| The aim of this thesis was to experimentally and theoretically elucidate mechanisms of drug release in PLGA microspheres. We showed the effect of microsphere size and presence of an antacid on the stability and release of plasmid DNA from PLGA microspheres. We demonstrated that the use of Mg(OH)2 as a stabilizing excipient affected the surface porosity of the microspheres, which in turn affected the burst of drug during early release. We were further able to modulate release using size---following the burst, smaller spheres released faster than their larger counterparts, due to the larger surface to volume ratio. Although we were able to control release, there is always a desire to generate more complex release profiles. We also developed a general three-dimensional Monte Carlo/diffusion model for predicting drug release from polymeric microparticles. We demonstrated the applicability of the code as a tool to account for drug release governed by diffusion as well as degradation and erosion. The key benefit to the code is its adaptability. Whereas most models for drug release are highly specific for a certain geometry or polymer-drug interaction, the Monte Carlo/diffusion base model can easily be modified to account for several scenarios including: core/shell geometry, non-homogeneous drug distribution, and non-homogeneous particle erosion. We later developed a procedure to measure the radial and temporal evolution of porosity in PLGA microspheres to account for non-homogeneous microsphere erosion. This temporal and radial porosity evolution was then input to the model as a replacement for the degradation constant. Its use proved a good fit to DNA release from 47 mum PLGA microspheres. |
