Injectable PLGA-Based Formulations for Sustained Delivery of Therapeutic Agents for Intraocular Applications

Abstract

Purpose: : The purpose was to utilize JPE1375 as a model compound to assess the feasibility of preparing poly(lactic-co-glycolic acid)(PLGA) based microparticles for sustained intraocular delivery of JOI’s drug candidates.

Methods: : The C5aR peptidomimetic antagonist JPE1375 was encapsulated in PLGA microparticles using a proprietary emulsion forming technology (Zeigerson, E WO 2005/003180). The microparticles were characterized for drug content and purity (HPLC), residual solvents (GC), and particle size (LLS). In vitro release kinetics and stability were measured in PBS (37°C) by HPLC assay. In vitro bioactivity was evaluated using rat basophil leukemia (RBL) cells transfected with human C5aR. The in vivo performance of select formulations was assessed after intravitreous injection in New Zealand rabbits by LC-MS.

Results: : The formulation process provided defined microparticles with good drug content (5-15%) and narrow particle size distribution compatible with injection through a 27 gauge needle. Residual solvent levels were low in the pilot formulations. In vitro release kinetics showed a limited burst release (<10%) followed by PLGA-dependent sustained release over a period of 90 to >250 days. In vitro drug stability was supported by HPLC analysis of PBS release media and bioactivity in a C5aR bioassay. In vivo evaluation of formulations revealed systemic exposures below the limit of quantification at all time points while sustained retina levels of JPE1375 were maintained above the in vitro IC₅₀ for multiple weeks.

Conclusions: : Injectable PLGA-based formulations are a viable platform for delivery of JPE1375 to the posterior segment of the eye for months after intravitreous administration.

Keywords: age-related macular degeneration • vitreous