Peloso Charlotte, Yvorra Etienne, Delamare Romain, Campana Mélanie, Grizot Sylvestre, Lopez-Noriega Adolfo
MedinCell S.A., 3 rue des Frères Lumi ère, 34830 Jacou, France.
MedinCell S.A., 3 rue des Frères Lumi ère, 34830 Jacou, France.
Int J Pharm. 2025 Aug 20;681:125884. doi: 10.1016/j.ijpharm.2025.125884. Epub 2025 Jun 20.
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.
拥有一种能提供有意义且可转化数据的体外溶出方法对于早期研发至关重要。对于长效注射剂，如原位形成 depot（ISFD），释放测试的延长时间以及所涉及的不同释放机制不允许使用经典的体外溶出系统。为了促进从实验室研究到动物研究的过渡，开发了一种替代溶出装置。这种流通系统设计得更具生物相关性，增加了填充有琼脂糖水凝胶的温度控制反应室。这使得在溶出测试期间 depot 能持续受到约束，并且在开路中有连续的缓冲液流动。使用大量条件（即温度范围从 25°C 到 45°C，缓冲液流速从 1 到 10 mL/h）以及不同的活性药物成分研究了相转化 ISFD 技术 BEPO® 的释放特性。在使用新的溶出装置时，可以调整体外释放曲线。特别是，温度是关键参数，较高温度导致释放速率增加，并且通常体外释放曲线与各自的体内数据更具可转化性。流速对改变释放动力学的影响比温度小。总体而言，最具可转化性的释放条件并非最具生物相关性，但能产生与体内获得的释放曲线相当的结果。因此，所开发的体外装置可被视为体内评估的一种有趣且有价值的替代方法。
