Abstract

Lopinavir/ritonavir is a potent coformulation of protease inhibitors used against HIV infection. Lopinavir is the main responsible for viral load suppression, whereas ritonavir is a pharmacokinetic enhancer. Both of them have recently gained relevance as candidate drugs against severe coronavirus disease (COVID-19). However, significant beneficial effects were not observed in randomized clinical trials. This review summarizes the main physical-chemical, pharmacodynamic, and pharmacokinetic properties of ritonavir and lopinavir, along with the analytical methodologies applied for biological matrices, pharmaceutical formulations, and stability studies. The work also aimed to provide a comprehensive impurity profile for the combined formulation. Several analytical methods in four different pharmacopeias and 37 articles in literature were evaluated and summarized. Chromatographic methods for these drugs frequently use C8 or C18 stationary phases with acetonitrile and phosphate buffer (with ultraviolet detection) or acetate buffer (with tandem mass spectrometry detection) as the mobile phase. Official compendia methods show disadvantages as extended total run time and complex mobile phases. HPLC tandem-mass spectrometry provided high sensitivity in methodologies applied for human plasma and serum samples, supporting the therapeutic drug monitoring in HIV patients. Ritonavir and lopinavir major degradation products arise in alkaline and acidic environments, respectively. Other non-chromatographic methods were also summarized. Establishing the impurity profile for the combined formulation is challenging due to a large number of impurities reported. Easier and faster analytical methods for impurity assessment are still needed.

摘要

洛匹那韦/利托那韦是用于抗 HIV 感染的蛋白酶抑制剂的有效复合制剂。洛匹那韦主要负责抑制病毒载量，而利托那韦是一种药代动力学增强剂。它们最近都获得了作为针对严重冠状病毒病（COVID-19）的候选药物的相关性。然而，在随机临床试验中没有观察到显着的有益效果。本综述总结了利托那韦和洛匹那韦的主要物理化学、药效学和药代动力学特性，以及应用于生物基质、药物制剂和稳定性研究的分析方法。该工作还旨在为组合配方提供全面的杂质概况。对四种不同药典和37篇文献中的几种分析方法进行了评估和总结。这些药物的色谱方法经常使用 C8 或 C18 固定相，以乙腈和磷酸盐缓冲液（紫外检测）或醋酸盐缓冲液（串联质谱检测）作为流动相。官方药典方法的缺点是总运行时间延长和流动相复杂。HPLC 串联质谱法在用于人血浆和血清样品的方法中提供了高灵敏度，支持 HIV 患者的治疗药物监测。利托那韦和洛匹那韦的主要降解产物分别出现在碱性和酸性环境中。还总结了其他非色谱方法。由于报告了大量杂质，因此确定组合配方的杂质谱具有挑战性。仍然需要更简单、更快速的杂质评估分析方法。