Zhao Wei, Wang Fengyu, Huang Liying, Song Bo, Wu Junzi, Zhang Yongbo, Du Wuyi, Li Yan, Tong Sen
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China.
Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming 650500, China.
Gels. 2025 Jun 5;11(6):435. doi: 10.3390/gels11060435.
The rapid pace of modern life has contributed to a significant decline in sleep quality, which has become an urgent global public health issue. Melatonin, an endogenous hormone that regulates circadian rhythms, is vital in maintaining normal sleep cycles. While oral melatonin supplementation is widely used, transdermal delivery systems present advantages that include the avoidance of first-pass metabolism effects and enhanced bioavailability. In this study, a novel melatonin transdermal delivery system was successfully developed using a thermosensitive poly(N-vinylcaprolactam) [p(NVCL)]-based carrier. The p(NVCL) polymer was synthesized through free radical polymerization and characterized for its structural properties and phase transition temperature, in alignment with skin surface conditions. Orthogonal optimization experiments identified 3% azone, 3% menthol, and 4% borneol as the optimal enhancer combination for enhanced transdermal absorption. The formulation demonstrated exceptional melatonin loading characteristics with high encapsulation efficiency and stable physicochemical properties, including an appropriate pH and optimal moisture content. Comprehensive in vivo evaluation using normal mouse models revealed significant sleep quality improvements, specifically a shortened sleep latency and extended non-rapid eye movement sleep duration, with elevated serum melatonin and serotonin levels. Safety assessments including histopathological examination, biochemical analysis, and 28-day continuous administration studies confirmed excellent biocompatibility with no adverse reactions or systemic toxicity. Near-infrared fluorescence imaging provided direct evidence of enhanced transdermal absorption and superior biodistribution compared to oral administration. These findings indicate that the p(NVCL)-based melatonin transdermal gel system offers a safe, effective and convenient non-prescription option for sleep regulation, with promising potential for clinical translation as a consumer sleep aid.
现代生活的快节奏导致睡眠质量显著下降，这已成为一个紧迫的全球公共卫生问题。褪黑素是一种调节昼夜节律的内源性激素，对维持正常睡眠周期至关重要。虽然口服补充褪黑素被广泛使用，但经皮给药系统具有避免首过代谢效应和提高生物利用度等优点。在本研究中，使用基于热敏聚（N-乙烯基己内酰胺）[p（NVCL）]的载体成功开发了一种新型褪黑素经皮给药系统。通过自由基聚合合成了p（NVCL）聚合物，并根据其结构性质和相变温度进行了表征，使其与皮肤表面条件相匹配。正交优化实验确定3%氮酮、3%薄荷醇和4%冰片为增强经皮吸收的最佳增强剂组合。该制剂表现出优异的褪黑素负载特性，具有高包封率和稳定的物理化学性质，包括合适的pH值和最佳水分含量。使用正常小鼠模型进行的全面体内评估显示睡眠质量有显著改善，特别是睡眠潜伏期缩短和非快速眼动睡眠时间延长，同时血清褪黑素和血清素水平升高。包括组织病理学检查、生化分析和28天连续给药研究在内的安全性评估证实了其优异的生物相容性，无不良反应或全身毒性。近红外荧光成像提供了直接证据，表明与口服给药相比，经皮吸收增强且生物分布更佳。这些发现表明，基于p（NVCL）的褪黑素经皮凝胶系统为睡眠调节提供了一种安全、有效且方便的非处方选择，作为消费者睡眠辅助剂具有有望进行临床转化的潜力。
