Abstract Purpose: Astragaloside IV (AGS-IV), the main active constituent of the Chinese medical herb, Astragalus membranaceus, is reported to exhibit a variety of cardiovascular pharmacological actions. However its poor aqueous solubility affects its oral absorption which limits its development as a treatment and its preclinical investigation. The effect of 2-hydroxypropyl-beta-cyclodextrin (HPCD), a novel solubility enhancer, on the oral bioavailability of AGS-IV in Sprague Dawley rats was evaluated with the aim of preparing a stable and effective oral formulation suitable for clinical application. Methods: Inclusion compounds in aqueous solution were prepared by solution-agitating technique, and identified by observation under a microscope, differential scanning calorimetry, solubility and phase solubility diagrams. The concentrations of AGS-IV in rat plasma were determined by liquid chromatograph-mass spectrometry/mass spectrometry. Results: Both methods involving novel optical rotation continuous variation plotting and the analysis of phase solubility diagrams consistently proved that AGS-IV and HPCD can form an inclusion compound with a molar ratio of 1: 1. The solubility of AGS-IV in neutral aqueous solution at 25˚C was increased from 22.2 µg/ml to 286.8 µg/ml. The concentration-time profiles in plasma samples after oral administration of AGS-IV and the inclusion compound both fitted a two-compartment model. The t1/2 of the inclusion compound was 12.88 h, and the AUC was 5275.49 ng·h/ml, whereas the t1/2 of AGS-IV was 4.54 h, and the AUC was 1184.32 ng·h/ml. Conclusion: Complexation with HPCD can significantly increase AGS-IV oral bioavailability in rats, reducing the variability in its systemic concentration and pharmacological effects. The continuous variation plot based on the optical rotation increment is a reliable addition to the classical continuous variation method used widely in the pharmaceutical sciences.
Zhenhua Chen,
Bing Gu
.Enhanced oral bioavailability of Astragaloside IV in rats through complexation with 2-hydroxypropyl-beta-cyclodextrin[J] AJPS, 2009,V4(1): 56-64
2009, Vol. 4 