State Key Laboratory of Component-based Chinese Medicine, Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
State Key Laboratory of Component-based Chinese Medicine, Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
Int J Pharm. 2021 Jun 15;603:120667. doi: 10.1016/j.ijpharm.2021.120667. Epub 2021 Apr 30.
The orally administrated antidepressants not only caused side effects such as dizziness, diarrhea, and drug resistance, but also worked slowly. Therefore, new antidepressants and preparations derived from natural medicines play an important role in the study of antidepressant drugs. It was reported that the two components of Zuojin pill, berberine (BBR) and evodiamine (EVO), were used in combination to improve depressive disorder. In our study, a self-assembled thermosensitive in-situ hydrogel was prepared to achieve sustained co-delivery of BBR and EVO. The preparation process of hydrogel consists of two steps, namely, the inclusion of the drugs and thermosensitive self-assembly of the hydrogel. In vitro experimental results indicated that the prepared hydrogel showed a good thermosensitive property under physiological temperature. The hydrogel had a slow and controlled release behavior for BBR and EVO, according with first-order equation. In vivo experimental results indicated that compared to intragastric administration of drug solution, the intranasal administration of hydrogel increased bioavailability of BBR and EVO, approximately 135 and 112 folds, respectively. The hydrogel at a low dose significantly reversed behavioral despair of the mice, improved depressive symptom of rats, and treated depressive disorder by regulating the abnormal levels of monoamine neurotransmitters (including 5-hydroxytryptamine, noradrenalin and dopamine) metabolism and related metabolic pathways such as purine, citrate cycle, scorbate and aldarate, butanoate, vitamin B6, and pyrimidine metabolism. Therefore, as a drug co-delivery system, the intranasally administrated hydrogels with a good release and high bioavailability provides a non-invasive therapeutic strategy for the clinical treatment of depression, which attains antidepressant effects by regulation of the monoamine neurotransmitters metabolism and related metabolic pathways.
口服抗抑郁药不仅会引起头晕、腹泻和耐药等副作用，而且作用缓慢。因此，新型抗抑郁药和天然药物来源的制剂在抗抑郁药物研究中发挥着重要作用。据报道，左金丸的两种成分小檗碱（BBR）和吴茱萸碱（EVO）联合使用可改善抑郁障碍。在我们的研究中，制备了一种自组装温敏原位水凝胶，以实现 BBR 和 EVO 的持续共递送。水凝胶的制备过程包括两步，即药物包封和水凝胶的温敏自组装。体外实验结果表明，所制备的水凝胶在生理温度下表现出良好的温敏性。水凝胶对 BBR 和 EVO 具有缓慢且可控的释放行为，符合一级方程。体内实验结果表明，与灌胃给药溶液相比，鼻腔给药水凝胶可分别使 BBR 和 EVO 的生物利用度增加约 135 倍和 112 倍。低剂量水凝胶可显著逆转小鼠的行为绝望，改善大鼠的抑郁症状，并通过调节单胺神经递质（包括 5-羟色胺、去甲肾上腺素和多巴胺）代谢及嘌呤、柠檬酸循环、抗坏血酸和醛酸盐、丁酸盐、维生素 B6 和嘧啶代谢等相关代谢途径来治疗抑郁症。因此，作为一种药物共递送系统，鼻腔给药的水凝胶具有良好的释放和高生物利用度，为临床治疗抑郁症提供了一种非侵入性的治疗策略，通过调节单胺神经递质代谢及相关代谢途径来发挥抗抑郁作用。
