Transdermal delivery of nobiletin using ionic liquids
Transdermal delivery of nobiletin using ionic liquids
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DOI：
10.1038/s41598-019-56731-1
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发表时间：
2019-12-27
影响因子：
4.6
通讯作者：
Iwao, Yasunori
中科院分区：
文献类型：
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作者：
Hattori, Tadashi;Tagawa, Hiroki;Iwao, Yasunori
Nobiletin （NOB）是一种黄酮类化合物，水溶性极低，口服生物利用度低；然而，尽管存在这些问题，人们已经在体外研究了各种生理效应。在本研究中，我们研究了胆碱和天竺葵酸（CAGE）的透皮给药，这是一种生物相容性材料，据报道是一种很有前途的透皮给药方法。通过一组体外和体内试验对其可行性进行了评估。溶解度评价表明，通过笼与NOB之间的多点氢键，笼诱导NOB具有良好的溶解度。使用Franz扩散池进行的体外透皮试验表明，与其他透皮促进剂相比，CAGE可有效促进NOB的透皮吸收。随后的体内实验表明，CAGE显著提高了NOB在体内浓度-时间曲线下的面积，NOB/CAGE样品的生物利用度比口服NOB晶体高20倍。此外，NOB/CAGE样品还显示，NOB的降糖作用使大鼠的血糖水平显著下降。由此可见，利用CAGE经皮给药NOB是可行的，这表明CAGE的使用可能适用于其他同样具有低水溶性和低渗透性的黄酮类化合物。
Nobiletin (NOB), a flavonoid, has extremely low water solubility and low oral bioavailability; however, despite these problems, various physiological effects have been investigated in vitro. In the present study, we investigated the transdermal delivery of NOB using choline and geranic acid (CAGE), which is a biocompatible material that has been reported to be a promising transdermal delivery approach. The feasibility was evaluated by a set of in vitro and in vivo tests. A solubility evaluation demonstrated that CAGE induced excellent solubility of NOB induced by multipoint hydrogen bonding between NOB and CAGE. In vitro transdermal tests using a Franz diffusion cell showed that CAGE was effective in enhancing transdermal absorption of NOB, compared to other penetration enhancers. Subsequent in vivo tests demonstrated that CAGE significantly improved area under the concentration-time curve of NOB in vivo and NOB/CAGE sample showed 20-times higher bioavailability than oral administration of NOB crystal. Furthermore, NOB/CAGE sample also showed significant drops of the blood glucose level in rats derived from hypoglycemic activity of NOB. Thus, transdermal administration of NOB using CAGE was shown to be feasible, which indicates that the use of CAGE may be adapted for other flavonoids that also show both low water solubility and low permeability.