Abstract：
Doxepin, a Class-I Biopharmaceutics Drug Disposition Classification System (BDDCS) drug, exhibits poor bioavailability due to extensive first-pass metabolism. This research focuses on enhancing the delivery of doxepin by formulating nanostructured lipid carriers (NLCs) through the utilization of the Box-Behnken Design methodology. These optimized NLCs are intended for intranasal administration, with the ultimate goal of improving nose-to-brain drug delivery. NLCs were formulated using a high-speed homogenization technique. The optimized batch had a small particle size (75.80 ± 5.48 nm, PDI = 0.286), high entrapment efficiency (94.10 ± 0.16%), and sustained ex vivo release (82.25 ± 4.61% at 24 h). Characterization studies confirmed the conversion of doxepin from a crystalline to an amorphous state with uniform distribution in the lipid matrix. In vivo pharmacokinetic studies in rats showed significantly higher doxepin concentration in the brain tissue (Cmax = 16.77 µg/g, tmax = 30 min) after intranasal administration compared to intravenous administration (Cmax = 2.53 µg/g, tmax = 6 h). High-drug targeting efficiency (DTE = 284.3%) and direct transport percentage (DTP = 64.8%) suggested direct penetration of NLCs in the brain via olfactory and trigeminal pathways. In conclusion, the study highlights the potential of NLCs to improve the bioavailability of doxepin through nose-to-brain delivery and thereby potentially enable the treatment of neurological disorders.
摘要：
多塞平,I类生物制药药物处置分类系统（BDDCS）药物，由于广泛的首过代谢，生物利用度差。这项研究的重点是通过利用Box-Behnken设计方法配制纳米结构脂质载体（NLC）来增强多塞平的递送。这些优化的NLC用于鼻内给药，最终目标是改善鼻脑药物输送。使用高速均质化技术配制NLC。优化后的批料粒径较小(75.80±5.48nm,PDI=0.286),高包封率（94.10±0.16%），和持续体外释放（24h为82.25±4.61%）。表征研究证实多塞平从晶体向无定形状态的转化,在脂质基质中均匀分布。大鼠体内药代动力学研究显示，脑组织中多塞平浓度明显更高（Cmax=16.77µg/g，tmax=30分钟）鼻内给药后与静脉给药相比（Cmax=2.53µg/g，tmax=6小时)。高药物靶向效率（DTE=284.3％）和直接转运百分比（DTP=64.8％）表明NLC通过嗅觉和三叉神经途径直接穿透大脑。总之,该研究强调了NLC通过鼻脑给药改善多塞平生物利用度的潜力,从而有可能治疗神经系统疾病.
