Factors defining the stability of poly(lactide-co-glycolide) spheres for the sustained release of a cysteine protease inhibitor.

Abstract

Colloidal stability and the regularity of the release kinetics benefit from the high circularity and the narrow size dispersion of polymeric particles as drug delivery carriers. A method for obtaining such particles composed of poly(lactide-co-glycolide) (PLGA), averaging at 1.0±0.3µm in size, is reported here, along with the analysis of the effects of different synthesis parameters on their morphological characteristics. As in agreement with the classical nucleation theory, the particle size and the degree of cohesion were inversely proportional to supersaturation. Consequently, the optimal conditions for the precipitation of small and narrowly dispersed particles involved an abrupt elevation of supersaturation. Owing to the high colloidal stability of the particles, centrifugation exhibited a counterintuitive effect on them, refining their morphological features and promoting their individuation. Polyvinyl alcohol (PVA) was used as a steric repulsion additive and its effect on the stability of PLGA spheres was concentration-dependent, with the particles aggregating, partially coalescing and losing their distinct features both with no PVA in the system and at PVA concentrations higher than the optimal. At its narrowest, the particle size distribution was bimodal, exhibiting the average circularity of 0.997±0.003 and the average roundness of 0.913±0.054. PLGA spheres were loaded with an inhibitor of EhCP4, a cysteine protease from E. histolytica, a parasite causing amoebic dysentery in the tropical and developing world. The burst release of the drug at early time points was followed by a zero-order release period, yielding a biphasic profile that can be of benefit in the delivery of anti-infective agents. The release profile fitted poorly with the Hixson-Crowell kinetic model and excellently with the Higuchi and the Korsmeyer-Peppas ones, indicating that the release is conditioned by diffusion rather than by the degradation of the polymer. The release and the erosion proceeded independently from one another, suggesting that the pore formation, water penetration and swelling are the primary driving forces for the release of the drug.