Improving in vivo release prediction from in situ forming depots with a novel flow-through in vitro dissolution...

Having an in vitro dissolution method providing meaningful and translatable data is critical for early-stage research and development. For long-acting injectables, such as in situ forming depots (ISFD), the extended duration of the release test and the different release mechanisms involved do not allow the use of classical in vitro dissolution systems. To facilitate the transition from bench to animal studies, an alternative dissolution apparatus was developed. This flow-through system was designed to be more biorelevant, with the addition of temperature-controlled reaction chambers filled with an agarose hydrogel. This allows for a continuous constraint of the depot during dissolution testing as well as a continuous buffer flow in an open circuit. The release properties of the phase-inverting ISFD technology BEPO® were investigated with a large range of conditions (i.e. temperatures ranging from 25 °C to 45 °C and buffer flow rates from 1 to 10 mL/h) and different active pharmaceutical ingredients. The in vitro release profiles could be tailored while using the new dissolution apparatus. In particular, the temperature was the critical parameter, with higher temperatures leading to an increase of the release rate and generally more translatable in vitro release profiles to the respective in vivo data. Flow rate had a lower impact than temperature in modifying release kinetics. Overall, the most translatable release conditions were not the most biorelevant but led to comparable release profiles to those obtained in vivo. The in vitro setup developed can thus be considered an interesting and valuable surrogate to in vivo evaluation.