CN111821310A - 一种瑞德西韦制剂及其适应症 - Google Patents
一种瑞德西韦制剂及其适应症 Download PDFInfo
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Abstract
本发明公开了瑞德西韦在制备用于治疗新型冠状病毒（2019‑nCoV）的药物中的用途。瑞德西韦制剂可使新型冠状病毒（2019‑nCoV）感染的患者有效改善呼吸窘迫、咳嗽咳痰，发热等全身症状，延缓疾病进展，可以提高患者的生活质量，具有广泛的应用价值。本发明经过药物研究确定得到产品稳定性较好，用于预防和治疗新型冠状病毒的制剂。
Description
技术领域
本发明涉及瑞德西韦及其制剂，具体涉及一种用于预防及治疗新型冠状病毒（2019-nCoV）的制剂及其制法和适应症，属于医药技术领域。
背景技术
瑞德西韦（Remdesivir）是由吉利德科学公司（Gilead Sciences）开发一种广谱抗病毒药物。瑞德西韦作为一种核苷类RNA依赖的RNA聚合酶（RdRp）竞争性抑制剂，其三磷酸核苷酸产物Remdesivir-TP可以与RdRp竞争底物ATP，因此可以干扰病毒vRNA合成。而RdRp是一种广泛分布于正链和双链RNA病毒的RNA聚合酶。
瑞德西韦（Remdesivir（GS-5734））是10个氰基取代的腺苷核苷酸类似物前药，对多种RNA病毒均具有广谱抗病毒活性。该化合物目前正在临床开发中，用于治疗埃博拉病毒病（EVD）。尽管已经在细胞培养物中和在非人类灵长类动物中证明了抗病毒作用，但埃博拉病毒（EBOV）抑制Remdesivir的作用机理仍有待充分阐明。最近，EBOV RNA依赖的RNA聚合酶（RdRp）复合物得以表达和纯化，从而可以用相关的三磷酸（TP）形式的瑞德西韦及其推定靶标进行生化研究。在这项研究中，证实了Remdesivir-TP能够与三磷酸腺苷（ATP）竞争加入。酶动力学表明，EBOV RdRp和呼吸道合胞病毒（RSV）RdRp以相似的效率结合了ATP和Remdesivir-TP。 ATP对Remdesivir-TP的选择性对于EBOV RdRp为〜4，对于RSV RdRp为〜3。相比之下，纯化的人线粒体RNA聚合酶（h-mtRNAP）可有效区分Remdesivir TP，选择性值为〜500倍。对于EBOV RdRp，在位置i处掺入的抑制剂不会影响在位置i 1处随之发生的核苷酸掺入事件。对于RSV RdRp，我们测量了在位置i 1处约6倍的抑制作用，尽管RNA合成并未终止。在这两种情况下，链终止均被延迟，并且主要在位置i 5处观察到。该模式特定于Remdesivir-TP及其10-氰基修饰。在20位修饰的化合物显示出不同的抑制方式。虽然未掺入20-C-甲基-ATP，但ara-ATP充当非专性链终止剂并阻止核苷酸在位置i 1处掺入。这些数据表明，瑞德西韦对EBOV RNA合成抑制的主要作用可以归因于延迟的链终止，从而减慢EBOV在细胞中的蔓延，以防止新一轮感染的发生和延迟疾病的发展。
综上所述，基于对瑞德西韦的作用机制进行分析，我司技术人员认为瑞德西韦对冠状病毒（SARS、MERS和2019-nCoV等），都具有一定抑制效果，且对目前蔓延较为严重的2019-nCoV有较高抑制活性。
发明内容
瑞德西韦在制备用于治疗新型冠状病毒（2019-nCoV）的药物中的用途。
瑞德西韦制剂在制备用于治疗新型冠状病毒（2019-nCoV）的药物中的用途。
瑞德西韦制剂选自口服固体制剂、口服液体制剂、冻干粉针。
瑞德西韦冻干粉针关键辅料为β-环糊精或磺丁基-β-环糊精钠, pH调节剂盐酸和/或氢氧化钠。
瑞德西韦冻干粉针制备工艺，将瑞德西韦与环糊精配置成溶液，调节pH值范围4.0~7.0。
瑞德西韦冻干粉针制备工艺，将瑞德西韦与环糊精配置成溶液，调节pH值范围5.0~6.0。
本发明公开了瑞德西韦在制备用于治疗新型冠状病毒（2019-nCoV）的药物中的用途。瑞德西韦及其制剂可使新型冠状病毒（2019-nCoV）感染的患者有效改善呼吸窘迫、咳嗽咳痰，发热等全身症状，延缓疾病进展，可以提高患者的生活质量，具有广泛的应用价值。本发明经过药物研究确定得到产品稳定性较好，用于预防和治疗新型冠状病毒的制剂。
具体实施方式
实施例1
瑞德西韦片剂制备工艺：将瑞德细微微粉化至粒径100微米以内，辅料加入山梨醇单月桂酸盐、甘露醇，湿法制粒干燥后加入硬脂酸镁，压制得片芯，包衣，得终产品。
实施例2
瑞德西韦液体制备工艺：将潜溶剂乙醇、丙二醇、甘油混合均匀，加入瑞德西韦搅拌至完全溶解，并用pH调节剂盐酸或氢氧化钠调节pH值在4~5，得终产品。
实施例3
瑞德西韦冻干粉针制备过程：将β-环糊精溶解于注射用水中，加入瑞德西韦搅拌不低于5小时，用盐酸或氢氧化钠调节pH值在4.0，分装于西林瓶中，进行冻干。
实施例4
瑞德西韦冻干粉针制备过程：将磺丁基-β-环糊精钠溶解于注射用水中，加入瑞德西韦搅拌不低于5小时，用盐酸或氢氧化钠调节pH值在7.0，分装于西林瓶中，进行冻干。
对比实施例1
瑞德西韦冻干粉针制备过程：将磺丁基-β-环糊精钠溶解于注射用水中，加入瑞德西韦搅拌不低于5小时，用盐酸或氢氧化钠调节pH值在7.5，分装于西林瓶中，进行冻干。
对比实施例2
瑞德西韦冻干粉针制备过程：将瑞德西韦溶解于注射用水中，用盐酸或氢氧化钠调节pH值在5.0，分装于西林瓶中，进行冻干。
实验结果：
将实施例1-6按《中国药典》2015版稳定性指导原则进行放样，样品0天及加速3月检测结果如下。
表1 实施例0天样品检测结果
表2 实施例加速3月样品检测结果
试验结论：
通过实施例1-4可知，瑞德西韦制剂以冻干粉针较为稳定，片剂与液体稳定性略差，符合质量标准草案。通过对比实施例1-2结果产品稳定性较差，不符合质量标准草案，说明冻干粉针在制备过程的pH值范围与包合剂环糊精对产品稳定性起关键作用。
瑞德西韦及其制剂可使新型冠状病毒（2019-nCoV）感染的患者有效改善呼吸窘迫、咳嗽咳痰，发热等全身症状，延缓疾病进展，可以提高患者的生活质量，具有广泛的应用价值。本发明经过药物研究确定得到产品稳定性较好，用于预防和治疗新型冠状病毒的制剂。
Claims (6)
1.瑞德西韦在制备用于治疗新型冠状病毒（2019-nCoV）的药物中的用途。
2.瑞德西韦制剂在制备用于治疗新型冠状病毒（2019-nCoV）的药物中的用途。
3.如权利要求2所述的用途，其中所述瑞德西韦制剂选自口服固体制剂、口服液体制剂、冻干粉针。
4.如权利要求2所述的用途，其中所述的瑞德西韦冻干粉针关键辅料为β-环糊精或磺丁基-β-环糊精钠, pH调节剂盐酸和/或氢氧化钠。
5.如权利要求2所述的用途，其中所述的瑞德西韦冻干粉针制备工艺，将瑞德西韦与环糊精配置成溶液，调节pH值范围4.0~7.0。
6.如权利要求2所述的用途，其中所述的瑞德西韦冻干粉针制备工艺，将瑞德西韦与环糊精配置成溶液，调节pH值范围5.0~6.0。
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| CN112274520A (zh) * | 2020-11-23 | 2021-01-29 | 天津济坤医药科技有限公司 | 瑞德西韦在制备治疗特发性肺纤维化的药物中的应用 |
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