Lambert Eric, Janjic Jelena M
Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA, 15282, USA.
Sci Rep. 2021 Mar 10;11(1):5569. doi: 10.1038/s41598-021-84076-1.
Perfluorocarbons (PFCs) exhibiting high solubility for oxygen are attractive materials as artificial oxygen carriers (AOC), an alternative to whole blood or Haemoglobin-based oxygen carriers (HBOCs). PFC-based AOCs, however, met clinical translation roadblocks due to product quality control challenges. To overcome these issues, we present an adaptation of Quality by Design (QbD) practices to optimization of PFC nanoemulsions (PFC-NEs) as AOCs. QbD elements including quality risk management, design of experiments (DoE), and multivariate data analysis facilitated the identification of composition and process parameters that strongly impacted PFC colloidal stability and oxygen transport function. Resulting quantitative relationships indicated a composition-driven tradeoff between stability and oxygen transport. It was found that PFC content was most predictive of in vitro oxygen release, but the PFC type (perfluoro-15-crown-5-ether, PCE or perfluorooctyl bromide, PFOB) had no effect on oxygen release. Furthermore, we found, under constant processing conditions, all PFC-NEs, comprised of varied PFC and hydrocarbon content, exhibited narrow droplet size range (100-150 nm) and narrow size distribution. Representative PFOB-NE maintained colloidal attributes upon manufacturing on larger scale (100 mL). QbD approach offers unique insights into PFC AOC performance, which will overcome current product development challenges and accelerate clinical translation.
对氧气具有高溶解度的全氟碳化物（PFCs）作为人工氧载体（AOC）是很有吸引力的材料，可替代全血或基于血红蛋白的氧载体（HBOCs）。然而，基于PFC的AOCs由于产品质量控制方面的挑战而遇到了临床转化障碍。为了克服这些问题，我们提出将质量源于设计（QbD）方法应用于优化作为AOCs的PFC纳米乳液（PFC-NEs）。包括质量风险管理、实验设计（DoE）和多变量数据分析在内的QbD要素有助于识别对PFC胶体稳定性和氧传输功能有重大影响的成分和工艺参数。由此得出的定量关系表明，在稳定性和氧传输之间存在成分驱动的权衡。研究发现，PFC含量对体外氧释放的预测性最强，但PFC类型（全氟-15-冠-5-醚，PCE或全氟辛基溴，PFOB）对氧释放没有影响。此外，我们发现，在恒定的加工条件下，所有由不同PFC和碳氢化合物含量组成的PFC-NEs都表现出较窄的液滴尺寸范围（100 - 150 nm）和较窄的尺寸分布。代表性的PFOB-NE在大规模生产（100 mL）时仍保持胶体特性。QbD方法为PFC AOC的性能提供了独特的见解，这将克服当前产品开发的挑战并加速临床转化。
