Posted by Oral drug delivery is a vital route because it is easy to administer, which improves patient compliance and allows for systemic and localized therapeutic effects. Cyclodextrins (CDs) are among the most common excipients used in oral drug delivery. The main challenge is their limited interaction with the mucus layer, leading to quick removal from the gastrointestinal tract. To address this drawback, thiolated CDs are employed because they can react with cysteine-rich subdomains of mucus glycoproteins through thiol/disulfide exchange, forming stable covalent bonds with the mucosal gel layer. This results in a prolonged carrier residence time, thereby enhancing both local effects as well as drug absorption. Therefore, cysteine and cysteamine were conjugated to β-CD via carbamate linkage, and their mucoadhesive properties were studied.
One of the main disadvantages of thiolated systems is their sensitivity to oxidation, which can lead to inter- and intramolecular disulfide bond formation, reducing free thiol content and lowering mucoadhesion. In this comparative study, various highly reactive thiolated CDs were synthesized and compared with CDs bearing unsaturated functionalities, exhibiting different reactivities. Double bonds are expected to react with mucosal cysteines, forming thioether bonds and also prolonging gastrointestinal residence time. Because of their potential for mucoadhesion and anticipated stability, β-CD allyl carbamate and methacrylate were synthesized, and their performance relative to the thiolated versions was evaluated.
The thiolated CDs demonstrated prolonged residence times on porcine intestine compared to native β-CD and allylated carriers; however, a higher degree of allylation (DA) led to improved performance. Specifically, over 97% of the cysteine- and cysteamine-modified CDs remained on the mucosal surface after rinsing with phosphate buffer for three hours, whereas the native CD was completely washed away within one hour, and only about 10% or less of allylated CD remained on the mucus layer after three hours. Increasing the DA by 4.5 times extended the residence time, with around 50% of this CD remaining on the mucosal surface after three hours of rinsing, and roughly 40% of the highly methacrylated version was still present at that time. Rheological measurements on CD-mucus mixtures confirmed the higher application potential of thiolated versions compared to allylated ones, with similar levels of modification but better performance of macrocycles highly substituted with unsaturated moieties.
Storage stability of the different functionalities reveals another aspect of selecting the right excipient. More than half of the free thiol groups are consumed within 4 hours of storage in aqueous solution due to the formation of inter- and intramolecular disulfide bonds, while no difference in double bonds was observed during this period for the allylated or methacrylated versions.
The results of this comparative study highlight the potential of thiolated and unsaturated CDs for oral drug delivery, along with their limitations. It also underscores the importance of customizing the selection of these carriers based on the specific application.
Kosti, EM., Huber, S.D., Mair, A., Gintsburg, D., Bernkop-Schnürch, A. & Kali, G.: Comparative study of thiolated and alkenylated functionalized β-CDs as highly mucopenetrating and mucoadhesive drug delivery systems. Drug Deliv. and Transl. Res. (2026). https://doi.org/10.1007/s13346-026-02063-3