Understanding drug release mechanisms of risperidone in situ forming implant depots in rabbits

Injectable poly(lactic-co-glycolic acid) (PLGA)-based in situ forming implants are a promising long-acting drug delivery system. They are liquid formulations that solidify through solvent exchange to form drug-PLGA depots that become isolated from the surrounding tissue following injection. There have been limited studies focusing on in vivo drug release mechanisms for this dosage form. However, such knowledge is necessary in order to modulate drug release rates on demand. To explore the in vivo drug release mechanisms, risperidone in situ forming implants with different PLGA attributes (i.e., molecular weight (MW), lactide:glycolide (L/G) ratio, blockiness, and end group) were prepared based on the reference listed drug Perseris (risperidone extended-release injectable suspension). Depot degradation (MW, weight loss and glass transition temperature (T_g) change kinetics) of the various implants as well as the underlying relationship between drug release and depot behavior were investigated using a rabbit model. The depot characteristics gave insight into depot degradation/erosion and drug diffusion. It was revealed that, in general, the PLGA properties (specifically higher L/G ratio and ester/acid end-cap) that lead to longer drug release durations in vivo appeared to result in slower depot degradation rates for risperidone in situ forming implants. The polymer degradation rates and the drug release durations demonstrated good correlations for most formulations. However, most of the implant depots did not experience significant weight loss nor T_g changes within 7 days despite significant PLGA degradation. These results indicate that drug release in vivo may be degradation dominated and that depot degradation followed bulk erosion. This study provides an understanding of the in vivo mechanisms controlling drug release from in situ forming implant formulations.