Physicochemical characteristics and bioavailability of a novel intestinal metabolite of ginseng saponin (IH901) complexed with β-cyclodextrin

In an effort to improve the bioavailability (BA) of the insoluble compound 20-O-(β-d-glucopyranosyl)-20(S)-protopanaxadiol (IH901), we prepared β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complexes containing IH901. IH901 is a major metabolite formed by intestinal bacteria from protopanaxadiol ginseng saponins. We developed and validated an HPLC-based method to measure IH901 levels from samples prepared in vitro. The phase solubility profiles with both cyclodextrins (CDs) were classified as AL-type, indicating the formation of a 1:1 stoichiometric inclusion complex. Stability constants (Ks) calculated from the phase solubility diagrams showed that the βCD complex was more stable than the HPβCD complex. Consequently, complexes of IH901 and βCD were prepared by a freeze-drying method and were analyzed by fourier transformation-infrared spectroscopy (FT-IR), X-ray diffraction, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). From these physicochemical characterizations, we confirmed the presence of a new solid phase in the freeze-dried samples. The IH901 released from the complex in a pH 1.2 solution, the pH range of gastric fluids, was considerably lower than the amount released in the other solutions. The IH901 released from the complex in pH 6.8 solution, the range of intestinal fluids, was 9.0-fold greater than pure IH901 powder. However, the amount of IH901 released from the complex in pH 4.0–8.0 was less than 20%. After oral administration of the IH901–βCD inclusion complex (30 mg/kg IH901) into rats, plasma concentrations were determined by LC/MS/MS. The peak concentration (Cmax) for the inclusion complex was 2.8-fold higher than that for pure IH901 powder. The BA, calculated from the ratio of the AUCoral to the AUCi.v., for the pure IH901 powder, the IH901–βCD physical mixture, and the inclusion complex was 3.52, 4.34, and 6.57%, respectively. These results indicate that the BA for the inclusion complex was 1.9-fold higher than that for the pure IH901 powder.