DEHP Nanodroplets Leached From Polyvinyl Chloride IV Bags Promote Aggregation of IVIG and Activate Complement in Human Serum.
DEHP Nanodroplets Leached From Polyvinyl Chloride IV Bags Promote Aggregation of IVIG and Activate Complement in Human Serum.
复制标题
从聚氯乙烯静脉注射袋中浸出的 DEHP 纳米液滴可促进 IVIG 的聚集并激活人血清中的补体。
DOI：
10.1016/j.xphs.2019.06.015
复制
发表时间：
2020
影响因子：
3.8
通讯作者：
Randolph,TheodoreW
中科院分区：
文献类型：
--
作者：
Snell,JaredR;Monticello,ConnorR;Her,Cheng;Ross,EmmaL;Frazer-Abel,AshleyA;Carpenter,JohnF;Randolph,TheodoreW
考虑到不可见颗粒杂质对治疗性蛋白质产品的安全性和有效性的影响，制造商已经实施了在制造、储存和运输过程中尽量减少蛋白质聚集和颗粒形成的策略。然而，一旦这些产品发布，制造商对产品处理的控制有限。在这项工作中，我们研究了聚氯乙烯（PVC）袋装静脉（IV）生理盐水中产生的邻苯二甲酸二（2-乙基己基）酯（DEHP）纳米液滴对静脉免疫球蛋白（IVIG）配方的稳定性和免疫原性的影响。我们表明，在临床环境中，当搅拌或使用气动管道运输系统运输时，含有生理盐水的PVC IV袋可以将DEHP液滴释放到溶液中。我们接下来研究了乳化DEHP纳米液滴对IVIG稳定性和免疫原性的影响。IVIG被DEHP纳米液滴强烈吸附，形成单层。此外，DEHP纳米液滴加速了IVIG在搅拌样品中的聚集。利用人体血清补体活化的蛋白体外测定法，对这些配方中产生的DEHP纳米液滴和IVIG聚集体的免疫原性进行了评估。结果表明，从PVC IV袋中脱落的DEHP纳米液滴可能会降低蛋白质的稳定性并诱导补体系统的激活，从而可能导致治疗蛋白的不良免疫反应。
Concerns regarding the impact of subvisible particulate impurities on the safety and efficacy of therapeutic protein products have led manufacturers to implement strategies to minimize protein aggregation and particle formation during manufacturing, storage, and shipping. However, once these products are released, manufacturers have limited control over product handling. In this work, we investigated the effect of di(2-ethylhexyl) phthalate (DEHP) nanodroplets generated in polyvinyl chloride (PVC) bags of intravenous (IV) saline on the stability and immunogenicity of IV immunoglobulin (IVIG) formulations. We showed that PVC IV bags containing saline can release DEHP droplets into the solution when agitated or transported using a pneumatic tube transportation system in a clinical setting. We next investigated the effects of emulsified DEHP nanodroplets on IVIG stability and immunogenicity. IVIG adsorbed strongly to DEHP nanodroplets, forming a monolayer. In addition, DEHP nanodroplets accelerated IVIG aggregation in agitated samples. The immunogenicity of DEHP nanodroplets and IVIG aggregates generated in these formulations were evaluated using anin vitroassay of complement activation in human serum. The results suggested DEHP nanodroplets shed from PVC IV bags could reduce protein stability and induce activation of the complement system, potentially contributing to adverse immune responses during the administration of therapeutic proteins.