This study aims to develop optimized leuprolide acetate (LA) nanoparticles (NPs) for intranasal delivery in the treatment of Alzheimer's disease. Box–Behnken Design was used to optimize LA polylactide-co-glycolic acid (PLGA) NPs. The independent variables chosen were PLGA concentration, surfactant concentration, and the ratio of water to oil phase, whereas the dependent variables were particle size and % entrapment efficiency. The optimized NPs were evaluated by in vitro drug release study, ex vivo diffusion study, histopathology study, hemolytic stability study, and stability in simulated nasal fluid (SNF). The optimized NPs had particle size of 182.6 ± 1.5 nm, polydispersity index (0.3), % entrapment efficiency (77.3 ± 0.6), and zeta potential (−5.6 mv ±0.2). The in vitro drug release indicated 96% of pure drug release in 6 h, whereas only 66.35% of the drug was released from the optimized formulation at 48 h. The ex vivo diffusion study indicated an apparent permeability coefficient of 5.0 + 0.3 × 10⁴ for drug-containing NPs, which was higher than for plain drug solution (2.0 + 0.2 × 10⁴). Sheep nasal toxicity and hemolytic study proved the safety of formulation. The optimized NPs were found to be stable in SNF. Thus, nanoparticulate formulation of LA was optimized by quality by design approach.

中文翻译：

---

使用响应面法制备和优化醋酸亮丙瑞林纳米颗粒：体外和离体评价

本研究旨在开发优化的醋酸亮丙瑞林 (LA) 纳米粒子 (NPs)，用于鼻内给药治疗阿尔茨海默病。Box-Behnken Design 用于优化 LA 聚乳酸-共-乙醇酸 (PLGA) NP。选择的自变量是 PLGA 浓度、表面活性剂浓度和水与油相的比率，而因变量是颗粒大小和截留效率百分比。通过体外药物释放研究评估优化的 NPs，离体扩散研究、组织病理学研究、溶血稳定性研究和模拟鼻液 (SNF) 中的稳定性。优化后的纳米颗粒的粒径为 182.6 ± 1.5 nm，多分散指数 (0.3)，截留效率百分比 (77.3 ± 0.6) 和 zeta 电位 (-5.6 mv ±0.2)。体外药物释放表明 96% 的纯药物在 6 小时内释放，而在 48 小时时只有 66.35% 的药物从优化配方中释放出来。体外扩散研究表明，含药纳米粒子的表观渗透系数为 5.0 + 0.3 × 10 ⁴，高于普通药物溶液（2.0 + 0.2 × 10 ⁴）。绵羊鼻毒性和溶血研究证明了制剂的安全性。发现优化的 NP 在 SNF 中是稳定的。因此，LA 的纳米颗粒配方通过设计方法通过质量优化。