Article

Enhanced oral bioavailability of Astragaloside IV in rats through complexation with 2-hydroxypropyl-beta-cyclodextrin

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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.

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In this study, the pharmacokinetics of Astragaloside iv (AGS-IV) in Beagle dogs was studied by high performance liquid chromatography (HPLC) coupled with tandem mass spectrometry (MS). The concentrations of the drugs in plasma were determined after i.v. administration of 0.5, 1, 2 mg.kg(-1) AGS-IV and p.o. administration of 10 mg.kg(-1) AGS-IV. The areas under concentration-time curve (AUC) were linearly correlated to the doses administrated. The absolute bioavailability of AGS-IV after p.o. administration was found to be 7.4%. The plasma protein binding rate of AGS-IV was about 90% within a concentration range of 250-1000 ng.ml(-1). There was no significant species difference regarding the pharmacokinetics of AGS-IV between the rat and the Beagle dog.
Phase-solubility techniques
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