Handa Tarun, Jhajra Shalu, Bhagat Shweta, Bharatam P V, Chakraborti Asit K, Singh Saranjit
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar 160 062, Punjab, India.
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar 160 062, Punjab, India.
J Pharm Biomed Anal. 2017 Mar 20;136:66-80. doi: 10.1016/j.jpba.2016.12.035. Epub 2016 Dec 29.
Combination therapy with the use of fixed-dose combinations (FDCs) is evincing increasing interest of prescribers, manufacturers and even regulators, evidently due to the primary benefit of improved patient compliance. However, owing to potential of drug-drug interaction, FDCs require closer scrutiny with respect to their physical and chemical stability. Accordingly, the purpose of the present study was to explore stability behavior of a popular antihypertensive combination of amlodipine besylate (AML) and losartan potassium (LST). Physical mixtures of the two drugs and multiple marketed formulations were stored under accelerated conditions of temperature and humidity (40°C/75% RH) in a stability chamber and samples were withdrawn after 1 and 3 months. The physical changes were observed visibly, while chemical changes were monitored by HPLC employing a method that could separate the two drugs and all other components present. The combination revealed strong physical instability and also chemical degradation of AML in the presence of LST. Interestingly, three isomeric interaction products of AML were formed in the combination, which otherwise were reported in the literature to be generated on exposure of AML free base above its melting point. The same unusual products were even formed when multiple marketed FDCs were stored under accelerated conditions outside their storage packs. However, these were absent when AML alone was stored in the same studied conditions. Therefore, reasons for physical and chemical incompatibility and the mechanism of degradation of AML in the presence of LST were duly explored at the molecular level. The outcomes of the study are expected to help in development of stable FDCs of the two drugs.
使用固定剂量复方制剂（FDCs）的联合治疗正引起处方医生、制造商甚至监管机构越来越多的关注，显然这是由于其在改善患者依从性方面的主要益处。然而，由于存在药物相互作用的可能性，FDCs在物理和化学稳定性方面需要更严格的审查。因此，本研究的目的是探索一种常用的抗高血压复方制剂——苯磺酸氨氯地平（AML）和氯沙坦钾（LST）的稳定性行为。将两种药物的物理混合物和多种市售制剂在稳定性试验箱中于温度和湿度加速条件（40°C/75%相对湿度）下储存，1个月和3个月后取出样品。肉眼观察物理变化，同时通过高效液相色谱法（HPLC）监测化学变化，该方法能够分离两种药物以及所有其他存在的成分。该复方制剂显示出强烈的物理不稳定性，并且在LST存在的情况下AML发生化学降解。有趣的是，该复方制剂中形成了AML的三种异构体相互作用产物，而在文献中报道这些产物是在AML游离碱暴露于其熔点以上时产生的。当多种市售FDCs在加速条件下在其储存包装外储存时，甚至也形成了相同的异常产物。然而，当单独将AML在相同的研究条件下储存时，这些产物不存在。因此，在分子水平上对物理和化学不相容的原因以及在LST存在的情况下AML的降解机制进行了适当的探索。该研究结果有望有助于开发这两种药物的稳定FDCs。
