CN116570570A - 一种含有大环类化合物的药物组合物及其制备方法和应用 - Google Patents
一种含有大环类化合物的药物组合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种含有大环类化合物的药物组合物及其制备方法和应用,该药物组合物包括式I化合物和/或其立体异构体和/或其药学上可接受的盐、填充剂、崩解剂、粘合剂、润滑剂和包衣材料。本发明通过调整填充剂比例,结合先干法再湿法制粒的方法,有效解决了片剂生产中流动性、填充性和可压性的问题,同时,制备得到的片剂溶出度高、稳定性好,体外溶出10min可达到95%以上,使式I化合物更好地发挥抑制肿瘤生长的作用。
Description
技术领域
本发明涉及药物制剂技术领域,特别涉及一种含有大环类化合物的药物组合物及其制备方法和应用。
背景技术
大环类化合物其结构如下式I所示,为淡黄色至黄绿色粉末,在乙酸中易溶、在甲醇、乙醇和乙腈中微溶,在水中几乎不溶。
式I化合物是一种大环类激酶抑制剂,具有良好的原肌球蛋白相关激酶(Trk激酶)抑制活性和选择性。Trk激酶是一类神经生长因子受体,其家族由高度同源性的TrkA、TrkB以及TrkC组成,分别由NTRK1、NTRK2和NTRK3基因编码。正常生理条件下,Trk蛋白是神经生长因子的高亲和力受体。在器官形成过程中,Trk蛋白在神经元组织中表达,它们在中枢和外周神经系统发育中起关键作用。当染色体变异发生NTRK基因融合,导致嵌合型Trk蛋白的高表达,致使Trk激酶下游信号通路调控失常,该通路的过度激活可导致癌症产生。NTRK基因融合出现在多种成人和儿童实体瘤之中,包括乳腺癌、结直肠癌、非小细胞肺癌,以及各种肉瘤。目前靶向NTRK融合基因的临床在研新药有多种,它们都具有Trk激酶抑制活性,大多通过与ATP竞争结合位点实现抑制激酶催化活性。现有技术公开了式I化合物具有良好的体内肿瘤生长抑制作用,可用于治疗NTRK或ROS1基因融合的实体瘤患者。
鉴于式I化合物水中几乎不溶特性及其临床用途,开发式I化合物片剂,应达到快速释放的目的,起效和消除均较快,尽可能减少副作用。目前,尚无现有技术公开式I化合物片剂的制备方法。
发明内容
本发明旨在至少解决现有技术中存在的上述技术问题之一。为此,本发明的目的在于提供一种含有大环类化合物的药物组合物及其制备方法和应用。通过在原料药中加入填充剂、崩解剂、粘合剂、润滑剂和包衣材料等,结合先干法再湿法制粒的方法,有效解决了片剂生产中流动性、填充性和可压性的问题,同时,制备得到的片剂溶出度高、稳定性好。
为了实现上述目的,本发明所采取的技术方案是:
根据本发明的第一个方面,提供了一种含有大环类化合物的药物组合物,包括式I化合物和/或其立体异构体和/或其药学上可接受的盐、填充剂、崩解剂、粘合剂、润滑剂和包衣材料;
其中,R1选自氢、卤素;
X选自CR2、N;
R2选自氢、卤素、-CN、-C(O)Ra、-C(O)ORa、-C(O)NRaRb;
Ra、Rb分别独自选自氢、C1~6烷基;
L选自C1~6的亚烷基;
Y选自O;
选自苯环、吡啶环;
n、r分别独立选自1~3的任意自然数。
在本发明的一些实施方式中,所述卤素包括F、Cl、Br、I的任意一种。
在本发明的一些实施方式中,n为1、2;r为1。
在本发明的一些实施方式中,所述式I化合物包括以下化合物的至少一种:
在本发明的一些实施方式中,所述药物组合物包括式I化合物和/或其立体异构体和/或其药学上可接受的盐5wt%~40wt%、填充剂50wt%~80wt%、崩解剂4wt%~16wt%、粘合剂2wt%~6wt%、润滑剂0.4wt%~1.5wt%和包衣材料3wt%~5wt%。
在本发明的一些实施方式中,所述药物组合物包括式I化合物和/或其立体异构体和/或其药学上可接受的盐10wt%~30wt%、填充剂55wt%~75wt%、崩解剂6wt%~14wt%、粘合剂2wt%~4wt%、润滑剂0.5wt%~1.3wt%和包衣材料3wt%~4wt%。
在本发明的一些实施方式中,所述药物组合物包括式I化合物和/或其立体异构体和/或其药学上可接受的盐20wt%~30wt%、填充剂50wt%~70wt%、崩解剂5wt%~15wt%、粘合剂2wt%~4wt%、润滑剂0.5wt%~1.5wt%和包衣材料3wt%~4wt%。
在本发明的一些实施方式中,所述式I化合物颗粒的粒径为:D50为5μm~15μm;D90为20μm~40μm。
在本发明的一些实施方式中,所述填充剂包括甘露醇160C、微晶纤维素PH101的至少一种。
在本发明的一些实施方式中,所述填充剂包括甘露醇160C和微晶纤维素PH101的混合物。
在本发明的一些实施方式中,所述填充剂包括质量比为(1-2):1的甘露醇160C和微晶纤维素PH101的混合物;优选地,所述填充剂包括质量比为1.5:1的甘露醇160C和微晶纤维素PH101的混合物。
在本发明的一些实施方式中,所述崩解剂包括交联羧甲基纤维素钠(SD-711)、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、低取代羟丙基纤维素、羧甲基纤维素钙或十二烷基硫酸钠中的至少一种;优选为交联羧甲基纤维素钠(SD-711)。
在本发明的一些实施方式中,所述粘合剂包括交联羧甲基纤维素钠(SD-711)、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素、甲基纤维素、乙基纤维素、淀粉浆、聚乙烯醇、聚乙二醇、海藻酸钠或聚维酮中的至少一种;优选为交联羧甲基纤维素钠(SD-711)。
在本发明的一些实施方式中,所述润滑剂包括硬脂酸镁、硬脂酸、滑石粉或微粉硅胶的至少一种。
在本发明的一些实施方式中,所述包衣材料为薄膜包衣预混剂(胃溶型)03B680013。
在本发明的一些实施方式中,所述药物组合物的剂型为片剂。
根据本发明的第二个方面,提供了一种所述药物组合物的制备方法,包括以下步骤:
(1)微粉化:将式I化合物粉碎,制得式I化合物颗粒;
(2)干混:将式I化合物颗粒与填充剂、崩解剂混合,制得干混颗粒;
(3)湿混:向干混颗粒加入粘合剂混匀,过筛后制得湿整粒;
(4)总混:向湿整粒加入润滑剂进行混合后,压片、包衣即得。
在本发明的一些实施方式中,步骤(1)中,所述式I化合物颗粒的粒径为:D50为5μm~15μm;D90为20μm~40μm。
在本发明的一些实施方式中,步骤(2)中,所述干混颗粒的均匀度RSD<1%。
在本发明的一些实施方式中,步骤(2)中,所述干混采用湿法制粒机进行;优选地,所述制粒机内混合的参数为搅拌桨200rpm~300rpm,切割刀1500rpm~2300rpm。
在本发明的一些实施方式中,步骤(2)中,所述干混的时间为10min~20min。
在本发明的一些实施方式中,步骤(3)中,所述湿整粒的粒径为0.6mm~1.0mm;优选为0.7mm~0.8mm。
在本发明的一些实施方式中,步骤(3)中,所述湿混采用湿法制粒机进行;优选地,所述制粒机内混合的参数为搅拌桨250rpm~350rpm,切割刀1500rpm~2300rpm。
在本发明的一些实施方式中,步骤(4)中,所述混合的时间为3min~10min。
在本发明的一些实施方式中,步骤(4)中,所述压片控制片芯硬度为20mg规格4g~6g或50mg规格6g~9g。
根据本发明的第三个方面,提供了一种所述药物组合物在制备治疗与Trk激酶活性异常相关的疾病中的应用。
在本发明的一些实施方式中,所述与Trk激酶活性异常相关的疾病是与神经退行性疾病、疼痛、癌症、炎症相关的疾病中的任一种或几种。
在本发明的一些实施方式中,所述疾病为多发性硬化症、帕金森氏症、阿茨海默症、炎性疼痛、神经性疼痛、手术疼痛、神经细胞瘤、黑色素瘤、乳腺癌、胃癌、哮喘、炎性肠病或特异性皮炎。
术语“药学上可接受的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明的有益效果是:本发明通过调整填充剂比例,结合先干法再湿法制粒的方法,有效解决了片剂生产中流动性、填充性和可压性的问题,同时,制备得到的片剂溶出度高、稳定性好,体外溶出10min可达到95%以上,使式I化合物更好地发挥抑制肿瘤生长的作用。
附图说明
图1为本发明实施例1不同粒径API样品的溶出曲线。
具体实施方式
以下通过具体的实施例对本发明的内容作进一步详细的说明。实施例和对比例中所用的原料、试剂或装置如无特殊说明,均可从常规商业途径得到,或者可以通过现有技术方法得到。除非特别说明,试验或测试方法均为本领域的常规方法。
实施例1
本实施例优化式I-a化合物的粒度,具体过程为:
溶解度研究结果显示,式I化合物的水溶性较差,且在pH 1.0~6.8介质中的溶解度具有pH依赖性,因此在制剂生产时对式I化合物进行了微粉化处理,并对粒度进行控制,以增加式I-a化合物片剂的溶出及最大限度保证产品的均一性。以式I-a化合物为代表,粒度控制范围的筛选过程如下:
首先通过气流粉碎得到不同粒径范围的API,然后配制成混悬液(分散介质的组成为:0.5%E5型号的羟丙甲纤维素+5%蛋黄卵磷脂+水),考察其在含有0.3%十二烷基硫酸钠(SDS)的pH 6.8磷酸盐缓冲液中的溶出情况。气流粉碎后得到不同粒径API的粒径测定结果见表1,溶出曲线如图1所示。
表1粉碎前后粒径测定结果(单位:μm)
根据结果可知,当D90降低至~40μm以下时,体外溶出速度明显快于未微粉化。进一步微粉化后,如增加粉碎次数进一步降低粒径至D50小于5μm,D90小于12μm时,溶出显著加快。考虑到粒径分布达到D50约5μm,D90约12μm,需要较慢的喂料速度和较多的粉碎次数,生产的可操作性和重复性不佳。因此,将粒径范围控制为D50为5μm~15μm,D90为20μm~40μm。
实施例2
本实施例对药物组合物的填充剂比例进行优化,具体过程为:
分别取式I-a化合物20g,填充剂共66g(见表2),交联羧甲基纤维素钠SD-711 10g,羟丙纤维素EXF 3.2g,硬脂酸镁0.8g,按下述方法制得片剂(20mg规格)。
表2填充剂配方(单位:g)
填充剂种类 | 样6 | 样7 | 样8 | 样9 | 样10 | 样11 |
甘露醇160C | 66 | 55 | 40.4 | 21 | 11 | 0 |
微晶纤维素PH101 | 0 | 11 | 25.6 | 45 | 55 | 66 |
本实施例药物组合物片剂的制备方法包括以下步骤:
(1)原料药微粉化:将式I-a化合物粉碎,粉碎后的式I-a化合物粒径范围为D50为5μm~15μm,D90为20μm~40μm;
(2)干混:将上述微粉化的原料药与填充剂、交联羧甲基纤维素钠SD-711在湿法制粒机中混合15min,混合参数为搅拌桨200rpm~300rpm,切割刀1500rpm~2300rpm,混合后混合均匀度RSD<1%;
(3)湿混:向上述物料中加入羟丙纤维素EXFa,在湿法制粒机中混合,混合参数为搅拌桨250rpm~350rpm,切割刀1500rpm~2300rpm,混合后制得过24目筛的湿整粒;
(4)总混:将上述制粒后的物料加入硬脂酸镁进行总混3分钟;
(5)压片、包衣:将总混后的物料进行压片、包衣,包衣材料为薄膜包衣预混剂(胃溶型)03B680013,其中包衣增重控制在3.44%,即制得片剂。
检测溶出度和有关物质。取所得片剂,照溶出度测定法,以0.08mol/L的盐酸溶液900mL为溶出介质,转速为每分钟60rpm,依法操作,在30min时,取溶液适量,过滤,弃去初滤液,续滤液作为供试品溶液(20mg规格);或精密量取续滤液4mL置10mL的量瓶中,用溶出介质稀释至刻度,作为供试品溶液(50mg规格);另精密称取式I-a化合物的对照品12.5mg,置50mL的量瓶中,加入溶出介质使溶解并稀释至刻度,精密量取10mL置100mL的量瓶中,用溶出介质稀释至刻度,摇匀,作为对照品溶液。取供试品溶液和对照品溶液,照紫外-可见分光光度法,在292nm波长处测定吸光度,计算每片在不同时间点的溶出量,结果见表3。
表3
参数 | 样6 | 样7 | 样8 | 样9 | 样10 | 样11 |
溶出度% | 80.1 | 93.2 | 99.7 | 95.2 | 92.2 | 85.7 |
含量% | 98.2 | 98.9 | 99.4 | 99 | 98.1 | 97.8 |
有关物质% | 0.22 | 0.29 | 0.21 | 0.31 | 0.28 | 0.27 |
裂片率% | 2.1 | 2.4 | 1.9 | 2.3 | 2.2 | 2.7 |
试验结果表明:单独采用甘露醇160C或微晶纤维素PH101作为填充剂制备的片剂的溶出度并不理想;而采用甘露醇160C和微晶纤维素PH101混合物作为填充剂制备的片剂的溶出度显著提高,裂片率显著降低,其中,当甘露醇160C或微晶纤维素PH101的质量比为1.5:1时,制备出的样品综合各项指标最好。因此后续选择采用质量比为1.5:1的甘露醇160C和微晶纤维素PH101的混合物作为填充剂用于制备式I-a化合物片剂。
实施例3
本实施例制备了一种分别包含式I-a、I-c或I-i化合物的药物组合物(20mg规格),具体处方见表4。
表4处方表(mg/片)
制备方法:
(1)原料药微粉化:将式I化合物粉碎,粉碎后的式I化合物粒径范围为为D50为5μm~15μm,D90为20μm~40μm;
(2)干混:将上述微粉化的原料药与甘露醇160C、微晶纤维素PH101、交联羧甲基纤维素钠SD-711在湿法制粒机中混合15min,混合参数为搅拌桨200rpm,切割刀1500rpm,混合后混合均匀度RSD<1%;
(3)湿混:向上述物料中加入羟丙纤维素EXF,在湿法制粒机中混合,混合参数为搅拌桨250rpm,切割刀1500rpm,混合后制得过24目筛的湿整粒;
(4)总混:将上述制粒后的物料加入硬脂酸镁进行总混3min;
(5)压片、包衣:将总混后的物料进行压片、包衣,包衣材料为薄膜包衣预混剂(胃溶型)03B680013,其中包衣增重控制在3%,即制得片剂。
实施例4
本实施例制备了一种包含式I-a化合物的药物组合物(示例4),具体过程为:
药物组合物的组成与实施例3相同。
制备方法为:
(1)原料药微粉化:将式I-a化合物粉碎,粉碎后的式I-a化合物粒径范围为为D50为5μm~15μm,D90为20μm~40μm;
(2)干混:将上述微粉化的原料药与甘露醇160C、微晶纤维素PH101、交联羧甲基纤维素钠SD-711在湿法制粒机中混合12min,混合参数为搅拌桨300rpm,切割刀2300rpm,混合后混合均匀度RSD<1%;
(3)湿混:向上述物料中加入羟丙纤维素EXF,在湿法制粒机中混合,混合参数为搅拌桨350rpm,切割刀2300rpm,混合后制得过24目筛的湿整粒;
(4)总混:将上述制粒后的物料加入硬脂酸镁进行总混3min;
(5)压片、包衣:将总混后的物料进行压片、包衣,包衣材料为薄膜包衣预混剂(胃溶型)03B680013,其中包衣增重控制在3.44%,即制得片剂。
实施例5
本实施例制备了一种分别包含式I-a、I-c或I-i化合物的药物组合物(50mg规格),具体处方见表5。
表5处方表(mg/片)
制备方法:
(1)原料药微粉化:将式I化合物粉碎,粉碎后的式I化合物粒径范围为D50为5μm~15μm,D90为20μm~40μm;
(2)干混:将上述微粉化的原料药与甘露醇160C、微晶纤维素PH101、交联羧甲基纤维素钠SD-711在湿法制粒机中混合15min,混合参数为搅拌桨200rpm,切割刀1500rpm,混合后混合均匀度RSD<1%;
(3)湿混:向上述物料中加入羟丙纤维素EXF,在湿法制粒机中混合,混合参数为搅拌桨250rpm,切割刀1500rpm,混合后制得过24目筛的湿整粒;
(4)总混:将上述制粒后的物料加入硬脂酸镁进行总混3min;
(5)压片、包衣:将总混后的物料进行压片、包衣,包衣材料为薄膜包衣预混剂(胃溶型)03B680013,其中包衣增重控制在4%,即制得片剂。
试验例
本试验例对实施例3~5制得的片剂进行流动性(休止角符合GB-T11986-89表面活性剂粉体和颗粒休止角测定技术规范)、溶出度(《中国药典》2020年版四部通则0931第二法)及脆碎度(《中国药典》2020年版四部通则0923),具体结果如表6所示:
表6实验结果
由上述结果可知,实施例3~5制得的片剂的流动性符合要求,能顺利完成压片、包衣操作,制备素片的脆碎度符合要求,包衣后的溶出度符合预期,在20分钟内溶出度在80%左右。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (12)
1.一种含有大环类化合物的药物组合物,其特征在于:包括式I化合物和/或其立体异构体和/或其药学上可接受的盐、填充剂、崩解剂、粘合剂、润滑剂和包衣材料;
其中,R1选自氢、卤素;
X选自CR2、N;
R2选自氢、卤素、-CN、-C(O)Ra、-C(O)ORa、-C(O)NRaRb;
Ra、Rb分别独自选自氢、C1~6烷基;
L选自C1~6的亚烷基;
Y选自O;
选自苯环、吡啶环;
n、r分别独立选自1~3的任意自然数。
2.根据权利要求1所述的药物组合物,其特征在于:所述药物组合物包括式I化合物和/或其立体异构体和/或其药学上可接受的盐20wt%~30wt%、填充剂50wt%~70wt%、崩解剂5wt%~15wt%、粘合剂2wt%~4wt%、润滑剂0.5wt%~1.5wt%和包衣材料3wt%~4wt%。
3.根据权利要求1所述的药物组合物,其特征在于:所述填充剂包括甘露醇160C、微晶纤维素PH101的至少一种。
4.根据权利要求1所述的药物组合物,其特征在于:所述填充剂包括质量比为(1-2):1的甘露醇160C和微晶纤维素PH101的混合物。
5.根据权利要求1所述的药物组合物,其特征在于:所述崩解剂包括交联羧甲基纤维素钠(SD-711)、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、低取代羟丙基纤维素、羧甲基纤维素钙或十二烷基硫酸钠中的至少一种。
6.根据权利要求1所述的药物组合物,其特征在于:所述粘合剂包括交联羧甲基纤维素钠(SD-711)、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素、甲基纤维素、乙基纤维素、淀粉浆、聚乙烯醇、聚乙二醇、海藻酸钠或聚维酮中的至少一种。
7.根据权利要求1所述的药物组合物,其特征在于:所述润滑剂包括硬脂酸镁、硬脂酸、滑石粉或微粉硅胶的至少一种。
8.根据权利要求1所述的药物组合物,其特征在于:所述包衣材料为薄膜包衣预混剂03B680013。
9.根据权利要求1所述的药物组合物,其特征在于:所述药物组合物的剂型为片剂。
10.一种如权利要求1~9任一项所述的药物组合物的制备方法,其特征在于:包括以下步骤:
(1)微粉化:将式I化合物粉碎,制得式I化合物颗粒;
(2)干混:将式I化合物颗粒与填充剂、崩解剂混合,制得干混颗粒;
(3)湿混:向干混颗粒加入粘合剂混匀,过筛后制得湿整粒;
(4)总混:向湿整粒加入润滑剂进行混合后,压片、包衣即得。
11.根据权利要求10所述的药物组合物的制备方法,其特征在于:步骤(1)中,所述式I化合物颗粒的粒径为:D50为5μm~15μm;D90为20μm~40μm。
12.一种如权利要求1~9任一项所述的药物组合物在制备治疗与Trk激酶活性异常相关的疾病中的应用。
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