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 (Papp) 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 sulfhydrylmodified
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.