Repurposing simvastatin with piperine through β-cyclodextrin inclusion complex: a dual-drug strategy to enhance solubility and antiproliferative activity in hepatic cancer cells.

The purpose of this feasibility study was to develop a co-delivery inclusion complex of Simvastatin (SIM) and Piperine (PIP) using different cyclodextrins to enhance solubility and evaluate its antiproliferative activity in hepatocellular carcinoma (HCC) cells. SIM has recently been repurposed as a potential anticancer agent; however, its low bioactivity is mainly driven by its poor aqueous solubility. SIM and PIP inclusion complexes were prepared using Beta-cyclodextrin (βCD), Methyl β-cyclodextrin (M βCD), and Hydroxypropyl β-cyclodextrin (HP βCD) via solvent evaporation (SE) and microwave irradiation (MI). Phase solubility studies revealed AL-type profiles, with a higher stability constant for M βCD. The optimized ternary complex PIP-SIM-M βCD (F6-SE) increased the solubility of PIP and SIM to 708.58 ± 19.1 and 127.1 ± 4.9 µg/mL, respectively. In vitro cytotoxicity studies demonstrated that the PIP-SIM-M βCD complex significantly inhibited HepG2 cell viability. Apoptosis data indicated a higher proportion of late apoptotic cells and suggested G1 phase arrest. Overall, these findings support the use of M βCD-based inclusion complexes as a promising formulation strategy for co-delivering SIM and PIP and enhancing their in vitro antiproliferative activity in liver cancer cells.