Novel formulation strategies for enhancing oral delivery of methoxyflavones in Kaempferia parviflora by SMEDDS or complexation with 2-hydroxypropyl-β-cyclodextrin

Abstract

The Kaempferia parviflora (KP) plant contains several methoxyflavones including 5,7-dimethoxyflavone (DMF), 5,7,4'-trimethoxyflavone (TMF), and 3,5,7,3',4'-pentamethoxyflavone (PMF). Ethanolic extracts of KP have shown various pharmacological effects and have been used as an aphrodisiac, a antimicrobial agent and for the treatment of inflammation, and peptic ulcers. Given its poor water solubility and low oral bioavailability (1-4%), there are limitations to the utilization of KP. Accordingly, self-microemulsifying drug delivery system (SMEDDS) and cyclodextrin (CD) complex formulations were developed to improve the oral absorption of methoxyflavones. Polyoxyethylene castor oil (53.3%), propylene glycol (26.7%), and triglyceride of coconut oil (20%) were combined to form KP-SMEDDS. A complex of 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) and KP was prepared by lyophilization. The developed formulations were then evaluated for their physicochemical properties, in vitro dissolution tests, permeability through Caco-2 cells, and in vivo oral absorption in rats by using PMF, TMF, and DMF as the markers for quantitation. The results showed that KP-SMEDDS and KP-2-HP-β-CD complex improved the dissolution rate of methoxyflavones in both 0.1N HCl and 0.2M PBS pH 6.8 compared to KP dissolved in a solution of propylene glycol, PEG 400, ethanol, and water. KP-SMEDDS and KP-2-HP-β-CD formulations showed about 10- and 3.5-fold greater Papp values of methoxyflavones in Caco-2 cells. The oral bioavailability values of KP-SMEDDS formulations were higher than those of KP (25.38-, 42.00-, and 26.01-fold for PMF, TMF, and DMF, respectively). For the KP-2-HP-β-CD complex, oral bioavailability values were 21.63-, 34.20-, and 22.90-fold greater than those of KP, respectively. Therefore, these two novel formulations, KP-SMEDDS and KP-2-HP-β-CD, were successfully developed to improve the dissolution rate, drug permeability through Caco-2 cells and oral bioavailability of methoxyflavones in KP.