Synthesis and characterization of thiolated β-cyclodextrin as a novel mucoadhesive excipient for intra-oral drug delivery

The objective of the present study was to synthesize and characterize cysteamine conjugated β-cyclodextrin (β-CD-Cys) as a novel mucoadhesive oligomeric excipient for intra-oral drug delivery. β-CD-Cys conjugates were obtained in a two-step synthetic pathway, whereby, vicinal diol groups of the oligomer were oxidized using increasing concentrations of sodium-per-iodate (NaIO4), prior to the covalent coupling of cysteamine via reductive amination. Quantification of immobilized thiol groups through Ellman's test revealed 561.56 ± 81 μmol/g, 1054.26 ± 131 μmol/g and 1783.92 ± 201 μmol/g of free thiol groups attached to the oligomer backbone depending on the extent of oxidation. β-CD-Cys conjugates at concentrations of 0.5% (m/v) showed no toxic effects on Caco-2 cells within 72 h. Furthermore, β-CD-Cys conjugates displayed a 4-fold improved water solubility compared to the parent oligomer. β-CD-Cys conjugates (β-CD-Cys561, β-CD-Cys1054 and β-CD-Cys1783) showed 2.86-, 15.09- and 49.08-fold improved retention time on porcine intestinal mucosa and 9.66-, 16.43- and 34.51-fold improved on the porcine buccal mucosa, respectively. Formation of inclusion complexes of miconazole nitrate and β-CD-Cys1054 resulted in 150-fold increased solubility of miconazole nitrate. According to these results, it seems that β-CD-Cys conjugates might provide a new promising tool for delivery of poorly water soluble therapeutic agents, such as miconazole nitrate for intra-oral delivery.