Mechanistic Analysis of In Vitro and In Vivo Drug Release from PLGA Microspheres.

Abstract

Poly (lactic-co-glycolic) acid (PLGA) microspheres have been extensively studied for controlled drug delivery, and more than a dozen PLGA formulations are currently on the market. However, surprisingly little information is available about how the administration environment affects microsphere properties that result in drug release in vivo, and there is a lack of in vitro-in vivo correlation data for microsphere formulations. As a result, in vitro tests used to predict drug release during development are rarely designed to represent actual formulation behavior in vivo. Two microsphere formulations encapsulating a model drug, triamcinolone acetonide, were prepared from PLGAs of different molecular weights and end-capping (18 kDa acid-capped, 54 kDa ester-capped). In vitro release and the corresponding mechanisms (hydrolysis, erosion, water uptake, and diffusion) were studied in four release media: PBST pH 7.4 (standard condition), PBST pH 6.5, PBS + 1.0% triethyl citrate (TC), and HBST pH 7.4. The release mechanism in PBST and HBST without TC was primarily polymer erosion-controlled in both formulations as indicated by the similarity of release and mass loss kinetics. The addition of TC resulted in primarily diffusion-controlled release from the low MW PLGA. By using a novel cage implant to restrain microspheres in the SC space, similar analyses were performed on microspheres administered in vivo. Drug release was much faster in vivo than in any of the in vitro media studied (release over 2-3 weeks vs. 4-7 weeks). Furthermore, PLGA water uptake, hydrolysis and mass loss were greatly augmented in the subcutaneous space. The study of microsphere morphology revealed an osmotically induced pore network in the higher MW formulation, indicating the potential for release controlled by water uptake, a mechanism previously unseen in vitro. Therefore, in vitro tests could benefit by incorporating relevant components of interstitial fluid, which more closely mimic those conditions that control key release mechanisms in vivo. The novel application of the cage model to uncover significant changes to mechanism-indicating processes of PLGA microspheres in vivo is highly significant. Hence, this thesis demonstrates the importance of understanding in vivo release mechanisms in order to design release tests, which accurately predict release upon administration.