CN114642664A - 一种仑伐替尼药物组合物及其制备方法和其应用 - Google Patents
一种仑伐替尼药物组合物及其制备方法和其应用 Download PDFInfo
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- CN114642664A CN114642664A CN202011520160.0A CN202011520160A CN114642664A CN 114642664 A CN114642664 A CN 114642664A CN 202011520160 A CN202011520160 A CN 202011520160A CN 114642664 A CN114642664 A CN 114642664A
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- calcium phosphate
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- A—HUMAN NECESSITIES
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Abstract
本发明提供一种溶出快速且完全的仑伐替尼药物组合物及其制备方法，按重量百分比，仑伐替尼药物组合物包括仑伐替尼或其药学上可接受的盐或其溶剂合物2％‑10％、磷酸钙10％‑45％和其他药学上可接受的载体。所述仑伐替尼药物组合物能使得难溶药物仑伐替尼快速且完全溶出，进而有效保障了药物被快速吸收进入体内发挥疗效。并且，所制备的仑伐替尼药物组合物生产成本低，制备方法操作简便，生产周期短，适合于大规模工业化生产。
Description
技术领域
本发明属于药物制剂领域，具体涉及一种仑伐替尼药物组合物及其制备方法和其应用。
背景技术
仑伐替尼(lenvatinib)由日本卫材(Eisai)开发，为多受体酪氨酸激酶抑制剂，临床适用于复发或进展性及放射性碘难治的分化型甲状腺癌、与依维莫司联用治疗晚期抗血管生成治疗后的晚期肾细胞癌(RCC)和无法切除的肝细胞癌(HCC)患者的一线治疗。
仑伐替尼具有引湿性，在加湿、加热条件下化学不稳定，容易分解，而且药物表面易发生凝胶化，聚集成团导致溶出出现延迟。
CN102470133A公开了一种仑伐替尼胶囊剂，采用碱性物质碳酸镁或碳酸钙，经过湿法制粒，所得组合物的溶出改善且保持稳定。
CN101001629A公开了另外一种仑伐替尼片剂，采用不同类型的碱性稳定剂，如氧化镁、氧化钙、碳酸钠、磷酸氢二钠、碳酸钙或碳酸镁等以及凝胶化防止剂硅酸钙、硅酸镁等，以解决原料溶解凝胶化而导致溶出偏低且保持稳定。
然而，由于碱性稳定剂在进入胃中，与胃酸中和，局部pH偏高，不利于仑伐替尼前期快速溶出。
为此，如何开发快速溶出且完全以满足快速吸收的仑伐替尼成为本领域急需解决的技术难题。
发明内容
本发明的目的在于提供一种溶出快速且完全的仑伐替尼药物组合物，按重量百分比，包括仑伐替尼或其药学上可接受的盐或其溶剂合物2％-10％、磷酸钙10％-45％和其他药学上可接受的载体。
本发明优选技术方案中，所述药物组合物包括仑伐替尼3％-5％、磷酸钙15％-40％和其他药学上可接受的载体。
本发明优选技术方案中，所述其他药学上可接受的载体选自填充剂、崩解剂、粘合剂、润滑剂中的任一种或其组合。
本发明优选技术方案中，所述的药物组合物包括仑伐替尼或其药学上可接受的盐或其溶剂合物3％-5％、磷酸钙15％-40％、崩解剂15％-35％、粘合剂2％-10％、润滑剂1％-5％及剩余量的填充剂。
本发明优选技术方案中，所述的药物组合物包括仑伐替尼或其药学上可接受的盐或其溶剂合物3％-5％、磷酸钙25％-40％、崩解剂15％-35％、粘合剂2％-10％、润滑剂1％-5％及剩余量的填充剂。
本发明优选技术方案中，所述仑伐替尼药学上可接受的盐选自甲磺酸盐、对甲苯磺酸盐、盐酸盐、氢溴酸盐、硫酸盐的任一种。
本发明优选技术方案中，所述仑伐替尼溶剂合物选自水合物或乙酸合物的任一种。
本发明优选技术方案中，所述崩解剂选自羧甲基纤维素钠、交联聚维酮、低取代羟丙纤维素的一种或其组合。
本发明优选技术方案中，所述粘合剂选自聚维酮、羟丙基纤维素、羟丙甲基纤维素的一种或其组合。
本发明优选技术方案中，所述润滑剂选自滑石粉、硬脂酸镁、二氧化硅的一种或其组合。
本发明优选技术方案中，所述填充剂选自微晶纤维素、甘露醇、预胶化淀粉、山梨醇、乳糖的一种或其组合。
本发明优选技术方案中，所述填充剂为微晶纤维素和甘露醇的组合。
本发明优选技术方案中，按重量比，所述磷酸钙：甘露醇的比例为1:1-5:1。
本发明优选技术方案中，按重量比，所述磷酸钙与甘露醇的用量总和占比不低于40％，优选为40％-60％。
本发明优选技术方案中，所述药物组合物的制剂形式选自片剂、胶囊剂、颗粒剂、丸剂、粉剂、散剂的任一种。
本发明的目的之一还在于提供一种仑伐替尼药物组合物的制备方法，所述制备方法包括如下步骤：
(1)将处方量的仑伐替尼或其药学上可接受的盐或其溶剂合物、磷酸钙、崩解剂、填充剂混合均匀；
(2)加入处方量的粘合剂进行制粒，干燥，整粒；
(3)加入处方量的润滑剂混合均匀后灌装。
本发明优选技术方案中，所述步骤(2)制粒过程中，搅拌速度为200-500rpm，剪切速度为1000-3000rpm。
本发明优选技术方案中，所述步骤(2)干燥至水分小于3.0％。
本发明优选技术方案中，所述步骤(2)整粒所用筛网目数为20-30目。
本发明的目的之一还在于提供仑伐替尼药物组合物用于制备治疗和/或预防癌症的药物中的应用。
本发明优选技术方案中，所述的癌症选自甲状腺癌、肾癌(含肾细胞癌RCC)、肝癌(含肝细胞癌HCC)、乳腺癌、结直肠癌、头颈癌、子宫内膜癌或黑色素瘤、胰腺癌、胃癌、大肠癌、乳癌、前列腺癌、肺癌、脑肿瘤、血癌、卵巢癌、睾丸癌、咽喉癌、食道癌、胃肠道间质瘤、肉瘤、骨肉瘤、血管瘤、恶性淋巴瘤、骨髓性白血病、神经瘤、神经胶质瘤的任一种或其组合或其并发症。
本发明的目的之一还在于提供一种仑伐替尼药物组合物与其他药物联用的应用。
本发明的优选技术方案中，所述的其他药物选自索拉非尼、来那度胺、帕博利珠单抗(pembrolizumab)、纳武单抗(nivolumab)、贝伐单抗(Bevacizumab)、依维莫司、艾日布林、伊马替尼、环磷酰胺、异环磷酰胺、甲氨蝶呤、氟尿嘧啶、紫杉烷、长春新碱、依托泊苷的任一种或其组合。
本发明中，所述“仑伐替尼”涵盖化合物“4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺”的任意结晶形式或无定形态。
与现有技术相比，本发明具有下述有益的技术效果：
1、本发明采用磷酸钙作为抗凝胶化辅料，不仅解决了其凝胶化的问题，还能使得难溶药物仑伐替尼快速且完全溶出，进而有效保障了药物被快速吸收进入体内发挥疗效。
2、本发明组合物采用制剂常规辅料，生产成本低，制备方法操作简便，生产周期短，适合于大规模工业化生产。
除非另有说明，本发明涉及液体与液体之间的百分比时，所述的百分比为体积/体积百分比；本发明涉及液体与固体之间的百分比时，所述百分比为体积/重量百分比；本发明涉及固体与液体之间的百分比时，所述百分比为重量/体积百分比；其余为重量/重量百分比。
附图说明
附图1pH4.0的Mcllvaine介质中的溶出度曲线
具体实施方式
以下对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明权利要求保护的范围。
对比例1仑伐替尼组合物的制备
表1处方组成(单位剂量)
制备方法：将500份处方量的甲磺酸仑伐替尼、碳酸钙、甘露醇、低取代羟丙纤维素、微晶纤维素投入湿法制粒机中混合均匀，加入处方量的羟丙基纤维素进行制粒(搅拌速度为300rpm，剪切速度为1500rpm)，干燥至水分小于3.0％，对颗粒进行整粒(24目筛)，加入滑石粉混合均匀后灌装胶囊。
实施例1-3仑伐替尼组合物的制备
表2处方组成(单位剂量)
制备方法：将500份处方量的甲磺酸仑伐替尼、磷酸钙、甘露醇、低取代羟丙纤维素、微晶纤维素投入湿法制粒机中混合均匀，加入处方量的羟丙基纤维素进行制粒(搅拌速度为300rpm，剪切速度为1500rpm)，干燥至水分小于3.0％，对颗粒进行整粒(24目筛)，加入滑石粉混合均匀后灌装胶囊。
试验例1溶出度测定
溶出度检测方法1：根据《中国药典》2015年版四部通则0931第二法，以pH4.0的Mcllvaine介质(配置方法：取十二水合磷酸氢二钠17.91g，加水溶解并稀释至1000ml，即得0.05mol/L的磷酸氢二钠溶液；另取一水合柠檬酸5.25g，加水溶解并稀释至1000ml，即得0.025mol/L的柠檬酸溶液；取柠檬酸溶液调节磷酸氢二钠溶液pH至4.0即得)900ml为溶出介质，转速50rpm，温度37℃。结果见表3及图1。
表3
| 时间(min) | 对比例 | 实施例1 | 实施例2 | 实施例3 |
| 5 | 4.66 | 8.65 | 8.69 | 3.16 |
| 10 | 29.65 | 45.55 | 43.53 | 18.93 |
| 15 | 44.26 | 64.99 | 59.53 | 31.09 |
| 20 | 51.83 | 73.15 | 70.22 | 44.01 |
| 30 | 62.38 | 82.49 | 81.94 | 59.78 |
| 45 | 71.53 | 89.55 | 89.48 | 72.68 |
| 60 | 77.1 | 93.1 | 93.88 | 79.26 |
溶出度检测方法2：根据《中国药典》2015年版四部通则0931第二法，以枸橼酸-磷酸氢二钠的缓冲液900ml为溶出介质(pH6.8)，转速75rpm，温度37℃。结果见表4。
表4
试验例2凝胶化现象考察
按试验例1中溶出度检测方法1进行溶出度检测时，观察囊壳溶解后内容物颗粒在不同的溶出介质中是否会出现凝胶化现象，结果见表5。
表5
| / | 对比例 | 实施例1 | 实施例2 | 实施例3 |
| 凝胶化现象 | 无结团 | 无结团，分散良好 | 无结团，分散良好 | 结团后缓慢溶解 |
试验例3含量均一度考察
取实施例1样品，采用《中国药典》2015年版四部0941含量均匀度检查法进行测定，结果如下(A：理论含量减去平均含量的绝对值。S：相对含量的标准差)。
表6
以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明权利要求保护的范围。
Claims (10)
1.一种仑伐替尼药物组合物，其特征在于，按重量百分比，包括仑伐替尼或其药学上可接受的盐或其溶剂合物2％-10％、磷酸钙10％-45％和其他药学上可接受的载体。
2.权利要求1所述的药物组合物，其特征在于，所述的药物组合物包括仑伐替尼3％-5％、磷酸钙15％-40％和其他药学上可接受的载体。
3.权利要求2所述的药物组合物，其特征在于，所述的药物组合物包括仑伐替尼或其药学上可接受的盐或其溶剂合物3％-5％、磷酸钙15％-40％、崩解剂15％-35％、粘合剂2％-10％、润滑剂1％-5％及剩余量的填充剂。
4.权利要求3所述的药物组合物，其特征在于，所述的药物组合物包括仑伐替尼或其药学上可接受的盐或其溶剂合物3％-5％、磷酸钙25％-40％、崩解剂15％-35％、粘合剂2％-10％、润滑剂1％-5％及剩余量的填充剂。
5.权利要求4所述的药物组合物，其特征在于，所述仑伐替尼药学上可接受的盐选自甲磺酸盐、对甲苯磺酸盐、盐酸盐、氢溴酸盐、硫酸盐的任一种；优选地，所述仑伐替尼溶剂合物选自水合物或乙酸合物的任一种；优选地，所述崩解剂选自羧甲基纤维素钠、交联聚维酮、低取代羟丙纤维素的一种或其组合；优选地，所述粘合剂选自聚维酮、羟丙基纤维素、羟丙甲基纤维素的一种或其组合；优选地，所述润滑剂选自滑石粉、硬脂酸镁、二氧化硅的一种或其组合；优选地，所述填充剂选自微晶纤维素、甘露醇、预胶化淀粉、山梨醇、乳糖的一种或其组合；优选地，所述填充剂为微晶纤维素和甘露醇的组合。
6.权利要求5所述的药物组合物，其特征在于，按重量比，所述磷酸钙：甘露醇的比例为1:1-5:1；优选地，所述磷酸钙与甘露醇的用量总和占比不低于40％，优选为40％-60％。
7.一种如权利要求1-6任一项所述的仑伐替尼药物组合物的制备方法，所述制备方法包括如下步骤：
(1)将处方量的仑伐替尼或其药学上可接受的盐或其溶剂合物、磷酸钙、崩解剂、填充剂混合均匀；
(2)加入处方量的粘合剂进行制粒，干燥，整粒；
(3)加入处方量的润滑剂混合均匀后灌装。
8.权利要求7所述的制备方法，其特征在于，所述步骤(2)制粒过程中，搅拌速度为200-500rpm，剪切速度为1000-3000rpm；优选地，所述步骤(2)干燥至水分小于3.0％；优选地，所述步骤(2)整粒所用筛网目数为20-30目。
9.一种权利要求1-6任一项所述的仑伐替尼药物组合物用于制备治疗和/或预防癌症的药物中的应用。
10.一种权利要求1-6任一项所述的仑伐替尼药物组合物与其他药物联用的应用。
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