Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians-Universität München, Munich, Germany.
Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians-Universität München, Munich, Germany.
Eur J Pharm Biopharm. 2021 Jan;158:53-61. doi: 10.1016/j.ejpb.2020.11.003. Epub 2020 Nov 11.
Amino acids are not only used as buffering agents in lyophilisation, but also exhibit cryo- and lyoprotecting characteristics. L-Arginine based lyophilisates were tested regarding their ability to stabilise a monoclonal antibody (mAb) at different residual moisture (RM) levels. Arginine base was formulated with citric, hydrochloric, lactobionic, phosphoric, and succinic acid for pH adjustment. Lyophilisates with less than 0.5% and approx. 2.5%RM were stored for up to 6 months at 40 °C. The mAb aggregation in arginine in combination with hydrochloric acid and succinic acid was similar or even less compared to a sucrose reference formulation. Arginine in combination with citric acid, lactobionic acid, and phosphoric acid resulted in lower protein stability. Overall, arginine formulations with high RM levels resulted in better protein stabilisation despite decreased glass transition temperatures (T). Whereas we detected mAb glycation in the sucrose based formulations, this chemical reaction did not occur in arginine based formulations. Arginine hydrochloride and succinate, especially at high RM levels, could be promising alternatives to sucrose for stabilisation of mAb in lyophilisates.
氨基酸不仅可用作冻干中的缓冲剂，而且还具有抗冷冻和抗冻干保护特性。测试了基于 L-精氨酸的冻干制剂在不同残余水分 (RM) 水平下稳定单克隆抗体 (mAb) 的能力。精氨酸碱与柠檬酸、盐酸、乳糖酸、磷酸和琥珀酸一起用于 pH 值调节。残余水分含量低于 0.5%和约 2.5%的冻干制剂在 40°C 下储存长达 6 个月。与蔗糖参考制剂相比，mAb 在精氨酸与盐酸和琥珀酸的组合中的聚集情况相似，甚至更低。精氨酸与柠檬酸、乳糖酸和磷酸的组合导致蛋白质稳定性降低。总体而言，尽管玻璃化转变温度 (T) 降低，但 RM 水平较高的精氨酸制剂仍能更好地稳定蛋白质。虽然我们在基于蔗糖的制剂中检测到 mAb 的糖化，但这种化学反应并未在基于精氨酸的制剂中发生。盐酸精氨酸和琥珀酸盐，尤其是在高 RM 水平下，可能是蔗糖的有前途的替代品，可用于稳定冻干制剂中的 mAb。
