Design of PLGA Microparticle Drug Delivery Systems Using a Mechanistic Reaction-Diffusion Model

Ashlee Ford, University of Illinois at Urbana-Champaign

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. Proteins and pharmaceuticals can be encapsulated into biodegradable polymer microparticles of controlled size including microspheres, core-shell microparticles, and microcapsules. Microparticles present important options for encapsulating drugs for delivery in a multi-stage pulsatile release fashion or for protecting proteins from being deactivated. Despite advantages of using polymer microparticle controlled-release systems, the design depends heavily on experiments due to lack of understanding of the mechanisms that control the release processes. An accurate mechanistic model of drug release from polymer microparticles would be useful for determining the optimal fabrication parameters to yield desired drug concentration profiles. Such a model would be a useful tool for planning experiments and could be used in the design of pharmaceutical manufacturing of microparticles. A reaction-diffusion model has been developed to capture the degradation heterogeneities observed in PLGA microparticles of different sizes due to autocatalytic polymer hydrolysis. The model has been used to predict drug release profiles for a variety of formulation variables in order to optimally design polymer microparticles for controlled-release drug delivery. Changing the core diameter and shell thickness along with the distribution of molecular weights and pore sizes enables the design of microparticles to produce a large spectrum of obtainable release profiles including zeroth-order and pulsatile release with a range of shapes for the individual pulses.

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