Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut 06269.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut 06269.
J Pharm Sci. 2020 May;109(5):1681-1691. doi: 10.1016/j.xphs.2020.02.006. Epub 2020 Feb 15.
Long reconstitution times before patient administration remain an undesirable quality attribute for high concentration lyophilized protein formulations. In this study, 3 approaches were developed to study reconstitution behavior of lyophilized, amorphous cakes of a highly concentrated monoclonal antibody (mAb) by exploring their wetting, disintegration, and hydration behavior. As the mAb concentration increased from 0 to 83 mg/mL, reconstitution times were longer with poorer wetting, slower hydration, and disintegration rates. Furthermore, the effect of controlling ice nucleation temperature at -5 and -10°C during freezing followed by either conservative or aggressive drying conditions on the reconstitution times was explored in formulations containing 40 and 83 mg/mL mAb. Although no effect of either of the 2 processing conditions was noted at 40 mg/mL, aggressive drying led to faster reconstitution at both the nucleation temperatures with 83 mg/mL mAb. The present study combined with literature data suggests that below a protein-to-sugar ratio of 1, reconstitution was complete within 1 min, and when the ratio was greater than 1, the reconstitution times increased nonlinearly. Disintegration and hydration were determined to be the key mechanisms contributing to the complete reconstitution of the lyophilized, amorphous cakes of the highly concentrated mAb in vials.
在给患者用药之前，较长的复溶时间仍然是高浓度冻干蛋白制剂的一个不理想的质量属性。在这项研究中，开发了 3 种方法来研究高浓度单克隆抗体（mAb）的冻干无定形块状物的复溶行为，探索其润湿、崩解和水合行为。当 mAb 浓度从 0 增加到 83mg/mL 时，复溶时间延长，润湿效果变差，水合和崩解速率变慢。此外，还研究了在含有 40 和 83mg/mL mAb 的制剂中，在冷冻过程中控制冰核温度在-5°C 和-10°C 并随后采用保守或激进干燥条件对复溶时间的影响。虽然在 40mg/mL 时两种处理条件均无明显影响，但在 83mg/mL mAb 时，激进干燥导致在两种成核温度下的复溶时间更快。本研究结合文献数据表明，在蛋白与糖的比例低于 1 时，复溶在 1 分钟内完成，而当比例大于 1 时，复溶时间呈非线性增加。崩解和水合被确定为高浓度 mAb 冻干无定形块状物在小瓶中完全复溶的关键机制。
