WO2025140560A1

WO2025140560A1 - Pharmaceutical composition of anaplastic lymphoma kinase inhibitor and preparation method therefor

Info

Publication number: WO2025140560A1
Application number: PCT/CN2024/143207
Authority: WO
Inventors: 李嘉逵; 王云灵; 王国骅
Original assignee: Xuanzhu Biopharmaceutical Co Ltd
Current assignee: Xuanzhu Biopharmaceutical Co Ltd
Priority date: 2023-12-28
Filing date: 2024-12-27
Publication date: 2025-07-03
Anticipated expiration: 2026-06-28
Also published as: CN120227378A

Abstract

A pharmaceutical composition of a polycyclic anaplastic lymphoma kinase inhibitor, a preparation method therefor, and use thereof. In particular, the present disclosure relates to a pharmaceutical preparation of 5-chloro-N⁴-(2-(isopropylsulfonyl)phenyl)-N²-(7-methyl-8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrimidine-2,4-diamine, a preparation method therefor, and use thereof.

Description

Pharmaceutical composition of anaplastic lymphoma kinase inhibitor and preparation method thereof

Technical Field

本发明属于医药领域，具体涉及一种5-氯-N⁴-(2-(异丙基磺酰基)苯基)-N²-(7-甲基-8-(哌啶-4-基)-2,3-二氢苯并[b][1,4]二恶英-5-基)嘧啶-2,4-二胺(简称式(I)化合物)的药物组合物，本发明还涉及式(I)化合物的药物组合物的制备方法，及其在制备用于治疗肿瘤患者的药物中的用途。The present invention belongs to the field of medicine, and specifically relates to a pharmaceutical composition of 5-chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(7-methyl-8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrimidine-2,4-diamine (referred to as the compound of formula (I)). The present invention also relates to a method for preparing the pharmaceutical composition of the compound of formula (I), and its use in preparing a drug for treating tumor patients.

Background Art

间变性淋巴瘤激酶(Anaplastic lymphoma kinase，ALK)是受体酪氨酸激酶家族成员，可通过自身磷酸化募集下游蛋白，进而表达特定的基因，调节细胞代谢和生长。间变性淋巴瘤激酶最早发现于间变性大细胞淋巴瘤(Anaplastic large cell lymphoma，ALCL)中，后来发现在非小细胞肺癌(NSCLC)中亦有高表达。Anaplastic lymphoma kinase (ALK) is a member of the receptor tyrosine kinase family. It can recruit downstream proteins through autophosphorylation, thereby expressing specific genes and regulating cell metabolism and growth. Anaplastic lymphoma kinase was first discovered in anaplastic large cell lymphoma (ALCL), and was later found to be highly expressed in non-small cell lung cancer (NSCLC).

ALK在某些ALCL/NSCLC中的异常表达来源于不同的染色体易位。这些染色体易位均可产生相应的融合蛋白。对这些融合蛋白的基因分析表明，它们都含有ALK基因3’端编码胞内激酶区的基因序列，而与ALK融合的基因片段均含启动子元件及编码介导自身二聚化的序列，从而导致细胞内具有ALK激酶活性的融合蛋白高表达及过度激活，引起细胞的恶性转化。所以，ALK胞内激酶区的活性及相应的信号传导途径是导致ALCL形成的重要分子机制。ROS1是目前继ALK之后在肺腺癌中研究比较火热的靶向基因。ROS1是受体酪氨酸激酶家族的一员，ROS1在NSCLC中的发病率为1.7％左右。ROS1和间变性淋巴瘤激酶ALK之间在氨基酸激酶结构域范围内有49％的同源性，并且在ATP结合位点77％的存在同一性，这使得运用ALK激酶抑制剂治疗ROS1重排阳性的NSCLC成为可能。The abnormal expression of ALK in some ALCL/NSCLC is derived from different chromosomal translocations. These chromosomal translocations can all produce corresponding fusion proteins. Genetic analysis of these fusion proteins showed that they all contained the gene sequence encoding the intracellular kinase region at the 3' end of the ALK gene, and the gene fragments fused with ALK all contained promoter elements and sequences encoding self-dimerization, which led to high expression and overactivation of fusion proteins with ALK kinase activity in cells, causing malignant transformation of cells. Therefore, the activity of the intracellular kinase region of ALK and the corresponding signal transduction pathway are important molecular mechanisms leading to the formation of ALCL. ROS1 is currently a hot target gene in lung adenocarcinoma after ALK. ROS1 is a member of the receptor tyrosine kinase family, and the incidence of ROS1 in NSCLC is about 1.7%. There is 49% homology between ROS1 and anaplastic lymphoma kinase ALK in the amino acid kinase domain, and 77% identity in the ATP binding site, which makes it possible to use ALK kinase inhibitors to treat ROS1 rearrangement-positive NSCLC.

专利申请PCT/CN2015/090712中公开了式(I)化合物及其制备方法。研究表明，式(I)化合物具有优异的ALK/ROS1抑制活性，显示出良好的抗肿瘤作用，为癌症患者的治疗提供了可能性，且具有良好的安全性。
Patent application PCT/CN2015/090712 discloses a compound of formula (I) and a method for preparing the same. Studies have shown that the compound of formula (I) has excellent ALK/ROS1 inhibitory activity, exhibits good anti-tumor effects, provides a possibility for the treatment of cancer patients, and has good safety.

为了满足制剂、生产、运输等的要求，申请人对式(1)化合物进行了深入研究，发现了化合物存在较粘等问题，需要在制剂研发中进一步解决这些问题。In order to meet the requirements of formulation, production, transportation, etc., the applicant conducted an in-depth study on the compound of formula (1) and found that the compound has problems such as high viscosity, which need to be further solved in formulation research and development.

申请人对式(I)化合物的自身特点，进行了针对性的研究，以期发现具有良好稳定性、溶出性能的药物制剂，满足临床用药的需求。The applicant has conducted targeted research on the characteristics of the compound of formula (I) in order to find a pharmaceutical preparation with good stability and dissolution properties to meet the needs of clinical medication.

Summary of the invention

本申请发明人在研究中发现，本申请涉及的式(I)化合物在制备制剂时，由于式(I)化合物占比较大，且较粘，出现制剂比较困难的现象。申请人在研究中出人意料的发现：无水磷酸氢钙可以分散式(I)化合物的粘性；填充剂中包含无水磷酸氢钙能够解决式(I)化合物较粘且制剂比较困难的问题。The inventors of the present application have found in their research that when preparing the compound of formula (I) involved in the present application, the compound of formula (I) accounts for a large proportion and is relatively viscous, which makes the preparation difficult. The applicant unexpectedly found in the research that anhydrous calcium hydrogen phosphate can disperse the viscosity of the compound of formula (I); the inclusion of anhydrous calcium hydrogen phosphate in the filler can solve the problem that the compound of formula (I) is relatively viscous and the preparation is difficult.

本发明提供一种式(I)所示化合物的药物组合物，其包含式(I)所示化合物：
The present invention provides a pharmaceutical composition of a compound represented by formula (I), comprising the compound represented by formula (I):

所述药物组合物还包含一种或多种药用辅料，其中所述式(I)化合物以所述药物组合物的25％至70％的重量存在，优选25％至60％、30％至60％、40％至60％，更优选25％至55％、30％至55％、40％至55％、45％至55％，进一步优选50％±2％。The pharmaceutical composition further comprises one or more pharmaceutical excipients, wherein the compound of formula (I) is present in an amount of 25% to 70% by weight of the pharmaceutical composition, preferably 25% to 60%, 30% to 60%, 40% to 60%, more preferably 25% to 55%, 30% to 55%, 40% to 55%, 45% to 55%, and further preferably 50%±2%.

在一些实施方案中，本发明所述药用辅料包含填充剂、粘合剂、崩解剂、润滑剂以及助流剂。In some embodiments, the pharmaceutical excipients of the present invention include fillers, binders, disintegrants, lubricants and glidants.

在一些实施方案中，本发明所述药用辅料包含填充剂、粘合剂、崩解剂、润滑剂、助流剂，以及润湿剂。In some embodiments, the pharmaceutical excipients of the present invention include fillers, binders, disintegrants, lubricants, glidants, and wetting agents.

在一些实施方案中，所述的填充剂至少包含无水磷酸氢钙。In some embodiments, the filler comprises at least anhydrous calcium hydrogen phosphate.

在一些实施方案中，所述的填充剂至少包含预胶化淀粉和无水磷酸氢钙。在一些实施方案中，所述填充剂进一步包含微晶纤维素、甘露醇、玉米淀粉、葡萄糖、蔗糖、糊精中的一种或两种以上。在一些实施方案中，所述填充剂进一步包含微晶纤维素、玉米淀粉中的一种或两种以上。在一些实施方案中，所述填充剂包含微晶纤维素、无水磷酸氢钙、预胶化淀粉的组合。在一些实施方案中，所述填充剂不包含乳糖。In some embodiments, the filler comprises at least pregelatinized starch and anhydrous calcium hydrogen phosphate. In some embodiments, the filler further comprises one or more of microcrystalline cellulose, mannitol, corn starch, glucose, sucrose, and dextrin. In some embodiments, the filler further comprises one or more of microcrystalline cellulose and corn starch. In some embodiments, the filler comprises a combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch. In some embodiments, the filler does not comprise lactose.

在一些实施方案中，所述的填充剂至少包含微晶纤维素和无水磷酸氢钙。在一些实施方案中，所述填充剂进一步包含预胶化淀粉、甘露醇、玉米淀粉、葡萄糖、蔗糖、糊精中的一种或两种以上。在一些实施方案中，所述填充剂进一步包含预胶化淀粉、玉米淀粉中的一种或两种以上。在一些实施方案中，所述填充剂包含微晶纤维素、无水磷酸氢钙、预胶化淀粉的组合。在一些实施方案中，所述填充剂不包含乳糖。In some embodiments, the filler comprises at least microcrystalline cellulose and anhydrous calcium hydrogen phosphate. In some embodiments, the filler further comprises one or more of pregelatinized starch, mannitol, corn starch, glucose, sucrose, and dextrin. In some embodiments, the filler further comprises one or more of pregelatinized starch and corn starch. In some embodiments, the filler comprises a combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch. In some embodiments, the filler does not comprise lactose.

在一些实施方案中，所述填充剂以所述药物组合物的30％至65％的重量存在，优选30％至60％、35％至65％，更优选30％至50％，进一步优选35％至45％，更进一步优选40％±2％。In some embodiments, the filler is present in 30% to 65% by weight of the pharmaceutical composition, preferably 30% to 60%, 35% to 65%, more preferably 30% to 50%, further preferably 35% to 45%, and even more preferably 40% ± 2%.

在一些实施方案中，所述预胶化淀粉以所述药物组合物的2％至15％的重量存在，优选3％至15％，更优选3％至12％，进一步优选3.5％至10％，更进一步优选4％至9.5％。In some embodiments, the pregelatinized starch is present in an amount of 2% to 15% by weight of the pharmaceutical composition, preferably 3% to 15%, more preferably 3% to 12%, further preferably 3.5% to 10%, and even further preferably 4% to 9.5%.

在一些实施方案中，所述无水磷酸氢钙以所述药物组合物的5％至15％的重量存在，优选8％至13％，更优选10％至12％，进一步优选11％±0.5％。In some embodiments, the anhydrous calcium hydrogen phosphate is present in an amount of 5% to 15% by weight of the pharmaceutical composition, preferably 8% to 13%, more preferably 10% to 12%, and further preferably 11% ± 0.5%.

在一些实施方案中，所述微晶纤维素以所述药物组合物的10％至35％的重量存在，优选10％至30％，更优选14％至26％，进一步优选18％至22％，更进一步优选20％±1％。In some embodiments, the microcrystalline cellulose is present in an amount of 10% to 35% by weight of the pharmaceutical composition, preferably 10% to 30%, more preferably 14% to 26%, further preferably 18% to 22%, and even more preferably 20%±1%.

在一些实施方案中，所述填充剂至少包含微晶纤维素、无水磷酸氢钙、预胶化淀粉的组合，其中，微晶纤维素与预胶化淀粉的重量比为1:1至10:1，优选1:1至8:1，更优选2:1至8:1。In some embodiments, the filler comprises at least a combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch, wherein the weight ratio of microcrystalline cellulose to pregelatinized starch is 1:1 to 10:1, preferably 1:1 to 8:1, and more preferably 2:1 to 8:1.

在一些实施方案中，所述填充剂为微晶纤维素、无水磷酸氢钙、预胶化淀粉的组合，其中，微晶纤维素与预胶化淀粉的重量比为1:1至10:1，优选1:1至8:1，更优选2:1至8:1。In some embodiments, the filler is a combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch, wherein the weight ratio of microcrystalline cellulose to pregelatinized starch is 1:1 to 10:1, preferably 1:1 to 8:1, and more preferably 2:1 to 8:1.

在一些实施方案中，所述药用辅料包含粘合剂，优选地，所述的粘合剂选自聚维酮、共聚维酮、海藻酸、壳聚糖、糊精、麦芽糊精、麦芽糖、卡波姆、阿拉伯胶、羟丙纤维素、羟丙甲纤维素中的一种或两种以上，更优选地，所述粘合剂选自聚维酮、共聚维酮中的一种或两种以上。In some embodiments, the pharmaceutical excipient comprises a binder. Preferably, the binder is selected from one or more of povidone, copovidone, alginate, chitosan, dextrin, maltodextrin, maltose, carbomer, gum arabic, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. More preferably, the binder is selected from one or more of povidone and copovidone.

在一些实施方案中，所述粘合剂以所述药物组合物的1％至5％的重量存在，优选1％至4％，更优选1.5％至3.5％，进一步优选2％至3％，更进一步优选2.5％±0.2％。In some embodiments, the binder is present in an amount of 1% to 5% by weight of the pharmaceutical composition, preferably 1% to 4%, more preferably 1.5% to 3.5%, further preferably 2% to 3%, and even further preferably 2.5% ± 0.2%.

在一些实施方案中，所述药用辅料包含至少一种崩解剂。在一些实施方案中，所述崩解剂选自交联羧甲基纤维素钠、羟甲基淀粉钠、羟丙基纤维素、交联聚维酮、淀粉中的一种或两种以上。在一些实施方案中，所述崩解剂选自交联羧甲基纤维素钠、交联聚维酮中的一种或两种以上。In some embodiments, the pharmaceutical excipient comprises at least one disintegrant. In some embodiments, the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium hydroxymethyl starch, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and starch. In some embodiments, the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone.

在一些实施方案中，所述的崩解剂以所述药物组合物的1％至10％的重量存在，优选1％至8％，更优选2％至6％，进一步优选3％至5％，进一步优选3.5％至4.5％，更进一步优选4.0％±0.2％。In some embodiments, the disintegrant is present in an amount of 1% to 10% by weight of the pharmaceutical composition, preferably 1% to 8%, more preferably 2% to 6%, further preferably 3% to 5%, further preferably 3.5% to 4.5%, and further preferably 4.0% ± 0.2%.

在一些实施方案中，所述崩解剂采用内加和外加相结合的方式，内加和外加的比例为1:3至3:2，优选1:3至3:1，更优选1:1。In some embodiments, the disintegrant is added internally and externally in a ratio of 1:3 to 3:2, preferably 1:3 to 3:1, and more preferably 1:1.

在一些实施方案中，本发明所述组合物的药用辅料包含至少一种助流剂。在一些实施方案中，所述的助流剂选自二氧化硅、胶态二氧化硅、胶态硅石、玉米淀粉、滑石粉中的一种或两种以上。在一些实施方案中，所述的助流剂选自二氧化硅或胶态二氧化硅。在一些实施方案中，所述的助流剂选自胶态二氧化硅。在一些实施方案中，所述助流剂以所述药物组合物的0.2％至2％的重量存在，优选0.5％至1.5％，更优选1％±0.2％。In some embodiments, the pharmaceutical excipients of the composition of the present invention include at least one glidant. In some embodiments, the glidant is selected from one or more of silicon dioxide, colloidal silicon dioxide, colloidal silica, corn starch, and talc. In some embodiments, the glidant is selected from silicon dioxide or colloidal silicon dioxide. In some embodiments, the glidant is selected from colloidal silicon dioxide. In some embodiments, the glidant is present in an amount of 0.2% to 2% by weight of the pharmaceutical composition, preferably 0.5% to 1.5%, and more preferably 1% ± 0.2%.

在一些实施方案中，本发明所述组合物的药用辅料包含至少一种润滑剂。在一些实施方案中，所述的润滑剂选自硬脂酸镁、硬脂酸钙、滑石粉、二氧化硅、硬脂酸中的一种或两种以上的混合物。在一些实施方案中，所述的润滑剂选自硬脂酸镁。在一些实施方案中，所述润滑剂以所述药物组合物的0.5％至5％的重量存在，优选1％至5％、0.5％至3％，更优选1％至3％，进一步优选1.5％至2.5％，更进一步优选2％±0.2％。In some embodiments, the pharmaceutical excipients of the composition of the present invention include at least one lubricant. In some embodiments, the lubricant is selected from one or more of magnesium stearate, calcium stearate, talc, silicon dioxide, and stearic acid. In some embodiments, the lubricant is selected from magnesium stearate. In some embodiments, the lubricant is present in an amount of 0.5% to 5% by weight of the pharmaceutical composition, preferably 1% to 5%, 0.5% to 3%, more preferably 1% to 3%, further preferably 1.5% to 2.5%, and further preferably 2% ± 0.2%.

在一些实施方案中，所述的润湿剂选自水、75％乙醇、90％乙醇、95％乙醇或无水乙醇。在一些实施方案中，所述的润湿剂选自纯化水。In some embodiments, the wetting agent is selected from water, 75% ethanol, 90% ethanol, 95% ethanol or anhydrous ethanol. In some embodiments, the wetting agent is selected from purified water.

在一些实施方案中，本发明所述药物组合物各组分的总含量小于等于100％。In some embodiments, the total content of each component of the pharmaceutical composition of the present invention is less than or equal to 100%.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；并且基于所述药物组合物的总重量，所述的式(I)化合物含量为25％至70％，所述的粘合剂含量为1％至5％，所述的填充剂含量为30％至65％，所述的崩解剂含量为1％至10％，所述的润滑剂含量为0.5％至5％，所述的助流剂含量为0.2％至2％，所述的填充剂至少包含无水磷酸氢钙。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 70%, the content of the binder is 1% to 5%, the content of the filler is 30% to 65%, the content of the disintegrant is 1% to 10%, the content of the lubricant is 0.5% to 5%, the content of the glidant is 0.2% to 2%, and the filler contains at least anhydrous calcium hydrogen phosphate.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；并且基于所述药物组合物的总重量，所述的式(I)化合物含量为25％至55％，所述的粘合剂含量为1％至5％，所述的填充剂含量为30％至65％，所述的崩解剂含量为1％至10％，所述的润滑剂含量为0.5％至5％，所述的助流剂含量为0.2％至2％，所述的填充剂至少包含无水磷酸氢钙，且填充剂不含乳糖。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 55%, the content of the binder is 1% to 5%, the content of the filler is 30% to 65%, the content of the disintegrant is 1% to 10%, the content of the lubricant is 0.5% to 5%, the content of the glidant is 0.2% to 2%, the filler contains at least anhydrous calcium hydrogen phosphate, and the filler does not contain lactose.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；并且基于所述药物组合物的总重量，所述的式(I)化合物含量为25％至55％，所述的粘合剂含量为1％至5％，所述的填充剂含量为35％至65％，所述的崩解剂含量为3％至5％，所述的润滑剂含量为0.5％至3％，所述的助流剂含量为0.5％至1.5％，所述的填充剂至少包含微晶纤维素和无水磷酸氢钙，且填充剂不含乳糖。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 55%, the content of the binder is 1% to 5%, the content of the filler is 35% to 65%, the content of the disintegrant is 3% to 5%, the content of the lubricant is 0.5% to 3%, the content of the glidant is 0.5% to 1.5%, the filler comprises at least microcrystalline cellulose and anhydrous calcium hydrogen phosphate, and the filler does not contain lactose.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；并且基于所述药物组合物的总重量，所述的式(I)化合物含量为25％至70％，所述的粘合剂含量为1％至5％，所述的填充剂含量为30％至60％，所述的崩解剂含量为1％至10％，所述的润滑剂含量为1％至5％，所述的助流剂含量为0.2％至2％，所述的填充剂至少包含预胶化淀粉和无水磷酸氢钙。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 70%, the content of the binder is 1% to 5%, the content of the filler is 30% to 60%, the content of the disintegrant is 1% to 10%, the content of the lubricant is 1% to 5%, the content of the glidant is 0.2% to 2%, and the filler comprises at least pregelatinized starch and anhydrous calcium hydrogen phosphate.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；并且基于所述药物组合物的总重量，所述的式(I)化合物含量为25％至70％，所述的粘合剂含量为1％至5％，所述的填充剂含量为30％至60％，所述的崩解剂含量为1％至10％，所述的润滑剂含量为1％至5％，所述的助流剂含量为0.2％至2％，所述的填充剂至少包含预胶化淀粉和无水磷酸氢钙，且填充剂不含乳糖。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 70%, the content of the binder is 1% to 5%, the content of the filler is 30% to 60%, the content of the disintegrant is 1% to 10%, the content of the lubricant is 1% to 5%, the content of the glidant is 0.2% to 2%, the filler comprises at least pregelatinized starch and anhydrous calcium hydrogen phosphate, and the filler does not contain lactose.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；并且基于所述药物组合物的总重量，所述的式(I)化合物含量为25％至55％，所述的粘合剂含量为1％至5％，所述的填充剂含量为35％至65％，所述的崩解剂含量为3％至5％，所述的润滑剂含量为0.5％至3％，所述的助流剂含量为0.5％至1.5％，所述的填充剂至少包含预胶化淀粉和无水磷酸氢钙。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 55%, the content of the binder is 1% to 5%, the content of the filler is 35% to 65%, the content of the disintegrant is 3% to 5%, the content of the lubricant is 0.5% to 3%, the content of the glidant is 0.5% to 1.5%, and the filler comprises at least pregelatinized starch and anhydrous calcium hydrogen phosphate.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；并且基于所述药物组合物的总重量，所述的式(I)化合物含量为25％至55％，所述的粘合剂含量为1％至4％，所述的填充剂含量为30％至50％，所述的崩解剂含量为3％至5％，所述的润滑剂含量为1％至3％，所述的助流剂含量为0.5％至1.5％，所述的填充剂包含微晶纤维素、预胶化淀粉和无水磷酸氢钙。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 55%, the content of the binder is 1% to 4%, the content of the filler is 30% to 50%, the content of the disintegrant is 3% to 5%, the content of the lubricant is 1% to 3%, the content of the glidant is 0.5% to 1.5%, and the filler comprises microcrystalline cellulose, pregelatinized starch and anhydrous calcium hydrogen phosphate.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；并且基于所述药物组合物的总重量，所述的式(I)化合物含量为25％至70％，所述的粘合剂含量为1％至5％，所述的填充剂含量为30％至60％，所述的崩解剂含量为1％至10％，所述的润滑剂含量为1％至5％，所述的助流剂含量为0.2％至2％，所述的填充剂至少包含预胶化淀粉和无水磷酸氢钙；其中所述预胶化淀粉以所述药物组合物的3％至12％的重量存在，优选3.5％至10％，进一步优选4％至9.5％。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 70%, the content of the binder is 1% to 5%, the content of the filler is 30% to 60%, the content of the disintegrant is 1% to 10%, the content of the lubricant is 1% to 5%, the content of the glidant is 0.2% to 2%, and the filler comprises at least pregelatinized starch and anhydrous calcium hydrogen phosphate; wherein the pregelatinized starch is present in an amount of 3% to 12% by weight of the pharmaceutical composition, preferably 3.5% to 10%, and further preferably 4% to 9.5%.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；所述的填充剂至少包含预胶化淀粉和无水磷酸氢钙。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; the filler comprises at least pregelatinized starch and anhydrous calcium hydrogen phosphate.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；所述的填充剂至少包含预胶化淀粉和无水磷酸氢钙，且不含乳糖。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; the filler comprises at least pregelatinized starch and anhydrous calcium hydrogen phosphate, and does not contain lactose.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；所述的填充剂包含微晶纤维素、预胶化淀粉和无水磷酸氢钙。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; the filler comprises microcrystalline cellulose, pregelatinized starch and anhydrous calcium hydrogen phosphate.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；所述的填充剂由微晶纤维素、预胶化淀粉和无水磷酸氢钙组成；其中预胶化淀粉以所述药物组合物的3％至12％的重量存在，优选3.5％至10％，进一步优选4％至9.5％。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; the filler consists of microcrystalline cellulose, pregelatinized starch and anhydrous calcium hydrogen phosphate; wherein the pregelatinized starch is present in an amount of 3% to 12% by weight of the pharmaceutical composition, preferably 3.5% to 10%, and further preferably 4% to 9.5%.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；式(I)化合物以所述药物组合物的25％至60％的重量存在；所述的填充剂由微晶纤维素、预胶化淀粉和无水磷酸氢钙组成；其中预胶化淀粉以所述药物组合物的3％至12％的重量存在；所述粘合剂为聚维酮；所述崩解剂为交联羧甲基纤维素钠或交联聚维酮。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; the compound of formula (I) is present in an amount of 25% to 60% by weight of the pharmaceutical composition; the filler is composed of microcrystalline cellulose, pregelatinized starch and anhydrous calcium hydrogen phosphate; wherein the pregelatinized starch is present in an amount of 3% to 12% by weight of the pharmaceutical composition; the binder is povidone; and the disintegrant is cross-linked sodium carboxymethyl cellulose or cross-linked povidone.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；式(I)化合物以所述药物组合物的40％至60％的重量存在；所述的填充剂由微晶纤维素、预胶化淀粉和无水磷酸氢钙组成；其中预胶化淀粉以所述药物组合物的3.5％至10％的重量存在；所述粘合剂为聚维酮；所述崩解剂为交联羧甲基纤维素钠或交联聚维酮；所述助流剂为胶态二氧化硅；所述润滑剂为硬脂酸镁。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; the compound of formula (I) is present in 40% to 60% by weight of the pharmaceutical composition; the filler is composed of microcrystalline cellulose, pregelatinized starch and anhydrous calcium hydrogen phosphate; wherein the pregelatinized starch is present in 3.5% to 10% by weight of the pharmaceutical composition; the binder is povidone; the disintegrant is cross-linked sodium carboxymethyl cellulose or cross-linked povidone; the glidant is colloidal silicon dioxide; and the lubricant is magnesium stearate.

在一些实施方案中，本发明所述药物组合物为口服制剂，优选地，所述口服制剂为片剂，更优选地，所述片剂经薄膜包衣。In some embodiments, the pharmaceutical composition of the present invention is an oral preparation, preferably, the oral preparation is a tablet, and more preferably, the tablet is film-coated.

在一些实施方案中，所述药物组合物包含40％至60％重量的式(I)化合物、30％至50％重量的填充剂、1％至4％重量的粘合剂、3％至5％重量的崩解剂、0.5％至1.5％重量的助流剂、1.5％至2.5％重量的润滑剂。In some embodiments, the pharmaceutical composition comprises 40% to 60% by weight of a compound of formula (I), 30% to 50% by weight of a filler, 1% to 4% by weight of a binder, 3% to 5% by weight of a disintegrant, 0.5% to 1.5% by weight of a glidant, and 1.5% to 2.5% by weight of a lubricant.

在一些实施方案中，所述药物组合物包含45％至55％重量的式(I)化合物、35％至45％重量的填充剂、1.5％至3.5％重量的粘合剂、3.5％至4.5％重量的崩解剂、0.5％至1.5％重量的助流剂、1.5％至2.5％重量的润滑剂。In some embodiments, the pharmaceutical composition comprises 45% to 55% by weight of a compound of formula (I), 35% to 45% by weight of a filler, 1.5% to 3.5% by weight of a binder, 3.5% to 4.5% by weight of a disintegrant, 0.5% to 1.5% by weight of a glidant, and 1.5% to 2.5% by weight of a lubricant.

在一些实施方案中，所述药物组合物包含50％±2％重量的式(I)化合物、40％±2％重量的填充剂、2.5％±0.2％重量的粘合剂、4.0％±0.2％重量的崩解剂、1％±0.2％重量的助流剂、2％±0.2％重量的润滑剂。In some embodiments, the pharmaceutical composition comprises 50%±2% by weight of a compound of formula (I), 40%±2% by weight of a filler, 2.5%±0.2% by weight of a binder, 4.0%±0.2% by weight of a disintegrant, 1%±0.2% by weight of a glidant, and 2%±0.2% by weight of a lubricant.

在一些实施方案中，其中所述药用辅料包含填充剂、粘合剂、崩解剂、润滑剂以及助流剂，其中填充剂选自微晶纤维素、无水磷酸氢钙和预胶化淀粉的组合，所述粘合剂选自聚维酮，所述崩解剂选自交联羧甲基纤维素钠或交联聚维酮，所述润滑剂为硬脂酸镁，所述助流剂为胶态二氧化硅。In some embodiments, the pharmaceutical excipients comprise a filler, a binder, a disintegrant, a lubricant and a glidant, wherein the filler is selected from a combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate and pregelatinized starch, the binder is selected from povidone, the disintegrant is selected from cross-linked sodium carboxymethyl cellulose or cross-linked povidone, the lubricant is magnesium stearate, and the glidant is colloidal silicon dioxide.

在一些实施方案中，一种药物组合物，其含有：In some embodiments, a pharmaceutical composition comprising:

(1)40％至60％重量的式(I)化合物；(1) 40% to 60% by weight of a compound of formula (I);

(2)30％至50％重量的填充剂，所述填充剂至少包含无水磷酸氢钙和预胶化淀粉；优选地，所述填充剂由微晶纤维素、无水磷酸氢钙和预胶化淀粉组成；(2) 30% to 50% by weight of a filler, wherein the filler comprises at least anhydrous calcium hydrogen phosphate and pregelatinized starch; preferably, the filler consists of microcrystalline cellulose, anhydrous calcium hydrogen phosphate and pregelatinized starch;

(3)1％至4％重量的粘合剂，所述粘合剂为聚维酮；(3) 1% to 4% by weight of a binder, wherein the binder is povidone;

(4)3％至5％重量的崩解剂，所述崩解剂为交联羧甲基纤维素钠或交联聚维酮；(4) 3% to 5% by weight of a disintegrant, wherein the disintegrant is cross-linked sodium carboxymethylcellulose or cross-linked polyvinylpyrrolidone;

(5)0.5％至1.5％重量的助流剂，所述助流剂为胶态二氧化硅；(5) 0.5% to 1.5% by weight of a glidant, wherein the glidant is colloidal silicon dioxide;

(6)1％至3％重量的润滑剂，所述润滑剂为硬脂酸镁。(6) 1% to 3% by weight of a lubricant, wherein the lubricant is magnesium stearate.

在一些实施方案中，本发明提供另一种包含式(I)化合物或式(I)化合物的药物组合物，其中，式(I)化合物以10mg-500mg的量存在。优选地，所述的式(I)化合物以20mg-300mg的量存在；更优选地，所述的式(I)化合物以50mg-250mg的量存在，进一步优选地，所述的式(I)化合物以50mg、100mg、150mg、200mg、250mg的量存在。In some embodiments, the present invention provides another pharmaceutical composition comprising a compound of formula (I) or a compound of formula (I), wherein the compound of formula (I) is present in an amount of 10 mg-500 mg. Preferably, the compound of formula (I) is present in an amount of 20 mg-300 mg; more preferably, the compound of formula (I) is present in an amount of 50 mg-250 mg, and further preferably, the compound of formula (I) is present in an amount of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg.

在一些实施方案中，在本发明提供药物组合物中，所述的式(I)化合物，在制粒之前，进行过筛或粉碎处理。在一些实施方案中，在本发明提供药物组合物中，所述的式(I)化合物，其粒径分布的D90为5-150μm，优选10-100μm，更优选10-85μm。In some embodiments, in the pharmaceutical composition provided by the present invention, the compound of formula (I) is sieved or crushed before granulation. In some embodiments, in the pharmaceutical composition provided by the present invention, the compound of formula (I) has a particle size distribution D90 of 5-150 μm, preferably 10-100 μm, more preferably 10-85 μm.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；所述的填充剂由微晶纤维素、预胶化淀粉和无水磷酸氢钙组成；所述的式(I)化合物其粒径分布的D90为10-100μm。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; the filler consists of microcrystalline cellulose, pregelatinized starch and anhydrous calcium hydrogen phosphate; the particle size distribution D90 of the compound of formula (I) is 10-100 μm.

在一些实施方案中，本发明提供了一种药物组合物，其包含式(I)化合物、粘合剂、填充剂、崩解剂、润滑剂以及助流剂；所述的填充剂由微晶纤维素、预胶化淀粉和无水磷酸氢钙组成；其中预胶化淀粉以所述药物组合物的3％至12％的重量存在；所述的式(I)化合物其粒径分布的D90为10-100μm。In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; the filler consists of microcrystalline cellulose, pregelatinized starch and anhydrous calcium hydrogen phosphate; wherein the pregelatinized starch is present in an amount of 3% to 12% by weight of the pharmaceutical composition; and the particle size distribution D90 of the compound of formula (I) is 10-100 μm.

在一些实施方案中，式(I)化合物的药物组合物的溶出为：在45分钟后至少有75％、优选80％、更优选85％的式(I)化合物溶出。In some embodiments, the dissolution of the pharmaceutical composition of the compound of formula (I) is such that at least 75%, preferably 80%, and more preferably 85% of the compound of formula (I) is dissolved after 45 minutes.

在一些实施方案中，本发明还提供一种式(I)化合物药物组合物的制备方法，所述制备方法包括式(I)化合物与填充剂、崩解剂预先混合的步骤。In some embodiments, the present invention also provides a method for preparing a pharmaceutical composition of a compound of formula (I), the method comprising the step of premixing the compound of formula (I) with a filler and a disintegrant.

在一些实施方案中，所述制备方法包括湿法制粒的步骤。In some embodiments, the preparation method comprises a step of wet granulation.

在一些实施方式中，所述制备方法包括崩解剂内加和外加的步骤。In some embodiments, the preparation method comprises the steps of internal and external addition of a disintegrant.

在一些实施方式中，所述制备方法包括以下步骤：In some embodiments, the preparation method comprises the following steps:

(1)混合式(I)化合物、填充剂、崩解剂，加入粘合剂，制粒；(1) mixing the compound of formula (I), a filler, and a disintegrant, adding a binder, and granulating;

(2)加入助流剂，进行干整粒；(2) adding a glidant and performing dry granulation;

(3)加入崩解剂、润滑剂，混合均匀；(3) Add disintegrant and lubricant and mix well;

(4)压制所述混合物获得所述片剂。(4) compressing the mixture to obtain the tablet.

在一些实施方式中，其中所述制备方法包括如下步骤：In some embodiments, the preparation method comprises the following steps:

(1)在制粒机中混合所述式(I)化合物、填充剂、崩解剂，获得预混合物；(1) mixing the compound of formula (I), a filler, and a disintegrant in a granulator to obtain a premix;

(2)将粘合剂溶解在纯化水中，配制成粘合剂溶液；(2) dissolving the binder in purified water to prepare a binder solution;

(3)将粘合剂溶液加入步骤(1)中的预混合物，制粒；(3) adding the binder solution to the premix in step (1) and granulating;

(4)用湿法制粒机进行整粒；(4) Granulation using a wet granulator;

(5)将湿颗粒投入流化床制粒机中进行干燥；(5) placing the wet granules into a fluidized bed granulator for drying;

(6)将助流剂置于干颗粒中，进行干整粒；(6) placing a glidant in the dry granules and performing dry granulation;

(7)加入崩解剂、润滑剂，用混合机混合均匀；(7) adding disintegrant and lubricant and mixing evenly using a mixer;

(8)压片。(8) Tableting.

在一些实施方案中，本发明提供一种药物组合物在制备用于治疗癌症的药物中的用途，任选地，还包括一种或多种第二治疗剂。In some embodiments, the present invention provides a use of a pharmaceutical composition in the preparation of a medicament for treating cancer, optionally further comprising one or more second therapeutic agents.

在一些实施方案中，所述的第二治疗剂选自抗代谢物、生长因子抑制剂、抗体、有丝分裂抑制剂、抗肿瘤激素类、烷化剂类、金属铂类、免疫抑制类、嘌呤类似物、抗生素类、肾上腺皮质抑制剂类或酶抑制剂。In some embodiments, the second therapeutic agent is selected from antimetabolites, growth factor inhibitors, antibodies, mitotic inhibitors, anti-tumor hormones, alkylating agents, metal platinums, immunosuppressants, purine analogs, antibiotics, adrenocortical inhibitors or enzyme inhibitors.

本发明所述的以上实施方案中的任一个或两个以上的任意组合，都包含在本发明的保护范围之内。Any one or any combination of two or more of the above embodiments described in the present invention is included in the protection scope of the present invention.

在一些实施方案中，本发明所述的癌症选自肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、结直肠癌、肝癌、肝母细胞瘤、乳头状肾细胞瘤、头颈部鳞状细胞瘤、肾母细胞瘤、肾癌、食管腺癌、食管鳞状细胞癌、中枢神经系统肿瘤、雌性生殖道癌、原位癌、淋巴瘤、成神经细胞瘤、神经纤维瘤病、甲状腺癌、骨癌、皮肤癌、脑癌、睾丸癌、胃肠道间质瘤、前列腺肿瘤、多发性骨髓瘤、黑色素瘤、神经母细胞瘤、肉瘤或神经胶质瘤。In some embodiments, the cancer described herein is selected from lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, hepatoblastoma, papillary renal cell tumor, head and neck squamous cell tumor, Wilms tumor, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, central nervous system tumors, female reproductive tract cancer, carcinoma in situ, lymphoma, neuroblastoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, brain cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, multiple myeloma, melanoma, neuroblastoma, sarcoma or glioma.

在一些实施方案中，所述肺癌选自非小细胞性肺癌或小细胞肺癌。In some embodiments, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

在一些实施方案中，所述癌症选自脑瘤、非霍奇金淋巴瘤、非小细胞性肺癌、小细胞肺癌、结肠癌、肥大细胞肿瘤或黑色素瘤。In some embodiments, the cancer is selected from a brain tumor, non-Hodgkin's lymphoma, non-small cell lung cancer, small cell lung cancer, colon cancer, mast cell tumor, or melanoma.

在一些实施方案中，所述癌症选自胶质瘤。In some embodiments, the cancer is selected from glioma.

在一些实施方案中，所述癌症选自星形细胞瘤。In some embodiments, the cancer is selected from astrocytoma.

本发明所述的“药物组合物”，为药学上可接受的任一剂型，以口服、肠胃外、直肠或经肺给药等方式施用于需要其的患者。用于口服给药时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于经肺给药时，可制成吸入剂或喷雾剂等。The "pharmaceutical composition" of the present invention is any pharmaceutically acceptable dosage form, which is administered to patients in need thereof by oral, parenteral, rectal or transpulmonary administration. When used for oral administration, it can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When made into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. When used for transpulmonary administration, it can be made into inhalants or sprays, etc.

本发明所述的药用辅料为本领域技术人员所知的，包括但不仅限于：填充剂、粘合剂、润湿剂、崩解剂、润滑剂、助流剂、包衣预混剂、包衣分散剂。The pharmaceutical excipients described in the present invention are known to those skilled in the art, and include but are not limited to: fillers, binders, wetting agents, disintegrants, lubricants, glidants, coating premixes, and coating dispersants.

本发明所述的填充剂为本领域技术人员所知的，包括但不限于选自微晶纤维素、无水磷酸氢钙、预胶化淀粉、甘露醇、玉米淀粉、葡萄糖、蔗糖、糊精中的一种或两种以上的组合。The filler described in the present invention is known to those skilled in the art, including but not limited to one or a combination of two or more selected from microcrystalline cellulose, anhydrous calcium hydrogen phosphate, pregelatinized starch, mannitol, corn starch, glucose, sucrose, and dextrin.

本发明所述的粘合剂为本领域技术人员所知的，包括但不限于海藻酸、壳聚糖、聚维酮、共聚维酮、糊精、麦芽糊精、麦芽糖、卡波姆、阿拉伯胶、羟丙纤维素、羟丙甲纤维素。The adhesive of the present invention is known to those skilled in the art, including but not limited to alginate, chitosan, povidone, copovidone, dextrin, maltodextrin, maltose, carbomer, gum arabic, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.

本发明所述的润湿剂为本领域技术人员所知的，包括但不限于水、75％乙醇、90％乙醇、95％乙醇、无水乙醇。The wetting agent described in the present invention is known to those skilled in the art, including but not limited to water, 75% ethanol, 90% ethanol, 95% ethanol, and anhydrous ethanol.

本发明所述的崩解剂为本领域技术人员所知的，包括但不限于交联羧甲基纤维素钠、羟甲基纤维素、羟丙基纤维素、交联聚维酮羟甲基纤维素钙、低取代羟丙甲基纤维素、交联聚乙烯吡咯烷酮、淀粉、羟甲基淀粉钠、羟丙基淀粉。The disintegrants described in the present invention are known to those skilled in the art, including but not limited to cross-linked sodium carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone hydroxymethyl cellulose calcium, low-substituted hydroxypropyl methyl cellulose, cross-linked polyvinyl pyrrolidone, starch, sodium hydroxymethyl starch, and hydroxypropyl starch.

本发明所述的润滑剂为本领域技术人员所知的，包括但不限于硬脂酸镁、硬脂酸钙、滑石粉、微粉硅胶、二氧化硅、硬脂酸、氢化油、聚乙二醇、月桂醇硫酸镁。The lubricant described in the present invention is known to those skilled in the art, including but not limited to magnesium stearate, calcium stearate, talc, micro-powder silica gel, silicon dioxide, stearic acid, hydrogenated oil, polyethylene glycol, and magnesium lauryl sulfate.

本发明所述的助流剂为本领域技术人员所知的，包括但不限于二氧化硅、胶态二氧化硅、水合二氧化硅、滑石、硅酸镁、三硅酸镁。The glidant described in the present invention is known to those skilled in the art, including but not limited to silicon dioxide, colloidal silicon dioxide, hydrated silicon dioxide, talc, magnesium silicate, and magnesium trisilicate.

本发明的药物组合物可以包装在不影响药物制剂稳定性的任何包装内。例如内包装可以为PVC铝塑泡罩包装，外包装为复合膜袋。The pharmaceutical composition of the present invention can be packaged in any packaging that does not affect the stability of the pharmaceutical preparation. For example, the inner packaging can be a PVC aluminum-plastic blister packaging, and the outer packaging can be a composite film bag.

本发明提供式(I)化合物的组合物在制备治疗癌症患者的药物中的用途。本发明还提供式(I)化合物的药物组合物在制备延缓癌症患者的进展的药物中的用途。The present invention provides the use of a composition of a compound of formula (I) in preparing a drug for treating cancer patients. The present invention also provides the use of a pharmaceutical composition of a compound of formula (I) in preparing a drug for delaying the progression of cancer patients.

本发明还提供式(I)化合物的组合物治疗癌症的方法，其包括向需要此治疗的患者给予治疗有效量的式(1)化合物的组合物，可以通过本领域中已知的任何常规和可接受的方式给药，治疗有效量根据患者的种族、性别、年龄、体重、医疗条件、疾病的类型、疾病的严重程度、施用途径和相关健康状况以及本领域技术人员已知的其他因素进行调整。The present invention also provides a method for treating cancer with a composition of the compound of formula (I), which comprises administering a therapeutically effective amount of the composition of the compound of formula (I) to a patient in need of such treatment. The administration can be carried out in any conventional and acceptable manner known in the art, and the therapeutically effective amount is adjusted according to the patient's race, sex, age, weight, medical condition, type of disease, severity of the disease, route of administration and related health conditions, as well as other factors known to those skilled in the art.

如本文中所使用的“治疗有效量”是指，足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如，对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄，体重和性别，药物的施用方式，以及同时施用的其他治疗等等。As used herein, "therapeutically effective amount" refers to an amount sufficient to cure or at least partially prevent the disease and its complications in a patient already suffering from the disease. Determining such an effective amount is well within the capabilities of those skilled in the art. For example, the amount effective for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the patient's general condition such as age, weight and sex, the mode of administration of the drug, and other treatments administered simultaneously, etc.

本发明还提供式(1)化合物的药物组合物与一种或多种其他治疗剂的组合物，可将这些其他治疗剂与式(1)化合物的组合物同时或相继给药，用于治疗肿瘤患者。The present invention also provides a pharmaceutical composition of the compound of formula (1) and a composition of one or more other therapeutic agents. These other therapeutic agents can be administered simultaneously or sequentially with the composition of the compound of formula (1) for treating tumor patients.

本发明所述的“D90”是指一个样品的累计粒度分布百分数达到90％时所对应的粒径。The "D90" mentioned in the present invention refers to the particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 90%.

本发明包含式(I)化合物的药物组合物，具有如下优点：The pharmaceutical composition of the present invention comprising the compound of formula (I) has the following advantages:

(1)具有良好的稳定性，可以提供较长的保质期；(1) It has good stability and can provide a long shelf life;

(2)具有良好的溶出性能；(2) Having good dissolution performance;

(3)具有良好的抗肿瘤作用。(3) It has good anti-tumor effect.

BRIEF DESCRIPTION OF THE DRAWINGS

图1为实施例3填充剂比例筛选溶出曲线。FIG. 1 is a dissolution curve for filler ratio screening in Example 3.

图2为实施例4粘合剂比例筛选曲线。FIG. 2 is a screening curve of adhesive ratio of Example 4.

图3为实施例7处方验证试验的溶出曲线。FIG. 3 is a dissolution curve of the prescription verification test of Example 7.

DETAILED DESCRIPTION

以下结合具体实施例及实验例对本发明的上述内容作进一步的详细说明。应理解，以下实施例和实验例仅用于说明本公开，但并不以此来限定本公开的保护范围。下面实施例中未注明具体条件者，按照常规条件或制造商建议的进行。所用药品或试剂未注明生产厂商者，均为可以通过市购获得的常规产品。The above contents of the present invention are further described in detail below in conjunction with specific embodiments and experimental examples. It should be understood that the following embodiments and experimental examples are only used to illustrate the present disclosure, but are not used to limit the protection scope of the present disclosure. In the following embodiments, if no specific conditions are specified, they are carried out according to conventional conditions or those recommended by the manufacturer. If the manufacturer of the drugs or reagents used is not specified, they are all conventional products that can be obtained commercially.

以下实施例或实验例中所用到的式(I)化合物按照专利申请PCT/CN2015/090712中说明书实施例4的制备方法制备获得。The compounds of formula (I) used in the following examples or experimental examples were prepared according to the preparation method of Example 4 in the specification of patent application PCT/CN2015/090712.

实施例1：原辅料相容性试验Example 1: Compatibility test of raw materials and auxiliary materials

取式(1)化合物与各辅料进行混合，高温60℃放置10天，考察结果见表1。The compound of formula (1) was mixed with various auxiliary materials and placed at a high temperature of 60° C. for 10 days. The results are shown in Table 1.

表1辅料相容性试验

Table 1 Excipient compatibility test

由上述结果可知，式(1)化合物与一水乳糖以1:5的比例60℃放置10天，有关物质增加明显，式(1)化合物与其他辅料以上述比例60℃放置10天，无明显变化，说明式(1)化合物与多种辅料相容性良好。From the above results, it can be seen that when the compound of formula (1) and lactose monohydrate were placed at 60°C in a ratio of 1:5 for 10 days, the related substances increased significantly, and when the compound of formula (1) and other excipients were placed at 60°C in the above ratio for 10 days, there was no obvious change, indicating that the compound of formula (1) has good compatibility with various excipients.

实施例2：片剂制备工艺Example 2: Tablet preparation process

将式(1)化合物、填充剂、崩解剂按照下述表格中各处方的用量投入湿法制粒机中，搅拌，获得预混合物；将粘合剂溶解在纯化水中，配制成粘合剂溶液；将粘合剂溶液加入预混合物，制粒，用湿法制粒机进行整粒；将湿颗粒投入流化床制粒机干燥；将助流剂置于干颗粒中，进行干整粒；加入崩解剂、润滑剂，用混合机混合均匀，压片，或根据需求包衣。The compound of formula (1), filler and disintegrant are placed in a wet granulator according to the dosage of each prescription in the following table, stirred to obtain a premix; the binder is dissolved in purified water to prepare a binder solution; the binder solution is added to the premix, granulated, and granulated with a wet granulator; the wet granules are placed in a fluidized bed granulator for drying; the glidant is placed in the dry granules for dry granulation; the disintegrant and lubricant are added, mixed evenly with a mixer, and tableted or coated as required.

实施例3：填充剂种类及比例考察Example 3: Investigation of filler types and proportions

1、填充剂种类筛选1. Filler type screening

为选择合适的填充剂，保证制剂制备过程顺利且在溶出介质中的较快崩解，以压片过程现象及崩解时限为判断依据，对填充剂进行考察：In order to select the appropriate filler to ensure a smooth preparation process and rapid disintegration in the dissolution medium, the filler was examined based on the tableting process phenomenon and disintegration time limit:

表2填充剂的筛选
Table 2 Screening of fillers

以微晶纤维素和无水磷酸氢钙作为填充剂，考察其硬度及崩解时限。结果如下所示：Using microcrystalline cellulose and anhydrous calcium hydrogen phosphate as fillers, the hardness and disintegration time were investigated. The results are as follows:

表3硬度及崩解时限考察结果
Table 3 Results of hardness and disintegration time

由上述结果可知，选用微晶纤维素和无水磷酸氢钙作为填充剂时，不存在粘冲现象，且崩解速度合适，因此微晶纤维素和无水磷酸氢钙可以作为填充剂。该处方在低规格的处方中较为稳定，当处方规格加大后，处方存在片重比较大、可压性差等问题，因此，对填充剂进行进一步的筛选。From the above results, it can be seen that when microcrystalline cellulose and anhydrous calcium hydrogen phosphate are used as fillers, there is no sticking phenomenon and the disintegration rate is appropriate, so microcrystalline cellulose and anhydrous calcium hydrogen phosphate can be used as fillers. The prescription is relatively stable in low-specification prescriptions. When the prescription specifications are increased, the prescription has problems such as large tablet weight and poor compressibility. Therefore, the filler is further screened.

表4填充剂的筛选

Table 4 Screening of fillers

从上表中可以看出，处方1可压性差，且片重比较大，病人吞咽比较困难；处方2增加预胶化淀粉作为填充剂，可压性好，且降低了片重，可以增加患者顺应性。As can be seen from the above table, Prescription 1 has poor compressibility and a relatively heavy tablet weight, which makes it difficult for patients to swallow; Prescription 2 adds pregelatinized starch as a filler, which has good compressibility and reduces the tablet weight, thereby increasing patient compliance.

2、填充剂比例的筛选2. Screening of filler ratio

表5填充剂比例考察
Table 5 Filler ratio investigation

不同比例的预胶化淀粉和微晶纤维素对颗粒的成粒性无明显影响，但预胶化淀粉占比较高会影响颗粒的可压性，微晶纤维素与预胶化淀粉的质量比小于1、预胶化淀粉的重量占比为15％的处方5，其颗粒的可压性明显较差。Different proportions of pregelatinized starch and microcrystalline cellulose have no obvious effect on the granulation property of the particles, but a high proportion of pregelatinized starch will affect the compressibility of the particles. The mass ratio of microcrystalline cellulose to pregelatinized starch is less than 1 and the weight proportion of pregelatinized starch is 15% of the formulation 5, and the compressibility of the particles is significantly poor.

表6溶出度测定结果
Table 6 Dissolution test results

从如图1所示的溶出曲线上看，上述不同比例的预胶化淀粉其处方片剂的溶出曲线几乎完全重合，表明预胶化淀粉用量对片剂溶出行为无影响。From the dissolution curves shown in FIG1 , the dissolution curves of the prescription tablets with the above-mentioned different proportions of pregelatinized starch almost completely overlap, indicating that the amount of pregelatinized starch has no effect on the dissolution behavior of the tablets.

实施例4：粘合剂种类及比例考察Example 4: Investigation of adhesive types and proportions

根据辅料相容性的结果考察了不同粘合剂羟丙基纤维素、聚维酮对制剂的影响，通过制剂观察发现，羟丙基纤维素比较难溶解，需要干粉加入，其本身呈絮状又容易结块，需要过筛才能保证粉料混合均匀。因此，选择聚维酮作为粘合剂，并对聚维酮的比例进行筛选，分别选择聚维酮比例为1.5％、2.5％、3.5％，处方设计如下表所示，According to the results of the compatibility of excipients, the effects of different adhesives, hydroxypropyl cellulose and povidone, on the preparation were investigated. Through the preparation observation, it was found that hydroxypropyl cellulose was difficult to dissolve and needed to be added as a dry powder. It was flocculent and easy to clump, so it needed to be sieved to ensure that the powder was mixed evenly. Therefore, povidone was selected as the adhesive, and the proportion of povidone was screened. The proportion of povidone was selected as 1.5%, 2.5%, and 3.5%, respectively. The prescription design is shown in the following table.

表7粘合剂比例的筛选
Table 7 Screening of binder ratio

对上述三个处方进行溶出度测定，溶出数据如下所示：The dissolution data of the above three prescriptions are shown below:

表8溶出度测定结果
Table 8 Dissolution test results

由图2和表8可知，3个处方的溶出曲线几乎重合，证明不同比例的粘合剂对片剂的溶出没有影响。As shown in Figure 2 and Table 8, the dissolution curves of the three prescriptions are almost identical, proving that different proportions of binders have no effect on the dissolution of tablets.

实施例5：崩解剂种类及比例考察Example 5: Investigation of disintegrant types and proportions

选择原辅料相容性良好的崩解剂交联聚维酮和交联羧甲基纤维素钠，进行崩解剂种类的筛选。崩解剂内加与外加的比例分别为2％，其他辅料及比例参考实施例3处方2，崩解剂为交联羧甲基纤维素钠与交联聚维酮的颗粒卡尔系数分别为15.1％、10.5％，颗粒压片，溶出60min，溶出度均达到90％以上，说明了选择交联聚维酮或交联羧甲基纤维素钠作为崩解剂，颗粒流动性比较好，且溶出符合质量标准要求。进一步对崩解剂内加与外加的比例进行筛选，内加、外加比例分别选择1:3、2:2、3:1，其他辅料及比例参考实施例3处方2，颗粒压片，溶出60min，溶出度均达到90％以上，说明了加入上述不同比例的内外崩解剂对溶出速率没有显著影响。Select disintegrants cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose with good compatibility of raw materials and excipients to screen the types of disintegrants. The ratio of internal and external disintegrants is 2% respectively, and other excipients and ratios refer to prescription 2 of Example 3. The granule Karl coefficients of cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone are 15.1% and 10.5% respectively. The granules are compressed into tablets, and the dissolution is 60min. The solubility is more than 90%, which shows that cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose is selected as a disintegrant. The granule fluidity is better and the dissolution meets the quality standard requirements. The ratio of internal and external disintegrants is further screened, and the ratio of internal and external addition is selected as 1:3, 2:2, and 3:1 respectively. Other excipients and ratios refer to prescription 2 of Example 3. The granules are compressed into tablets, and the dissolution is 60min. The dissolution is more than 90%, which shows that the addition of the above-mentioned different proportions of internal and external disintegrants has no significant effect on the dissolution rate.

实施例6：粒径考察Example 6: Particle size investigation

分别用不同的处理方式对式(1)化合物进行处理，得到不同粒度分布的式(1)化合物，以相同的处方(参考实施例3处方2的组分及比例)和工艺进行制粒，压片，考察溶出度，实验结果如下表9所示。The compound of formula (1) was treated in different ways to obtain compounds of formula (1) with different particle size distributions. The same prescription (the components and proportions of prescription 2 in reference example 3) and process were used for granulation and tableting, and the dissolution was investigated. The experimental results are shown in Table 9 below.

表9粒径考察

Table 9 Particle size investigation

可见，上述不同粒径的式(1)化合物，当原料药粒径分布的D90小于5μm(处方9)时，工艺无法正常进行，当原料药粒径分布的D90大于200μm(处方10)时，溶出速率较慢，而当粒径分布的D90在约10-100μm时，制粒过程中成形性均较好，且制成片剂时，在45分钟溶出度均达到90％以上。It can be seen that for the compounds of formula (1) with different particle sizes, when the D90 of the particle size distribution of the raw material drug is less than 5 μm (formulation 9), the process cannot proceed normally. When the D90 of the particle size distribution of the raw material drug is greater than 200 μm (formulation 10), the dissolution rate is slow. When the D90 of the particle size distribution is about 10-100 μm, the formability during the granulation process is good, and when the tablets are made, the solubility reaches more than 90% in 45 minutes.

实施例7：处方验证试验Example 7: Prescription Verification Test

参考实施例3处方2的组分及比例分别制备50mg和250mg规格的处方，考察含量、有关物质及溶出度。The components and proportions of Prescription 2 in Reference Example 3 were used to prepare prescriptions of 50 mg and 250 mg, respectively, and the content, related substances and solubility were investigated.

表10含量、有关物质及溶出度试验结果
Table 10 Content, related substances and dissolution test results

由上表可知，片剂含量、有关物质及溶出度均符合质量标准要求。It can be seen from the above table that the tablet content, related substances and dissolution all meet the quality standard requirements.

Claims

A pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 70%, the content of the binder is 1% to 5%, the content of the filler is 30% to 65%, the content of the disintegrant is 1% to 10%, the content of the lubricant is 0.5% to 5%, the content of the glidant is 0.2% to 2%, and the filler comprises at least anhydrous calcium hydrogen phosphate;

The pharmaceutical composition according to claim 1, wherein the content of the compound of formula (I) is 40% to 60% based on the total weight of the pharmaceutical composition.

The pharmaceutical composition of claim 1 or 2, wherein the filler further comprises one or more of microcrystalline cellulose, mannitol, and corn starch; optionally, based on the total weight of the pharmaceutical composition, the filler content is 30% to 50%.

The pharmaceutical composition according to any one of claims 1 to 3, wherein the binder is selected from: one or more of povidone, copovidone, alginate, chitosan, dextrin, maltodextrin, maltose, carbomer, gum arabic, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, preferably one or more of povidone and copovidone; optionally, based on the total weight of the pharmaceutical composition, the binder content is 1% to 4%.

The pharmaceutical composition according to any one of claims 1 to 4, wherein the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium hydroxymethyl starch, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and starch; optionally, the content of the disintegrant is 3% to 5% based on the total weight of the pharmaceutical composition.

The pharmaceutical composition according to any one of claims 1 to 5, wherein the lubricant is selected from one or more of magnesium stearate, calcium stearate, talc, silicon dioxide, and stearic acid; optionally, the lubricant content is 1% to 3% based on the total weight of the pharmaceutical composition.

The pharmaceutical composition according to any one of claims 1 to 6, wherein the glidant is selected from one or more of silicon dioxide, colloidal silicon dioxide, colloidal silica, corn starch, and talc; optionally, the glidant content is 0.5% to 1.5% based on the total weight of the pharmaceutical composition.

The pharmaceutical composition according to any one of claims 1 to 7, wherein the filler is selected from a combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate and pregelatinized starch, the binder is povidone, the disintegrant is selected from cross-linked sodium carboxymethyl cellulose or cross-linked povidone, the lubricant is magnesium stearate, and the glidant is selected from silicon dioxide or colloidal silicon dioxide.

The pharmaceutical composition according to any one of claims 1 to 8, comprising:

(1) 40% to 60% by weight of a compound of formula (I);

(2) 30% to 50% by weight of a filler, wherein the filler comprises at least anhydrous calcium hydrogen phosphate and pregelatinized starch; preferably, the filler consists of microcrystalline cellulose, anhydrous calcium hydrogen phosphate and pregelatinized starch;

(3) 1% to 4% by weight of a binder, wherein the binder is povidone;

(4) 3% to 5% by weight of a disintegrant, wherein the disintegrant is cross-linked sodium carboxymethylcellulose or cross-linked polyvinylpyrrolidone;

(5) 0.5% to 1.5% by weight of a glidant, wherein the glidant is colloidal silicon dioxide;

(6) 1% to 3% by weight of a lubricant, wherein the lubricant is magnesium stearate.

The pharmaceutical composition according to any one of claims 1 to 9, wherein the compound of formula (I) has a particle size distribution D90 of 10-100 μm.

A method for preparing a pharmaceutical composition according to any one of claims 1 to 10, comprising the steps of:

(1) mixing the compound of formula (I), a filler, and a disintegrant, and adding a binder to granulate;

(2) adding a glidant and performing dry granulation;

(3) Add disintegrant and lubricant and mix well;

(4) compressing the mixture to obtain the tablet.

The invention relates to a method for preparing a medicament for treating cancer comprising using the pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition further comprises one or more second therapeutic agents.

The use according to claim 12, wherein the second therapeutic agent is selected from antimetabolites, growth factor inhibitors, antibodies, mitotic inhibitors, antitumor hormones, alkylating agents, metal platinums, immunosuppressants, purine analogs, antibiotics, adrenocortical inhibitors or enzyme inhibitors.

The use according to claim 12, wherein the cancer is selected from lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, hepatoblastoma, papillary renal cell tumor, head and neck squamous cell tumor, Wilms tumor, renal cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, central nervous system tumors, female reproductive tract cancer, carcinoma in situ, lymphoma, neuroblastoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, brain cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, multiple myeloma, melanoma, neuroblastoma, sarcoma or glioma.