Co-amorphous system of icaritin-sodium taurodeoxycholate with improved solubility, antitumor efficacy and oral bioavailability

Abstract

Icaritin (ICT), a bioactive flavonoid derived from Epimedium brevicornu Maxim, is a first-in-class immune-modulating small molecule for the treatment of advanced hepatocellular carcinoma. However, its therapeutic potential is severely hampered by extremely poor aqueous solubility (< 0.2 μg/mL), which results in low oral bioavailability. To surmount these limitations, this study aimed to develop a co-amorphous system (CAM) of ICT by employing sodium taurodeoxycholate (STD), a biocompatible biosurfactant. An ICT-STD CAM with a 1:1 molar ratio was successfully prepared via the solvent evaporation method. Solid-state characterization techniques, including scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and Fourier-transform infrared spectroscopy, confirmed the formation of a homogeneous, single-phase amorphous system. Notably, the ICT-STD CAM1:1 exhibited a significant enhancement in equilibrium solubility, particularly in pure water (780.30 ± 5.28 μg/mL), significantly outperforming both crystalline ICT and the corresponding physical mixtures. Dissolution studies revealed that over 95% of the drug was released from the ICT-STD CAM1:1 in water within 120 min. Furthermore, the ICT-STD CAM1:1 maintained excellent physical stability under accelerated storage conditions (25 °C/60% relative humidity) for 180 days. In vitro, the ICT-STD CAM1:1 demonstrated superior cytotoxicand pro-apoptotic effects, along with the ability to prevent the spread and migration of Huh-7 cells, compared with crystalline ICT. Pharmacokinetic studies in rats showed that the relative bioavailability of the ICT-STD CAM1:1, calculated as the ratio of the area under the plasma concentration - time curve (AUC) of the CAM1:1 to that of ICT, was 4.72 times that of ICT after oral administration. Collectively, these findings indicate that the CAM strategy using STD is a highly promising approach for developing an effective oral delivery system for ICT.