Abstract

To overcome problems associated with topical delivery of tacrolimus (TCS), a thermoresponsive in situ gel system containing pluronic F127 (PL), and chitosan (CS) was developed, to enhance the precorneal retention, and to sustain the release of the drug. The PL-CS in situ gel was optimized using a 2-factor-3-level central composite experimental design by selecting the concentration of PL and CS as independent variables while gelation time, gelation temperature, and spreadability as dependent variables. The optimized formulation was developed using 22.5 g PL and 0.3 g CS, gels at 33.6 °C, in 22.93 s, and showed the spreadability of 6.2 cm. In vitro studies conducted for the optimized gel revealed the sustained release of TCS (81.73% in 4 h) and improved corneal permeation (74.13% in 4 h), compared with TCS solution. The mechanism of release of TCS followed the Higuchi model with Fickian diffusion transport. Further, histopathology and HET-CAM studies revealed that the developed gel was non-irritating and safe for ocular administration.

摘要

为了克服与他克莫司 (TCS) 局部给药相关的问题，开发了一种含有普朗尼克 F127 (PL) 和壳聚糖 (CS) 的热敏原位凝胶系统，以增强角膜前保留并维持药物的释放。通过选择 PL 和 CS 的浓度作为自变量，而凝胶时间、凝胶温度和铺展性作为因变量，使用 2 因子 3 水平中心复合实验设计对 PL-CS原位凝胶进行了优化。使用 22.5 g PL 和 0.3 g CS，在 33.6 °C 下凝胶，在 22.93 秒内开发出优化的配方，并显示出 6.2 cm 的铺展性。体外对优化凝胶进行的研究表明，与 TCS 溶液相比，TCS 的持续释放（4 小时内 81.73%）和角膜渗透性改善（4 小时内 74.13%）。TCS 的释放机制遵循具有 Fickian 扩散传输的 Higuchi 模型。此外，组织病理学和 HET-CAM 研究表明，开发的凝胶无刺激性，可安全用于眼部给药。