Thermal reversible microemulsion system for poorly water-soluble YH439 for oral delivery.

To improve bioavailability of poorly water-soluble YH439, a thermal reversible microemulsion system was prepared using modified fatty acids such as capric acid and palmitic acid with PEG 400. A combination of Capric-PEG 400 and Palmitic-PEG 400 with a ratio of 1 : 3 used as a lipid matrix and Cremophor RH40 and Neobee M-5 were selected as an oil and a surfactant, respectively. The microemulsion with melting point of 36.5 degrees C was produced by mixing the lipid matrices, Cremophor RH40 and Neobee M-5 with a volume ratio of 5 : 4 : 1. After the microemulsion was dispersed in the aqueous medium, the average particle size of 28 nm was obtained. At the release measurements of YH439 after 45 min suspension in pH 1.2 aqueous medium, about 80%, 65%, 10% and less than 5% of drug were released from the thermal reversible microemulson, Gelucire formulation, 5% Ca-carboxymethylcellulose (CMC) suspension and YH439 powder, respectively. The apparent permeability of YH439 in microemulsion either from apical to basolateral or basolateral to apical after measuring YH439 across a Caco-2 cell monolayer in a Transwell larger than Gelucire formulation or 5% Na-CMC suspension. The area under the drug concentration-time curves (AUC) and maximal blood concentration (C(max)) after oral administration of YH439 loaded on thermal reversible microemulsion were significantly increased than drug loaded on either Gelucire formulation or 5% Na-CMC suspension. Thus, the present work demonstrates that the thermal reversible microemulsion system of YH439 greatly enhances the bioavailability of YH439 after oral administration due to the improvement of solubility and dispersion of the drug in the artificial gastrointestinal tract without pepsin.