Gilbert Peter H, Zhang Zhenhuan, Qian Ken K, Allen David P, Wagner Norman J, Liu Yun
Department of Chemical and Biomolecular Engineering Department, Center for Neutron Science, University of Delaware, Newark, DE 19716; NIST Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, MD 20899.
Eli Lilly and Company, Indianapolis, IN 46225.
J Pharm Sci. 2021 Jun;110(6):2395-2404. doi: 10.1016/j.xphs.2020.12.030. Epub 2020 Dec 30.
Small angle neutron scattering (SANS) studies of a model pharmaceutical formulation reveal how formulation stability depends on the compatibility of individual components. Solutions of two common protein formulation excipients, polysorbate 80 (PS80), a nonionic surfactant that prevents aggregation, and m-cresol, an antimicrobial agent for multi-dose injectable formulations, are investigated. The addition of m-cresol to PS80 solutions leads to solution turbidity and irreversibly alters PS80 micelle morphology. This slow preservative-induced destabilization of PS80 micelles progresses over days or even weeks, which highlights the essential role that aggregation kinetics plays in preservative-surfactant interactions. The temperature-dependence of PS80 micelle growth kinetics is quantified by SANS in the presence of m-cresol. Aggregation is a two-step process, where initial formation of small aggregates is followed by a period of monotonic power-law growth, providing evidence for the mechanism. Total aggregate mass stays constant after initial aggregate formation, and addition of a pH-regulating citrate buffer dramatically accelerates aggregation kinetics.
对一种模型药物制剂进行的小角中子散射（SANS）研究揭示了制剂稳定性如何取决于各个组分的相容性。研究了两种常见蛋白质制剂辅料的溶液，即聚山梨酯80（PS80），一种防止聚集的非离子表面活性剂，以及间甲酚，一种用于多剂量注射剂的抗菌剂。向PS80溶液中添加间甲酚会导致溶液浑浊，并不可逆地改变PS80胶束形态。这种由防腐剂引起的PS80胶束的缓慢失稳过程会持续数天甚至数周，这突出了聚集动力学在防腐剂 - 表面活性剂相互作用中所起的重要作用。在间甲酚存在的情况下，通过SANS对PS80胶束生长动力学的温度依赖性进行了量化。聚集是一个两步过程，首先是小聚集体的初始形成，随后是一段单调的幂律生长时期，这为该机制提供了证据。初始聚集体形成后，总聚集体质量保持不变，添加pH调节柠檬酸盐缓冲液会显著加速聚集动力学。
