WO2023138667A1

WO2023138667A1 - Compound preparation of senaparib and temozolomide and preparation method therefor

Info

Publication number: WO2023138667A1
Application number: PCT/CN2023/073208
Authority: WO
Inventors: 蔡遂雄; 马宁; 赵立平
Original assignee: 上海瑛派药业有限公司
Priority date: 2022-01-21
Filing date: 2023-01-19
Publication date: 2023-07-27

Abstract

The present invention provides a compound preparation of senaparib and temozolomide and a preparation method therefor. The compound preparation contains active ingredients and pharmaceutically acceptable adjuvants, the active ingredients being senaparib and temozolomide, wherein based on the total weight of the compound preparation, the content of senaparib is 2.0-15.0%, and the content of temozolomide is 1.0-10.0%. In the compound preparation prepared by the method of the present invention, the two drugs have a good dissolution rate and content uniformity and stability.

Description

Senaparib和替莫唑胺的复方制剂及其制备方法Compound preparation of Senaparib and temozolomide and preparation method thereof

技术领域technical field

本发明涉及senaparib和替莫唑胺的复方制剂及其制备方法。The invention relates to a compound preparation of senaparib and temozolomide and a preparation method thereof.

背景技术Background technique

多聚(ADP-核糖)聚合酶(PARP)催化由NAD+向目标蛋白分子上添加多聚(ADP-核糖)，是修复DNA过程的重要组成部分。这个过程对保持DNA及染色体的完整和稳定至关重要，是哺乳类细胞存活的重要保障。细胞内的绝大多数ADP-核糖聚合活力是由PARP-1催化而成。多个PARP抑制剂，包括Olaparib，已批准上市用于治疗BRCA突变卵巢癌，乳腺癌，***癌和胰腺癌等。Poly(ADP-ribose) polymerase (PARP) catalyzes the addition of poly(ADP-ribose) to target protein molecules by NAD+, which is an important part of the DNA repair process. This process is crucial to maintaining the integrity and stability of DNA and chromosomes, and is an important guarantee for the survival of mammalian cells. Most of the ADP-ribose polymerization activity in cells is catalyzed by PARP-1. Several PARP inhibitors, including olaparib, have been approved for the treatment of BRCA-mutated ovarian, breast, prostate and pancreatic cancers.

用PARP抑制剂来治疗癌症主要基于两种机制。其一，对有DNA修复缺陷的癌细胞PARP抑制剂能独立地作为抗癌药物，直接杀死这些细胞(合成致死，Synthetic lethality)，比如BRCA1或BRCA2缺失的三重阴性乳腺癌等癌细胞。其二，由于癌症细胞的快速增长，其DNA复制远远高于正常细胞，因此DNA损伤类药物能有选择地造成癌细胞的死亡。但由于DNA修复酶如PARP的存在，这类药物的药性不能充分发挥。The use of PARP inhibitors to treat cancer is primarily based on two mechanisms. First, PARP inhibitors can be independently used as anticancer drugs for cancer cells with DNA repair defects to directly kill these cells (synthetic lethality), such as triple negative breast cancer cells with BRCA1 or BRCA2 deletion. Second, due to the rapid growth of cancer cells, their DNA replication is much higher than that of normal cells, so DNA-damaging drugs can selectively cause the death of cancer cells. However, due to the existence of DNA repair enzymes such as PARP, the medicinal properties of these drugs cannot be fully exerted.

PARP抑制剂与常用的DNA损伤类化疗抗癌药物联合使用，由于其能抑制DNA修复，可以产生协同效应，从而极大地增强DNA损伤类抗癌药物的药效。When PARP inhibitors are used in combination with commonly used DNA-damaging chemotherapy and anticancer drugs, they can inhibit DNA repair and produce synergistic effects, thereby greatly enhancing the efficacy of DNA-damaging anticancer drugs.

替莫唑胺(Temozolamide，TMZ)化学名为3，4-二氢-3-甲基-4-氧代咪唑并[5，1-d]-1，2，3，5-四嗪-8-甲酰胺，是一种口服新型烷化剂类抗肿瘤药，具有广谱抗肿瘤活性，可通过血脑屏障，口服生物利用度接近100％，可有效治疗新诊断及复发的胶质母细胞瘤和间变性星形细胞瘤，延长患者生存期，而且安全性和耐受性良好。替莫唑胺作为前药，口服后不直接发挥作用，在生理pH下，它经非酶途径快速转化为活性化合物MTIC(5-(3-甲基三氮烯-1-)咪唑-4-酰胺)。Temozolomide (Temozolamide, TMZ) chemical name is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, is a new oral alkylating agent antineoplastic drug, has broad-spectrum antitumor activity, can pass through the blood-brain barrier, oral bioavailability is close to 100%, can effectively treat newly diagnosed and recurrent glioblastoma and anaplastic astrocytoma, and prolong the survival period of patients , and was safe and well tolerated. As a prodrug, temozolomide does not directly play a role after oral administration. At physiological pH, it is rapidly converted into the active compound MTIC (5-(3-methyltriazene-1-)imidazole-4-amide) through a non-enzymatic pathway.

PARP抑制剂联用TMZ，具备增效减毒的临床治疗优势。通常联合用药采用每个药物单独给药形式，病人服药数量多，负担重，顺应性差；且医师需要根据病人所需剂量开具处方；如果存在多厂家的单独药品，用药的可控性较差。因此固定组合制剂形式的开发非常必要，可以提升用药安全性、顺应性；多规格复方制剂的开发也利于医师开具处方；复方制剂还利于存储和运输管理。The combination of PARP inhibitors and TMZ has the clinical therapeutic advantage of synergizing efficacy and reducing toxicity. Usually, each drug is administered separately in the combination drug, and the patient takes a large amount of drugs, the burden is heavy, and the compliance is poor; and the doctor needs to adjust according to the patient The required dose is prescribed; if there are individual drugs from multiple manufacturers, the controllability of drug use is poor. Therefore, the development of fixed combination preparations is very necessary, which can improve the safety and compliance of medication; the development of multi-specification compound preparations is also beneficial for doctors to prescribe; compound preparations are also conducive to storage and transportation management.

Senaparib固体分散体制剂虽然可获得较高的溶解度和口服生物利用度，但由于其引湿性可能导致固体分散体粘结和团聚，所以在制备复方制剂时，该成分的混合均匀性以及含量均匀性存在较大挑战。同时，复方制剂中的另一主成分替莫唑胺在复方制剂处方中含量较小，且在中性和碱性条件下易水解，可能存在混合均匀性、含量均匀性和稳定性的问题。因此，本领域仍然需要可以解决上述问题，并可以满足制剂生产需要的制剂处方和生产工艺，且制备的制剂具备适当的溶出速度及优异的存储稳定性，生产成本合理。Although Senaparib solid dispersion preparations can obtain high solubility and oral bioavailability, due to its hygroscopicity may cause solid dispersion bonding and agglomeration, there are great challenges in the mixing uniformity and content uniformity of the ingredients when preparing compound preparations. At the same time, temozolomide, another main component in the compound preparation, has a small content in the compound preparation prescription and is easily hydrolyzed under neutral and alkaline conditions, which may have problems with mixing uniformity, content uniformity and stability. Therefore, there is still a need in the art for formulation formulations and production processes that can solve the above problems and meet the needs of formulation production, and the prepared formulations have an appropriate dissolution rate and excellent storage stability, and the production cost is reasonable.

发明内容Contents of the invention

本发明第一方面提供一种复方制剂，其含有活性成分和药学上可接受的辅料，所述活性成分为senaparib和替莫唑胺，其中，以复方制剂总重计，senaparib的含量为2.0％～15.0％，替莫唑胺的含量为1.0％～10.0％。The first aspect of the present invention provides a compound preparation, which contains an active ingredient and a pharmaceutically acceptable auxiliary material, the active ingredient is senaparib and temozolomide, wherein, based on the total weight of the compound preparation, the content of senaparib is 2.0% to 15.0%, and the content of temozolomide is 1.0% to 10.0%.

本发明第二方面提供本发明任一实施方案所述的复方制剂的制备方法，所述方法包括：提供含有替莫唑胺与部分辅料的第1混合物，将senaparib和余下的辅料与该第1混合物混合，最后再将所得混合物与全部润滑剂混合；或者先将senaparib和余下的所有辅料混合，制备得到第2混合物，再将第1混合物和第2混合物混合，制备最终混合物。The second aspect of the present invention provides a method for preparing the compound preparation according to any embodiment of the present invention, the method comprising: providing a first mixture containing temozolomide and some adjuvants, mixing senaparib and the remaining adjuvants with the first mixture, and finally mixing the resulting mixture with all the lubricants; or first mixing senaparib and all the remaining adjuvants to prepare a second mixture, and then mixing the first mixture and the second mixture to prepare the final mixture.

本发明第三方面提供一种药盒，其含有本发明任一实施方案所述的复方制剂。The third aspect of the present invention provides a kit containing the compound preparation according to any embodiment of the present invention.

本发明第四方面提供本发明任一实施方案所述的复方制剂在制备治疗癌症的药物中的应用。The fourth aspect of the present invention provides the application of the compound preparation according to any embodiment of the present invention in the preparation of a drug for treating cancer.

本发明第五方面提供一种治疗癌症的方法，所述方法包括给予需要的对象治疗有效量的本发明任一实施方案所述的复方制剂；其中，所述治疗有效量为senaparib20～100mg的日剂量，优选为20～80mg的日剂量；和替莫唑胺5～30mg的日剂量，优选为10～20mg的日剂量。The fifth aspect of the present invention provides a method for treating cancer, the method comprising administering a therapeutically effective amount of the compound preparation according to any embodiment of the present invention to a subject in need; wherein, the therapeutically effective amount is a daily dose of senaparib of 20-100 mg, preferably a daily dose of 20-80 mg; and a daily dose of temozolomide of 5-30 mg, preferably a daily dose of 10-20 mg.

本发明各方面的方案的详细描述如下文所述。A detailed description of aspects of the invention is set forth below.

具体实施方式 Detailed ways

应理解，在本发明范围中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成优选的技术方案。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a preferred technical solution.

除非另有定义，本发明所使用的技术和科学术语具有所属技术领域人员通常理解的相同含义。Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

本发明所使用的术语“包含”、“包括”或其语法变型表示所述组合物和方法等包括所列举的要素且不排除其他。The term "comprising", "including" or its grammatical variants used in the present invention means that the compositions, methods, etc. include the listed elements and do not exclude others.

除非明确地有相反指示，否则本文中引用的所有范围都是包含性质的；即，所述范围包括所述范围的上限和下限的值以及在中间的所有值。例如，本文描述的温度范围、百分比、当量范围等包括所述范围的上限和下限以及在其中间的连续区间的任何值。此外，应理解的是，本发明药物组合物中所有组分的重量百分比之和应等于100％。Unless expressly indicated to the contrary, all ranges recited herein are inclusive; that is, the stated ranges include the upper and lower values of the stated range and all values in between. For example, temperature ranges, percentages, equivalent ranges, etc. described herein include the upper and lower limits of the stated ranges and any values in the continuum therebetween. In addition, it should be understood that the sum of weight percentages of all components in the pharmaceutical composition of the present invention should be equal to 100%.

本发明所述的组合物包括活性成分与其他化学成分的混合物。The compositions described herein comprise the active ingredient in admixture with other chemical ingredients.

本发明所述的“任选地”和“任选的”，表示可以选择或不选择，如任选的填充剂表示含有填充剂或不含有填充剂。"Optional" and "optional" in the present invention mean that it can be selected or not, such as optional filler means that it contains filler or does not contain filler.

PARP抑制剂与常用的DNA损伤类化疗抗癌药物联合使用时，由于PARP抑制剂被作为化疗抗癌药物的增敏剂，一般都采用高剂量的化疗抗癌药物与低剂量的PARP抑制剂联合。在临床实验上，一般也是采用高剂量的化疗抗癌药物与低剂量的PARP抑制剂联合。例如Olaparib与TMZ治疗脑瘤的临床一期联合用药实验中，确定的临床二期剂量(RP2D)是Olaparib 150mg和TMZ 75mg/m²(按60kg成人的体表面积1.62m²折算后的剂量为121.5mg)每天一次(Catherine Hanna et al.2020，Neuro Oncol.1-11)。现有的替莫唑胺药物在与放疗联合治疗新诊断的多形性胶质母细胞瘤时，日剂量为75mg/m²(相当于121.5mg)，和用于单药辅助治疗时，日剂量为150mg/m²(相当于243mg)相近。When PARP inhibitors are used in combination with commonly used DNA-damaging chemotherapeutic anticancer drugs, since PARP inhibitors are used as sensitizers of chemotherapeutic anticancer drugs, high doses of chemotherapeutic anticancer drugs are generally combined with low doses of PARP inhibitors. In clinical trials, high doses of chemotherapy and anticancer drugs are generally combined with low doses of PARP inhibitors. For example, in the clinical phase I combination trial of Olaparib and TMZ in the treatment of brain tumors, the determined clinical phase II dose (RP2D) is Olaparib 150 mg and TMZ 75 mg/m ² (the dose after conversion based on the body surface area of a 60 kg adult is 1.62 m ² is 121.5 mg) once a day (Catherine Hanna et al. 2020, Neuro Oncol. 1-11). The daily dose of temozolomide is 75mg/m ² (equivalent to 121.5mg) when it is combined with radiotherapy in the treatment of newly diagnosed glioblastoma multiforme, which is similar to the daily dose of 150mg/m ² (equivalent to 243mg) when it is used as adjuvant single drug therapy.

本发明发现，应用非毒性低剂量的烷化剂类抗癌药(如TMZ)引发DNA损伤，与有效剂量的具有捕获功能的PARP抑制剂(如5-氟-1-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)喹唑啉-2，4(1H，3H)-二酮，senaparib)联用，能引发合成致死，获得低毒高抗癌药效。The present invention finds that the use of a non-toxic low dose of an alkylating agent anticancer drug (such as TMZ) to cause DNA damage, combined with an effective dose of a PARP inhibitor with a capture function (such as 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione, senaparib), can cause synthetic lethality, and obtain low toxicity and high anticancer efficacy.

因此，本发明提供一种抗肿瘤复方制剂，其含有活性成分和药学上可接受的辅料，所述活性成分为senaparib和替莫唑胺；其中，以复方制剂总重计，senaparib的含量为2.0％～15.0％，替莫唑胺的含量为1.0％～10.0％。在一些实施方案中，以复方制剂总重计，senaparib的含量为2.0％～10.0％。在一些实施方案中，以复方制剂总重计，senaparib的含量为4.0％～10.0％。在一些实施方案中，以复方制剂总重计，替莫唑胺的含量为2.0％～8.0％。Therefore, the present invention provides an anti-tumor compound preparation, which contains active ingredients and pharmaceutically acceptable adjuvants, and the active ingredients are senaparib and temozolomide; wherein, based on the total weight of the compound preparation, the content of senaparib is 2.0% to 15.0%, and the content of temozolomide is 1.0% to 10.0%. In some embodiments, the complex Based on the total weight of the prescription, the content of senaparib is 2.0%-10.0%. In some embodiments, based on the total weight of the compound preparation, the content of senaparib is 4.0%-10.0%. In some embodiments, based on the total weight of the compound preparation, the content of temozolomide is 2.0%-8.0%.

在一些实施方案中，本发明所述复方制剂中，senaparib含量与替莫唑胺含量的比值为1～8。在一些实施方案中，本发明所述复方制剂中，senaparib含量与替莫唑胺含量的比值为2～4。在一些实施方案中，所述复方制剂所含的替莫唑胺的量满足：当给予一剂或多剂该复方制剂以满足每日给药剂量时，个体所摄入的替莫唑胺的量为已知替莫唑胺单用或与其它药物联用时的日剂量的约1/12到约1/5。更进一步地，当给予一剂或多剂该复方制剂时，个体所摄入的替莫唑胺的日剂量为约5mg到约40mg；在一些实施方案中，个体所摄入的替莫唑胺的日剂量为约5mg到约30mg；在一些实施方案中，个体所摄入的替莫唑胺的日剂量为约10mg到约20mg。在一些实施方案中，一剂所述复方制剂所含的senaparib与替莫唑胺即可满足日剂量要求。In some embodiments, in the compound preparation of the present invention, the ratio of senaparib content to temozolomide content is 1-8. In some embodiments, in the compound preparation of the present invention, the ratio of the content of senaparib to the content of temozolomide is 2-4. In some embodiments, the amount of temozolomide contained in the compound preparation is such that when one or more doses of the compound preparation are administered to meet the daily dosage, the amount of temozolomide ingested by the individual is about 1/12 to about 1/5 of the known daily dose of temozolomide when used alone or in combination with other drugs. Furthermore, when one or more doses of the compound preparation are administered, the daily dose of temozolomide ingested by the individual is about 5 mg to about 40 mg; in some embodiments, the daily dose of temozolomide ingested by the individual is about 5 mg to about 30 mg; in some embodiments, the daily dose of temozolomide ingested by the individual is about 10 mg to about 20 mg. In some embodiments, one dose of the compound preparation contains senaparib and temozolomide to meet the daily dosage requirement.

在一些实施方案中，所述复方制剂中，每剂所述复方制剂含有10mg到80mg的senaparib。在一些实施方案中，所述复方制剂中，每剂所述复方制剂含有20mg到40mg的senaparib。In some embodiments, in the compound preparation, each dose of the compound preparation contains 10 mg to 80 mg of senaparib. In some embodiments, in the compound preparation, each dose of the compound preparation contains 20 mg to 40 mg of senaparib.

在一些实施方案中，本发明所述复方制剂中，以复方制剂总重计，senaparib的含量为4.0％～10.0％，替莫唑胺的含量为2.0％～8.0％，且每剂所述复方制剂含有5mg到30mg的替莫唑胺。在一些实施方案中，所述复方制剂中，每剂所述复方制剂含有10mg到80mg的senaparib。在一些实施方案中，所述复方制剂中，每剂所述复方制剂含有10mg到40mg的senaparib。In some embodiments, in the compound preparation of the present invention, based on the total weight of the compound preparation, the content of senaparib is 4.0% to 10.0%, the content of temozolomide is 2.0% to 8.0%, and each dose of the compound preparation contains 5 mg to 30 mg of temozolomide. In some embodiments, in the compound preparation, each dose of the compound preparation contains 10 mg to 80 mg of senaparib. In some embodiments, in the compound preparation, each dose of the compound preparation contains 10 mg to 40 mg of senaparib.

在一些实施方案中，本发明复方制剂所含的senaparib中，少于5wt％、更优选少于1wt％的senaparib为结晶形式。In some embodiments, less than 5wt%, more preferably less than 1wt%, of senaparib contained in the compound preparation of the present invention is in crystalline form.

本文所述的药学上可接受的辅料包括载体、填充剂、崩解剂、助流剂、润滑剂、粘合剂、增溶剂、表面活性剂和pH调节剂中的一种或多种。The pharmaceutically acceptable auxiliary materials described herein include one or more of carriers, fillers, disintegrants, glidants, lubricants, binders, solubilizers, surfactants and pH regulators.

本文中，所述载体为用于制备活性药物成分的固体分散体的常用载体，包括醋酸琥珀羟丙甲纤维素酸、羟丙基甲基纤维素邻苯二甲酸酯和任选的表面活性剂等，优选为羟丙基甲基纤维素邻苯二甲酸酯。本文中，所述载体为符合各国药典规定的载体。按干燥品计算，示例性的羟丙基甲基纤维素邻苯二甲酸酯中，甲氧基的含量为12.0％～28.0％，2-羟丙氧基的含量为4.0％～23.0％，乙酰基的含量为2.0％～16.0 ％，琥珀酰基的含量为4.0％～28.0％。示例性的羟丙基甲基纤维素邻苯二甲酸酯为HP-55。Herein, the carrier is a commonly used carrier for preparing solid dispersions of active pharmaceutical ingredients, including succinic hypromellose acetate, hydroxypropylmethylcellulose phthalate, and optional surfactants, etc., preferably hydroxypropylmethylcellulose phthalate. Herein, the carrier is a carrier that complies with the regulations of various pharmacopoeias. Calculated on a dry basis, in the exemplary hydroxypropyl methylcellulose phthalate, the content of methoxyl group is 12.0% to 28.0%, the content of 2-hydroxypropoxyl group is 4.0% to 23.0%, and the content of acetyl group is 2.0% to 16.0%. %, the content of succinyl group is 4.0%～28.0%. An exemplary hydroxypropyl methylcellulose phthalate is HP-55.

本文所述的复方制剂中，senaparib和载体的重量比可为1∶2到1∶3。在一些实施方案中，以复方制剂总重计，羟丙基甲基纤维素邻苯二甲酸酯的含量为7％～30％，更优选13％～20％。In the compound preparation described herein, the weight ratio of senaparib to the carrier may be 1:2 to 1:3. In some embodiments, based on the total weight of the compound preparation, the content of hydroxypropyl methylcellulose phthalate is 7%-30%, more preferably 13%-20%.

在一些实施方案中，本文所述的复方制剂含有表面活性剂。示例性的表面活性剂包括泊洛沙姆。含有时，表面活性剂的含量为复方制剂总重的0.5％～2.2％，优选0.9％～1.5％。In some embodiments, the combination formulations described herein contain a surfactant. Exemplary surfactants include poloxamers. When contained, the content of the surfactant is 0.5% to 2.2% of the total weight of the compound preparation, preferably 0.9% to 1.5%.

在一些实施方案中，本文所述的复方制剂含有senaparib的固体分散体，该固体分散体含有senaparib、本文所述的羟丙基甲基纤维素邻苯二甲酸酯和任选的表面活性剂。优选地，senaparib和羟丙基甲基纤维素邻苯二甲酸酯的重量比为1∶2到1∶3。在一些实施方案中，本文所述的固体分散体为PCT/CN2016/078262中披露的固体分散体，本文将其全部内容以引用的方式纳入本文。优选地，所述固体分散体中，羟丙基甲基纤维素邻苯二甲酸酯占固体分散体总重的65％～77％，更优选73％～77％；senaparib占固体分散体总重的23％～35％。在优选的实施方案中，所述固体分散体由重量比为1∶2到1∶3的senaparib和羟丙基甲基纤维素邻苯二甲酸酯组成。在一些实施方案中，所述固体分散体由重量比为1∶2或1∶3的senaparib和羟丙基甲基纤维素邻苯二甲酸酯组成。在其它一些实施方案中，所述固体分散体还含有所述表面活性剂。优选地，以固体分散体总重计，表面活性剂的含量为2～5％。在一些实施方案中，所述固体分散体由senaparib、羟丙基甲基纤维素邻苯二甲酸酯和泊洛沙姆组成，三者的重量比为1∶2.8∶0.2。优选地，本申请所使用固体分散体中的senaparib中，少于10wt％、优选少于5wt％、更优选少于1wt％的senaparib为结晶形式，最优选无结晶形式的senaparib。In some embodiments, the combination formulations described herein comprise a solid dispersion of senaparib comprising senaparib, hydroxypropylmethylcellulose phthalate as described herein, and optionally a surfactant. Preferably, the weight ratio of senaparib to hydroxypropylmethylcellulose phthalate is 1:2 to 1:3. In some embodiments, the solid dispersion described herein is the solid dispersion disclosed in PCT/CN2016/078262, the entire contents of which are incorporated herein by reference. Preferably, in the solid dispersion, hydroxypropyl methylcellulose phthalate accounts for 65%-77% of the total weight of the solid dispersion, more preferably 73%-77%; senaparib accounts for 23%-35% of the total weight of the solid dispersion. In a preferred embodiment, the solid dispersion consists of senaparib and hydroxypropylmethylcellulose phthalate in a weight ratio of 1:2 to 1:3. In some embodiments, the solid dispersion consists of senaparib and hydroxypropylmethylcellulose phthalate in a weight ratio of 1:2 or 1:3. In some other embodiments, the solid dispersion further contains the surfactant. Preferably, based on the total weight of the solid dispersion, the content of the surfactant is 2-5%. In some embodiments, the solid dispersion consists of senaparib, hydroxypropylmethylcellulose phthalate and poloxamer in a weight ratio of 1:2.8:0.2. Preferably, less than 10 wt%, preferably less than 5 wt%, more preferably less than 1 wt% of senaparib in the solid dispersion used in the present application is in crystalline form, most preferably no senaparib in crystalline form.

在一些实施方案中，所述复方制剂中，以复方制剂总重计，固体分散体的含量为8％～60％。在一些实施方案中，以复方制剂总重计，固体分散体的含量为8％～40％。在一些实施方案中，以复方制剂总重计，固体分散体的含量为15％～40％。In some embodiments, in the compound preparation, based on the total weight of the compound preparation, the content of the solid dispersion is 8% to 60%. In some embodiments, based on the total weight of the compound preparation, the content of the solid dispersion is 8%-40%. In some embodiments, based on the total weight of the compound preparation, the content of the solid dispersion is 15%-40%.

本文中，所述填充剂可选自淀粉、预胶化淀粉、甘露醇、乳糖、蔗糖、环糊精和微晶纤维素中的一种或多种。在一些实施方案中，用于本文所述复方制剂的填充剂为微晶纤维素、甘露醇和乳糖中的一种或多种。本文中，以复方制剂总重计，填充剂的含量可为20％～85％。在一些实施方案中，以复方制剂总重计，填充剂的含量为56％～85％。在一些实施方案中，以复方制剂总重计，填充剂的含量为70％～82％。在一些实施方案中，以复方制剂总重计，填充剂的含量为75％～82％。Herein, the filler may be selected from one or more of starch, pregelatinized starch, mannitol, lactose, sucrose, cyclodextrin and microcrystalline cellulose. In some embodiments, the filler used in the compound preparation described herein is one or more of microcrystalline cellulose, mannitol and lactose. Herein, based on the total weight of the compound preparation, the content of the filler may be 20%-85%. In some embodiments, based on the total weight of the compound preparation, the filler contains The amount is 56% to 85%. In some embodiments, based on the total weight of the compound preparation, the filler content is 70%-82%. In some embodiments, based on the total weight of the compound preparation, the filler content is 75%-82%.

优选地，所述填充剂包括微晶纤维素。优选地，所述微晶纤维素的D90为170～480μm。在一些实施方案中，所述微晶纤维素的D90为170～283μm。在另外一些实施方案中，所述微晶纤维素的D90为275～480μm。所述D90采用Malvern Mastersizer 2000激光粒度分析仪，按照粒度和粒度分布测定法，以测试样品的折射率为1.45测定。Preferably, the filler comprises microcrystalline cellulose. Preferably, the D90 of the microcrystalline cellulose is 170-480 μm. In some embodiments, the D90 of the microcrystalline cellulose is 170-283 μm. In other embodiments, the D90 of the microcrystalline cellulose is 275-480 μm. Described D90 adopts Malvern Mastersizer 2000 laser particle size analyzer, according to particle size and particle size distribution measurement method, is measured with the refractive index of test sample 1.45.

优选地，以复方制剂总重计，微晶纤维素的含量为8％～50％。在一些实施方案中，以药物组合物总重计，微晶纤维素的含量为10％～28％，优选15％～20％。Preferably, based on the total weight of the compound preparation, the content of microcrystalline cellulose is 8% to 50%. In some embodiments, based on the total weight of the pharmaceutical composition, the content of microcrystalline cellulose is 10%-28%, preferably 15%-20%.

优选地，所述填充剂还包括甘露醇。优选地，所述甘露醇中，颗粒尺寸＞75μm的粒度分布不小于70％，优选不小于80％。在特别优选的实施方案中，所述甘露醇颗粒尺寸＞75μm的粒度分布不小于90％。所述粒度分布采用激光粒度仪进行干法测定；其中，振动进样速度为15％～30％，Auger Speed为30％～45％，遮光度范围为4％～12％。Preferably, the filler also includes mannitol. Preferably, in the mannitol, the particle size distribution of particle size > 75 μm is not less than 70%, preferably not less than 80%. In a particularly preferred embodiment, the particle size distribution of said mannitol with a particle size >75 μm is not less than 90%. The particle size distribution is measured by a dry method using a laser particle size analyzer; wherein, the vibration injection speed is 15% to 30%, the Auger Speed is 30% to 45%, and the shading range is 4% to 12%.

优选地，以复方制剂总重计，甘露醇的含量为20％～70％。在一些实施方案中，以药物组合物总重计，甘露醇的含量为50％～65％，优选55％～65％。Preferably, based on the total weight of the compound preparation, the content of mannitol is 20%-70%. In some embodiments, based on the total weight of the pharmaceutical composition, the content of mannitol is 50%-65%, preferably 55%-65%.

在优选的实施方案中，本发明的复方制剂中，填充剂为微晶纤维素和甘露醇，其中，微晶纤维素的D90为170～480μm、优选275～480μm，所述甘露醇中，颗粒尺寸＞75μm的粒度分布不小于70％、优选不小于80％、更优选不小于90％。优选地，以复方制剂总重计，微晶纤维素的含量为8％～50％，优选10％～28％，更优选15％～20％；甘露醇的含量为20％～70％，优选50％～65％，更优选55％～65％。In a preferred embodiment, in the compound preparation of the present invention, the fillers are microcrystalline cellulose and mannitol, wherein the D90 of the microcrystalline cellulose is 170-480 μm, preferably 275-480 μm, and in the mannitol, the particle size distribution of the particle size > 75 μm is not less than 70%, preferably not less than 80%, more preferably not less than 90%. Preferably, based on the total weight of the compound preparation, the content of microcrystalline cellulose is 8% to 50%, preferably 10% to 28%, more preferably 15% to 20%; the content of mannitol is 20% to 70%, preferably 50% to 65%, more preferably 55% to 65%.

优选地，本发明的复方制剂中，甘露醇的用量为微晶纤维素用量(以重量计)的0.5倍到8倍，如0.5～1倍，或2～8倍。Preferably, in the compound preparation of the present invention, the amount of mannitol used is 0.5 to 8 times, such as 0.5 to 1, or 2 to 8 times the amount of microcrystalline cellulose (by weight).

本文中，所述崩解剂可选自羧甲基淀粉钠、低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、羧甲基纤维素钙、预胶化淀粉、海藻酸钠以及它们的任意组合。在一些实施方案中，所述崩解剂为交联聚维酮、羧甲基淀粉钠或其混合物。通常，以复方制剂总重计，崩解剂的含量可为0.1％～10％，优选为0.5％～4％。在优选的实施方案中，所述崩解剂为交联聚维酮和/或羧甲基淀粉钠，以复方制剂总重计，交联聚维酮和/或羧甲基淀粉钠的总含量为0.5％～4％。在一些实施方案中，交联聚维酮的粒径控制范围为D90：270～385μm。 Herein, the disintegrating agent may be selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, carboxymethyl cellulose calcium, pregelatinized starch, sodium alginate and any combination thereof. In some embodiments, the disintegrant is crospovidone, sodium starch glycolate, or a mixture thereof. Usually, based on the total weight of the compound preparation, the content of the disintegrant may be 0.1%-10%, preferably 0.5%-4%. In a preferred embodiment, the disintegrant is crospovidone and/or sodium starch glycolate, and the total content of crospovidone and/or sodium starch glycolate is 0.5%-4% based on the total weight of the compound preparation. In some embodiments, the particle size control range of crospovidone is D90: 270-385 μm.

本文中，所述助流剂可选自粉状纤维素、三硅酸镁、胶态二氧化硅、滑石粉以及它们的任意组合。优选的助流剂是胶态二氧化硅。以复方制剂总重计，助流剂的含量可为0.1％～10％，优选为0.5％～3％，更优选为1％～3％。Herein, the glidant may be selected from powdered cellulose, magnesium trisilicate, colloidal silicon dioxide, talc and any combination thereof. A preferred glidant is colloidal silicon dioxide. Based on the total weight of the compound preparation, the content of the glidant may be 0.1%-10%, preferably 0.5%-3%, more preferably 1%-3%.

本文中，所述润滑剂可选自硬脂酸锌、单硬脂酸甘油酯、硬脂酸棕榈酸甘油酯、硬脂酸镁、硬脂酸富马酸钠以及它们的任意组合。优选的润滑剂为硬脂酸镁。以复方制剂总重计，润滑剂的含量可为0.1％～3％，优选为0.3％～1％，如0.5±0.1％。Herein, the lubricant may be selected from zinc stearate, glyceryl monostearate, glyceryl palmitate stearate, magnesium stearate, sodium stearate fumarate and any combination thereof. A preferred lubricant is magnesium stearate. Based on the total weight of the compound preparation, the content of the lubricant may be 0.1%-3%, preferably 0.3%-1%, such as 0.5±0.1%.

本文中，所述pH调节剂为酸性pH调节剂，可选自柠檬酸、酒石酸、山梨酸、苹果酸、乳酸、富马酸、己二酸中的一种或多种；优选的pH调节剂为酒石酸。以复方制剂总重计，所述酸性pH调节剂的含量为0.1％～5％，优选0.1％～3％。Herein, the pH regulator is an acidic pH regulator, which can be selected from one or more of citric acid, tartaric acid, sorbic acid, malic acid, lactic acid, fumaric acid and adipic acid; the preferred pH regulator is tartaric acid. Based on the total weight of the compound preparation, the content of the acidic pH regulator is 0.1%-5%, preferably 0.1%-3%.

在一些实施方案中，本文的复方制剂中还可含有粘合剂。所述粘合剂可选自羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、聚维酮以及他们的任意组合。优选的粘合剂为羟丙基纤维素。在一些实施方案中，所述粘合剂的含量为0.1％～5％，优选为0.1％～3％。In some embodiments, the compound preparation herein may also contain binders. The binder can be selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, povidone and any combination thereof. A preferred binder is hydroxypropyl cellulose. In some embodiments, the content of the binder is 0.1%-5%, preferably 0.1%-3%.

在一些实施方案中，本文的复方制剂中还可含有表面活性剂和/或包衣材料。所述表面活性剂可选自十二烷基硫酸钠、泊洛沙姆、牛磺酸、月桂酰聚氧乙烯(6、8、12、32)甘油酯和聚山梨酯类中的一种或多种。所述包衣材料可选自欧巴代全配方薄膜包衣***。In some embodiments, the compound preparation herein may also contain surfactants and/or coating materials. The surfactant may be selected from one or more of sodium lauryl sulfate, poloxamer, taurine, lauroyl polyoxyethylene (6, 8, 12, 32) glyceride and polysorbates. The coating material can be selected from Opadry full formula film coating system.

应理解，药物组合物中所含的各种辅料，如载体、表面活性剂、填充剂、崩解剂、助流剂、润滑剂、粘合剂、pH调节剂和包衣材料等均为本领域常规使用的药学上可接受的载体，符合各国药典的要求。It should be understood that various adjuvants contained in the pharmaceutical composition, such as carriers, surfactants, fillers, disintegrants, glidants, lubricants, binders, pH regulators and coating materials, etc. are all pharmaceutically acceptable carriers routinely used in this field and meet the requirements of various pharmacopoeias.

在一些实施方案中，以复方制剂总重计，本发明的复方制剂含有：senaparib，2.0％～15.0％、优选2.0％～10.0％、更优选4.0％～10.0％；替莫唑胺，1.0％～10.0％、优选2.0％～8.0％；载体，7％～30％、优选13％～20％；填充剂，56％～85％、优选70％～82％、更优选75％～82％；崩解剂，0.1％～10％、优选0.5％～4％；助流剂，0.1％～10％、优选0.5％～3％、更优选1％～3％；润滑剂，0.1％～3％、优选0.3％～1％；pH调节剂，0.1％～5％、优选0.1％～3％；任选的粘合剂，0.1％～5％、优选为0.1％～3％；和任选的表面活性剂，0.5％～2.2％；优选地，所述载体为羟丙基甲基纤维素邻苯二甲酸酯，进一步优选为HP-55；优选地，所述senaparib和载体的重量比为1∶2到1∶3，如1∶2或1∶3；所述填充剂为微晶纤维素和甘露醇，其中，微晶纤维素的D90为170～480μm、优选275～480μm，所述甘露醇中，颗粒尺寸＞75μm的粒度分布不小于70％、优选不小于80％、更优选不小于90％，优选地，以复方制剂总重计，微晶纤维素的含量为8％～50％，优选10％～28％，更优选15％～20％；甘露醇的含量为20％～70％，优选50％～65％，更优选55％～65％；优选地，所述崩解剂为交联聚维酮和/或羧甲基淀粉钠，优选地，交联聚维酮的粒径控制范围为D90：270～385μm；优选地，所述助流剂为胶态二氧化硅；优选地，所述润滑剂为硬脂酸镁和/或硬脂酸；优选地，所述粘合剂为羟丙基纤维素。In some embodiments, based on the total weight of the compound preparation, the compound preparation of the present invention contains: senaparib, 2.0% to 15.0%, preferably 2.0% to 10.0%, more preferably 4.0% to 10.0%; temozolomide, 1.0% to 10.0%, preferably 2.0% to 8.0%; carrier, 7% to 30%, preferably 13% to 20%; filler, 56% to 85%, preferably 70% %～82%, more preferably 75%～82%; disintegrant, 0.1%～10%, preferably 0.5%～4%; glidant, 0.1%～10%, preferably 0.5%～3%, more preferably 1%～3%; lubricant, 0.1%～3%, preferably 0.3%～1%; pH regulator, 0.1%～5%, preferably 0.1%～3%; 0.1% to 3%; and optional surfactant, 0.5% to 2.2%; preferably, the carrier is hydroxypropyl methylcellulose phthalate, more preferably HP-55; preferably, the weight ratio of the senaparib to the carrier is 1:2 to 1:3, such as 1:2 or 1:3; the filler is microcrystalline cellulose and mannitol, wherein the D90 of microcrystalline cellulose is 170 to 480 μm, preferably 275 to 480 μm , in the mannitol, the particle size distribution of the particle size > 75 μm is not Less than 70%, preferably not less than 80%, more preferably not less than 90%, preferably, based on the total weight of the compound preparation, the content of microcrystalline cellulose is 8% to 50%, preferably 10% to 28%, more preferably 15% to 20%; the content of mannitol is 20% to 70%, preferably 50% to 65%, more preferably 55% to 65%; The particle size control range of polyvidone is D90: 270-385 μm; preferably, the glidant is colloidal silicon dioxide; preferably, the lubricant is magnesium stearate and/or stearic acid; preferably, the binder is hydroxypropyl cellulose.

在一些实施方案中，以复方制剂总重计，本发明的复方制剂含有：senaparib的固体分散体，8％～60％；替莫唑胺，1.0％～10.0％、优选2.0％～8.0％；填充剂，56％～85％、优选70％～82％、更优选75％～82％；崩解剂，0.1％～10％、优选0.5％～4％；助流剂，0.1％～10％、优选0.5％～3％、更优选1％～3％；润滑剂，0.1％～3％、优选0.3％～1％；pH调节剂，0.1％～5％、优选0.1％～3％；和任选的粘合剂，0.1％～5％、优选为0.1％～3％；优选地，所述固体分散体粉末由重量比为1∶2到1∶3的senaparib和羟丙基甲基纤维素邻苯二甲酸酯组成，且senaparib中少于5wt％、更优选少于1wt％为结晶形式；优选地，所述填充剂为微晶纤维素和甘露醇，其中，微晶纤维素的D90为170～480μm、优选275～480μm，所述甘露醇中，颗粒尺寸＞75μm的粒度分布不小于70％、优选不小于80％、更优选不小于90％，优选地，以复方制剂总重计，微晶纤维素的含量为8％～50％，优选10％～28％，更优选15％～20％；甘露醇的含量为20％～70％，优选50％～65％，更优选55％～65％；优选地，所述崩解剂为交联聚维酮和/或羧甲基淀粉钠，优选地，交联聚维酮的粒径控制范围为D90：270～385μm；优选地，所述助流剂为胶态二氧化硅；优选地，所述润滑剂为硬脂酸镁和/或硬脂酸；优选地，所述粘合剂为羟丙基纤维素。In some embodiments, based on the total weight of the compound preparation, the compound preparation of the present invention contains: solid dispersion of senaparib, 8%-60%; temozolomide, 1.0%-10.0%, preferably 2.0%-8.0%; filler, 56%-85%, preferably 70%-82%, more preferably 75%-82%; disintegrant, 0.1%-10%, preferably 0.5%-4%; .1% to 10%, preferably 0.5% to 3%, more preferably 1% to 3%; lubricant, 0.1% to 3%, preferably 0.3% to 1%; pH regulator, 0.1% to 5%, preferably 0.1% to 3%; and optional binder, 0.1% to 5%, preferably 0.1% to 3%; It is composed of acid ester, and less than 5wt%, more preferably less than 1wt% of senaparib is in crystalline form; preferably, the filler is microcrystalline cellulose and mannitol, wherein the D90 of microcrystalline cellulose is 170-480 μm, preferably 275-480 μm, and in the mannitol, the particle size distribution of particle size > 75 μm is not less than 70%, preferably not less than 80%, more preferably not less than 90%, preferably, based on the total weight of the compound preparation, the microcrystalline The content of cellulose is 8% to 50%, preferably 10% to 28%, more preferably 15% to 20%; the content of mannitol is 20% to 70%, preferably 50% to 65%, more preferably 55% to 65%; preferably, the disintegrant is crospovidone and/or sodium carboxymethyl starch, preferably, the particle size control range of crospovidone is D90: 270 to 385 μm; silicon oxide; preferably, the lubricant is magnesium stearate and/or stearic acid; preferably, the binder is hydroxypropyl cellulose.

在一些实施方案中，所述复方制剂为口服固体制剂，优选为片剂、胶囊或颗粒剂。在一些实施方案中，所述复方制剂为胶囊剂，优选地，所述胶囊剂的胶囊壳选自植物胶囊壳和明胶胶囊壳，优选为明胶胶囊壳。In some embodiments, the compound preparation is an oral solid preparation, preferably a tablet, capsule or granule. In some embodiments, the compound preparation is a capsule, preferably, the capsule shell of the capsule is selected from a vegetable capsule shell and a gelatin capsule shell, preferably a gelatin capsule shell.

在一些实施方案中，本发明提供本发明复方制剂的制备方法，所述方法包括提供含有替莫唑胺与部分辅料的混合物，然后将senaparib和余下的辅料与该混合物混合，制备最终混合物，并由该最终混合物制备所述复方制剂，如胶囊剂或片剂。在将senaparib和余下的辅料与含替莫唑胺的混合物混合的情况中，可最后加入润滑剂(复方制剂所含全部润滑剂的一部分可含于含有替莫唑胺与部分辅料的混合物中，或者其一部分可与senaparib一起与所述含有替莫唑胺与部分辅料的混合物混合，因此最后加入的润滑剂是余下的润滑剂)，与先前制备得到的含senaparib和替莫唑胺的混合物再次进行混合，从而获得最终混合物。In some embodiments, the present invention provides a method for preparing the compound preparation of the present invention, the method comprising providing a mixture containing temozolomide and some adjuvants, then mixing senaparib and the remaining adjuvants with the mixture to prepare a final mixture, and preparing the compound preparation, such as capsules or tablets, from the final mixture. In the case of mixing senaparib and the rest of the excipients with the mixture containing temozolomide, the lubricant can be added last (part of the total lubricant contained in the compound preparation can be contained in the mixture containing temozolomide and part of the excipients, or part of it can be mixed with the mixture containing temozolomide and part of the excipients together with senaparib combined, so the lubricant added last is the remaining lubricant) and mixed again with the previously prepared mixture containing senaparib and temozolomide to obtain the final mixture.

具体而言，所述方法包括：将senaparib和余下的除润滑剂外的其它辅料与该第1混合物混合，得到第2混合物，然后再将第2混合物与余下的润滑剂混合，制备得到最终混合物；或者将senaparib和部分润滑剂和部分助流剂以及余下的其它全部辅料与该第1混合物混合，得到第2混合物，然后再将第2混合物与余下的润滑剂和助流剂混合，制备得到最终混合物。Specifically, the method comprises: mixing senaparib and the remaining auxiliary materials except the lubricant with the first mixture to obtain a second mixture, and then mixing the second mixture with the remaining lubricant to prepare the final mixture; or mixing senaparib with part of the lubricant, part of the glidant, and all the remaining other auxiliary materials with the first mixture to obtain the second mixture, and then mixing the second mixture with the remaining lubricant and glidant to prepare the final mixture.

所述第1混合物可含有替莫唑胺、填充剂、崩解剂和pH调节剂，以及任选的助流剂、润滑剂和和粘合剂中的一种或多种。应理解的是，第1混合物中所含的各类辅料可以仅是复方制剂所含相应辅料的一部分，或者是全部。例如，第1混合物中的填充剂可以是该复方制剂所用的两种以上填充剂中的一种或两种；例如，当使用本文所述的甘露醇和微晶纤维素作为填充剂时，该第1混合物所含的填充剂可以是复方制剂所含的全部微晶纤维素。或者，该第1混合物中的填充剂是复方制剂所用的每一种填充剂的一部分；如当使用本文所述的甘露醇和微晶纤维素作为填充剂时，第1混合物可含有5～15wt％或8～12wt％的甘露醇和15～28wt％或20～24wt％的微晶纤维素，该重量百分百以该复方制剂中所用的甘露醇和微晶纤维素各自的总重量计。类似的，当第1混合物含有助流剂时，助流剂可以是复方制剂所含的全部助流剂，也可以是部分如1～5wt％的助流剂；当第1混合物含有润滑剂时，润滑剂可以是复方制剂所含的全部润滑剂，也可以是部分如2～10wt％的润滑剂；当第1混合物含有崩解剂时，崩解剂可以是复方制剂所含的全部崩解剂，也可以是部分如15～25wt％的崩解剂。The first mixture may contain temozolomide, fillers, disintegrants and pH regulators, and optionally one or more of glidants, lubricants and binders. It should be understood that the various excipients contained in the first mixture may be only a part or all of the corresponding excipients contained in the compound preparation. For example, the filler in the first mixture can be one or both of the two or more fillers used in the compound preparation; for example, when using mannitol and microcrystalline cellulose as described herein as fillers, the filler contained in the first mixture can be all the microcrystalline cellulose contained in the compound preparation. Alternatively, the filler in the first mixture is a part of each filler used in the compound preparation; as when using mannitol and microcrystalline cellulose as described herein as fillers, the first mixture may contain 5 to 15 wt% or 8 to 12 wt% of mannitol and 15 to 28 wt% or 20 to 24 wt% of microcrystalline cellulose, and the percentage by weight is based on the respective total weight of the mannitol and microcrystalline cellulose used in the compound preparation. Similarly, when the first mixture contains a glidant, the glidant can be all the glidant contained in the compound preparation, or a part such as 1-5wt% of the glidant; when the first mixture contains a lubricant, the lubricant can be all the lubricant contained in the compound preparation, or a part such as 2-10wt% of the lubricant; Disintegrant.

在一些实施方案中，所述第1混合物为混合物a，其含有替莫唑胺、pH调节剂(如酒石酸)、占复方制剂甘露醇总重5～15wt％或8～12wt％的甘露醇、占复方制剂二氧化硅总重1～5wt％的助流剂(如二氧化硅)、占复方制剂所含润滑剂2～10wt％的润滑剂(如硬脂酸)、占复方制剂微晶纤维素总重15～28wt％或20～24wt％的微晶纤维素、粘合剂和占复方制剂崩解剂总重15～25wt％的崩解剂(如交联聚维酮)。In some embodiments, the first mixture is mixture a, which contains temozolomide, a pH regulator (such as tartaric acid), mannitol accounting for 5-15wt% or 8-12wt% of the total weight of mannitol in the compound preparation, a glidant (such as silicon dioxide) accounting for 1-5wt% of the total weight of silica in the compound preparation, a lubricant (such as stearic acid) accounting for 2-10wt% of the lubricant contained in the compound preparation, and 15-28wt in the total weight of microcrystalline cellulose in the compound preparation. % or 20-24wt% of microcrystalline cellulose, binder and 15-25wt% of disintegrating agent (such as crospovidone) accounting for the total weight of disintegrating agent of compound preparation.

在一些实施方案中，所述第1混合物为混合物b，其含有替莫唑胺、微晶纤维素、pH调节剂和崩解剂。In some embodiments, the first mixture is mixture b, which contains temozolomide, microcrystalline cellulose, a pH regulator and a disintegrant.

在一些实施方案中，所述第1混合物为混合物c，其含有替莫唑胺、微晶纤维素、pH调节剂、崩解剂和粘合剂。 In some embodiments, the first mixture is mixture c, which contains temozolomide, microcrystalline cellulose, pH regulator, disintegrant and binder.

在一些实施方案中，第1混合物的制备包括：将第1混合物的各组分加入混合机中，在40～55rpm的转速下混合。应理解，混合的时间可根据物料的多少以及混合机的性能等确定。示例性的混合时间为1～5分钟。In some embodiments, the preparation of the first mixture includes: adding each component of the first mixture into a mixer, and mixing at a rotational speed of 40-55 rpm. It should be understood that the mixing time can be determined according to the amount of materials and the performance of the mixer. Exemplary mixing times are 1 to 5 minutes.

在一些实施方案中，对于所述混合物a，混合第1混合物后，可先将该混合物过20目筛，然后再在40～55rpm的转速下混合一段时间，如5～15分钟，然后干法制粒。干法制粒的参数可设为辊压压力2～4kN，滚轮转速1～5rpm，饲料速度25～35rpm，过24目筛。In some embodiments, for the mixture a, after mixing the first mixture, the mixture can be passed through a 20-mesh sieve, and then mixed at a speed of 40-55 rpm for a period of time, such as 5-15 minutes, and then dry granulated. The parameters of dry granulation can be set as roller pressure 2-4kN, roller speed 1-5rpm, feed speed 25-35rpm, and pass through a 24-mesh sieve.

在一些实施方案中，所述第2混合物含有所述第1混合物、senaparib和余下的除润滑剂外的其余物料。在这些实施方案中，制备得到第1混合物后，将除润滑剂以外的其余全部物料(包括senaparib)与第1混合物混合，在40～55rpm的转速下混合1～5分钟，得到第2混合物，使第2混合物过30目筛，然后与润滑剂混合，得到所述最终混合物，可将该最终混合物制成胶囊剂或片剂。In some embodiments, the second mixture comprises the first mixture, senaparib, and the remaining materials except lubricant. In these embodiments, after the first mixture is prepared, all other materials (including senaparib) except the lubricant are mixed with the first mixture, and mixed at a rotation speed of 40-55 rpm for 1-5 minutes to obtain the second mixture. The second mixture is passed through a 30-mesh sieve, and then mixed with the lubricant to obtain the final mixture, which can be made into capsules or tablets.

在一些实施方案中，所述第2混合物含有所述第1混合物、senaparib、占复方制剂所含助流剂40～60wt％的助流剂、占复方制剂所含润滑剂55～75wt％的润滑剂以及余下的其它物料。在这些实施方案中，制备得到第1混合物后，将senaparib、占复方制剂所含助流剂40～60wt％的助流剂、占复方制剂所含润滑剂55～75wt％的润滑剂以及余下的其它物料与第1混合物混合，在40～55rpm的转速下混合1～5分钟，得到第2混合物，使第2混合物过30目筛，然后与余下的助流剂和润滑剂混合，得到所述最终混合物，可将该最终混合物制成片剂。In some embodiments, the second mixture contains the first mixture, senaparib, a glidant accounting for 40-60 wt% of the glidant contained in the compound preparation, a lubricant accounting for 55-75 wt% of the lubricant contained in the compound preparation, and the remaining other materials. In these embodiments, after the first mixture is prepared, senaparib, the glidant accounting for 40-60 wt% of the glidant contained in the compound preparation, the lubricant accounting for 55-75 wt% of the lubricant contained in the compound preparation, and the remaining other materials are mixed with the first mixture, and mixed at a speed of 40-55 rpm for 1-5 minutes to obtain the second mixture. The second mixture is passed through a 30-mesh sieve, and then mixed with the remaining glidant and lubricant to obtain the final mixture. The final mixture is made into tablets.

本文中，该senaparib可以本文所述的固体分散体的方式提供。因此，在一些实施方案中，本发明复方制剂的制备方法还包括所述固体分散体的制备方法。示例性的分散体的制备方法包括：将senaparib和邻苯二甲酸羟丙甲纤维素酯溶于四氢呋喃和甲醇(7∶3，v/v)混合溶液中，将所得溶液进行喷雾干燥，真空干燥收集得到的喷雾干燥颗粒，获得所述分散体。Herein, the senaparib may be provided as a solid dispersion as described herein. Therefore, in some embodiments, the preparation method of the compound preparation of the present invention also includes the preparation method of the solid dispersion. The preparation method of an exemplary dispersion includes: dissolving senaparib and hypromellose phthalate in a mixed solution of tetrahydrofuran and methanol (7:3, v/v), spray-drying the resulting solution, and collecting the spray-dried particles obtained by vacuum drying to obtain the dispersion.

在一些实施方案中，含senaparib的混合物中通常含有一定量的填充剂和助流剂，任选含有崩解剂、粘合剂和润滑剂中的一种或多种。含替莫唑胺的混合物通常可含有一定量的填充剂、pH调节剂和崩解剂，任选含有粘合剂、助流剂和润滑剂中的一种或多种。对各混合物中各辅料的含量并无特殊限制，只要能将活性成分混匀即可。本发明的制备方法的特征是逐步递加辅料并增加预混次数，从而提高替莫唑胺的混合均匀度。 In some embodiments, the senaparib-containing mixture generally contains a certain amount of fillers and glidants, and optionally contains one or more of disintegrants, binders and lubricants. The mixture containing temozolomide may generally contain a certain amount of fillers, pH regulators and disintegrants, and may optionally contain one or more of binders, glidants and lubricants. There is no special limitation on the content of each auxiliary material in each mixture, as long as the active ingredients can be mixed evenly. The preparation method of the present invention is characterized in that auxiliary materials are gradually added and premixing times are increased, thereby improving the mixing uniformity of temozolomide.

在一些实施方案中，本发明提供一种药盒，其含有本文任一实施方案所述的复方制剂。优选地，所述药盒所含的复方制剂的数量满足患者至少1天的给药；其中，1天的给药量为：senaparib 20～100mg，替莫唑胺5～30mg；更优选地，1天的给药量为：senaparib 20～80mg，替莫唑胺10～20mg。In some embodiments, the present invention provides a kit, which contains the compound preparation described in any embodiment herein. Preferably, the quantity of the compound preparation contained in the kit satisfies the patient's administration for at least one day; wherein, the dosage for one day is: 20-100 mg of senaparib, and 5-30 mg of temozolomide; more preferably, the dosage for one day is: 20-80 mg of senaparib, and 10-20 mg of temozolomide.

本发明还提供本文任一实施方案所述的复方制剂在制备治疗癌症的药物中的应用；优选地，所述癌症选自：肝癌、黑素瘤、霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、维尔姆斯瘤、子***、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、非小细胞肺癌、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、绒毛膜癌、蕈様肉芽腫、头颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、横纹肌肉瘤、卡波西肉瘤、泌尿生殖***肿瘤病、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生症、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌和***癌。还提供一种治疗癌症的方法，所述方法包括给予需要的对象治疗有效量的本发明任一实施方案所述的复方制剂；其中，所述治疗有效量为senaparib 20～100mg的日剂量和替莫唑胺5～30mg的日剂量；优选地，所述治疗有效量为senaparib 20～80mg的日剂量和替莫唑胺10～20mg的日剂量。The present invention also provides the application of the compound preparation described in any embodiment herein in the preparation of a drug for treating cancer; preferably, the cancer is selected from: liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary Brain cancer, non-small cell lung cancer, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid cancer, choriocarcinoma, mycosis granuloma, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary system tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, red vera Cytosis, essential thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer. Also provided is a method for treating cancer, said method comprising administering a therapeutically effective dose of the compound preparation according to any embodiment of the present invention to a subject in need; wherein said therapeutically effective dose is a daily dose of 20-100 mg of senaparib and a daily dose of 5-30 mg of temozolomide; preferably, said therapeutically effective dose is a daily dose of 20-80 mg of senaparib and a daily dose of 10-20 mg of temozolomide.

本发明制备的药物制剂具有以下优点：The pharmaceutical preparation prepared by the present invention has the following advantages:

(1)本发明的药物组合物中的两个活性成分之间可以产生协同作用，可以同时降低PARP抑制剂和替莫唑胺的用量，提高用药安全耐受性。(1) The two active ingredients in the pharmaceutical composition of the present invention can produce a synergistic effect, can reduce the dosage of PARP inhibitor and temozolomide at the same time, and improve the safety and tolerance of medication.

(2)本发明针对性地开发制剂处方和工艺，采用合适的药学上可接受辅料及工艺，顺利地实现将senaparib和替莫唑胺在同一制剂单位中组合，获得口服生物利用度良好、含量均匀及稳定性良好的口服固体复方制剂，在提高患者用药顺应性的同时，实现规模化生产。(2) The present invention develops formulation prescriptions and processes in a targeted manner, adopts suitable pharmaceutically acceptable excipients and processes, successfully realizes the combination of senaparib and temozolomide in the same formulation unit, obtains oral solid compound preparations with good oral bioavailability, uniform content and good stability, and realizes large-scale production while improving drug compliance of patients.

下面结合实施例对本发明作进一步解释。应当理解的是，以下实施例仅用于解释本发明，而不是以任何方式限制本发明的范围。The present invention will be further explained below in conjunction with embodiment. It should be understood that the following examples are only used to explain the present invention, but not to limit the scope of the present invention in any way.

下述实施例中使用到以下方法：The following methods are used in the following examples:

松密度/振实密度检测方法：取待测样品，精密称定质量M，缓慢倾入玻璃刻度量筒，小心刮平顶部，应避免压紧粉末，以最接近的刻度线，记录表观体积V₀。将上述量筒固定于密度测试仪，振实10次、500次、1250次，记录对应体积V₁₀、V₅₀₀、V₁₂₅₀，并精确至最小刻度。若V₅₀₀与V₁₂₅₀之差小于2mL，取V₁₂₅₀作为振实体积；若V₅₀₀与V₁₂₅₀之差大于2mL，则增加振实次数至两次连续记录的体积之差小于2mL。松密度＝m/V₀；振实密度＝m/V_n，式中V_n为振实体积；卡尔指数＝(振实密度-松密度)/振实密度*100％。Bulk density/tap density test method: Take the sample to be tested, accurately weigh the mass M, slowly pour it into a glass graduated cylinder, carefully scrape the top, avoid compacting the powder, and record the apparent volume V ₀ at the nearest scale line. Fix the above-mentioned graduated cylinder to a density tester, vibrate 10 times, 500 times, and 1250 times, record the corresponding volumes V ₁₀ , V ₅₀₀ , and V ₁₂₅₀ , and be accurate to the smallest scale. If the difference between V ₅₀₀ and V ₁₂₅₀ is less than 2mL, take V ₁₂₅₀ as the tapped volume; if the difference between V ₅₀₀ and V ₁₂₅₀ is greater than 2mL, increase the number of taps until the difference between two consecutive recorded volumes is less than 2mL. Bulk density=m/V ₀ ; tap density=m/V _n , where V _n is the tapped volume; Carr index=(tap density-bulk density)/tap density*100%.

休止角检测方法：采用注入法测定，即将待测样品倒入漏斗，样品自漏斗自由落下，在半径为r的圆盘上形成一个高为h的圆锥体，tanA＝h/r，A为休止角。Angle of repose detection method: use the injection method to measure, that is, the sample to be tested is poured into the funnel, the sample falls freely from the funnel, and forms a cone with a height h on a disc with a radius r, tanA=h/r, A is the angle of repose.

水分检测方法：取待测样品进行称量，然后用红外辐射体进行加热，连续记录损失的质量，当达到规定要求时结束干燥，通过差重自动计算出水分含量。Moisture detection method: take the sample to be tested and weigh it, then heat it with an infrared radiator, continuously record the lost mass, stop drying when the specified requirements are met, and automatically calculate the moisture content through the differential weight.

实施例中提及的其它材料、试剂和方法，除非另有说明，否则使用的为本领域常规的材料、试剂和方法。Other materials, reagents and methods mentioned in the examples, unless otherwise stated, are conventional materials, reagents and methods in the art.

实施例一：senaparib联合TMZ对人小细胞肺癌细胞NCI-H209生长的影响Example 1: Effect of senaparib combined with TMZ on the growth of human small cell lung cancer cell NCI-H209

本实施例采用CCK-8检测法测定senaparib联合TMZ对人小细胞肺癌细胞NCI-H209增长的抑制作用。将复苏好的人小细胞肺癌细胞NCI-H209接种到培养皿，加入实验培养基(RPMI1640+20％FBS)，置于37℃、5％CO₂培养箱静置培养。取生长状态良好，汇合度合适的细胞用于实验，800rpm离心5min，弃上清，用新鲜培基重悬，以合适细胞密度接种至96孔细胞培养板，每孔接种190μL细胞悬液。受试化合物(包括senaparib，TMZ和参考化合物AZD2281)母液用DMSO按1∶3和1∶10比例分别进行连续系列稀释至10个浓度(最后一个浓度为DMSO阴性对照)，每个浓度取5μL加入到120μL培基(25倍稀释)，振荡混匀。单独用药：分别加入5μL稀释好的含相应浓度化合物的培基和5μL培基；联合用药：分别加入5μL稀释好的含相应浓度化合物的培基和5μL含终浓度为50μM TMZ的培基。DMSO终浓度为2‰。随后将培养板置于37℃、5％CO₂培养箱培养5天。每孔加20μL CCK-8检测试剂，继续培养2小时后，震荡10分钟置于多功能读数仪读取450/650nm波长的吸光值(OD值)。用软件Graph Pad Prism 6.0分析数据，化合物对细胞增殖的抑制活性以细胞存活率和化合物浓度为坐标绘图。细胞存活率％＝OD_化合物/OD_DMsO×100。IC₅₀值以S形剂量反应曲线方程拟合，曲线方程为：Y＝100/(1+10^(LogC-LogIC₅₀))，C是化合物浓度。联合用药指数使用CalcμSyn软件计算。 In this example, the CCK-8 detection method was used to determine the inhibitory effect of senaparib combined with TMZ on the growth of human small cell lung cancer cell NCI-H209. The resuscitated human small cell lung cancer cells NCI-H209 were inoculated into a culture dish, added with experimental medium (RPMI1640+20% FBS), and placed in a 37°C, 5% CO ₂ incubator for static culture. Cells in good growth state and suitable confluence were used for the experiment, centrifuged at 800 rpm for 5 minutes, discarded the supernatant, resuspended with fresh medium, inoculated into a 96-well cell culture plate at an appropriate cell density, and inoculated 190 μL of cell suspension per well. The mother solutions of the test compounds (including senaparib, TMZ and the reference compound AZD2281) were serially diluted with DMSO at a ratio of 1:3 and 1:10 respectively to 10 concentrations (the last concentration was the DMSO negative control), and 5 μL of each concentration was added to 120 μL medium (25-fold dilution), shaken and mixed. Single drug: add 5 μL diluted culture medium containing the corresponding concentration of compound and 5 μL medium respectively; combined drug: add 5 μL diluted medium containing the corresponding concentration of compound and 5 μL medium containing the final concentration of 50 μM TMZ respectively. The final concentration of DMSO was 2‰. The plate was then placed in a 37°C, 5% CO ₂ incubator for 5 days. Add 20 μL of CCK-8 detection reagent to each well, continue to incubate for 2 hours, shake for 10 minutes and place in a multi-function reader to read the absorbance value (OD value) at 450/650 nm wavelength. The data was analyzed with the software Graph Pad Prism 6.0, and the inhibitory activity of the compound on cell proliferation was plotted against the cell viability and the compound concentration. % cell viability = OD _compound /OD _DMsO x 100. The IC ₅₀ value was fitted with a sigmoid dose-response curve equation, the curve equation is: Y=100/(1+10^(LogC-LogIC ₅₀ )), C is the compound concentration. The combined drug index was calculated using CalcμSyn software.

表1汇总了各化合物及其组合对人小细胞肺癌细胞NCI-H209增长的抑制作用数据(IC₅₀)。表2列出了senaparib和TMZ联合用药指数(CI)。CI＜0.1表示药物联合用极强的协同效应；0.1＜CI＜1表示药物联合有协同效应，CI＞1表示没有协同效应。Table 1 summarizes the inhibitory effect data (IC ₅₀ ) of each compound and its combination on the growth of human small cell lung cancer cell NCI-H209. Table 2 lists the combination index (CI) of senaparib and TMZ. CI<0.1 means that the drug combination has a strong synergistic effect; 0.1<CI<1 means that the drug combination has a synergistic effect, and CI>1 means that there is no synergistic effect.

表1：化合物对人小细胞肺癌细胞NCI-H209增长的抑制作用数据(IC₅₀)
Table 1: Inhibitory effect data of compounds on human small cell lung cancer cell NCI-H209 growth (IC ₅₀ )

表2：senaparib和TMZ联合用药指数(CI)
Table 2: Combination index (CI) of senaparib and TMZ

因此，经CCK-8检测法测定，结果显示senaparib与TMZ联用对抑制人小细胞肺癌NCI-H209细胞的增殖有极强的协同效应。Therefore, as determined by the CCK-8 assay, the results show that the combination of senaparib and TMZ has a strong synergistic effect on inhibiting the proliferation of human small cell lung cancer NCI-H209 cells.

实施例二：senaparib联合TMZ在NCI-H209人小细胞肺癌裸鼠异种移植瘤模型中的体内药效学研究Example 2: In vivo pharmacodynamic study of senaparib combined with TMZ in NCI-H209 human small cell lung cancer xenograft model in nude mice

评价化合物senaparib联合TMZ在NCI-H209人小细胞肺癌裸鼠异种移植瘤模型中的抗肿瘤活性。为此目的，将人小细胞肺癌细胞NCI-H209接种于裸鼠右侧腋窝皮下乳腺区。细胞接种量为2×10⁶个对数生长期细胞，接种形成移植瘤后使用。将生长旺盛的肿瘤组织切成1×1×1mm³的小块，接种于每只BALB/c裸鼠的右侧腋窝处乳腺区皮下。当肿瘤平均体积达到约124.08(57.16-280.79)mm³时，根据瘤体积随机分组并开始给药，分组及给药方案见表3。To evaluate the antitumor activity of compound senaparib combined with TMZ in NCI-H209 human small cell lung cancer xenograft model in nude mice. For this purpose, human small cell lung cancer cells NCI-H209 were inoculated into the subcutaneous mammary gland area of the right axilla of nude mice. The inoculum amount of cells was 2×10 ⁶ cells in the logarithmic growth phase, which were used after inoculation to form xenograft tumors. The vigorously growing tumor tissue was cut into small pieces of 1×1×1 mm ³ and inoculated in the right side of each BALB/c nude mouse. Under the skin of the mammary gland in the lateral armpit. When the average volume of the tumor reached about 124.08 (57.16-280.79) mm ³ , they were randomly divided into groups according to the tumor volume and started to administer the drugs. See Table 3 for the grouping and drug regimen.

表3：senaparib联合TMZ体内药效实验动物分组及给药方案
Table 3: Animal grouping and dosing regimen for senaparib combined with TMZ in vivo efficacy experiments

注1：根据裸鼠体重20μL/g给药。Note 1: The administration was based on the body weight of nude mice at 20 μL/g.

注2：N为动物数，每组10只荷瘤裸鼠；p.o.为口服给药；QD为每天一次；持续服用21天。Note 2: N is the number of animals, 10 tumor-bearing nude mice in each group; p.o. is oral administration; QD is once a day; continuous administration for 21 days.

注3：溶媒，成分为10％DMSOin10％HP-β-CD PBS。Note 3: The solvent, the composition is 10% DMSOin10% HP-β-CD PBS.

注4：溶媒对照组根据体重灌胃给予20μL/g溶媒；TMZ和senaparib单独给药组先灌胃给予10μL/g的溶媒，然后再灌胃给药10μL/g的药物；联合给药组先灌胃给予10μL/g的TMZ，30min后再灌胃给予10μL/g相应浓度的senaparib。Note 4: The vehicle control group was intragastrically administered 20 μL/g vehicle according to body weight; the TMZ and senaparib single administration group was intragastrically administered 10 μL/g vehicle first, and then intragastrically administered 10 μL/g drug; the combined administration group was intragastrically administered 10 μL/g TMZ first, and then 30 minutes later intragastrically administered 10 μL/g senaparib of the corresponding concentration.

分组给药后，裸鼠体重每周称量2次，并记录，体重变化(％)＝(W_t-W₁)/W₁×100％，其中W₁为分组给药时(即D1)测量所得体重，W_t为记录当天体重。体重变化(％)是治疗相关毒性的量度(平均体重下降超过15％，治疗停止或方案调整，直至恢复；平均体重下降超过20％，实验终止)。每周用游标卡尺测量2次肿瘤直径(长和宽)，计算肿瘤体积(长×宽²/2)，及相对肿瘤体积RTV＝V_t/V₁，其中V₁为分组给药时(即D1)测量所得肿瘤体积，V_t为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标表示为相对肿瘤增殖率T/C(％)和肿瘤生长抑制率TGI(％)。T/C(％)＝T_RTV/C_RTV×100％，其中T_RTV为治疗组RTV，具有低于50的T/C(％)的化合物被定义为有活性(有效)；C_RTV为溶媒对照组RTV；TGI(％)＝[(CV_t-CV₁)-(TV_t-TV₁)]/(CV_t-CV₁)×100％，其中CV_t为溶媒对照组记录当天的肿瘤体积，CV₁为溶媒对照组分组给药时的肿瘤体积，TV_t为给药组记录当天的肿瘤体积，TV₁为给药组分组给药时的肿瘤体积。After group administration, the nude mice were weighed twice a week and recorded, body weight change (%)=(W _t -W ₁ )/W ₁ ×100%, where W ₁ was the body weight measured during the group administration (i.e. D1), and W _t was the body weight on the recording day. Body weight change (%) was a measure of treatment-related toxicity (mean weight loss greater than 15%, treatment stopped or regimen adjusted until recovery; mean body weight loss greater than 20%, experiment terminated). The tumor diameter (length and width) was measured twice a week with a vernier caliper, and the tumor volume (length× ^width2 /2) was calculated, and the relative tumor volume RTV=V _t /V ₁ , where V ₁ was the tumor volume measured during group administration (that is, D1), and V _t was the tumor volume at each measurement. The evaluation index of anti-tumor activity is expressed as relative tumor proliferation rate T/C (%) and tumor growth inhibition rate TGI (%). T/C (%)=T _RTV /C _RTV ×100%, wherein T _RTV is the RTV of the treatment group, and compounds with a T/C (%) lower than 50 are defined as active (effective); C _RTV is the RTV of the vehicle control group; TGI (%)=[(CV _t -CV ₁ )-(TV _t -TV ₁ )]/(CV _t -CV ₁ )×100%, wherein CV _t is the tumor volume of the vehicle control group on the day of recording, CV ₁ is the tumor volume of the vehicle control group when administered in groups, TV _t is the tumor volume of the administration group on the recording day, and TV ₁ is the tumor volume of the administration group when administered in groups.

实验结束后，每组随机选取3只裸鼠，眼眶采集300μL全血到BD K2 EDTA抗凝管(REF367841)中，进行血常规检测。After the experiment, 3 nude mice were randomly selected in each group, and 300 μL of whole blood was collected from the orbits into BD K2 EDTA anticoagulant tubes (REF367841) for blood routine testing.

采用Graph-Pad Prism 6.0软件two-way ANOVA进行各组间肿瘤体积均值及相对肿瘤体积均值的比较。与对照组(溶媒)相比，^*p＜0.05(有统计学差异)，^**p＜0.01(有显著性统计学差异)，^***p＜0.001(有极显著性统计学差异)；与TMZ组相比，^#p＜0.05(有统计学差异)，^##p＜0.01(有显著性统计学差异)，^###p＜0.001(有极显著性统计学差异)；与senaparib组相比，⁺p＜0.05(有统计学差异)，⁺⁺p＜0.01(有显著性统计学差异)，⁺⁺⁺p＜0.001(有极显著性统计学差异)。Graph-Pad Prism 6.0 software two-way ANOVA was used to carry out mean and relative tumor volumes among the groups. Comparison of mean tumor volumes. Compared with the control group (vehicle), ^* p<0.05 (with statistical difference), ^** p<0.01 (with significant statistical difference), ^*** p<0.001 (with extremely significant statistical difference); compared with TMZ group, ^# p<0.05 (with statistical difference), ^## p<0.01 (with significant statistical difference), ^### p<0.001 (with extremely significant statistical difference); compared with senaparib group, ⁺ p<0.05 (statistical difference), ⁺⁺ p<0.01 (significant statistical difference), ⁺⁺⁺ p<0.001 (very significant statistical difference).

实验结果Experimental results

1、体重1. Weight

给药期间，与溶媒对照组相比，TMZ单独给药组小鼠体重变化无差异；senaparib单独给药组在给药后期体重增长稍缓；联合给药组(senaparib 5mg/kg+TMZ 3mg/kg)给药期间，体重没有增加；联合给药组(senaparib 10mg/kg+TMZ 3mg/kg)给药期间，平均体重略有下降，但没有超过5％，如下表4所示。During the administration period, compared with the vehicle control group, there was no difference in the weight change of the mice in the TMZ administration group alone; the weight gain of the senaparib administration group alone was slightly slower in the later stage of administration; the body weight of the joint administration group (senaparib 5mg/kg+TMZ 3mg/kg) did not increase during the administration period; the average body weight of the joint administration group (senaparib 10mg/kg+TMZ 3mg/kg) decreased slightly during the administration period, but did not exceed 5%, as shown in Table 4 below.

表4：平均体重及体重变化
Table 4: Average body weight and weight change

注1：平均体重变化(％)：与治疗开始时的初始体重相比的各组裸鼠的体重变化(％)平均值。Note 1: Average body weight change (%): the average weight change (%) of nude mice in each group compared with the initial body weight at the beginning of treatment.

2、肿瘤体积2. Tumor volume

与溶媒对照组相比，TMZ 3mg/kg和senaparib 10mg/kg单独给药组对肿瘤的增殖没有明显的抑制作用，而联合给药对肿瘤增殖具有极显著的抑制作用(p＜0.0001)；与单独给药组相比，两个联合给药组都显示了TMZ和senaparib联用有显著的协同作用(p＜0.0001)。senaparib 10mg/kg和TMZ 3mg/kg联合给药组肿瘤体积与0天相比有下降。具体结果如下表5所示。Compared with the vehicle control group, the TMZ 3mg/kg and senaparib 10mg/kg single administration groups had no significant inhibitory effect on tumor proliferation, while the combined administration had a very significant inhibitory effect on tumor proliferation (p<0.0001); compared with the single administration group, the two combined administration groups showed a significant synergistic effect of the combination of TMZ and senaparib (p<0.0001). Tumor volume decreased in the co-administered group of senaparib 10mg/kg and TMZ 3mg/kg compared with day 0. The specific results are shown in Table 5 below.

表5：各组裸鼠平均肿瘤大小变化(Mean±SD，n＝10，肿瘤体积：mm³)

Table 5: Changes in average tumor size of nude mice in each group (Mean±SD, n=10, tumor volume: mm ³ )

注：与对照组(溶媒)比较，*p＜0.05，**p＜0.01，***p＜0.001，****p＜0.0001；Note: Compared with the control group (vehicle), *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001;

与TMZ组相比，#p＜0.05，##p＜0.01，###p＜0.001，####p＜0.0001；Compared with TMZ group, #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001;

与senaparib组相比，+p＜0.05，++p＜0.01，+++p＜0.001，++++p＜0.0001。Compared with senaparib group, +p<0.05, ++p<0.01, +++p<0.001, ++++p<0.0001.

3、抗肿瘤活性的评价指标3. Evaluation index of anti-tumor activity

实验期间各组相对肿瘤增殖率[T/C(％)]和肿瘤生长抑制率[TGI(％)]如下表6所示。The relative tumor proliferation rate [T/C (%)] and tumor growth inhibition rate [TGI (%)] of each group during the experiment are shown in Table 6 below.

表6：抗肿瘤活性的评价指标
Table 6: Evaluation indicators of anti-tumor activity

注1：与对照组(vehicle)相比，^*p＜0.05，^**p＜0.01，^***p＜0.001，^****p＜0.0001；Note 1: Compared with the control group (vehicle), ^* p<0.05, ^** p<0.01, ^*** p<0.001, ^**** p<0.0001;

与TMZ组相比，^#p＜0.05，^##p＜0.01，^###p＜0.001，^####p＜0.0001； ^# p<0.05, ^## p<0.01, ^### p<0.001, ^#### p<0.0001 compared to TMZ group;

与senaparib组相比，⁺p＜0.05，⁺⁺p＜0.01，⁺⁺⁺p＜0.001，⁺⁺⁺⁺p＜0.0001。Compared with senaparib group, ⁺ p<0.05, ⁺⁺ p<0.01, ⁺⁺⁺ p<0.001, ⁺⁺⁺⁺ p<0.0001.

4、血常规检测结果4. Blood routine test results

实验结束时，每组取3只小鼠进行血常规检测。所有药物组的红细胞没有明显减少，在正常范围内；血小板变化不大，联合用药组略有升高。所有给药组都出现了白细胞的减少。联合药物组的减少较明显，但还是在合理范围内，对动物的毒性影响有限。At the end of the experiment, 3 mice in each group were taken for blood routine testing. The erythrocytes in all the drug groups did not decrease significantly, and were within the normal range; the platelets did not change much, but increased slightly in the combination drug group. All administration groups showed a decrease in leukocytes. The reduction in the combination drug group was more obvious, but it was still within a reasonable range, and the toxic effects on animals were limited.

综上所述，senaparib联合TMZ每天给药一次，连续给药21天，对NCI-H209人小细胞肺癌裸鼠异种移植瘤模型表现出极显著的抗肿瘤效果，且具有明显的协同作用，同时高剂量联合给药组体重仅有轻微下降，没有观察到明显的毒副反应。In summary, senaparib combined with TMZ administered once a day for 21 consecutive days showed a very significant anti-tumor effect on the NCI-H209 human small cell lung cancer nude mouse xenograft tumor model, and had obvious synergistic effects. At the same time, the body weight of the high-dose combined administration group only slightly decreased, and no obvious toxic and side effects were observed.

实施例三：senaparib固体分散体的制备Embodiment three: the preparation of senaparib solid dispersion

固体分散体的处方如表7所示。The formulation of the solid dispersion is shown in Table 7.

表7
Table 7

采用PCT/CN2016/078262中所披露的方法制备用于各实施例的senaparib固体分散体。示例性的制备方法包括：将senaparib和邻苯二甲酸羟丙甲纤维素酯HP-55溶于四氢呋喃和甲醇(7∶3，v/v)混合溶液中，然后将该溶液进行喷雾干燥，将收集的喷雾干燥颗粒在真空干燥器中干燥，得到senaparib固体分散体。经检测，该固体分散体粉末中，senaparib的结晶形式＜1wt％。The method disclosed in PCT/CN2016/078262 was used to prepare the senaparib solid dispersion used in each example. An exemplary preparation method includes: dissolving senaparib and hypromellose phthalate HP-55 in a mixed solution of tetrahydrofuran and methanol (7:3, v/v), then spray-drying the solution, and drying the collected spray-dried particles in a vacuum dryer to obtain a solid dispersion of senaparib. After testing, in the solid dispersion powder, the crystalline form of senaparib is less than 1wt%.

实施例四：辅料筛选Embodiment four: auxiliary material screening

按照下表8所示的配方(各成分用量以mg计)制备胶囊剂，进行辅料筛选。Capsules were prepared according to the formula shown in Table 8 below (the dosage of each component is in mg), and the excipients were screened.

表8
Table 8

*：微晶纤维素的粒径控制范围为D90：170～283μm。*: The particle size control range of microcrystalline cellulose is D90: 170-283 μm.

**：甘露醇粒径控制：大于75μm(200目)的粒度分布不小于70％。**: Mannitol particle size control: the particle size distribution greater than 75 μm (200 mesh) is not less than 70%.

***：交联聚维酮的粒径控制范围为D90：270～385μm。 ***: The particle size control range of crospovidone is D90: 270-385 μm.

胶囊剂制备方法：将胶囊剂各自的成分加入至万向混合器中，在40rpm转速下混合5分钟。然后使用40目筛网过筛；将过筛后的物料在40rpm转速下混合8分钟。将硬脂酸镁过30目筛并加入到万向混合器中，然后在40rpm转速下混合3分钟。将所获得的混粉装入明胶空心胶囊壳中得到口服胶囊剂。Capsule preparation method: Add the respective components of the capsule into a universal mixer, and mix at 40 rpm for 5 minutes. Then use a 40-mesh sieve to sieve; the sieved material was mixed at 40 rpm for 8 minutes. Magnesium stearate was passed through a 30-mesh sieve and added to the universal mixer, and then mixed at 40 rpm for 3 minutes. The obtained mixed powder is filled into gelatin hollow capsule shells to obtain oral capsules.

检测各胶囊剂的混粉以及senaparib固体分散体的休止角、水分、松密度、振实密度及卡尔指数。结果如下表9所示。The angle of repose, moisture, bulk density, tap density and Carr index of the mixed powder of each capsule and the solid dispersion of senaparib were detected. The results are shown in Table 9 below.

表9
Table 9

从表9中结果可以看出，胶囊剂1-4的混粉和固体分散体粉末相比，松密度明显增大，卡尔指数明显降低，物料流动性明显改善。胶囊剂1-4中的填充剂(微晶纤维素)粒径控制范围为D90：170～283μm，甘露醇的粒径控制范围为大于75μm(200目)的粒度分布不小于70％，有效的改善了物料的流动性，满足灌装要求。It can be seen from the results in Table 9 that compared with the solid dispersion powder, the mixed powder of capsules 1-4 has significantly increased bulk density, significantly decreased Carr index, and significantly improved material fluidity. The particle size control range of the filler (microcrystalline cellulose) in capsules 1-4 is D90: 170-283 μm, and the particle size control range of mannitol is greater than 75 μm (200 mesh) and the particle size distribution is not less than 70%, which effectively improves the fluidity of the material and meets the filling requirements.

按照下表10所示的配方(各成分用量以mg计)制备含senaparib固体分散体的口服胶囊剂5-7。单粒10mg规格胶囊的处方为：Oral capsules 5-7 containing senaparib solid dispersion were prepared according to the formula shown in Table 10 below (the dosage of each component is in mg). The prescription for a single 10mg capsule is:

表10

Table 10

*：微晶纤维素的粒径控制范围为D90：275～480μm。*: The particle size control range of microcrystalline cellulose is D90: 275-480 μm.

**：甘露醇粒径控制：大于75μm(200目)的粒度分布不得小、于90％。**: Mannitol particle size control: the particle size distribution greater than 75 μm (200 mesh) must not be smaller than 90%.

***：交联聚维酮的粒径控制范围为D90：270～385μm。***: The particle size control range of crospovidone is D90: 270-385 μm.

制备方法：将各胶囊剂的成分加入至料斗混合机中，在15rpm转速条件下混合3分钟。然后使用30目筛网过筛；将过筛后的物料在15rpm转速下混合10分钟。将硬脂酸镁过30目筛并加入到混合机中，然后在15rpm转速下混合3分钟。将所获得的混粉装入明胶空心胶囊壳中得到口服胶囊剂。Preparation method: Add the ingredients of each capsule into a hopper mixer and mix for 3 minutes at 15 rpm. Then use a 30-mesh sieve to sieve; the sieved material was mixed at 15 rpm for 10 minutes. Magnesium stearate was passed through a 30-mesh sieve and added to the mixer, and then mixed at 15 rpm for 3 minutes. The obtained mixed powder is filled into gelatin hollow capsule shells to obtain oral capsules.

检测各胶囊剂的混粉以及senaparib固体分散体的休止角、水分、松密度、振实密度及卡尔指数。结果如下表11所示。The angle of repose, moisture, bulk density, tap density and Carr index of the mixed powder of each capsule and the solid dispersion of senaparib were detected. The results are shown in Table 11 below.

表11
Table 11

从表11中结果可以看出，胶囊剂5-7的混粉和固体分散体粉末相比，松密度明显增大，卡尔指数明显降低，物料流动性明显增强。It can be seen from the results in Table 11 that compared with the solid dispersion powder, the mixed powder of capsules 5-7 has significantly increased bulk density, significantly decreased Carr index, and significantly enhanced material fluidity.

胶囊灌装测试Capsule filling test

采用In-CAP全自动胶囊灌装机对胶囊剂5-7制备的混粉进行胶囊灌装，调试机器达到目标灌装重量后，正式灌装并检测胶囊的重量，检测结果见表12-14。Use the In-CAP automatic capsule filling machine to fill the mixed powder prepared by Capsule 5-7. After debugging the machine to reach the target filling weight, formally fill and test the weight of the capsules. The test results are shown in Table 12-14.

表12：胶囊剂5制备的混粉灌装过程中胶囊称重结果

Table 12: Capsule weighing results during the filling process of mixed powder prepared by Capsule 5

表13：胶囊剂6制备的混粉灌装过程中胶囊称重结果

Table 13: Capsule weighing results during the filling process of mixed powder prepared by Capsule 6

表14：胶囊剂7制备的混粉灌装过程中胶囊称重结果
Table 14: Capsule weighing results during the filling process of mixed powder prepared by Capsule 7

制备胶囊剂5-7时，每10分钟进行一次中控。表12-14的结果显示，灌装70min的过程中，所有的胶囊重量均在限度范围内，而且相对标准偏差较小。结果证明胶囊剂5-7中的辅料有效地改善了物料的流动性，可以满足设备胶囊灌装要求。When preparing capsules 5-7, perform a central control every 10 minutes. The results in Table 12-14 show that during the filling process of 70 minutes, all capsule weights were within the limit range, and the relative standard deviation was small. The results prove that the excipients in capsules 5-7 can effectively improve the fluidity of the material, which can meet the capsule filling requirements of the equipment.

含量均匀度检测Content Uniformity Testing

对胶囊剂5-7的含量均匀度进行检测，结果见表15。The content uniformity of capsules 5-7 was tested, and the results are shown in Table 15.

表15：胶囊剂5-7的含量均匀度检测数据

Table 15: Test data of content uniformity of capsules 5-7

表15的结果显示，胶囊剂5-7的含量均匀度均符合规定。The results in Table 15 show that the content uniformity of capsules 5-7 all meet the requirements.

胶囊剂5-7中的填充剂(微晶纤维素)的粒径为D90：275～480μm，甘露醇的粒径控制范围为大于75μm(200目)的粒度分布不小于90％，填充剂的粒径较胶囊剂1～4增加了近一倍，进一步改善了物料的流动性和全自动设备上胶囊灌装适应性。同时令人惊奇地发现，辅料粒径的增大并不会导致物料在混合和灌装过程中出现分层、含量不均匀等现象。经放大试制，配方物料的混合均一性较好，胶囊成品的含量均匀度较好，表明所述配方可以很好地改善固体分散体粉末理化性质上的不足，在满足直混灌装胶囊工艺需求的同时，具备所需的溶出特性。The particle size of the filler (microcrystalline cellulose) in capsules 5-7 is D90: 275-480 μm. The particle size control range of mannitol is greater than 75 μm (200 mesh) and the particle size distribution is not less than 90%. The particle size of the filler is nearly double that of capsules 1-4, which further improves the fluidity of materials and the adaptability of capsule filling on automatic equipment. At the same time, it is surprisingly found that the increase of the particle size of the auxiliary material will not lead to the phenomenon of stratification and uneven content of the material during the mixing and filling process. After scale-up trial production, the mixing uniformity of the formula materials is better, and the content uniformity of the finished capsule is better, indicating that the formula can well improve the physical and chemical properties of the solid dispersion powder, and meet the requirements of the direct mixing filling capsule process. At the same time, it has the required dissolution characteristics.

实施例五：不同制备工艺对复方制剂中替莫唑胺混合均匀度的影响Example 5: Effects of Different Preparation Processes on the Mixing Uniformity of Temozolomide in Compound Preparations

本实施例的复方制剂配方及制备工艺如下表16所示。The formula and preparation process of the compound preparation of this embodiment are shown in Table 16 below.

表16：不同复方胶囊及制备工艺

Table 16: Different Compound Capsules and Preparation Process

*：固体分散体由senaparib和邻苯二甲酸羟丙甲纤维素酯HP-55组成，重量比例为1∶3，经检测，该固体分散体中，senaparib的结晶形式＜1wt％。*: The solid dispersion is composed of senaparib and hypromellose phthalate HP-55 in a weight ratio of 1:3. It has been detected that the crystalline form of senaparib in the solid dispersion is <1wt%.

**：微晶纤维素的粒径控制范围为D90：275～480μm。**: The particle size control range of microcrystalline cellulose is D90: 275-480 μm.

***：甘露醇粒径控制：大于75μm(200目)的粒度分布不得小于90％。***: Mannitol particle size control: the particle size distribution greater than 75μm (200 mesh) shall not be less than 90%.

****：交联聚维酮的粒径控制范围为D90：270～385μm。****: The particle size control range of crospovidone is D90: 270-385 μm.

对比复方胶囊1的制备：将替莫唑胺和其余辅料过筛混合10min，得替莫唑胺预混物，用胶囊灌装机装入明胶空心胶囊壳中，得对比复方胶囊剂1。Preparation of comparative compound capsule 1: Temozolomide and other auxiliary materials were sieved and mixed for 10 minutes to obtain a temozolomide premix, which was packed into a gelatin hollow capsule shell by a capsule filling machine to obtain comparative compound capsule 1.

复方胶囊1的制备：干法制粒灌装胶囊Preparation of Compound Capsule 1: Dry Granulation and Filling Capsules

(1)将替莫唑胺、酒石酸、部分甘露醇(占甘露醇总重比例11％)、部分二氧化硅(占二氧化硅总重比例3％)、部分硬脂酸(占硬脂酸总重比例6％)、部分微晶纤维素(占微晶纤维素总重比例22％)、羟甲基纤维素和部分交联聚维酮(占交联聚维酮总重比例18％)加入到万向混合机中，在46rpm转速下混合3分钟，得到第1混合物；(1) Temozolomide, tartaric acid, part of mannitol (accounting for 11% of the total weight ratio of mannitol), part of silicon dioxide (accounting for 3% of the total weight ratio of silicon dioxide), part of stearic acid (accounting for 6% of the total weight ratio of stearic acid), part of microcrystalline cellulose (accounting for 22% of the total weight ratio of microcrystalline cellulose), hydroxymethyl cellulose and part of crospovidone (accounting for 18% of the total weight ratio of crospovidone) are added in the universal mixer, and mixed for 3 minutes at a speed of 46 rpm, Obtain the first mixture;

(2)将第1混合物过20目筛，将过筛后的物料重新加入到步骤(1)的万向混合机中，在46rpm转速下混合10分钟后，用干法制粒机采用以下参数进行干法制粒：辊压压力3kN，滚轮转速2rpm，饲料速度30rpm，大片过筛筛网为24目； (2) The first mixture is passed through a 20-mesh sieve, and the sieved material is re-added to the universal mixer of step (1), and after mixing for 10 minutes at a rotating speed of 46 rpm, dry granulation is carried out with a dry granulator using the following parameters: roller pressure 3kN, roller speed 2rpm, feed speed 30rpm, large sieve sieve mesh is 24 mesh;

(3)将senaparib固体分散体、剩余甘露醇、剩余二氧化硅、剩余微晶纤维素和剩余交联聚维酮加入步骤(1)的万向混合机中，与步骤(2)制得的颗粒在46rpm转速下混合3分钟，得到第2混合物；(3) Add the senaparib solid dispersion, the remaining mannitol, the remaining silicon dioxide, the remaining microcrystalline cellulose and the remaining crospovidone into the universal mixer of step (1), and mix with the granules prepared in step (2) at a speed of 46 rpm for 3 minutes to obtain the second mixture;

(4)将第2混合物取出过20目筛后，重新投入步骤(1)万向混合机中，在46rpm转速下混合10分钟，然后加入过20目筛的余下的硬脂酸，在10rpm转速下混合3分钟，得到最终混合物；(4) After the second mixture was taken out and passed through a 20-mesh sieve, it was put back into the universal mixer in step (1), and mixed for 10 minutes at a speed of 46 rpm, then the remaining stearic acid passed through a 20-mesh sieve was added, and mixed for 3 minutes at a speed of 10 rpm to obtain the final mixture;

(5)将最终混合物用胶囊灌装机装入明胶空心胶囊壳中，得所述复方胶囊剂1。(5) Fill the final mixture into gelatin hollow capsule shells with a capsule filling machine to obtain the compound capsule 1.

复方胶囊2的制备：直混灌装胶囊Preparation of Compound Capsule 2: Direct Mix Filling Capsules

(1)将替莫唑胺、微晶纤维素、酒石酸和交联聚维酮加入万向混合机中，在46rpm转速下混合3分钟，得到第1混合物；(1) Add temozolomide, microcrystalline cellulose, tartaric acid and crospovidone into the universal mixer, and mix for 3 minutes at 46 rpm to obtain the first mixture;

(2)将senaparib的固体分散体、甘露醇和胶态二氧化硅加入步骤(1)的万向混合机中，与第1混合物在46rpm转速下混合3分钟，得到第2混合物；(2) Add the solid dispersion of senaparib, mannitol and colloidal silicon dioxide into the universal mixer of step (1), and mix with the first mixture for 3 minutes at 46 rpm to obtain the second mixture;

(3)将第2混合物过30目筛，将过筛后的物料重新加入到步骤1的万向混合机中，再加入过30目筛的硬脂酸镁，进行混合，得到最终混合物；(3) Pass the second mixture through a 30-mesh sieve, re-join the sieved material in the universal mixer of step 1, then add magnesium stearate crossed through a 30-mesh sieve, and mix to obtain the final mixture;

(4)将步骤(3)中获得的最终混合物用胶囊灌装机装入明胶空心胶囊壳中，得所述复方胶囊剂2。(4) Pack the final mixture obtained in step (3) into gelatin hollow capsule shells with a capsule filling machine to obtain the compound capsule 2.

复方片剂3的制备：直混压片Preparation of Compound Tablet 3: Direct Mix Tablet Compression

(1)将替莫唑胺、微晶纤维素、酒石酸和交联聚维酮用适合体积的混合设备进行预混合，得到第1混合物；(1) premixing temozolomide, microcrystalline cellulose, tartaric acid and crospovidone with a mixing device suitable for volume to obtain the first mixture;

(2)将senaparib的固体分散体、甘露醇和二氧化硅加入步骤(1)的混合设备中与第1混合物进行混合，得到第2混合物；(2) adding the solid dispersion of senaparib, mannitol and silicon dioxide into the mixing equipment of step (1) to mix with the first mixture to obtain the second mixture;

(3)将第2混合物过筛，将过筛后的物料重新加入到步骤1的混合设备中，再加入过筛后的润滑剂，进行混合，得到最终混合物；(3) Sieve the second mixture, re-add the sieved material to the mixing equipment in step 1, add the sieved lubricant, and mix to obtain the final mixture;

(4)将步骤(3)中获得的最终混合物压制成素片，再将压制好的片剂进行包衣，以获得所述口服片剂3。(4) Compress the final mixture obtained in step (3) into a plain tablet, and then coat the compressed tablet to obtain the oral tablet 3 .

复方片剂4的制备：干法制粒压片 Preparation of Compound Tablet 4: Dry Granulation and Tablet Compression

(1)将替莫唑胺、微晶纤维素、酒石酸、交联聚维酮和羟丙基纤维素，得到第1混合物；(1) Temozolomide, microcrystalline cellulose, tartaric acid, crospovidone and hydroxypropyl cellulose were used to obtain the first mixture;

(2)混合senaparib的固体分散体、乳糖、部分助流剂(占助流剂总重比例50％)和部分润滑剂(占润滑剂总重比例67％)与第1混合物，得到第2混合物；(2) mixing the solid dispersion of senaparib, lactose, part of the glidant (accounting for 50% of the total weight of the glidant) and part of the lubricant (accounting for 67% of the total weight of the lubricant) with the first mixture to obtain the second mixture;

(3)将第2混合物取出采用干法制粒设备进行制粒，将完成制粒的物料与剩余助流剂和剩余润滑剂混合，得到最终混合物；(3) The second mixture is taken out and granulated by dry granulation equipment, and the granulated material is mixed with the remaining glidant and the remaining lubricant to obtain the final mixture;

(4)将步骤(3)中获得的最终混合物压制成素片，再素片包衣，获得所述口服片剂。(4) Compress the final mixture obtained in step (3) into a plain tablet, and then coat the plain tablet to obtain the oral tablet.

采用高效液相色谱方法测试对比复方胶囊1、复方胶囊1和2以及复方片剂3和4制备过程中替莫唑胺的混合均匀度。结果如下表17所示。The mixing uniformity of temozolomide in the preparation process of Compound Capsule 1, Compound Capsules 1 and 2, and Compound Tablets 3 and 4 was tested and compared by HPLC. The results are shown in Table 17 below.

表17
Table 17

复方胶囊1和2以及复方片剂3的中控数据如下表18所示。The intermediate control data of Compound Capsules 1 and 2 and Compound Tablet 3 are shown in Table 18 below.

表18

Table 18

对比复方胶囊的混合均匀度检测结果(表17)显示，小批量条件下替莫唑胺和其余辅料简单混合，物料的混合均匀性较差(RSD＝4.2％)，以此工艺进行放大生产，物料混合不均匀的风险很大。复方胶囊1和2以及复方片剂3和4采用等量递增法进行混合，替莫唑胺的混合均匀性得到显著改善(RSD均小于1％)，可明显降低放大生产时的混合均匀度风险。同时表18的中控结果显示，复方胶囊1和2以及复方片剂3在胶囊灌装或压片工艺中，粒(片)重差异较小，工艺很稳定，说明其处方流动性能满足灌装或压片工艺的需求。Comparing the test results of compound uniformity of compound capsules (Table 17) shows that simple mixing of temozolomide and other excipients under small batch conditions results in poor mixing uniformity (RSD=4.2%). Large-scale production with this process has a high risk of uneven mixing of materials. Compound capsules 1 and 2 and compound tablets 3 and 4 were mixed using the method of equal increments, and the mixing uniformity of temozolomide was significantly improved (RSDs were all less than 1%), which can significantly reduce the risk of mixing uniformity during scale-up production. At the same time, the results of the central control in Table 18 show that in the capsule filling or tableting process of compound capsules 1 and 2 and compound tablet 3, the difference in grain (tablet) weight is small, and the process is very stable, indicating that the flow properties of the prescription meet the requirements of the filling or tableting process.

实施例六：senaparib和替莫唑胺口服复方胶囊的制备和溶出度Embodiment 6: Preparation and dissolution rate of senaparib and temozolomide oral compound capsule

按下表19所示的配方制备复方胶囊3-6。Compound capsules 3-6 were prepared according to the formula shown in Table 19.

表19
Table 19

*：固体分散体由senaparib和邻苯二甲酸羟丙甲纤维素酯HP-55组成，重量比例为1∶3，经检测，该固体分散体粉末中，senaparib的结晶形式＜1％。*: The solid dispersion is composed of senaparib and hypromellose phthalate HP-55 in a weight ratio of 1:3, and the crystalline form of senaparib in the solid dispersion powder is less than 1%.

***：甘露醇粒径控制：大于75μm(200目)的粒度分布不得小于90％。 ***: Mannitol particle size control: the particle size distribution greater than 75μm (200 mesh) shall not be less than 90%.

复方胶囊3-6的制备方法包括以下步骤：The preparation method of compound capsule 3-6 comprises the following steps:

(4)将步骤(3)中获得的最终混合物装入明胶空心胶囊壳中，得复方胶囊剂。(4) Pack the final mixture obtained in the step (3) into a gelatin hollow capsule shell to obtain a compound capsule.

对复方胶囊3-6的最终混合物中替莫唑胺的混合均匀度，以及终产品胶囊中senaparib的溶出度进行检测。溶出度检测方法：参考《中国药典》2015年版通则＜0931＞(溶出度与释放度测定法)第二法(桨法)，设定自动取样溶出仪水浴温度37±0.5℃，选用含1％CTAB的0.1N盐酸缓冲液作为溶出介质，体积为900mL。分别于10分钟、15分钟、20分钟、30分钟、45分钟、60分钟，之后再极限转速(每分钟250转)下旋转30分钟取样，将所有样品过尼龙针式滤膜，按样品溶出度测定方法测定分析。结果如表20所示。The mixing uniformity of temozolomide in the final mixture of compound capsules 3-6 and the dissolution rate of senaparib in the final product capsules were detected. Dissolution testing method: refer to the second method (paddle method) of "Chinese Pharmacopoeia" 2015 edition general rule <0931> (dissolution and release testing method), set the water bath temperature of the automatic sampling dissolution apparatus to 37±0.5°C, select 0.1N hydrochloric acid buffer solution containing 1% CTAB as the dissolution medium, and the volume is 900mL. Respectively at 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, and then rotate at the limit speed (250 rpm) for 30 minutes to take samples, pass all samples through nylon needle filters, and measure and analyze according to the sample dissolution method. The results are shown in Table 20.

表20

Table 20

*：复方胶囊7采用的溶出度方法中溶出介质为含3％CTAB的0.1N盐酸缓冲液，其他溶出条件同复方胶囊3-5。*: The dissolution medium used in compound capsule 7 is 0.1N hydrochloric acid buffer solution containing 3% CTAB, and other dissolution conditions are the same as compound capsule 3-5.

从表20的结果可以看出，替莫唑胺的混合均匀度和终产品胶囊中senaparib的溶出度均满足制剂质控要求。As can be seen from the results in Table 20, the mixing uniformity of temozolomide and the dissolution rate of senaparib in the final product capsules all meet the quality control requirements of the preparation.

实施例七：含有不同填充剂和崩解剂的senaparib和替莫唑胺的复方胶囊剂的制备和溶出度Embodiment seven: the preparation and the dissolution rate of the compound capsule of senaparib and temozolomide containing different fillers and disintegrants

采用实施例五中复方胶囊2所述的方法，按表21所示的配方制备复方胶囊7-9。检测复方胶囊7-9的最终混合物中替莫唑胺的混合均匀度以及终产品胶囊中senaparib的溶出度，溶出度检测方法同实施例六，结果如表22所示。Using the method described in Compound Capsule 2 in Example 5, Compound Capsules 7-9 were prepared according to the formula shown in Table 21. Detect the mixing uniformity of temozolomide in the final mixture of compound capsules 7-9 and the dissolution rate of senaparib in the final product capsules. The dissolution detection method is the same as in Example 6, and the results are shown in Table 22.

表21
Table 21

*：固体分散体由senaparib和邻苯二甲酸羟丙甲纤维素酯HP-55组成，重量比例为1∶3，经检测，该固体分散体粉末中，senaparib的结晶形式＜1wt％。*: The solid dispersion is composed of senaparib and hypromellose phthalate HP-55 in a weight ratio of 1:3, and the crystalline form of senaparib in the solid dispersion powder is <1 wt%.

表22
Table 22

从表22的结果可以看出，替莫唑胺的混合均匀度和终产品胶囊中senaparib的溶出度均满足制剂质控要求。It can be seen from the results in Table 22 that the mixing uniformity of temozolomide and the dissolution rate of senaparib in the final product capsules all meet the quality control requirements of the preparation.

实施例八：含不同比例填充剂和不同润滑剂的senaparib和替莫唑胺的口服复方胶囊剂的制备和溶出度Embodiment 8: Preparation and dissolution rate of oral compound capsules containing senaparib and temozolomide in different proportions of fillers and different lubricants

采用实施例五中复方胶囊2所述的方法，按下表23所示的配方制备含有不同比例填充剂和另外润滑剂的复方胶囊10-12所示的senaparib和替莫唑胺的口服复方胶囊剂。检测复方胶囊10-12的最终混合物中替莫唑胺的混合均匀度以及终产品胶囊中senaparib的溶出度，溶出度检测方法同实施例六，结果如下表24所示。Using the method described in Compound Capsule 2 in Example 5, oral compound capsules of senaparib and temozolomide as shown in Compound Capsules 10-12 containing different proportions of fillers and other lubricants were prepared according to the formula shown in Table 23. Detect the mixing uniformity of temozolomide in the final mixture of compound capsules 10-12 and the dissolution rate of senaparib in the final product capsules. The dissolution detection method is the same as in Example 6, and the results are shown in Table 24 below.

表23

Table 23

表24
Table 24

从表24的结果可以看出，替莫唑胺的混合均匀度和终产品胶囊中senaparib的溶出度均满足制剂质控要求。It can be seen from the results in Table 24 that the mixing uniformity of temozolomide and the dissolution rate of senaparib in the final product capsules all meet the quality control requirements of the preparation.

实施例九：不同崩解剂用量的senaparib和替莫唑胺的复方胶囊剂的制备和溶出度Embodiment 9: Preparation and dissolution rate of compound capsules of senaparib and temozolomide with different disintegrant dosages

采用实施例五中复方胶囊2所述的方法，按下表25所示的配方制备复方胶囊13。对复方胶囊13的最终混合物中senaparib和替莫唑胺各自的混合均匀度，以及终产品胶囊中两个活性成分的溶出度进行检测，溶出度检测方法同实施例六，结果如下表26所示。Using the method described in Compound Capsule 2 in Example 5, the formula shown in Table 25 was used to prepare Compound Capsule 13. The mixing uniformity of senaparib and temozolomide in the final mixture of compound capsule 13 and the dissolution rate of the two active ingredients in the final product capsule were tested. The dissolution test method was the same as in Example 6, and the results are shown in Table 26 below.

表25：复方胶囊13的配方

Table 25: Formula of Compound Capsule 13

表26
Table 26

从表26的结果可以看出，两个活性成分的混合均匀度和终产品胶囊的溶出度满足制剂中控和质控要求。From the results in Table 26, it can be seen that the mixing uniformity of the two active ingredients and the dissolution rate of the final product capsules meet the requirements of the preparation control and quality control.

实施例十：含有不同比例酸性pH添加剂的senaparib和替莫唑胺的口服复方胶囊剂的制备和溶出度Embodiment 10: Oral compound of senaparib and temozolomide containing different proportions of acidic pH additives Capsule preparation and dissolution

采用实施例五中复方胶囊2所述的制备方法，按下表27所示配方制备复方胶囊14-16，并采用前文所述方法检测各复方胶囊最终混合物中替莫唑胺的混合均匀度以及终产品胶囊中senaparib的溶出度，溶出度检测方法同实施例六，结果如表28所示。Using the preparation method described in Compound Capsule 2 in Example 5, Compound Capsules 14-16 were prepared according to the formula shown in Table 27, and the method described above was used to detect the mixing uniformity of temozolomide in the final mixture of each compound capsule and the dissolution rate of senaparib in the final product capsule. The dissolution detection method was the same as in Example 6, and the results were shown in Table 28.

表27
Table 27

表28

Table 28

从表28的结果可以看出，替莫唑胺的混合均匀度和终产品胶囊中senaparib的溶出度均满足制剂质控要求。From the results in Table 28, it can be seen that the mixing uniformity of temozolomide and the dissolution rate of senaparib in the final product capsules all meet the quality control requirements of the preparation.

实施例十一：复方胶囊14与TMZ单方参比制剂(上市产品)的稳定性对比Embodiment 11: Stability comparison of Compound Capsule 14 and TMZ single reference preparation (marketed product)

在加速条件下(40℃/75％RH)测试实施例十制备得到的复方胶囊14与TMZ单方参比制剂的稳定性。放样时间点分别为0/1/3月和0/3月。在各时间点对TMZ含量、有关物质等检项进行检测，结果如表29所示。The stability of the compound capsule 14 prepared in Example 10 and the TMZ single reference preparation was tested under accelerated conditions (40° C./75% RH). The staking time points are 0/1/3 month and 0/3 month respectively. The inspection items such as TMZ content and related substances were detected at each time point, and the results are shown in Table 29.

根据结果可知复方胶囊15在加速条件下放置3个月，含量没有明显变化，总杂含量略有增加，但增加幅度较TMZ单方参比制剂更小，可满足稳定性要求。According to the results, it can be seen that the compound capsule 15 was placed under accelerated conditions for 3 months, the content did not change significantly, and the total impurity content increased slightly, but the increase was smaller than that of the TMZ single prescription reference preparation, which could meet the stability requirements.

表29
Table 29

注：*TMZ单方参比制剂为上市产品，生产厂家为SUN Pharmaceutical Industries Ltd。Note: *TMZ unilateral reference preparation is a marketed product, and the manufacturer is SUN Pharmaceutical Industries Ltd.

对比例一：低剂量senaparib+高剂量TMZ在MX-1人乳腺癌小鼠模型中的毒性和肿瘤抑制作用Comparative Example 1: Toxicity and tumor inhibitory effects of low-dose senaparib+high-dose TMZ in MX-1 human breast cancer mouse model

评价低剂量化合物senaparib联合高剂量TMZ在MX-1人乳腺癌裸鼠异种移植瘤模型中的抗肿瘤活性。为此目的，将人乳腺癌细胞MX-1接种于裸鼠腋窝皮下。细胞接种量为1.0×10⁶个对数生长期细胞，接种形成移植瘤后在裸小鼠体内传3代后使用。选取生长状态较好，没有坏死的肿瘤用灭菌的PBS冲洗干净，快速剪碎。置入组织匀浆器中顺时针方向充分研磨，匀浆过200目滤网。将滤过细胞悬液置入无菌离心管中1000rpm，5min。弃上清，沉淀用无菌PBS重悬，1000rpm、5min洗涤一次。弃上清，加入适量PBS重悬，计数，调节细胞数至5×10⁶/mL。充分混匀细胞悬液，以每只小鼠5×10⁵个细胞(0.1mL)注射于小鼠右前肢腋窝处皮下。当肿瘤平均体积达到约50mm³时，根据瘤体积随机分组并开始给药，分组及给药方案见表30。To evaluate the antitumor activity of low-dose compound senaparib combined with high-dose TMZ in MX-1 human breast cancer xenograft model in nude mice. For this purpose, human breast cancer cells MX-1 were inoculated subcutaneously in the axilla of nude mice. The cell inoculation amount was 1.0×10 ⁶ cells in the logarithmic growth phase. After inoculation to form xenograft tumors, they were passed in nude mice for 3 generations before use. Choose tumors with good growth status and no necrosis, wash them with sterilized PBS, and quickly cut them into pieces. Put it into a tissue homogenizer and grind it clockwise, and pass the homogenate through a 200-mesh filter. Put the filtered cell suspension into a sterile centrifuge tube at 1000rpm for 5min. Discard the supernatant, resuspend the pellet with sterile PBS, and wash once at 1000 rpm for 5 min. Discard the supernatant, add an appropriate amount of PBS to resuspend, count, and adjust the number of cells to 5×10 ⁶ /mL. The cell suspension was mixed well, and 5×10 ⁵ cells (0.1 mL) per mouse were injected subcutaneously at the axilla of the right forelimb of the mouse. When the average volume of the tumor reaches about 50mm ³ , randomize the group according to the tumor volume and start dosing, grouping and dosing See Table 30 for the scheme.

表30：senaparib联合TMZ体内药效实验动物分组及给药方案
Table 30: Animal groups and dosing regimens for senaparib combined with TMZ in vivo efficacy experiments

注2：每组9只荷瘤裸鼠；p.o为口服给药；QD 5D为每天一次，连续5天，停药后继续观察1-2周，各组平均瘤体积达到5000mm³时及时处死。组别1和4，开始给药后第8天处死动物；组别2，开始给药后第14天处死动物；组别3，开始给药后第17天处死动物；组别5，开始给药后第21天处死动物。Note 2: There were 9 tumor-bearing nude mice in each group; po was administered orally; QD 5D was once a day for 5 consecutive days, and the observation was continued for 1-2 weeks after stopping the drug. The average tumor volume of each group reached 5000mm ³ and was killed in time. In groups 1 and 4, the animals were sacrificed on the 8th day after the start of dosing; in group 2, the animals were sacrificed on the 14th day after the start of dosing; in group 3, the animals were killed on the 17th day after the start of dosing; in group 5, the animals were sacrificed on the 21st day after the start of dosing.

注3：溶媒，成分为10％DMSO in 10％HP-β-CD PBS。Note 3: The vehicle, the composition is 10% DMSO in 10% HP-β-CD PBS.

注4：溶媒对照组根据体重灌胃给予20μL/g溶媒；TMZ和senaparib单独给药组灌胃给药20μL/g的药物；联合给药组先灌胃给予10μL/g相应浓度的AZD2281或senaparib，45min后再灌胃给予10μL/g的TMZ。Note 4: The vehicle control group was intragastrically administered 20 μL/g vehicle according to body weight; the TMZ and senaparib single administration group was intragastrically administered 20 μL/g of the drug; the combined administration group was first intragastrically administered 10 μL/g of AZD2281 or senaparib at the corresponding concentration, and then 10 μL/g TMZ was intragastrically administered after 45 minutes.

使用测量瘤径的方法，动态观察被试物抗肿瘤的药物效应。每天测量肿瘤体积及动物体重。Using the method of measuring tumor diameter, dynamically observe the anti-tumor drug effect of the test substance. Tumor volume and animal body weight were measured daily.

实验结果Experimental results

1、体重1. Weight

从体重变化情况来看，TMZ单独给药组和联合给药组都有不同程度的体重下降，连续给药5天后，senaparib 1mg/kg联合TMZ给药组的体重下降达15％，AZD2281 20mg/kg联合TMZ给药组体重下降约12％。各组平均体重见表31。In terms of body weight changes, both the TMZ administration group and the combined administration group had different degrees of weight loss. After 5 days of continuous administration, the body weight of the senaparib 1mg/kg combined with TMZ administration group decreased by 15%, and the AZD2281 20mg/kg combined with TMZ administration group lost about 12%. The average body weight of each group is shown in Table 31.

表31：平均体重
Table 31: Average body weight

2、抗肿瘤活性的评价指标2. Evaluation index of anti-tumor activity

实验期间各组给药5天后相对肿瘤增殖率[T/C(％)]如下表32所示。The relative tumor proliferation rate [T/C (%)] of each group after administration for 5 days during the experiment is shown in Table 32 below.

表32：抗肿瘤活性的评价指标
Table 32: Evaluation indicators of anti-tumor activity

各组裸鼠肿瘤大小变化见下表33。The changes in the tumor size of nude mice in each group are shown in Table 33 below.

表33：各组裸鼠肿瘤大小变化(Mean±SD，n＝9，肿瘤体积：mm³)
Table 33: Tumor size changes in nude mice in each group (Mean±SD, n=9, tumor volume: mm ³ )

综上所述，senaparib联合TMZ每天给药一次，连续给药5天，对MX-1人小细胞肺癌裸鼠异种移植瘤模型表现出显著的抗肿瘤效果，且具有协同作用，但1mg/kg senaparib联合给药组连续给药5天后，小鼠体重下降明显(达15％)，停药后，肿瘤体积于第10天开始持续增大。 In summary, senaparib combined with TMZ administered once a day for 5 consecutive days showed a significant anti-tumor effect on the nude mouse xenograft tumor model of MX-1 human small cell lung cancer, and had a synergistic effect. However, after 5 days of continuous administration in the 1 mg/kg senaparib combined administration group, the body weight of the mice decreased significantly (up to 15%). After stopping the drug, the tumor volume began to increase continuously on the 10th day.

虽然已经充分地描述了本发明，但是本领域技术人员应当理解，可在不影响本发明范围或其任何实施方案的情况下，在广泛且等同的条件、制剂和其它参数范围内进行相同实施。本文所引用的所有专利、专利申请和出版物都全文引入本文以供参考。 While the invention has been fully described, it will be understood by those skilled in the art that the same practice can be performed within a broad and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.

Claims

一种复方制剂，其含有活性成分和药学上可接受的辅料，所述活性成分为senaparib和替莫唑胺，其中，以复方制剂总重计，senaparib的含量为2.0％～15.0％，替莫唑胺的含量为1.0％～10.0％。A compound preparation, which contains active ingredients and pharmaceutically acceptable auxiliary materials, the active ingredients are senaparib and temozolomide, wherein, based on the total weight of the compound preparation, the content of senaparib is 2.0% to 15.0%, and the content of temozolomide is 1.0% to 10.0%.
如权利要求1所述的复方制剂，其特征在于，所述药学上可接受的辅料包括载体、填充剂、崩解剂、助流剂、润滑剂、粘合剂、表面活性剂和pH调节剂中的一种或多种；优选地，所述药物上可接受的辅料包括载体、填充剂、崩解剂、助流剂、润滑剂和pH调节剂，任选地还含有粘合剂和表面活性剂中的一种或两种。The compound preparation according to claim 1, wherein the pharmaceutically acceptable adjuvant includes one or more of carrier, filler, disintegrant, glidant, lubricant, binder, surfactant and pH regulator; preferably, the pharmaceutically acceptable adjuvant includes carrier, filler, disintegrant, glidant, lubricant and pH regulator, and optionally also contains one or both of the binder and the surfactant.
如权利要求2所述的复方制剂，其特征在于，compound preparation as claimed in claim 2, is characterized in that,

所述载体为醋酸琥珀羟丙甲纤维素酸、羟丙基甲基纤维素邻苯二甲酸酯或其混合物；和/或The carrier is hypromellose acetate succinate, hydroxypropyl methylcellulose phthalate or a mixture thereof; and/or

所述填充剂选自淀粉、预胶化淀粉、甘露醇、乳糖、蔗糖、环糊精、微晶纤维素中的一种或多种；优选的填充剂为微晶纤维素和/或甘露醇和/或乳糖；和/或The filler is selected from one or more of starch, pregelatinized starch, mannitol, lactose, sucrose, cyclodextrin, microcrystalline cellulose; preferred filler is microcrystalline cellulose and/or mannitol and/or lactose; and/or

所述崩解剂选自羧甲基淀粉钠、低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、羧甲基纤维素钙、预胶化淀粉、海藻酸钠以及它们的任意组合；优选地，所述崩解剂为交联聚维酮或羧甲基淀粉钠；和/或The disintegrating agent is selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, carmellose calcium, pregelatinized starch, sodium alginate and any combination thereof; preferably, the disintegrating agent is crospovidone or sodium carboxymethyl starch; and/or

所述助流剂选自粉状纤维素、三硅酸镁、胶态二氧化硅、滑石粉以及它们的任意组合；优选的助流剂是胶态二氧化硅；和/或The glidant is selected from powdered cellulose, magnesium trisilicate, colloidal silicon dioxide, talc and any combination thereof; preferred glidant is colloidal silicon dioxide; and/or

所述润滑剂选自硬脂酸锌、单硬脂酸甘油酯、硬脂酸棕榈酸甘油酯、硬脂酸镁、硬脂酸富马酸钠以及它们的任意组合；优选的润滑剂为硬脂酸镁；和/或The lubricant is selected from zinc stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium stearate fumarate and any combination thereof; preferred lubricant is magnesium stearate; and/or

所述粘合剂选自羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素和聚维酮中的一种或多种；和/或The binder is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and povidone; and/or

所述表面活性剂选自十二烷基硫酸钠、泊洛沙姆、牛磺酸、月桂酰聚氧乙烯甘油酯和聚山梨酯中的一种或多种；和/或The surfactant is selected from one or more of sodium lauryl sulfate, poloxamer, taurine, polyoxyethylene lauroyl glyceride and polysorbate; and/or

所述pH调节剂为酸性pH调节剂，选自柠檬酸、酒石酸、山梨酸、苹果酸、乳酸、富马酸、己二酸中的一种或多种；优选的pH调节剂为酒石酸。The pH regulator is an acidic pH regulator, selected from one or more of citric acid, tartaric acid, sorbic acid, malic acid, lactic acid, fumaric acid and adipic acid; the preferred pH regulator is tartaric acid.
如权利要求2或3所述的复方制剂，其特征在于，以复方制剂总重计，The compound preparation according to claim 2 or 3, characterized in that, based on the total weight of the compound preparation,

所述载体的含量为7％～30％，优选13％～20％；优选地，所述senaparib和载体的重量比为1∶2到1∶3；和/或The content of the carrier is 7% to 30%, preferably 13% to 20%; preferably, the senaparib and the carrier The body weight ratio is 1:2 to 1:3; and/or

所述填充剂的含量为56％～85％，优选70％～82％，更优选75％～82％；和/或The content of the filler is 56%-85%, preferably 70%-82%, more preferably 75%-82%; and/or

所述崩解剂的含量为0.1％～10％，优选为0.5％～4％；和/或The content of the disintegrant is 0.1% to 10%, preferably 0.5% to 4%; and/or

所述助流剂的含量为0.1％～10％，优选为1％～3％；和/或The content of the glidant is 0.1%-10%, preferably 1%-3%; and/or

所述润滑剂的含量为0.1％～3％，优选为0.3％～1％，如0.5±0.1％；和/或The content of the lubricant is 0.1%-3%, preferably 0.3%-1%, such as 0.5±0.1%; and/or

所述粘合剂的含量为0.1％～5％，优选为0.1％～3％；和/或The content of the binder is 0.1%-5%, preferably 0.1%-3%; and/or

所述表面活性剂的含量为0.5％～2.2％，优选0.9％～1.5％；和/或The content of the surfactant is 0.5% to 2.2%, preferably 0.9% to 1.5%; and/or

所述酸性pH调节剂的含量为0.1％～5％，优选0.1％～3％。The content of the acidic pH regulator is 0.1%-5%, preferably 0.1%-3%.
如权利要求1-4中任一项所述的复方制剂，其特征在于，所述复方制剂含有羟丙基甲基纤维素邻苯二甲酸酯，其中，所述senaparib和所述羟丙基甲基纤维素邻苯二甲酸酯的重量比为1∶2到1∶3；或所述复方制剂含有羟丙基甲基纤维素邻苯二甲酸酯和表面活性剂，其中，所述senaparib、所述羟丙基甲基纤维素邻苯二甲酸酯和所述表面活性剂的重量比为1∶2.8∶0.2。The compound preparation according to any one of claims 1-4, wherein said compound preparation contains hydroxypropyl methylcellulose phthalate, wherein the weight ratio of said senaparib to said hydroxypropyl methylcellulose phthalate is 1:2 to 1:3; or said compound preparation contains hydroxypropyl methylcellulose phthalate and a surfactant, wherein said senaparib, said hydroxypropyl methylcellulose phthalate and said surfactant are in a weight ratio of 1:2.8:0 .2.
如权利要求1-4中任一项所述的复方制剂，其特征在于，所述复方制剂含有所述senaparib的固体分散体；其中，所述固体分散体含有senaparib、羟丙基甲基纤维素邻苯二甲酸酯和任选的表面活性剂；The compound preparation according to any one of claims 1-4, wherein the compound preparation contains the solid dispersion of senaparib; wherein, the solid dispersion contains senaparib, hydroxypropyl methylcellulose phthalate and optional surfactants;

优选地，所述固体分散体中，以固体分散体总重计，羟丙基甲基纤维素邻苯二甲酸酯的含量为65％～77％，优选73％～77％；senaparib的含量为23％～35％；所述表面活性剂的含量为2％～5％；Preferably, in the solid dispersion, based on the total weight of the solid dispersion, the content of hydroxypropyl methylcellulose phthalate is 65% to 77%, preferably 73% to 77%; the content of senaparib is 23% to 35%; the content of the surfactant is 2% to 5%;

更优选地，所述固体分散体由重量比为1∶2或1∶3的活性成分senaparib和羟丙基甲基纤维素邻苯二甲酸酯组成，或由senaparib、羟丙基甲基纤维素邻苯二甲酸酯和泊洛沙姆组成，三者的重量比为1∶2.8∶0.2。More preferably, the solid dispersion is composed of active ingredients senaparib and hydroxypropylmethylcellulose phthalate in a weight ratio of 1:2 or 1:3, or is composed of senaparib, hydroxypropylmethylcellulose phthalate and poloxamer, and the weight ratio of the three is 1:2.8:0.2.
如权利要求3-6中任一项所述的复方制剂，其特征在于，按干燥品计算，所述羟丙基甲基纤维素邻苯二甲酸酯含甲氧基为12.0％～28.0％，2-羟丙氧基为4.0％～23.0％，乙酰基为2.0％～16.0％，琥珀酰基为4.0％～28.0％。The compound preparation according to any one of claims 3-6, wherein, calculated as a dry product, the hydroxypropyl methylcellulose phthalate contains 12.0% to 28.0% of methoxy, 4.0% to 23.0% of 2-hydroxypropoxy, 2.0% to 16.0% of acetyl, and 4.0% to 28.0% of succinyl.
如权利要求3-7中任一项所述的复方制剂，其特征在于，所述微晶纤维素的D90为170～480μm，优选为170～283μm或275～480μm；所述甘露醇的颗粒尺寸＞75μm的粒度分布不小于70％，优选不小于80％，更优选不小于90％。The compound preparation according to any one of claims 3-7, wherein the D90 of the microcrystalline cellulose is 170-480 μm, preferably 170-283 μm or 275-480 μm; the particle size distribution of the mannitol with a particle size > 75 μm is not less than 70%, preferably not less than 80%, more preferably not less than 90%.
如权利要求1-8中任一项所述的复方制剂，其特征在于，所述复方制剂中， senaparib的含量为替莫唑胺含量的1～8倍，优选为2～4倍；优选地，每剂所述复方制剂含有10～100mg、优选10～80mg的senaparib，和5～40mg、优选10～20mg的替莫唑胺。The compound preparation according to any one of claims 1-8, wherein, in the compound preparation, The content of senaparib is 1-8 times that of temozolomide, preferably 2-4 times; preferably, each dose of the compound preparation contains 10-100 mg, preferably 10-80 mg of senaparib, and 5-40 mg, preferably 10-20 mg of temozolomide.
如权利要求1-9中任一项所述的复方制剂，其特征在于，以其总重计，该复方制剂含有：The compound preparation according to any one of claims 1-9, characterized in that, by its gross weight, the compound preparation contains:

senaparib，2.0％～15.0％、优选2.0％～10.0％、更优选4.0％～10.0％；Senaparib, 2.0% to 15.0%, preferably 2.0% to 10.0%, more preferably 4.0% to 10.0%;

替莫唑胺，1.0％～10.0％、优选2.0％～8.0％；Temozolomide, 1.0% to 10.0%, preferably 2.0% to 8.0%;

载体，7％～30％、优选13％～20％；Carrier, 7% to 30%, preferably 13% to 20%;

填充剂，56％～85％、优选70％～82％、更优选75％～82％；Filler, 56% to 85%, preferably 70% to 82%, more preferably 75% to 82%;

崩解剂，0.1％～10％、优选0.5％～4％；Disintegrant, 0.1% to 10%, preferably 0.5% to 4%;

助流剂，0.1％～10％、优选0.5％～3％、更优选1％～3％；Glidant, 0.1% to 10%, preferably 0.5% to 3%, more preferably 1% to 3%;

润滑剂，0.1％～3％、优选0.3％～1％；Lubricant, 0.1% to 3%, preferably 0.3% to 1%;

pH调节剂，0.1％～5％、优选0.1％～3％；pH regulator, 0.1% to 5%, preferably 0.1% to 3%;

任选的粘合剂，0.1％～5％、优选为0.1％～3％；和optional binder, 0.1% to 5%, preferably 0.1% to 3%; and

任选的表面活性剂，0.5％～2.2％；Optional surfactant, 0.5% to 2.2%;

优选地，所述载体为羟丙基甲基纤维素邻苯二甲酸酯，进一步优选为HP-55；优选地，所述senaparib和载体的重量比为1∶2到1∶3；Preferably, the carrier is hydroxypropylmethylcellulose phthalate, more preferably HP-55; preferably, the weight ratio of the senaparib to the carrier is 1:2 to 1:3;

优选地，所述填充剂为微晶纤维素和甘露醇，其中，微晶纤维素的D90为170～480μm、优选275～480μm，所述甘露醇中，颗粒尺寸＞75μm的粒度分布不小于70％、优选不小于80％、更优选不小于90％，优选地，以复方制剂总重计，微晶纤维素的含量为8％～50％，优选10％～28％，更优选15％～20％；甘露醇的含量为20％～70％，优选50％～65％，更优选55％～65％；Preferably, the filler is microcrystalline cellulose and mannitol, wherein the D90 of microcrystalline cellulose is 170-480 μm, preferably 275-480 μm, and in the mannitol, the particle size distribution of particle size>75 μm is not less than 70%, preferably not less than 80%, more preferably not less than 90%, preferably, based on the total weight of the compound preparation, the content of microcrystalline cellulose is 8%-50%, preferably 10%-28%, more preferably 15% %～20%; the content of mannitol is 20%～70%, preferably 50%～65%, more preferably 55%～65%;

优选地，所述崩解剂为交联聚维酮和/或羧甲基淀粉钠，优选地，交联聚维酮的粒径控制范围为D90：270～385μm；Preferably, the disintegrant is crospovidone and/or sodium starch glycolate, preferably, the particle size control range of crospovidone is D90: 270-385 μm;

优选地，所述助流剂为胶态二氧化硅；Preferably, the glidant is colloidal silicon dioxide;

优选地，所述润滑剂为硬脂酸镁和/或硬脂酸；Preferably, the lubricant is magnesium stearate and/or stearic acid;

优选地，所述粘合剂为羟丙基纤维素；Preferably, the binder is hydroxypropyl cellulose;

优选地，所述pH调节剂为酒石酸。Preferably, the pH regulator is tartaric acid.
如权利要求1-9中任一项所述的复方制剂，其特征在于，以其总重计，所述复方制剂含有：The compound preparation according to any one of claims 1-9, characterized in that, in terms of its total weight, the Said compound preparation contains:

senaparib的固体分散体，8％～60％；Solid dispersion of senaparib, 8% to 60%;

替莫唑胺，1.0％～10.0％、优选2.0％～8.0％；Temozolomide, 1.0% to 10.0%, preferably 2.0% to 8.0%;

填充剂，56％～85％、优选70％～82％、更优选75％～82％；Filler, 56% to 85%, preferably 70% to 82%, more preferably 75% to 82%;

崩解剂，0.1％～10％、优选0.5％～4％；Disintegrant, 0.1% to 10%, preferably 0.5% to 4%;

助流剂，0.1％～10％、优选0.5％～3％、更优选1％～3％；Glidant, 0.1% to 10%, preferably 0.5% to 3%, more preferably 1% to 3%;

润滑剂，0.1％～3％、优选0.3％～1％；Lubricant, 0.1% to 3%, preferably 0.3% to 1%;

pH调节剂，0.1％～5％、优选0.1％～3％；和pH regulator, 0.1% to 5%, preferably 0.1% to 3%; and

任选的粘合剂，0.1％～5％、优选为0.1％～3％；Optional binder, 0.1% to 5%, preferably 0.1% to 3%;

优选地，所述固体分散体粉末由重量比为1∶2到1∶3的senaparib和羟丙基甲基纤维素邻苯二甲酸酯组成，且senaparib中少于5重量％、更优选少于1重量％为结晶形式；Preferably, the solid dispersion powder consists of senaparib and hydroxypropylmethylcellulose phthalate in a weight ratio of 1:2 to 1:3, and less than 5% by weight, more preferably less than 1% by weight, of senaparib is in crystalline form;

优选地，所述填充剂为微晶纤维素和甘露醇，其中，微晶纤维素的D90为170～480μm、优选275～480μm，所述甘露醇中，颗粒尺寸＞75μm的粒度分布不小于70％、优选不小于80％、更优选不小于90％，优选地，以复方制剂总重计，微晶纤维素的含量为8％～50％，优选10％～28％，更优选15％～20％；甘露醇的含量为20％～70％，优选50％～65％，更优选55％～65％；Preferably, the filler is microcrystalline cellulose and mannitol, wherein the D90 of microcrystalline cellulose is 170-480 μm, preferably 275-480 μm, and in the mannitol, the particle size distribution of particle size>75 μm is not less than 70%, preferably not less than 80%, more preferably not less than 90%, preferably, based on the total weight of the compound preparation, the content of microcrystalline cellulose is 8%-50%, preferably 10%-28%, more preferably 15% %～20%; the content of mannitol is 20%～70%, preferably 50%～65%, more preferably 55%～65%;

优选地，所述崩解剂为交联聚维酮和/或羧甲基淀粉钠，优选地，交联聚维酮的粒径控制范围为D90：270～385μm；Preferably, the disintegrant is crospovidone and/or sodium starch glycolate, preferably, the particle size control range of crospovidone is D90: 270-385 μm;

优选地，所述助流剂为胶态二氧化硅；Preferably, the glidant is colloidal silicon dioxide;

优选地，所述润滑剂为硬脂酸镁和/或硬脂酸；Preferably, the lubricant is magnesium stearate and/or stearic acid;

优选地，所述粘合剂为羟丙基纤维素；Preferably, the binder is hydroxypropyl cellulose;

优选地，所述pH调节剂为酒石酸。Preferably, the pH regulator is tartaric acid.
如权利要求1-11中任一项所述的复方制剂，其特征在于，所述复方制剂为口服固体制剂，优选为胶囊、片剂或颗粒剂。The compound preparation according to any one of claims 1-11, wherein the compound preparation is an oral solid preparation, preferably a capsule, tablet or granule.
如权利要求12所述的复方制剂，其特征在于，所述胶囊的胶囊壳选自植物胶囊壳和明胶胶囊壳，优选为明胶胶囊壳。The compound preparation according to claim 12, wherein the capsule shell of the capsule is selected from vegetable capsule shells and gelatin capsule shells, preferably gelatin capsule shells.
权利要求1-13中任一项所述的复方制剂的制备方法，其特征在于，所述方法包括：提供含有替莫唑胺与部分辅料的第1混合物；将senaparib和余下的除润滑剂外的其它辅料与该第1混合物混合，得到第2混合物，然后再将第2混合物与余下的润滑剂混合，制备得到最终混合物；或者将senaparib和部分润滑剂和部分助流剂以及余下的其它全部辅料与该第1混合物混合，得到第2混合物，然后再将第2混合物与余下的润滑剂和助流剂混合，制备得到最终混合物。The preparation method of the compound preparation described in any one of claims 1-13, is characterized in that, described method comprises: providing the first mixture containing temozolomide and some auxiliary materials; Other auxiliary materials other than the lubricant are mixed with the first mixture to obtain the second mixture, and then the second mixture is mixed with the remaining lubricant to prepare the final mixture; or senaparib, part of the lubricant, part of the glidant and all the remaining other auxiliary materials are mixed with the first mixture to obtain the second mixture, and then the second mixture is mixed with the remaining lubricant and glidant to prepare the final mixture.
如权利要求14所述的方法，其特征在于，所述方法包括以下步骤：The method according to claim 14, characterized in that said method comprises the steps of:

(1)混合替莫唑胺、一种填充剂、pH酸性调节剂和崩解剂，得到第1混合物；(1) mixing temozolomide, a filler, a pH acid regulator and a disintegrant to obtain the first mixture;

(2)将senaparib的固体分散体、另一种填充剂和助流剂与第1混合物进行混合，得到第2混合物；(2) mixing the solid dispersion of senaparib, another filler and glidant with the first mixture to obtain the second mixture;

(3)将第2混合物过筛，将过筛后的物料与润滑剂混合，得到最终混合物；(3) sieving the second mixture, and mixing the sieved material with a lubricant to obtain the final mixture;

(4)将步骤(3)中获得的最终混合物装入胶囊壳，得到口服胶囊剂；(4) packing the final mixture obtained in step (3) into a capsule shell to obtain oral capsules;

或者，所述方法包括以下步骤：Alternatively, the method comprises the steps of:

(1)混合替莫唑胺、部分填充剂、pH酸性调节剂、粘合剂、部分崩解剂、部分助流剂和部分润滑剂，得到第1混合物；(1) mixing temozolomide, part of filler, pH acidic regulator, binder, part of disintegrant, part of glidant and part of lubricant to obtain the first mixture;

(2)将第1混合物过筛后，再次进行混合，然后采用干法制粒设备对所得混合物进行制粒；(2) After the first mixture is sieved, mix again, and then use dry granulation equipment to granulate the resulting mixture;

(3)将senaparib的固体分散体、剩余填充剂、剩余助流剂和剩余崩解剂与步骤(2)的干法制粒后获得的物料进行混合，得到第2混合物；(3) mixing the solid dispersion of senaparib, the remaining filler, the remaining glidant and the remaining disintegrant with the material obtained after the dry granulation of step (2), to obtain the second mixture;

(4)将步骤(3)所得的第2混合物取出过筛后，与剩余润滑剂混合，得到最终混合物；(4) After the second mixture obtained in step (3) is taken out and sieved, it is mixed with the remaining lubricant to obtain the final mixture;

(5)将步骤(4)中获得的最终混合物装入胶囊壳，获得口服胶囊剂。(5) Pack the final mixture obtained in step (4) into a capsule shell to obtain oral capsules.
如权利要求14所述的方法，其特征在于，所述方法包括以下步骤：The method according to claim 14, characterized in that said method comprises the steps of:

(1)混合替莫唑胺、一种填充剂、pH酸性调节剂和崩解剂，得到第1混合物；(1) mixing temozolomide, a filler, a pH acid regulator and a disintegrant to obtain the first mixture;

(2)混合senaparib的固体分散体、另一种填充剂和助流剂与第1混合物，得到第2混合物；(2) mixing the solid dispersion of senaparib, another filler and glidant with the first mixture to obtain the second mixture;

(3)将第2混合物过筛，将过筛后的物料与润滑剂混合，得到最终混合物；(3) sieve the second mixture, and mix the sieved material with a lubricant to obtain the final mixture;

(4)将步骤(3)中获得的最终混合物压制成素片，再将素片包衣，获得所述口服片剂；(4) compressing the final mixture obtained in step (3) into a plain tablet, and then coating the plain tablet to obtain the oral tablet;

或者，所述方法包括以下步骤：Alternatively, the method comprises the steps of:

(1)混合替莫唑胺、一种填充剂、pH酸性调节剂、崩解剂和粘合剂，得到第 1混合物；(1) Mix temozolomide, a filler, pH acidic regulator, disintegrant and binding agent to obtain the first 1 mixture;

(2)混合senaparib的固体分散体、另一种填充剂、部分助流剂和部分润滑剂与第1混合物，得到第2混合物；(2) mixing the solid dispersion of senaparib, another filler, part of the glidant and part of the lubricant with the first mixture to obtain the second mixture;

(3)将第2混合物取出采用干法制粒设备进行制粒，将完成制粒的物料与剩余助流剂和剩余润滑剂混合，得到最终混合物；(3) The second mixture is taken out and granulated by dry granulation equipment, and the granulated material is mixed with the remaining glidant and the remaining lubricant to obtain the final mixture;

(4)将步骤(3)中获得的最终混合物压制成素片，再素片包衣，获得所述口服片剂。(4) Compress the final mixture obtained in step (3) into a plain tablet, and then coat the plain tablet to obtain the oral tablet.
一种药盒，其含有权利要求1-13中任一项所述的复方制剂。A kit containing the compound preparation according to any one of claims 1-13.
如权利要求17所述的药盒，其特征在于，所述药盒所含的复方制剂的数量满足患者至少1天的给药；其中，1天的给药量为：senaparib 20～100mg，优选20～80mg；替莫唑胺5～30mg，优选10～20mg。The kit according to claim 17, wherein the quantity of the compound preparation contained in the kit satisfies the patient’s administration for at least 1 day; wherein, the dosage for 1 day is: senaparib 20-100 mg, preferably 20-80 mg; temozolomide 5-30 mg, preferably 10-20 mg.
如权利要求1-13中任一项所述的复方制剂在制备治疗癌症的药物中的应用；优选地，所述癌症选自：肝癌、黑素瘤、霍奇金病、非霍奇金淋巴瘤、急性淋巴白血病、慢性淋巴白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、维尔姆斯瘤、子***、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞白血病、原发性脑癌、非小细胞肺癌、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌症、绒毛膜癌、蕈樣肉芽腫、头颈癌、骨原性肉瘤、胰腺癌、急性粒细胞白血病、毛细胞白血病、横纹肌肉瘤、卡波西肉瘤、泌尿生殖***肿瘤病、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生症、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌和***癌。Application of the compound preparation according to any one of claims 1-13 in the preparation of a drug for treating cancer; preferably, the cancer is selected from: liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary Oncogenic brain cancer, non-small cell lung cancer, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary system tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, red vera Cytosis, essential thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer.
一种治疗癌症的方法，其特征在于，所述方法包括给予需要的对象治疗有效量的权利要求1-13中任一项所述的复方制剂；其中，所述治疗有效量为senaparib 20-100mg的日剂量，优选为20～80mg的日剂量；和替莫唑胺5～30mg的日剂量，优选为10～20mg的日剂量。 A method for treating cancer, characterized in that the method comprises administering a therapeutically effective dose of the compound preparation according to any one of claims 1-13 to a subject in need; wherein the therapeutically effective dose is a daily dose of senaparib 20-100 mg, preferably a daily dose of 20-80 mg; and a daily dose of temozolomide 5-30 mg, preferably a daily dose of 10-20 mg.