Groël Sebastian, Menzen Tim, Winter Gerhard
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany.
Coriolis Pharma, Martinsried, Germany.
Int J Pharm. 2023 Nov 5;646:123445. doi: 10.1016/j.ijpharm.2023.123445. Epub 2023 Sep 23.
The value of correlating global α-relaxations with long term protein stability after freeze-drying is inconsistently reported. This study aims to clarify whether and to what extend the long term stability of a freeze-dried protein formulation can be predicted with this method. For this purpose, the α-relaxation parameter τ [h] of freshly prepared freeze-dried products is obtained by isothermal microcalorimetry. The concept is, that molecular movements in the amorphous matrix are strongly reduced in cakes with longer relaxation time and the product should therefore be more resistant against aggregation. To increase τ in comparison to a conventional freeze-drying cycle, aggressive drying cycles including structural collapse of the product as well as tempering protocols after freeze-drying are applied. The τ values are correlated with the aggregation rate of a freeze-dried IgG monoclonal antibody measured with high performance size exclusion chromatography. The antibody was used in its market formulation and 6 further compositions. A weak correlation between α-relaxation times and IgG aggregation was found. A higher mobility level through increased residual moisture helped to improve the correlation.
关于将整体α弛豫与冷冻干燥后蛋白质的长期稳定性相关联的价值，文献报道并不一致。本研究旨在阐明能否以及在何种程度上可以用这种方法预测冷冻干燥蛋白质制剂的长期稳定性。为此，通过等温微量热法获得新制备的冷冻干燥产品的α弛豫参数τ[小时]。其概念是，在具有较长弛豫时间的饼状物中，无定形基质中的分子运动大幅减少，因此产品应更抗聚集。为了与传统冷冻干燥循环相比增加τ，采用了包括产品结构坍塌的激进干燥循环以及冷冻干燥后的调温方案。τ值与用高效尺寸排阻色谱法测量的冷冻干燥IgG单克隆抗体的聚集速率相关。该抗体采用其市售配方以及另外6种配方。发现α弛豫时间与IgG聚集之间存在弱相关性。通过增加残留水分提高的迁移率水平有助于改善这种相关性。
