(178l) Mechanistic Modeling of PLGA Microparticle Drug Delivery Systems

Controlled-release drug delivery systems are being developed as alternatives 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 model-based design of controlled-release devices, such as biodegradable poly(lactic-co-glycolic acid) (PLGA) polymer microspheres, is challenging because of incomplete understanding of the mechanisms that regulate the release of drug molecules. This research focuses on modeling 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 primary mechanism by which the diffusive drug release is accelerated, and this process should depend strongly on particle size. The hypothesis of the present work 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 and the release of drug molecules--rather than independently modeling any of the phenomena in a purely sequential manner will accurately mimic the actual overall release process. The developed mechanistic model tracks acid concentration as a function of space and time with a system of nonlinear partial differential equations 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. The chemical reaction mechanism including autocatalytic effects is coupled to a simplified diffusion model and pore formation model to incorporate spatial variations in degradation rate for all species within the microspheres. The model equations are solved for small computational time steps for an extended period of time in order to capture an entire release profile. The high resolution simulation of the coupling between reaction and diffusion captures important dynamical phenomena observed in experiments that cannot be modeled with the models in the literature that have simpler numerical solution but do not take the coupling into account. The inclusion of the spatial variation of autocatalytic effects is a unique contribution of this modeling work. The model for PLGA microspheres is extended to apply to core-shell microparticles and microcapsules, which are important options for encapsulating drugs for delivery in a multi-stage pulsatile release fashion or for protecting proteins from being deactivated by suspension in an aqueous core for time-delayed delivery after polymer microcapsule degradation. The predictions for the core-shell microparticles and microcapsules are compared to experimental results.