Department of Pharmacy, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning, People's Republic of China; Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, Liaoning, People's Republic of China.
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, Liaoning, People's Republic of China.
Int J Pharm. 2020 Dec 15;591:119964. doi: 10.1016/j.ijpharm.2020.119964. Epub 2020 Oct 30.
The aim of this study was to resolve the lag time problem for peptides loaded PLGA-Hydrogel Microspheres (PLGA-gel-Ms) by blending low molecular PLGA (Mw. 1 kDa) into PLGA (Mw. 10 kDa) as an intrinsic porogen, and then assess the in vitro-in vivo relationship (IVIVR). Here, Goserelin acetate (GOS) was chosen as the model peptides. When compared to additional types of porogen, the intrinsic porogen avoided impurities remaining and protected the bioactivities of the peptides. By adding 10% PLGA (Mw. 1 kDa), the lag time was eliminated both in vitro and in vivo with a desirable EE (97.04% ± 0.51%). The release mechanisms were found to be: a) initial GOS release mainly controlled by pores diffusion and b) autocatalysis of PLGA (Mw. 1 kDa) which increased the quantity of aqueous pores, as revealed by SEM images. To solve the challenges caused by multiphasic release profiles, for the first time the Segmented phases IVIVR were proposed and developed, and showed improved linear fitting effects and supported the proposed release mechanisms. The application of PLGA blends could provide a new insight into PLGA microsphere initial release rate regulation.
本研究旨在解决载肽 PLGA-水凝胶微球（PLGA-gel-Ms）的滞后时间问题，方法是将低分子量 PLGA（Mw. 1 kDa）作为内在致孔剂混入 PLGA（Mw. 10 kDa）中，然后评估体外-体内相关性（IVIVR）。在这里，醋酸亮丙瑞林（GOS）被选为模型肽。与其他类型的致孔剂相比，内在致孔剂避免了杂质残留并保护了肽的生物活性。通过添加 10%的 PLGA（Mw. 1 kDa），在体外和体内都消除了滞后时间，同时具有理想的 EE（97.04%±0.51%）。释放机制为：a）初始 GOS 释放主要由孔扩散控制，b）PLGA（Mw. 1 kDa）的自催化增加了水相孔的数量，这可以通过 SEM 图像看出。为了解决多相释放曲线带来的挑战，首次提出并开发了分段相 IVIVR，显示出改善的线性拟合效果，并支持所提出的释放机制。PLGA 共混物的应用为调节 PLGA 微球初始释放速率提供了新的思路。
