Department of Neurosurgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, People's Republic of China.
Sichuan Higher Education Institute Key Laboratory of Structure-Specific Small Molecule Drugs, Institute of Materia Medica, School of Pharmacy, Chengdu Medical College, Chengdu, 610500, People's Republic of China.
Int J Nanomedicine. 2024 Oct 18;19:10569-10588. doi: 10.2147/IJN.S472287. eCollection 2024.
Acute alcohol intoxication (AAI) is a life-threatening medical condition resulting from excessive alcohol consumption. Our research revealed the potential of morin (MOR) in treating AAI. However, MOR's effectiveness against AAI was hindered by its poor solubility in water and low bioavailability. In this study, our aim was to develop a self-nanoemulsifying drug delivery system (SNEDDS) to enhance MOR's solubility and bioavailability, evaluate its anti-AAI effects, and investigate the underlying mechanism.
The composition of MOR-loaded self-nanoemulsifying drug delivery system (MOR-SNEDDS) was determined by constructing pseudo-ternary phase diagrams, and its formulation proportion was optimized using the Box-Behnken design. Following characterization of MOR-SNEDDS, we investigated its pharmacokinetics and biodistribution in healthy animals. Additionally, we assessed the anti-AAI effects and gastric mucosal protection of MOR-SNEDDS in an AAI mice model, exploring potential mechanisms.
After breaking down into tiny droplets, the optimized mixture of MOR-SNEDDS showed small droplet size on average, even distribution, strong stability, and permeability. Pharmacokinetic studies indicated that MOR-SNEDDS, compared to a MOR suspension, increased the area under the plasma concentration-time curve (AUC) by 10.43 times. Additionally, studies on how drugs move and are distributed in the body showed that MOR-SNEDDS had an advantage in passively targeting the liver. Moreover, in a mouse model for alcohol addiction, MOR not only decreased alcohol levels by boosting the activity of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the stomach and liver, which counteracted the loss of righting reflex (LORR), but also reduced alcohol-induced damage to the stomach lining by lowering malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD) levels. Furthermore, MOR-SNEDDS notably amplified these effects.
MOR exhibits significant potential as a new medication for treating AAI, and utilizing MOR-SNEDDS with high oral bioavailability represents a promising new strategy in combating AAI.
急性酒精中毒（AAI）是由过量饮酒引起的危及生命的医学病症。我们的研究表明，桑色素（MOR）在治疗 AAI 方面具有潜力。然而，MOR 的水溶性差和生物利用度低限制了其在治疗 AAI 方面的效果。本研究旨在开发一种自微乳给药系统（SNEDDS）来提高 MOR 的溶解度和生物利用度，评估其抗 AAI 作用，并探讨其潜在机制。
通过构建伪三元相图确定 MOR 负载自微乳给药系统（MOR-SNEDDS）的组成，并采用 Box-Behnken 设计优化其配方比例。对 MOR-SNEDDS 进行表征后，我们在健康动物中研究了其药代动力学和体内分布。此外，我们在 AAI 小鼠模型中评估了 MOR-SNEDDS 的抗 AAI 作用和胃黏膜保护作用，并探讨了潜在机制。
经过细化成微小液滴，优化后的 MOR-SNEDDS 混合物表现出平均粒径小、分布均匀、稳定性强、渗透性好的特点。药代动力学研究表明，与 MOR 混悬液相比，MOR-SNEDDS 使 AUC 增加了 10.43 倍。此外，关于药物在体内如何移动和分布的研究表明，MOR-SNEDDS 具有被动靶向肝脏的优势。此外，在酒精成瘾小鼠模型中，MOR 通过提高胃和肝脏中乙醇脱氢酶（ADH）和醛脱氢酶（ALDH）的活性来降低酒精水平，从而对抗翻正反射丧失（LORR），同时通过降低丙二醛（MDA）水平和增加超氧化物歧化酶（SOD）水平来减少酒精引起的胃黏膜损伤，MOR-SNEDDS 进一步放大了这些作用。
MOR 作为治疗 AAI 的一种新药物具有显著潜力，利用具有高口服生物利用度的 MOR-SNEDDS 是对抗 AAI 的一种有前途的新策略。
