In Vitro and In Vivo Hydrolytic Degradation Behaviors of a Drug-Delivery System Based on the Blend of PEG and PLA Copolymers

Abstract

This paper presents the in vitro and in vivo degradation of BEPO, a marketed in situ forming depot technology used for the formulation of long-acting injectables. BEPO is composed of a solution of a blend of poly(ethylene glycol)- block -poly(lactic acid) (PEG–PLA) triblock and diblock in an organic solvent, where a therapeutic agent may be dissolved or suspended. Upon contact with an aqueous environment, the solvent diffuses and the polymers precipitate, entrapping the drug and forming a reservoir. Two representative BEPO compositions were subjected to a 3-month degradation study in vitro by immersion in phosphate-buffered saline at 37 °C and in vivo after subcutaneous injection in minipig. The material erosion rate, as a surrogate of the bioresorption, determined via the depot weight loss, changed substantially, depending on the composition and content of polymers within the test item. The swelling properties and internal morphology of depots were shown to be highly dependent on the solvent exchange rate during the precipitation step. Thermal analyses displayed an increase of the depot glass transition temperature over the degradation process, with no crystallinity observed at any stage. The chemical composition of degraded depots was determined by 1 H NMR and gel permeation chromatography and demonstrated an enrichment in homopolymers, i.e., free PLA and (m)PEG, to the detriment of (m)PEG–PLA copolymers in both formulations. It was observed that the relative ratio of the degradants within the depot is driven by the initial polymer composition. Interestingly, in vitro and in vivo results showed very good qualitative consistency. Taken together, the outcomes from this study demonstrate that the different hydrolytic degradation behaviors of the BEPO compositions can be tuned by adjusting the polymer composition of the formulation.