Evaluation of in vivo-in vitro release of dexamethasone from PLGA microspheres

Two poly(lactic-co-glycolic acid) (PLGA) microsphere formulations, with different polymer molecular weights were investigated to determine whether an in vitro and in vivo relationship could be established for dexamethasone release. A USP apparatus 4 was used for in vitro testing. The in vivo release kinetics and pharmacodynamic effects of dexamethasone were evaluated using a Sprague Dawley rat model. The in vitro release from both formulations followed the typical triphasic profile of PLGA microspheres (initial burst release, followed by a lag phase and a secondary zero-order phase). The in vivo release profiles differed in that the lag phase was not observed and drug release rates were faster compared to the in vitro studies. It is speculated that the lack of lag phase in vivo may be a result of different PLGA degradation mechanisms in vivo as a consequence of the presence of enzymes as well as other in vivo factors such as interstitial fluid volume, and local pH. This may result in degradation of the PLGA microspheres proceeding from the surface inward in vivo. Whereas, in vitro an "inside out" degradation is thought to occur in some PLGA microsphere systems as a result of the autocatalytic degradation process where build up of acidic oligomeric units can occur within the microspheres. A linear in vitro-in vivo relationship was established after normalization of the time required to reach plateau for the in vitro and in vivo data and the in vitro release data were predictive of the in vivo release. Inflammation was significantly reduced in the tissue surrounding the dexamethasone microspheres compared to the positive control (empty microspheres) and the number of inflammatory cells was similar to that of normal tissue within one to three days.