Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States of America.
Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.
J Control Release. 2024 Nov;375:802-811. doi: 10.1016/j.jconrel.2024.09.045. Epub 2024 Oct 4.
In situ forming implants (ISFIs) composed of biodegradable polymers and biocompatible solvents are generally designed for sustained drug release. In this study, a non-invasive computed tomography (CT) imaging approach is used to achieve real time imaging of ISFIs in vivo and in vitro using leuprolide acetate in situ forming implant as a model drug product. The process of implant formation, inner structure change and their impact on drug release were elucidated. Real-time drug distribution was unveiled by the CT contrast agent, iohexol, where it shows a core-shell structure of the deposition. The incorporation of leuprolide acetate (LA) led to a reduced extent of burst release, prolongated release profile, and extended implant size expansion. LA was found to interact with the solvent and slowed down the polymer phase inversion, thus significantly changed the drug distribution in the implant and reduced the drug release. The implant inner structure identified through SEM, implant size change, and polymer degradation along with the CT real time imaging all consistently support the implant formation differences and their implant on the drug release. Similar patterns of implant size expansion and iohexol distribution in the implants were observed both in vitro and in vivo for the implants with and without LA. The comprehensive understanding of the impact of implant formation on drug release through real time CT imaging facilitates the ISFI product development and evaluation.
原位形成植入物（ISFI）由可生物降解的聚合物和生物相容的溶剂组成，通常设计用于持续释放药物。在这项研究中，使用非侵入性计算机断层扫描（CT）成像方法，以醋酸亮丙瑞林原位形成植入物作为模型药物产品，实现体内和体外 ISFI 的实时成像。阐明了植入物形成、内部结构变化及其对药物释放的影响。通过 CT 造影剂碘海醇揭示了实时药物分布，显示出沉积的核壳结构。醋酸亮丙瑞林（LA）的加入导致释放突释程度降低、释放时间延长、植入物尺寸扩张延长。发现 LA 与溶剂相互作用，减缓了聚合物相转化，从而显著改变了植入物中的药物分布并减少了药物释放。通过 SEM 鉴定的植入物内部结构、植入物尺寸变化以及聚合物降解以及 CT 实时成像都一致支持了植入物形成差异及其对药物释放的影响。对于有和没有 LA 的植入物，在体内和体外都观察到了植入物大小扩张和碘海醇分布的相似模式。通过实时 CT 成像对植入物形成对药物释放的影响的全面了解，有助于 ISFI 产品的开发和评估。
