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Abstract
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.
Highlights
Nobiletin (NOB), a flavonoid, has extremely low water solubility and low oral bioavailability; despite these problems, various physiological effects have been investigated in vitro
To elucidate the reason why the solubility was enhanced in NOB/choline and geranic acid (CAGE), the mixtures which had been prepared at different molar ratios [CAGE: NOB = 1:0 (NOB 0), 2:1 (NOB 0.5), 1:1 (NOB 1), 1:1.5 (NOB 1.5), and 1:2 (NOB 2)] were each analyzed by 1H NMR
This result indicated that NOB interacted with CAGE by hydrogen bondings[40,41]; that is, the H atom of the hydroxyl group in CAGE (6.1–6.5 ppm in NMR spectra) acts as a hydrogen bonding donor, and the O atoms of the carbonyl and methoxy groups in NOB might act as multipoint hydrogen bonding acceptors
Summary
Nobiletin (NOB), a flavonoid, has extremely low water solubility and low oral bioavailability; despite these problems, various physiological effects have been investigated in vitro. 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 show both low water solubility and low permeability. Flavonoids tend to have high lipophilicity[8] derived from the flavone skeletal structure, which leads poor water solubility Because of these characteristics, flavonoids are categorized as BCS class IV drugs. The solubility of NOB is extremely poor at 16.2 μg/mL14 and the BA is extremely low, 0.85%14 for the oral administration of NOB crystals to rats; NOB is classified as a BCS class IV compound. There is a need for improved drug delivery system for antidiabetic agents[24]
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