Gil-Alegre M E, Bernabeu J A, Camacho M A, Torres-Suarez A I
Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Complutense University of Madrid, Spain.
Farmaco. 2001 Nov;56(11):877-83. doi: 10.1016/s0014-827x(01)01142-9.
During the pharmaceutical development of a new drug, it is necessary to select as soon as possible the formulation with the best stability characteristics. The current International Commission for Harmonisation (ICH) regulations regarding stability testing requirements for a Registration Application provide the stress testing conditions with the aim of assessing the effect of severe conditions on the drug product. In practice, the well-known Arrhenius theory is still used to make a rapid stability prediction, to estimate a drug product shelf life during early stages of its pharmaceutical development. In this work, both the planning of a stress stability study to obtain a correct stability prediction from a temperature extrapolation and the suitable data treatment to discern the reliability of the stability results are discussed. The study was focused on the early formulation step of a very stable drug, Mitonafide (antineoplastic agent), formulated in a parenteral solution and in tablets. It was observed, for the solid system, that the extrapolated results using Arrhenius theory might be statistically good, but far from the real situation if the stability study is not designed in a correct way. The statistical data treatment and the stress-stability test proposed in this work are suitable to make a reliable stability prediction of different formulations with the same drug, within its pharmaceutical development.
在新药的药物研发过程中，有必要尽快选择具有最佳稳定性特征的制剂。当前国际协调会议（ICH）关于注册申请稳定性测试要求的法规提供了加速试验条件，目的是评估严苛条件对药品的影响。实际上，著名的阿仑尼乌斯理论仍被用于进行快速稳定性预测，以估计药品在其药物研发早期阶段的保质期。在这项工作中，讨论了进行加速稳定性研究以通过温度外推获得正确稳定性预测的规划，以及用于辨别稳定性结果可靠性的合适数据处理方法。该研究聚焦于一种非常稳定的药物米托萘胺（抗肿瘤药）在注射剂和片剂中的早期制剂阶段。对于固体剂型，研究发现，如果稳定性研究设计不当，使用阿仑尼乌斯理论的外推结果可能在统计学上良好，但与实际情况相差甚远。这项工作中提出的统计数据处理和加速稳定性测试适用于在药物研发过程中对含有相同药物的不同制剂进行可靠的稳定性预测。
