PDF(Pubmed)
Abstract：
The surfactants polysorbate 20 (PS20) and polysorbate 80 (PS80) are utilized to stabilize protein drugs. However, concerns have been raised regarding the degradation of PSs in biologics and the potential impact on product quality. Oxidation has been identified as a prevalent degradation mechanism under pharmaceutically relevant conditions. So far, a systematic stability comparison of both PSs under pharmaceutically relevant conditions has not been conducted and little is known about the dependence of oxidation on PS concentration. Here, we conducted a comparative stability study to investigate (i) the different oxidative degradation propensities between PS20 and PS80 and (ii) the impact of PS concentration on oxidative degradation. PS20 and PS80 in concentrations ranging from 0.1 mg⋅mL-1 to raw material were stored at 5, 25, and 40 °C for 48 weeks in acetate buffer pH 5.5 and water, respectively. We observed a temperature-dependent oxidative degradation of the PSs with strong (40 °C), moderate (25 °C), and weak/no degradation (5 °C). Especially at elevated temperatures such as 40 °C, fast oxidative PS degradation processes were detected. In this case study, a stronger degradation and earlier onset of oxidation was observed for PS80 in comparison to PS20, detected via the fluorescence micelle assay. Additionally, degradation was found to be strongly dependent on PS concentration, with significantly less oxidative processes at higher PS concentrations. Iron impurities, oxygen in the vial headspaces, and the pH values of the formulations were identified as the main contributing factors to accelerate PS oxidation.
摘要：
表面活性剂聚山梨酯20(PS20)和聚山梨酯80(PS80)用于稳定蛋白质药物。然而,人们对生物制品中PS的降解以及对产品质量的潜在影响提出了担忧。氧化已被确定为在药学相关条件下的普遍降解机制。到目前为止,尚未进行两种PS在药学相关条件下的系统稳定性比较,并且对氧化对PS浓度的依赖性知之甚少。这里,我们进行了比较稳定性研究，以研究（i）PS20和PS80之间的不同氧化降解倾向和（ii）PS浓度对氧化降解的影响。PS20和PS80的浓度范围为0.1mg·mL-1至原料，分别在5、25和40°C下在pH5.5的乙酸缓冲液和水中储存48周，分别。我们观察到PS的温度依赖性氧化降解与强（40°C），中等(25°C),和弱/无降解(5°C)。特别是在40°C等高温下，检测到PS的快速氧化降解过程。在这个案例研究中,通过荧光胶束测定检测到,与PS20相比,PS80具有更强的降解和更早的氧化开始。此外,发现降解强烈依赖于PS浓度，在较高的PS浓度下，氧化过程明显减少。铁杂质，小瓶顶部空间中的氧气，和制剂的pH值被确定为加速PS氧化的主要促成因素。
