Example 2;

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。Figure 2 shows the XRPD spectrum of Form I of the dihydrochloride salt of Compound 1 obtained in Preparation Example 2 in Test Example 3 after long-term stability testing.

具体实施方式Detailed ways

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。The technical solution of the present application will be further described in detail below with reference to specific preparation examples and examples. The following preparation examples and examples are only for illustrating and explaining the present application, and should not be construed as limiting the protection scope of the present application. Those skilled in the art can make non-essential improvements and adjustments to the embodiments based on the above invention content, which still fall within the protection scope of the present application. Unless otherwise stated, the raw materials and reagents (for example, organic solvents, inorganic solvents, buffers, excipients, etc.) used in the following preparation examples and examples are commercially available products, or can be prepared by known methods or reagent instructions. or formulation.

以下制备例中，分析检测条件如下：In the following preparation examples, the analysis and detection conditions are as follows:

1、含量或有关物质测试1. Content or related substance testing

检测仪器：Agilent 1260(LC1260-3-DAD)高效液相色谱仪Detection instrument: Agilent 1260 (LC1260-3-DAD) high performance liquid chromatograph

柱子：C18 4.6×250mm,5μmColumn: C18 4.6×250mm, 5μm

测试条件：波长252nm；柱温40±5℃。Test conditions: wavelength 252nm; column temperature 40±5℃.

2、溶解度(水及pH2·0缓冲液)2. Solubility (water and pH 2·0 buffer)

检测仪器：Agilent 1260高效液相色谱仪Detection instrument: Agilent 1260 high performance liquid chromatograph

检测介质：纯化水、pH2.0磷酸-磷酸氢二钠缓冲液Detection medium: purified water, pH2.0 phosphoric acid-disodium hydrogen phosphate buffer

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。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 μg/mL solution. Precisely measure 10 uL, and use HPLC to measure the content of compound 1 in the reference solution. .

3、X-射线粉末衍射(X-RayPowderDiffraction，XRPD) 3. X-Ray Powder Diffraction (XRPD)

检测仪器：Bruker D2PHASER型粉末X-射线衍射仪Testing instrument: Bruker D2PHASER powder X-ray diffractometer

测试条件：Test Conditions:

光管类型：Cu靶，陶瓷X光管；Light tube type: Cu target, ceramic X-ray tube;

X-射线波长：CuKα，1.5406；X-ray wavelength: CuKα, 1.5406;

电压电流：30kV，10mA；Voltage and current: 30kV, 10mA;

扫描范围：3～40°2θ；Scanning range: 3～40°2θ;

扫描总时间：40min；Total scanning time: 40min;

扫描速度：0.5秒/步；Scanning speed: 0.5 seconds/step;

样品用量：3mgSample dosage: 3mg

采集软件：Diffrac Plus XRD CommanderAcquisition software: Diffrac Plus XRD Commander

分析软件：MDI Jade 6.0。Analysis software: MDI Jade 6.0.

4差示扫描量热-热重分析(DimrentialScanningCalorimetry-ThermogravimetricAnalysis，DSC-TGA)4 Differential Scanning Calorimetry-Thermogravimetric Analysis (DimrentialScanningCalorimetry-ThermogravimetricAnalysis, DSC-TGA)

检测仪器：NETZSCH STA449F3同步热分析仪Testing instrument: NETZSCH STA449F3 synchronous thermal analyzer

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℃。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℃.

仪器控制软件：NETZSCH-proteusInstrument control software: NETZSCH-proteus

分析软件：Proteus Analysis。Analysis software: Proteus Analysis.

5、氯化物5. Chloride

检测仪器：戴安ICS-900离子色谱仪Detection instrument: Dionex ICS-900 ion chromatograph

柱子：Dionex Ion Pac AS11-HC阴离子色谱柱(规格：4×250mm)Column: Dionex Ion Pac AS11-HC anion chromatography column (specification: 4×250mm)

实验操作：Experimental operation:

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。Preparation of the 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.

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。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.

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。Determination method: Precisely measure 10 μL 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.

6、核磁氢谱6. Hydrogen nuclear magnetic spectrum

仪器型号：Bruker Advance 600型核磁共振谱仪Instrument model: Bruker Advance 600 nuclear magnetic resonance spectrometer

测定条件：以DMSO-d6为溶剂，在室温下(～25℃)进行测试。Measurement conditions: Use DMSO-d6 as the solvent and conduct the test at room temperature (~25°C).

7、生物溶媒中溶解度测定7. Determination of solubility in biological solvents

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：The preparation process of biosolvent media (SGF, FeSSIF and FaSSIF) used for solubility determination is shown in Table 1 below:

表1

Table 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。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.

8、溶出度测定8. Dissolution determination

溶出介质：1000ml水Dissolution medium: 1000ml water

溶出方法：中国药典2020年版四部0931第二法桨法Dissolution method: Chinese Pharmacopoeia 2020 Edition Part 4 Part 0931 Second Method Paddle Method

转速：50rpmSpeed: 50rpm

制备例1:化合物1的制备
Preparation Example 1: Preparation of Compound 1

使用CN106660970B中的方法(实施例22)制备化合物1。Compound 1 was prepared using the method in CN106660970B (Example 22).

制备例2:化合物1的二盐酸盐的制备
Preparation Example 2: Preparation of dihydrochloride of compound 1

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％。Weigh compound 1 (10g, 21.58mmol) obtained in Preparation Example 1 into an eggplant-shaped bottle, add methanol solvent (110mL), raise the temperature to 55±5°C, stir until dissolved, and add hydrochloric acid (3.7mL, 44.4mmol) dropwise. , stir for 20 minutes, slowly add 200mL of ethyl acetate, cool to 5±5°C, stir for 2±1h, filter with suction, and wash the filter cake with ethyl acetate (20mL) to obtain white dihydrochloride of compound 1 (11g ), the yield is 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). ¹ H-NMR (600MHz, DMSO-d ₆ ) 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。Determine the chloride ion content by ion chromatography and calculate the stoichiometric ratio of the hydrochloride (see Table 2 below). It can be inferred that the alkali/acid ratio of the hydrochloride is 1:2.

表2
Table 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。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℃, and decomposition occurs at around 205℃. The PLM image shows that the crystalline particles are in regular shape.

表3.制备例2所得二盐酸盐的晶型I的XRPD衍射峰数据表
Table 3. XRPD diffraction peak data table of the crystal form I of the dihydrochloride obtained in Preparation Example 2

测试例1:溶解度测试Test Example 1: Solubility Test

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：Take the sample of Preparation Example 2 and conduct a solubility test in water and pH 2.0 buffer. The test results are shown in Table 4 below:

表4.溶解度结果
Table 4. Solubility results

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。Results: The sample of Preparation Example 2 has high solubility in both water and pH2.0 buffer. Although under acidic conditions, the solubility of Preparation Example 2 is lower than its solubility in water, it still has >10 mg/mL. The solubility meets the formulation requirements.

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。According to the general requirements for the solubility of raw materials in pharmaceutical dosage forms, 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. Based on the solubility results in Table 4, 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.

测试例2:生物溶媒中的溶解度测试Test Example 2: Solubility test in biological media

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。Weigh the sample (20 mg) of Preparation Example 2, add different biological solvents (2 mL), and perform a solubility test. The results are shown in Table 5.

表5.样品在不同生物溶媒中的溶解度
Table 5. Solubility of samples in different biological solvents

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。Results: The samples obtained in Preparation Example 2 can maintain good solubility in different biological solvents, and the dissolution speed is fast.

测试例3:稳定性测试Test example 3: Stability test

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：Take an appropriate amount of the salt sample obtained in Preparation Example 2, seal it with a polyethylene film and place it for 5 months under the conditions of 40±2°C and 75%±5% RH, and conduct the test. The results are as follows:

表6.样品的稳定性结果及晶型检测结果

Table 6. Stability results and crystal form detection results of samples

表7.制备例2的晶体样品在稳定性测试后的XRPD数据表
Table 7. XRPD data table of the crystal sample of Preparation Example 2 after stability test

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。The XRPD spectrum of Form I of the dihydrochloride salt of Compound 1 obtained in Preparation Example 2 after the stability test is shown in Figure 2.

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。Results: 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.

测试例4:固体稳定性测试Test Example 4: Solid Stability Test

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。The dihydrochloride salt of Preparation Example 2 was taken and placed under 40° C./75% RH (open) conditions for 7 days to conduct a stability test. The results are shown in Table 8.

表8.稳定性结果及晶型检测结果
Table 8. Stability results and crystal form detection results

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。Results: 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.

测试例5:机械稳定性测试Test Example 5: Mechanical Stability Test

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。An appropriate amount of the dihydrochloride in Preparation Example 2 was taken, mechanically ground for 5 minutes, and then X-ray powder diffraction was performed. The results showed that the crystal form did not change.

实施例1·化合物2的片剂Example 1 Tablets of Compound 2

表9.实施例1的处方(制成1000片)
Table 9. Prescription of Example 1 (made into 1000 tablets)

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。Using dry granulation process, 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.

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。Results: The tableting process was smooth and non-sticky. The prepared tablet core had qualified content and rapid dissolution, and the prescription was qualified.

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)Example 2 Tablets of compound 2 (adjusting the composition and/or weight ratio of the lubricant)

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。Referring to the preparation method of Example 1, adjust the amount or composition of the lubricant to obtain tablets of Examples 2-1 to 2-6.

表10.实施例2的处方(制成1000片)
Table 10. Prescription of Example 2 (made into 1000 tablets)

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。Results: 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.

表10-1.实施例2的处方(制成1000片)
Table 10-1. Prescription of Example 2 (made into 1000 tablets)

实施例3·化合物2的片剂(离子型润滑剂的考察)Example 3 Tablets of compound 2 (investigation of ionic lubricants)

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。Referring to the preparation method of Example 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.

表11.实施例3的处方(制成1000片)
Table 11. Prescription of Example 3 (made into 1000 tablets)

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。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.

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。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.

表12.实施例3的处方(制成1000片)
Table 12. Prescription of Example 3 (made into 1000 tablets)

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。Results: The tableting process of the obtained prescriptions was smooth and non-sticky. The content of the prepared tablet cores met the requirements and the dissolution was rapid. The prescriptions were all qualified. It can be inferred that on the basis of the prescription of Example 3-2, by referring to the prescription of Example 3-6 and adjusting the disintegrant, a qualified prescription can be obtained.

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。Referring to the preparation method of Example 1, on the basis of Example 1, changing the type of lubricant, Examples 3-7 and 3-8 were obtained.

表13.实施例3-7和实施例3-8的处方(制成1000片)

Table 13. Prescriptions of Examples 3-7 and 3-8 (made into 1000 tablets)

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。Results: 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.

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。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.

表13-1.实施例3-9的处方(制成1000片)
Table 13-1. Prescription of Example 3-9 (made into 1000 tablets)

结果:所得处方合格。Result: The obtained prescription was qualified.

实施例4·化合物2的片剂(调整助流剂的用量)Example 4 Tablets of Compound 2 (Adjust the amount of glidant)

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。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.

表14.实施例4的处方(制成1000片)
Table 14. Prescription of Example 4 (made into 1000 tablets)

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。Results: 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.

实施例5·化合物2的片剂(崩解剂的考察) Example 5 Tablets of Compound 2 (Investigation of Disintegrating Agent)

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。Referring to the prescription and preparation method of Example 1, adjust the amount of disintegrant or the composition of the disintegrant to obtain Example 5-1, Example 5-2 and Example 5-3.

表15.实施例5的处方(制成1000片)
Table 15. Prescription of Example 5 (made into 1000 tablets)

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。Results: 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.

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。Referring to the preparation method of Example 1, changing the type of disintegrant, Example 5-4 and Example 5-5 were obtained.

表16.实施例5-4和实施例5-5的处方(制成1000片)
Table 16. Prescriptions of Example 5-4 and Example 5-5 (made into 1000 tablets)

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。Results: When using cross-linked carboxymethyl cellulose sodium (Example 5-4) or carboxymethyl starch sodium (Example 5-5) and other ionic disintegrants, although the tableting process went smoothly, the active ingredient of the resulting prescription ( API) content was significantly reduced and the prescription was unqualified.

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。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.

表15-1.实施例5的处方(制成1000片)

Table 15-1. Prescription of Example 5 (made into 1000 tablets)

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。Results: On the basis of the prescription in Example 5-3, the dosage of the disintegrant was reduced, and the tableting process of the obtained prescription was smooth, the content and dissolution were in compliance with the requirements, and the prescriptions were all qualified.

实施例6·化合物2的片剂(单一填充剂，种类调整)Example 6 Tablets of compound 2 (single filler, type adjustment)

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。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.

表17.实施例6的处方(制成1000片)
Table 17. Prescription of Example 6 (made into 1000 tablets)

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。Results: When using a single filler, microcrystalline cellulose was replaced with lactose (Example 6-1), pregelatinized starch (Example 6-2) or mannitol (Example 6-3), and the resulting prescription pressure The tableting process went smoothly, the content and dissolution were all up to standard, and the prescription was up to standard.

实施例7·化合物2的片剂(两种填充剂的组合)Example 7 Tablets of Compound 2 (combination of two fillers)

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。Referring to the prescription and preparation method of Example 1, a combination of two fillers was used to obtain Example 7-1, Example 7-2 and Example 7-3.

表18.实施例7的处方(制成1000片)

Table 18. Prescription of Example 7 (made into 1000 tablets)

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。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.

实施例8·化合物2的片剂(调整活性成分的用量)Example 8 Tablets of Compound 2 (Adjust the dosage of active ingredients)

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。Referring to the preparation method of Example 1 and the prescription of Example 2-3, the dosage of the active ingredient (API) was adjusted to obtain Example 8-1, Example 8-2 and Example 8-3.

表19.实施例8的处方(分别制成1000片)
Table 19. Prescription of Example 8 (made into 1000 tablets respectively)

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。Results: After adjusting the dosage of active ingredients, the tableting process of the obtained prescriptions was smooth, the content and dissolution were both qualified, and the prescriptions were all qualified.

实施例9·化合物2的片剂(使用不同的包衣材料)Example 9 Tablets of Compound 2 (using different coating materials)

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。Referring to the preparation method of Example 1 and the prescription of Example 2-3, a tablet core was prepared and coated with different coating materials to obtain Example 9-1, Example 9-2, Example 9-3 and Example 9-4.

表20.实施例9的包衣材料和结果(分别制成1000片)

Table 20. Coating materials and results of Example 9 (made into 1000 tablets respectively)

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。Results: Using different coating materials (or called coating powder), the coating process was smooth, the appearance of the obtained coated tablets was qualified, and the coating speed was fast and the coating efficiency was high, which was beneficial to reducing production costs.

实施例10·化合物2的胶囊Example 10·Capsules of Compound 2

表21.实施例10-1的处方(制成1000粒)
Table 21. Prescription of Example 10-1 (made into 1000 tablets)

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。Preparation: 1) Weighing or preparing materials: Weigh the active ingredient (API) compound 2 and the corresponding fillers, disintegrants, glidants and lubricants according to the prescription amount; 2) Premix: Combine the active ingredients, fillers, Add the glidant into the mixing container and premix to obtain a premixed powder; 3) Granulation: Use the premixed powder for dry granulation; 4) General mixing: Combine the granules obtained by dry granulation with the disintegrant and lubricant Carry out total mixing to obtain total mixed powder; 5) Filling capsules: Fill the total mixed powder into capsules.

结果:含量合格，溶出快速，所得实施例10-1处方合格。Results: The content was qualified, the dissolution was rapid, and the prescription of Example 10-1 was qualified.

表22.实施例10-2、10-3和10-4的处方(制成1000粒)
Table 22. Prescriptions of Examples 10-2, 10-3 and 10-4 (made into 1000 tablets)

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。Results: 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.

实施例11·化合物2的胶囊Example 11·Capsules of Compound 2

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。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.

表23.实施例11-1、11-2和11-3的处方(制成1000粒)
Table 23. Prescriptions of Examples 11-1, 11-2 and 11-3 (made into 1000 tablets)

表24.实施例11-4、11-5和11-6的处方(制成1000粒)
Table 24. Prescriptions of Examples 11-4, 11-5 and 11-6 (made into 1000 tablets)

表25.实施例11-7、11-8和11-9的处方(制成1000粒)
Table 25. Prescriptions of Examples 11-7, 11-8 and 11-9 (made into 1000 tablets)

结果：表23、表24和表25中各实施例对应的处方，均合格。Results: The prescriptions corresponding to the examples in Table 23, Table 24 and Table 25 were all qualified.

测试例6:活性成分与辅料相容性试验Test Example 6: Compatibility test of active ingredients and excipients

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。Use active ingredients and different excipients to conduct compatibility tests, and detect the content of relevant substances under the conditions of 4500lx light, high temperature 60℃, high humidity 75%RH±5%RH and high humidity 92.5%RH±5%RH. The results showed that the active ingredient (compound represented by Formula 2) had good compatibility with the tested excipients (especially nonionic excipients), and there was no significant increase in related substances.

测试例7:加速稳定性试验Test Example 7: Accelerated Stability Test

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。The oral preparations obtained in each example were packaged in aluminum-aluminum blister packaging, and stability testing was performed (accelerated conditions, temperature 40°C ± 2°C, relative humidity 75% ± 5%). The stability results of the exemplary embodiments are as follows: shown.

表26.加速(40℃)稳定性数据结果
Table 26. Accelerated (40°C) stability data results

表27.加速(40℃)稳定性数据结果
Table 27. Accelerated (40℃) stability data results

表27-1.加速(40℃)稳定性数据结果
Table 27-1. Accelerated (40℃) stability data results

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。Conclusion: The oral preparations (tablets or capsules) obtained in the four examples in Table 26, Table 27 and Table 27-1 all have the characteristics of good stability, there is no significant increase in related substances, the dissolution in water remains stable, and the content meets the requirements. . Other qualified prescriptions in this application also have good stability, and the water dissolution and content at the inspection time point meet the requirements.

测试例8:长期稳定性试验Test Example 8: Long-term stability test

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。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.

表28.稳定性数据结果
Table 28. Stability data results

表29.稳定性数据结果
Table 29. Stability data results

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。 Conclusion: The oral preparations (tablets) obtained in the three examples in Table 28 and Table 29 all have the characteristics of good long-term stability, there is no significant increase in related substances, the dissolution in water remains stable, and the content meets the requirements. Other qualified prescriptions in this application also have good stability, and the water dissolution and content at the inspection time point meet the requirements.

Claims

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，
A pharmaceutical composition, which is suitable for oral administration and contains as an active ingredient a compound represented by Formula 2 and an excipient,

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。Wherein, the excipients include disintegrants and fillers, and the disintegrants are nonionic disintegrants. Optionally, the excipients further include glidants and/or lubricants.
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。The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is made into an oral preparation form; preferably, the oral preparation is an oral solid preparation; more preferably, the oral solid preparation is a tablet or capsule agent.
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。The pharmaceutical composition according to claim 1 or 2, wherein each preparation unit of the oral preparation contains an active ingredient of 1 mg to 500 mg, or 10 to 450 mg, or 25 to 400 mg, or 50 to 350 mg, or 100 to 100 mg. 300mg, or 150 to 200mg, or 25 to 200mg.
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％。The pharmaceutical composition according to any one of claims 1 to 3, wherein the content of the active ingredient is 0.5% to 80% by weight; or 1% to 75%, based on the total weight of the pharmaceutical composition. %; 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% to 45%; or 20% to 50%; or 20% to 45%; or 20% to 40%.
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％。The pharmaceutical composition according to any one of claims 1 to 4, wherein the weight percentage of the nonionic disintegrant in the pharmaceutical composition is 8% to 40%; preferably 8% to 30%. %; preferably 10% to 40%; preferably 10% to 35%; preferably 10% to 30%; preferably 15% to 40%; preferably 15% to 30%; preferably 20% to 30%; Preferably it is 20% to 40%; Preferably it is 25% to 40%; Preferably it is 30% to 40%.
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％。The pharmaceutical composition according to any one of claims 1 to 5, wherein the weight percentage of the filler in the pharmaceutical composition is: 10% to 85%; or 10% to 80%; or 15 %～75%; or 17%～68%; or 15%～70%; or 15%～65%; or 20%～65%; or 30%～65%; or 30%～60%; or 30% ~55%; or 30% ~ 50%; or 35% ~ 50%; or 40% ~ 55%.
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，The pharmaceutical composition according to any one of claims 1 to 6, wherein the weight percentage of 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%; or,

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％。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%.
如权利要求7所述的药物组合物，其中：The pharmaceutical composition of claim 7, wherein:

(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(1) The lubricant is an ionic lubricant, the weight percentage of the active ingredient in the pharmaceutical composition is less than 40%, and the weight percentage of the ionic lubricant in the pharmaceutical composition is 1% ~3%; preferably 1% ~ 2.5%, preferably 1% ~ 2%, preferably 1% ~ 1.5%; or

(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(2) The lubricant includes both a nonionic lubricant and an ionic lubricant, and the nonionic lubricant is included in the pharmaceutical composition. The weight percentage in is 1% to 4%, preferably 1% to 3.5%, more preferably 1% to 3%, further preferably 1% to 2%; and

(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(i) The weight percentage of the active ingredient in the pharmaceutical composition is greater than or equal to 40%, and the weight percentage of the ionic lubricant in the pharmaceutical composition is less than 1%, preferably less than or equal to 0.8% , preferably less than or equal to 0.7%, preferably less than or equal to 0.6%, preferably less than or equal to 0.5%; or

(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％。(ii) The weight percentage of the active ingredient in the pharmaceutical composition is less than 40%, and 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 It is less than or equal to 1%, preferably less than or equal to 0.8%, more preferably less than or equal to 0.7%, still more preferably less than or equal to 0.6%, still more preferably less than or equal to 0.5%.
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，The pharmaceutical composition according to any one of claims 1 to 8, wherein the weight percentage of the glidant in the pharmaceutical composition is: 0% to 8%; or 0% to 7%; or 0% ~6%; or 0% ~ 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,

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％。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%.
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；The pharmaceutical composition according to any one of claims 1 to 9, wherein the nonionic disintegrant is selected from the group consisting of dry starch, microcrystalline cellulose, powdered cellulose, corn starch, pregelatinized starch, One or more of low-substituted hydroxypropylcellulose or crospovidone;

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；Preferably, 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;

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。More preferably, the non-ionic disintegrant is selected from crospovidone, a combination of crospovidone and low-substituted hydroxypropylcellulose.
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；The pharmaceutical composition according to any one of claims 1 to 10, wherein the filler comprises a nonionic filler, optionally, further comprising an ionic filler;

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；Preferably, the nonionic filler is selected from one or more of starch, microcrystalline cellulose, pregelatinized starch, mannitol, lactose, xylitol, dextrin, powdered sugar or sucrose;

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。Further preferably, 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.
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The pharmaceutical composition according to any one of claims 1 to 11, wherein the pharmaceutical composition comprises a lubricant, and when the lubricant comprises a nonionic lubricant, the nonionic lubricant is selected from the group consisting of One or more of stearic acid, palmitic acid, glyceryl palmitate stearate, glyceryl behenate, hydrogenated vegetable oil, talc or polyethylene glycols; preferably stearic acid; and/or

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。When the lubricant includes an ionic lubricant, 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.
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。The pharmaceutical composition according to any one of claims 1 to 12, wherein the pharmaceutical composition comprises a glidant, and wherein the glidant is a non-ionic glidant; preferably, the non-ionic glidant The ionic glidant is selected from colloidal silica.
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。The pharmaceutical composition according to any one of claims 1 to 13, the excipient comprises a filler, a disintegrant, a lubricant and a glidant, wherein the disintegrant is a non-ionic disintegrant. The lubricant includes a non-ionic lubricant, and optionally, further includes an ionic lubricant.
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。The pharmaceutical composition according to any one of claims 1 to 14, wherein the excipient comprises a filler, a disintegrant, a lubricant and a glidant, wherein the disintegrant is nonionic. disintegrant, the lubricant is an ionic lubricant, and the filler contains non- Ionic filler, the glidant is a non-ionic glidant.
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。Use of the pharmaceutical composition according to any one of claims 1 to 15 in the preparation of medicines.
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。The application according to claim 16, wherein the drug is used to treat or prevent diseases mediated by protein kinases, and the protein kinases are selected from the group consisting of: RET, FGFR, VEGFR, FLT, EGFR and one of their mutants. or more.
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；The application according to claim 17, wherein the disease is a cell proliferative disease;

优选地，所述细胞增殖性疾病为肿瘤或癌症；Preferably, the cell proliferative disease is tumor or cancer;

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；More preferably, the tumors include thyroid cancer, biliary tract cancer, epidermoid cancer, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, liver cancer, lung cancer and ovarian cancer;

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；More preferably, the thyroid cancer is medullary thyroid cancer, the lung cancer is non-small cell lung cancer, and the biliary tract cancer is intrahepatic cholangiocarcinoma;

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。 Further preferably, the non-small cell lung cancer is RET fusion non-small cell lung cancer.