Book Description

Polymeric micelles are nano-particulate core-shell structures that form spontaneously in aqueous solutions of block copolymers composed of hydrophilic and hydrophobic portions when their concentration surpasses the critical micelle concentration (CMC) at a given temperature. They are used as drug delivery systems for highly potent and extremely hydrophobic drugs such as anticancer or anti-inflammatory agents to enhance safety, efficacy, and solubility. Critical quality attributes of polymeric micelles, that tend to govern their destiny in the human body are their size and polydispersity. Ensuring manufacturing consistency for complex drug products such as polymeric nanoparticles is challenging. This can be attributed, in part, to the complex nature of the manufacturing processes and a lack of understanding of critical material attributes such as drug-polymer interactions and critical process parameters such as organic to aqueous phase ratios. Currently, the manufacturing of polymeric micelles in the pharmaceutical industry is via batch processing which has various disadvantages such as scalability, irreproducibility, down-time between batches and other issues leading to product waste, and increased expenses. To overcome potential batch-to-batch variation typically observed using traditional batch manufacturing processes, the current work focused on continuous processing of polymeric micelles and the establishment and assessment of key material attributes and process parameters. A modified continuous processing platform (based on the University of Connecticut prototype liposomal manufacturing platform) was successfully developed and built to produce polymeric micelles. Moreover, this study outlines the relationship between critical independent variables (such as polymer concentration, organic to aqueous flow rate ratios and temperature) and critical quality attributes (such as the size and polydispersity) of polymeric micelles produced by continuous processing. The controlled nanoprecipitation process achieved via co-axial co-flow and radial mixing of jets improved the control and reproducibility of polymeric micelle particle size and polydispersity compared to batch processing. Multiple design of experiments studies were implemented to produce polymeric micelles with controlled size in the range between 15 and 70 nm. Four different molecular weight block copolymers (i.e. PEG-PLA-4kD, and PEG-PCL 7kD, 14kD and 28kD) were investigated to produce polymeric micelles using the turbulent jet co-flow technology. Moreover, curcumin-loaded polymeric micelles, as an example of an API containing polymeric micelles, were produced to establish and validate the continuous processing system. Paclitaxel-loaded polymeric micelles were produced to demonstrate the system's capacity to produce Q1/Q2 equivalent drug product similar to the reference listed drug product: Genexol®PM.