Immobilization of 2-mercaptoethylamine on oxidized chitosan: a substantially mucoadhesive and permeation enhancing polymer

Thiolated chitosans are mucoadhesive polymers that are able to increase the paracellular permeability and improve the oral bioavailability of hydrophilic and macromolecular compounds. Due to the low hydratability of most thiolated chitosans at pH > 6.5, it was the aim of this study to develop a thiomer as a permeation enhancer for mucosal membranes where a comparatively high pH is prevalent. For this purpose chitosan was oxidized by means of sodium periodate to cleave the polysaccharide structure. The intermediate polymer was coupled with 2-mercaptoethylamine and reduced with sodium cyanoborohydride to obtain the secondary amine moiety. The permeation enhancing effect of 2-mercaptoethylamine-functionalized chitosan conjugate (chitosan-2-MEA) was assessed in Ussing-type chambers using FD4 as a model compound. Further in vitro characterization was conducted regarding water absorbing capacity, cohesive properties, mucoadhesion and cytotoxic effects on Caco-2 cells. By means of fundamental alteration of chitosan's backbone and following thiol immobilization, the paracellular transport of FD4 across rat intestinal mucosa was 5.1-fold improved compared with control (buffer) only. Mucoadhesion could be 20-fold improved likely based on increased chain flexibility and disulfide formation between chitosan-2-MEA and mucus glycoproteins. The novel thiomer showed excellent hydratability in aqueous media even up to pH 11 and was proven to be non-toxic. According to the above-mentioned properties, chitosan-2-MEA seems to be a promising mucoadhesive and permeation enhancing excipient for the development of drug delivery systems.