Microwave-assisted, sulfhydryl-modified β-cyclodextrin-silymarin inclusion complex: A diverse approach to improve oral drug bioavailability via enhanced mucoadhesion and permeation

The current study aimed to generate a sulfhydryl-modified β-cyclodextrin-silymarin complex (sulfhydryl-modified β-CD-SMN complex) and to evaluate the enchantment in solubility, permeability, and bioavailability of a model BCS Class IV drug silymarin (SMN). For this purpose, sulfhydryl-modified β-CD was synthesized by replacing all primary and secondary –OH groups at the β-CD backbone with sulfhydryl groups via a novel microwave-assisted technique. Afterward, sulfhydryl-modified β-CD was complexed with silymarin and characterized by FTIR and ¹H NMR spectroscopy. Moreover, no. of sulfhydryl groups and their oxidative stability, solubility, safety, mucoadhesion, release, diffusion, and rheological studies were performed. Furthermore, in-vivo studies were conducted to confirm enhanced pharmacokinetic properties of silymarin. Sulfhydryl-modified β-CD showed 8291 ± 418 μmol/g sulfhydryl groups that were prone to oxidation at pH ≥ 5, however, most of the sulfhydryl groups were found stable at pH 4 having a pKa value of 8.3. Modified β-CD oligomer showed improved solubility of SMN, significantly enhanced drug transport across goat intestinal mucosa, 78-fold improved mucoadhesion, improved drug dissolution and 4.4-fold enhanced dynamic viscosity. No toxic effects were reported to Caco-2 cells at 0.5% (m/v) concentration of sulfhydryl-modified β-CD for 24 h. The apparent permeability coefficient (P_app) of SMN was 6.9-fold enhanced on goat intestinal mucosa. Moreover, in-vivo studies confirmed a significantly enhanced oral bioavailability of SMN due to combination with sulfhydryl-modified β-CD. Based on these findings, the sulfhydryl-modified β-CD-silymarin inclusion complex can be a promising technique to enhance the bioavailability of BCS Class IV drugs via enhanced solubility, mucoadhesion, and permeability triple action.