从聚氯乙烯 IV 袋中浸出的 DEHP 纳米液滴促进 IVIG 聚集并激活人血清中的补体。
DEHP Nanodroplets Leached From Polyvinyl Chloride IV Bags Promote Aggregation of IVIG and Activate Complement in Human Serum.
机构信息
Department of Chemical and Biological Engineering, University of Colorado, Boulder, Colorado 80309.
Department of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045.
出版信息
J Pharm Sci. 2020 Jan;109(1):429-442. doi: 10.1016/j.xphs.2019.06.015. Epub 2019 Jun 21.
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 an in vitro assay 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.
人们对亚可见颗粒杂质对治疗性蛋白产品的安全性和疗效的影响表示担忧，这促使制造商在制造、储存和运输过程中实施策略来最小化蛋白质聚集和颗粒形成。然而，一旦这些产品被放行，制造商对产品处理的控制就很有限。在这项工作中，我们研究了聚氯乙烯（PVC）静脉输液袋中邻苯二甲酸二（2-乙基己基）酯（DEHP）纳米液滴对静脉注射免疫球蛋白（IVIG）制剂稳定性和免疫原性的影响。我们表明，在临床环境中，当用气动管输送系统搅拌或输送时，含有生理盐水的 PVC IV 袋会将 DEHP 液滴释放到溶液中。接下来，我们研究了乳化 DEHP 纳米液滴对 IVIG 稳定性和免疫原性的影响。IVIG 强烈吸附到 DEHP 纳米液滴上，形成单层。此外，DEHP 纳米液滴加速了搅拌样品中 IVIG 的聚集。通过人血清中补体激活的体外测定评估了 DEHP 纳米液滴和这些制剂中生成的 IVIG 聚集物的免疫原性。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稳定性并诱导补体系统的激活，这可能会导致在给予治疗性蛋白时产生不良的免疫反应。
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