4^th European Biopharma Congress

The goal of this study was to establish a new type of preactivated thiomers showing comparatively higher reactivity with mucus

and improved mucoadhesive properties. The dimeric form of 2-mercaptonicotinic acid (MNA-MNA) was directly attached

to the polymeric backbone of chitosan (CHI) to achieve a higher reactivity. Amide bond formation mediated by 1-ethyl-3-(3-

dimethylaminopropyl) carbodiimide (EDAC) was used as a coupling reagent. The remaining free amino groups were reacted with

succinic anhydride (Succ) to gain a homogeneously anionically charged polymer (CHI-Succ-MNA-MNA). Within our study, various

coupling rates of up to 170 μmol MNA-MNA per gram polymer were obtained. The coupling of the dimeric ligand resulted in

a preactivated thiomer with a more reactive disulfide substructure due to the additional nitrogen atom in conjugation over the

aromatic moieties. Furthermore, the obtained polymer is completely preactivated and therefore protected against unwanted oxidation

reactions. Our kinetic studies of disulfide exchange reactions showed a 3.8-fold higher reactivity of CHI-Succ-MNA-MNA compared

to a state-of-the-art preactivated thiomer. Rheological measurements showed that CHI-Succ-MNA-MNA with a coupling rate of 170

μmol (CHI-Succ-MNA-MNA 170) lead to a 5.7-fold higher mucus viscosity than the non-thiolated control polymer (CHI-Succ).

This indicates a rheological synergism due to mucoadhesive properties. These results were confirmed by an additional mucoadhesion

experiment, which showed a significantly prolonged retention time of CHI-Succ-MNA-MNA on the small intestinal mucosa

compared to CHI-Succ (P<0.02). According to the presented results, the double preactivation seems to be a promising strategy to

obtain entirely preactivated polymers with improved mucoadhesive properties.