NER: Continuous Flow Induced Phase Inversion: a New Method for Manufacturing Drug Delivery Biopolymer Nanoparticles

本项目旨在探索利用最近开发的流动诱导相转化技术（FIPI）连续制造含有牛血清白蛋白为模型药物的聚乳酸-共乙醇酸纳米颗粒的可行性。该项目的具体目标是：(i)系统地检查生物相容性聚合物、表面活性剂和溶剂组合的相转化特性。（ii）实施一个实验连续流系统，在该系统中可以检查材料特性、混合几何形状和操作条件对FIPI的影响。（iii）从理论上理解流体力学、表面张力和流变学对基本FIPI物理的影响。一个实验装置将被用来检验相变行为。聚合物将分散在溶剂中，然后与预定量的非溶剂混合以形成分散体，其中聚合物溶液为连续相。随后，将应用非常高的流体动力变形率来引发相反转，将粘性聚合物溶液转变为纳米分散相。所得的液滴将通过溶剂萃取硬化。在定制流变仪中表征该过程后，该信息将用于开发连续的在线工艺设备。成功与否取决于生物粒子的大小、数量和制造的难易程度。这个项目将促进对相位反转现象的理解，特别是对FIPI的理解。主要的知识价值将是证实了FIPI可以用来制造生物可降解药物纳米粒子的工作假设。预计拟议的工作将产生重大影响。由于目前许多药物由于溶解性差而在开发过程中失败，因此开发适当的方法来提高溶解性和生物利用度可以为许多“死亡”化合物注入新的生命，即最初有希望被制药公司丢弃的分子。此外，教育部分将包括实验室演示和向工业推广。

This project proposes to explore the feasibility of using a recently developed technique, Flow Induced Phase Inversion (FIPI), for continuous manufacturing of nanoparticles made of poly(DL-lactic-co-glycolic acid) containing bovine serum albumin as a model drug. The specific aims of this project are (i) to examine systematically the phase inversion properties of combinations of biocompatible polymers, surfactant, and solvents. (ii) To implement an experimental continuous flow system where the effects of material properties, mixing geometry, and operating conditions on FIPI can be examined. (iii) to develop a theoretical understanding of the effects of hydrodynamics, surface tension, and rheology on the fundamental FIPI physics. An experimental apparatus will be implemented to examine phase-inversion behavior. The polymer will be dispersed in a solvent and then mixed with predetermined amounts of a non-solvent to form a dispersion where the polymer solution is the continuous phase. Subsequently, very high rates of hydrodynamic deformation will be applied to elicit phase inversion, transforming the viscous polymer solution into a nanodispersed phase. The resulting droplets will be hardened by solvent extraction. After the process has been characterized in a customized rheometer, this information will be used to develop continuous in-line process equipment. Success will be determined based on the size, the amount, and the ease of manufacturing of bioparticles. This project will advance the understanding of phase inversion phenomena in general and of FIPI in particular. The main intellectual merit will be to confirm the working hypothesis that FIPI can be used to make biodegradable drug nanoparticles. The proposed work is expected to have substantial impact. Since many drugs currently fail during development due to poor dissolution properties, the development of suitable approaches for enhancing dissolution and bioavailability can breathe new life into many "dead" compounds, i.e., initially promising molecules that have been discarded by pharmaceutical companies. In addition, educational components will include laboratory demonstrations and outreach to industry.