Gerhardt Alana, Mcgraw Nicole R, Schwartz Daniel K, Bee Jared S, Carpenter John F, Randolph Theodore W
Department of Chemical and Biological Engineering, University of Colorado - Boulder, Boulder, Colorado.
J Pharm Sci. 2014 Jun;103(6):1601-12. doi: 10.1002/jps.23973. Epub 2014 Apr 11.
The stability of therapeutic proteins formulated in prefilled syringes (PFS) may be negatively impacted by the exposure of protein molecules to silicone oil-water interfaces and air-water interfaces. In addition, agitation, such as that experienced during transportation, may increase the detrimental effects (i.e., protein aggregation and particle formation) of protein interactions with interfaces. In this study, surfactant-free formulations containing either a monoclonal antibody or lysozyme were incubated in PFS, where they were exposed to silicone oil-water interfaces (siliconized syringe walls), air-water interfaces (air bubbles), and agitation stress (occurring during end-over-end rotation). Using flow microscopy, particles (≥2 μm diameter) were detected under all conditions. The highest particle concentrations were found in agitated, siliconized syringes containing an air bubble. The particles formed in this condition consisted of silicone oil droplets and aggregated protein, as well as agglomerates of protein aggregates and silicone oil. We propose an interfacial mechanism of particle generation in PFS in which capillary forces at the three-phase (silicone oil-water-air) contact line remove silicone oil and gelled protein aggregates from the interface and transport them into the bulk. This mechanism explains the synergistic effects of silicone oil-water interfaces, air-water interfaces, and agitation in the generation of particles in protein formulations.
预填充注射器（PFS）中配制的治疗性蛋白质的稳定性可能会受到蛋白质分子暴露于硅油 - 水界面和空气 - 水界面的负面影响。此外，搅拌，如运输过程中所经历的，可能会增加蛋白质与界面相互作用的有害影响（即蛋白质聚集和颗粒形成）。在本研究中，将含有单克隆抗体或溶菌酶的无表面活性剂制剂在PFS中孵育，使其暴露于硅油 - 水界面（硅化注射器壁）、空气 - 水界面（气泡）和搅拌应力（在端对端旋转过程中发生）。使用流动显微镜，在所有条件下均检测到颗粒（直径≥2μm）。在含有气泡的搅拌硅化注射器中发现颗粒浓度最高。在此条件下形成的颗粒由硅油滴和聚集的蛋白质组成，以及蛋白质聚集体和硅油的团聚物。我们提出了一种PFS中颗粒生成的界面机制，其中三相（硅油 - 水 - 空气）接触线处的毛细力将硅油和凝胶化的蛋白质聚集体从界面去除并将它们运输到主体中。该机制解释了硅油 - 水界面、空气 - 水界面和搅拌在蛋白质制剂颗粒生成中的协同作用。
