Self-Nanoemulsifying Drug Delivery System of Morin: A New Approach for Combating Acute Alcohol Intoxication

Jiamin Mao,1,2 Xiaoyuan Liu,2 Lie Zhang,1 Yu Chen,2 Shiyu Zhou,2 Yujiao Liu,2 Jing Ye,2 Xiaohong Xu,2 Quan Zhang1– 4 1Department of Neurosurgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, People’s Republic of China; 2Sichuan 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; 3Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histoembryology, Chengdu Medical College, Chengdu, 610500, People’s Republic of China; 4Chengdu Nature’s Grace Biological Technology Co., Ltd., Chengdu, 610213, People’s Republic of ChinaCorrespondence: Quan Zhang, Email [email protected]: 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.Methods: 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.Results: 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 (AUC0-t) 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.Conclusion: 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.Keywords: Morin, self-nanoemulsifying drug delivery system, acute alcohol intoxication, oral bioavailability, alcohol-induced tissue injury