OBJECTIVES: 20S-protopanaxadiol 20-O-β-D-glucopyranoside (compound K), a metabolite of ginsenoside, is only sparingly soluble in water. The aim of this study was to improve the low solubility, slow dissolution rate and low oral bioavailability of compound K by forming an inclusion complex with γ-cyclodextrin (γ-CyD), and to compare the results with those of β-CyD complex. METHODS: The interactions of compound K with β and γ-CyDs were studied by the solubility method and proton nuclear magnetic resonance spectroscopy. Solid forms of compound K/CyD complexes with different molar ratios were prepared by the kneading method, and the resulting complex was characterized by powder X-ray diffractometry. The dissolution rate of the complexes was measured by the rotary disk method. In-vivo absorption studies in rats were carried out, and the serum level of compound K, after its oral administration, was measured by a liquid chromatography-tandem mass spectrometry system. KEY FINDINGS: γ-CyD markedly improved the low solubility of compound K at lower CyD concentrations (<0.03 M), whereas the solubility was decreased at higher concentrations (>0.06 m). The enhancement in solubility by γ-CyD at a lower concentration was much higher than the corresponding values for β-CyD. The apparent 1:1 stability constant (1.5 × 10(5) m(-1) ) for the γ-CyD complex was 18-fold larger than that (8.2 × 10(3) m(-1) ) of the β-CyD complex. The dissolution rate of the 1:1 compound K/γ-CyD complex was faster than that for the 1:3 (guest : host) complex. These results suggest that the dissolution rate of the 1:1 complex, in which the drug is partially included, was faster than that of the 1:3 complex, in which the drug was completely included, due to the higher solubility and amorphous property of the former complex compared with the properties of the latter complex. The fast dissolution of the γ-CyD complex was reflected in the maximum plasma level (Cmax ) of the drug and the time (Tmax ) to reach the maximum plasma level after its oral administration to rats. CONCLUSIONS: The effect of γ-CyD on enhancing the solubility of compound K is much higher than that for the β-CyD complex, and the dissolution rate of the guest when it is partially included in the γ-CyD is faster the corresponding value when it is completely included in the cavity.
OBJECTIVES: 20S-protopanaxadiol 20-O-β-D-glucopyranoside (compound K), a metabolite of ginsenoside, is only sparingly soluble in water. The aim of this study was to improve the low solubility, slow dissolution rate and low oral bioavailability of compound K by forming an inclusion complex with γ-cyclodextrin (γ-CyD), and to compare the results with those of β-CyD complex. METHODS: The interactions of compound K with β and γ-CyDs were studied by the solubility method and proton nuclear magnetic resonance spectroscopy. Solid forms of compound K/CyD complexes with different molar ratios were prepared by the kneading method, and the resulting complex was characterized by powder X-ray diffractometry. The dissolution rate of the complexes was measured by the rotary disk method. In-vivo absorption studies in rats were carried out, and the serum level of compound K, after its oral administration, was measured by a liquid chromatography-tandem mass spectrometry system. KEY FINDINGS: γ-CyD markedly improved the low solubility of compound K at lower CyD concentrations (<0.03 M), whereas the solubility was decreased at higher concentrations (>0.06 m). The enhancement in solubility by γ-CyD at a lower concentration was much higher than the corresponding values for β-CyD. The apparent 1:1 stability constant (1.5 × 10(5) m(-1) ) for the γ-CyD complex was 18-fold larger than that (8.2 × 10(3) m(-1) ) of the β-CyD complex. The dissolution rate of the 1:1 compound K/γ-CyD complex was faster than that for the 1:3 (guest : host) complex. These results suggest that the dissolution rate of the 1:1 complex, in which the drug is partially included, was faster than that of the 1:3 complex, in which the drug was completely included, due to the higher solubility and amorphous property of the former complex compared with the properties of the latter complex. The fast dissolution of the γ-CyD complex was reflected in the maximum plasma level (Cmax ) of the drug and the time (Tmax ) to reach the maximum plasma level after its oral administration to rats. CONCLUSIONS: The effect of γ-CyD on enhancing the solubility of compound K is much higher than that for the β-CyD complex, and the dissolution rate of the guest when it is partially included in the γ-CyD is faster the corresponding value when it is completely included in the cavity.