Modeling Controlled Release Drug Delivery from PLGA Microspheres

Ashlee Ford, University of Illinois at Urbana-Champaign

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Controlled-release drug delivery systems are being developed as an alternative to conventional medical drug therapy regimens which require frequent administrations due to short pharmaceutical in vivo half-life and poor oral bioavailability. Controlled-release systems have the potential to provide better control of drug concentrations, reduce side effects, and improve compliance as compared to conventional regimens. The design of controlled-release devices, such as biodegradable poly(lactic-co-glycolic acid) (PLGA) polymer microspheres, is difficult because of incomplete understanding of the mechanisms that regulate the release of drug molecules. The goal of this project is to model the autocatalytic polymer degradation and release of dispersed drug molecules from PLGA microspheres to capture size-dependent heterogeneous degradation behavior observed experimentally but not accounted for by existing models. Recently, other researchers have suggested that the autocatalytic polymer degradation is the main mechanism by which the diffusive drug release is accelerated, and this process should depend strongly on particle size. My hypothesis is that simultaneously modeling the mathematics of diffusion, autocatalytic chemical reactions, chemical equilibria, and pore formation, the phenomena which are considered to contribute to the degradation of polymer particles, rather than independently modeling any of the phenomena in a purely sequential manner, will accurately mimic the actual overall release process. The current version of the developed model tracks acid concentration as a function of space and time for determination of intraparticle pH while modeling degradation kinetics, molecular weight distribution variation, and drug transport with varying diffusivity coupled to the concentrations of other reacting species – all of which influence drug release from the polymer microspheres. The autocatalytic chemical reaction mechanism is coupled to a simplified diffusion model and pore formation model to incorporate spatial variations in degradation rate within microspheres. The spatial variation of autocatalytic effects is the unique contribution of this modeling work.

Abstract Author(s): Ashlee N. Ford, Richard D. Braatz