Abstract

Koumine (KME) is an active alkaloid extracted from Gelsemium elegans, and its diverse bioactivities have been studied for decades. However, KME exhibits poor solubility and low oral bioavailability, which hampers its potential therapeutic exploitation. This work aimed to develop optimized inclusion complexes to improve the bioavailability of KME. The KME/hydroxypropyl-β-cyclodextrin (KME/HP-β-CD) inclusion complexes were prepared by the solvent evaporation method and later optimized using the Box-Behnken design. The optimal KME/HP-β-CD was characterized by scanning electron microscopy, Fourier transforms infrared spectroscopy, differential scanning calorimetry, and nuclear magnetic resonance spectroscopy. The physicochemical characterization results revealed that the crystalline state of KME was transformed into an amorphous form, forming KME/HP-β-CD inclusion complexes. Compared with KME, the solubility and in vitro release rate of KME/HP-β-CD was significantly enhanced by 52.34- and 1.3-fold, respectively. Further research was performed to investigate the intestinal absorption characteristics and in vivo bioavailability in rats. The optimal KME/HP-β-CD showed enhanced absorptive permeability and relative bioavailability increased more than two-fold compared to that of raw KME. These results indicate that the optimal KME/HP-β-CD can be used as an effective drug carrier to improve the solubility, intestinal absorption, and bioavailability of KME.

摘要

Koumine (KME) 是一种从Gelsemium elegans中提取的活性生物碱, 其多样化的生物活性已经研究了几十年。然而，KME 表现出较差的溶解度和低口服生物利用度，这阻碍了其潜在的治疗开发。这项工作旨在开发优化的包合物以提高 KME 的生物利用度。通过溶剂蒸发法制备 KME/羟丙基-β-环糊精 (KME/HP-β-CD) 包合物，随后使用 Box-Behnken 设计进行优化。通过扫描电子显微镜、傅里叶变换红外光谱、差示扫描量热法和核磁共振光谱对最佳 KME/HP-β-CD 进行了表征。理化表征结果表明，KME的晶态转变为无定形形式，形成KME/HP-β-CD包合物。与 KME 相比，溶解度和KME/HP-β-CD的体外释放率分别显着提高了 52.34 倍和 1.3 倍。进行了进一步的研究以研究大鼠的肠道吸收特性和体内生物利用度。与原始 KME 相比，最佳 KME/HP-β-CD 显示出增强的吸收渗透性和相对生物利用度增加了两倍以上。这些结果表明，最优的KME/HP-β-CD可以作为一种有效的药物载体来提高KME的溶解度、肠道吸收和生物利用度。