Development of in vitro-in vivo correlations for long-acting injectable suspensions

Abstract

Long-acting injectable (LAI) aqueous suspensions achieve extended drug release over a duration of weeks to months via slow dissolution of drug crystals with low solubility. There have been around ten LAI aqueous suspensions approved by the FDA to date and there are no generic equivalents for most of them. This may be largely due to the complex formulation development as well as the challenges in establishment of in vitro-in vivo correlation (IVIVC) for these products. Level A IVIVCs, using animal models, have been proven feasible for complex long-acting microsphere formulations with multiphasic release characteristics. Accordingly, it may be possible to develop IVIVCs for LAI aqueous drug suspensions since their release characteristics are relatively simple with only a drug dissolution phase. To establish IVIVCs for LAI drug suspensions, four compositionally equivalent medroxyprogesterone acetate LAIs with differences in processing and formulation factors (drug particle size and excipient source) were prepared using Depo-SubQ Provera 104 as the reference listed drug (RLD). Two in vitro release testing methods, modified based on USP apparatus 2 (with enhancer cells) and USP apparatus 4 (with semisolid adapters), were used. The in vivo release was investigated using a rabbit model. Level A IVIVCs were successfully established using the in vitro release profiles obtained with the USP apparatus 4. This is the first report of an IVIVC for LAI aqueous suspensions.