In vitro release testing method development for long-acting injectable suspensions

Abstract

Long-acting injectable (LAI) suspensions are complex parenterals intended to control drug release over a duration of weeks to months. Any unpredictive drug release behavior may cause serious side effects. Therefore, it is important to understand the in vitro and in vivo performance, as well as the in vitro-in vivo correlation (IVIVC) of these products. There are some US FDA recommended in vitro release testing methods for LAI suspensions. However, the release duration of all the recommended methods is less than two days which may not be appropriate for the establishment of IVIVCs for LAIs considering that their in vivo efficacies range from weeks to months. To develop in vitro release testing methods that may better correlate with in vivo release with longer durations, three compositionally equivalent medroxyprogesterone acetate suspensions were prepared with different particle size, using Depo-SubQ Provera 104® as the reference listed drug (RLD). Four different methods based on USP apparatus 2 (with dialysis sacs, enhancer cells or in-house designed devices) and USP apparatus 4 (with semisolid adapters) were utilized. USP apparatus 2 with enhancer cells and USP apparatus 4 with semisolid adapters showed the best discriminatory ability and reproducibility for the LAI suspensions investigated.