Mechano-chemically activated co-amorphous of oleanolic acid and sodium cholate: enhancement of solubility, dissolution and bioactivity against visceral pain in a rat model of colitis

Abstract

This study aimed to enhance the solubility and bioavailability of oleanolic acid (OA), a highly insoluble compound, using a mechanochemical approach to form co-ground (COG) with sodium cholate (NaC). Through high-energy grinding in a ball mill, the binary COG was prepared, and then characterized and evaluated. The initial screening of ten hydrophilic carriers identified NaC as the most effective, forming a COG with OA in a 1:1 wt ratio after 30 min of grinding. Detailed characterizations, including DSC, FT-IR, XRPD, and SEM, identified the mechanisms behind the substantial solubility enhancement of OA, achieving up to 623 μg/mL, and confirmed the formation of the co-ground. The formation of a co-amorphous structure, and the establishment of intermolecular interactions between OA and NaC were identified as key factors contributing to this improvement. Dissolution tests revealed that COG achieved an 80 % dissolution rate of OA within 2 h, compared to just 30 % for pure OA, demonstrating the effectiveness of COG in maintaining high solubility and preventing recrystallization. In vivo tests on a rat model of DNBS-induced colitis showed promising results. The acute administration of COG significantly reduced visceral pain compared to unformulated OA, suggesting enhanced bioavailability and therapeutic efficacy. While pure OA 15 mg/kg is inactive, COG 30 mg/kg, composed of OA 15 mg/kg and NaC 15 mg/kg, displays a statistically significant pharmacological effect, with a percentage reduction in AUC equal to 40 %. This research highlights the potential of mechanochemical activation in developing effective OA formulations, offering a green chemistry solution that is efficient, solvent-free, and environmentally friendly. The study provides a solid foundation for further exploration of OA-based treatments for chronic inflammatory conditions and pain management.