Effects of polymer degradation on drug release a mechanistic study of morphology and transport properties in 50:50 poly(dl-lactide-co-glycolide)

50:50 Poly(dl-lactide-co-glycolide) (50:50 PLGA) was used to investigate the effects of polymer degradation on drug release from bulk degradable polymers. 5-Fluorouracil (5-FU) and Cyclosporin A (CyA) were used as model drugs. Using scanning electron microscopy, it was observed that initially non-porous 50:50 PLGA underwent significant morphological changes, becoming increasingly porous,las degradation proceeded. Concomitant increases in the transport parameters permeability and diffusivity of the model drugs through degrading 50:50 PLGA membranes were observed. Sharp transitions were observed in the relationship between the transport parameters and the residual polymer molecular weight and porosity -at values of molecular weight and porosity of about 5000-6000, and 70-80%, respectively. These transitions suggest that a shift in transport mechanism occurs with polymer degradation: the initial dominant transport pathway through degrading PLGA is the dense polymer phase, but as degradation progresses, the increase in porosity results in an increasingly connected pore structure such that, at some point in time, the pore network becomes the dominant pathway. By comparing experimentally measured 5-FU release profiles from PLGA matrices with release profiles calculated from experimentally measured permeability through degrading PLGA membranes containing no drug, it was shown that the shift in transport mechanism is the likely cause for the onset of the rapid final release stage of typical tri-modal release profiles from bulk-degradable polymer matrices.