Abstract
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.
Highlights
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)
We focus on the roadblocks of perfluorocarbon-based AOC development, which we hypothesize can be overcome by utilizing a systematic product development strategy, Quality by Design (QbD)[18]
We present QbD-based development adapted to PFC nanoemulsions (PFC-NEs)-based AOCs with two PFC molecules commonly reported from clinical studies: perfluoro-15-crown-5-ether ( PCE2,3) and perfluorooctyl bromide ( PFOB13,39.) These two molecules have been extensively used in regenerative medicine preclinical studies and have the most well established biodistribution kinetics in vivo[18]
Summary
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, 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. In contrast to WB or blood products, PFC oxygen carrier function is minimally impacted by the environmental, chemical, and pharmacologic factors. QbD is applied to PFC-NE colloidal stability and oxygen transport characterization, resulting in designation of formulation and processing design space for a model PFC AOC in which both attributes can be controlled
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