Institute of Materia Medica, School of Pharmacy, Chengdu Medical College, No. 783 Xindu Avenue, Chengdu, 610500, China.
State Key Laboratory of Characteristic Chinese Drug Resources in Southwest China, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
AAPS PharmSciTech. 2021 Mar 21;22(3):111. doi: 10.1208/s12249-021-01983-2.
Dihydromyricetin (DMY) is highly effective in counteracting acute alcohol intoxication. However, its poor aqueous solubility and permeability lead to the low oral bioavailability and limit its clinic application. The aim of this work is to use Solutol®HS15 (HS 15) as surfactant to develop novel micelle to enhance the oral bioavailability of DMY by improving its solubility and permeability. The DMY-loaded Solutol®HS15 micelles (DMY-Ms) were prepared by the thin-film hydration method. The particle size of DMY-Ms was 13.97 ± 0.82 nm with an acceptable polydispersity index of 0.197 ± 0.015. Upon entrapped in micelles, the solubility of DMY in water was increased more than 25-fold. The DMY-Ms had better sustained release property than that of pure DMY. In single-pass intestinal perfusion models, the absorption rate constant (Ka) and permeability coefficient (Papp) of DMY-Ms were 5.5-fold and 3.0-fold than that of pure DMY, respectively. The relative bioavailability of the DMY-Ms (AUC) was 205% compared with that of pure DMY (AUC), indicating potential for clinical application. After administering DMY-Ms, there was much lower blood alcohol level and shorter duration of the loss of righting relax (LORR) in drunk animals compared with that treated by pure DMY. In addition, the oral administration of DMY-Ms greatly reduced oxidative stress, and significantly defended liver and gastric mucosa from alcoholic damages in mice with alcohol-induced tissue injury. Taken together, HS 15-based micelle system greatly improves the bioavailability of DMY and represents a promising strategy for the management of acute alcoholism. Graphical abstract.
二氢杨梅素（DMY）在对抗急性酒精中毒方面非常有效。然而，其较差的水溶性和渗透性导致其口服生物利用度较低，限制了其临床应用。本工作旨在使用 Solutol®HS15（HS 15）作为表面活性剂，通过提高其溶解度和渗透性来开发新型胶束以提高 DMY 的口服生物利用度。DMY 负载 Solutol®HS15 胶束（DMY-Ms）采用薄膜水化法制备。DMY-Ms 的粒径为 13.97±0.82nm，具有可接受的多分散指数为 0.197±0.015。包封在胶束中后，DMY 在水中的溶解度增加了 25 倍以上。DMY-Ms 具有比纯 DMY 更好的缓释性能。在单次肠灌流模型中，DMY-Ms 的吸收速率常数（Ka）和渗透系数（Papp）分别是纯 DMY 的 5.5 倍和 3.0 倍。DMY-Ms 的相对生物利用度（AUC）与纯 DMY（AUC）相比提高了 205%，表明具有临床应用潜力。与纯 DMY 相比，给予 DMY-Ms 后，醉酒动物的血液酒精水平更低，失去平衡的时间更短（LORR）。此外，DMY-Ms 的口服给药大大降低了氧化应激，并显著减轻了酒精诱导的组织损伤小鼠的肝和胃粘膜的酒精损伤。综上所述，基于 HS 15 的胶束系统极大地提高了 DMY 的生物利用度，代表了治疗急性酒精中毒的一种有前途的策略。
