Coriolis Pharma Research GmbH, D-82152 Martinsried, Germany; Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians-University, D-81377 Munich, Germany.
Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians-University, D-81377 Munich, Germany.
Eur J Pharm Biopharm. 2018 Aug;129:134-144. doi: 10.1016/j.ejpb.2018.05.025. Epub 2018 May 22.
This study provides the first systematic investigation of the impact of the nucleation protocol during freeze-drying on physico-chemical properties and long-term stability of two IgG1 antibodies in sugar formulations. We hypothesized that the lower specific surface area (SSA) generated by controlled nucleation could be beneficial for the stability of interface sensitive proteins. The study compares controlled nucleated (CN) and randomly nucleated (RN) lyophilizates with high and low antibody concentrations stored at different temperatures. Formulations with and without polysorbate (PS) were included. In the "high concentration" study the formulation without PS showed reduced particle formation for CN samples compared to RN samples. PS containing formulations had an overall lower particle level with no further advantage of CN on stability. Besides the intended comparison of CN and RN samples, we observed that PS promoted sucrose crystallization in both low concentration antibody studies during storage. Additionally, our results indicate that the nucleation temperature (T) was not the only determining factor for the resulting ice crystal size and consequently the product`s SSA. Overall, the application of CN had neither a positive nor a negative impact on the product's physico-chemical stability. The surfactant had a much higher stabilizing effect than the reduction of the SSA by CN.
本研究首次系统地考察了冻干过程中成核方案对两种 IgG1 抗体在糖配方中的物理化学性质和长期稳定性的影响。我们假设通过控制成核产生的较低比表面积（SSA）可能有利于界面敏感蛋白的稳定性。该研究比较了高浓度和低浓度抗体在不同温度下储存的有和无聚山梨酯（PS）的控制成核（CN）和随机成核（RN）冻干物。在“高浓度”研究中，与 RN 样品相比，无 PS 的 CN 样品的颗粒形成减少。含 PS 的制剂的颗粒水平总体较低，CN 对稳定性没有进一步的优势。除了对 CN 和 RN 样品的预期比较外，我们还观察到 PS 在储存过程中促进了两种低浓度抗体研究中蔗糖的结晶。此外，我们的结果表明，成核温度（T）不是决定冰晶大小和产品 SSA 的唯一因素。总体而言，CN 的应用对产品的物理化学稳定性没有积极或消极的影响。表面活性剂的稳定效果远高于通过 CN 降低 SSA 的效果。
