Preactivated thiolated nanoparticles: A novel mucoadhesive dosage form.

Within this study a novel form of mucoadhesive nanoparticles (NPs) exhibiting a prolonged residence time on mucosal tissues was developed. In order to achieve this goal a new thiomer was synthesized by the covalent attachment of the amino acid l-cysteine ethyl ester to poly(acrylic acid) (100 kDa). The free thiol groups were in the following preactivated with the aromatic thiol bearing ligand 2-mercaptonicotinic acid (2-MNA) and the amount of coupled l-cysteine ethyl ester as well as the amount of attached 2-MNA was determined. Based on this, preactivated thiomer NPs were prepared by ionic gelation with polyethylenimine (PEI). The resulting NPs were characterized regarding size and zeta potential. Furthermore their mucoadhesive properties were investigated via rheological measurements with porcine intestinal mucus and via determination of the particles' mucosal residence time. Results showed that 1666.74 μmol l-cysteine ethyl ester and 603.07 μmol 2-MNA could be attached per gram polymer. NPs were in a size range of 112.67-252.84 nm exhibiting a zeta potential of -29 mV. Thiolated NPs only led to a 2-fold increase in mucus viscosity whereas preactivated NPs showed a 6-fold higher mucus viscosity than unmodified NPs. The mucosal residence time of thiolated NPs was 1.6-fold prolonged and that of preactivated NPs even 4.4-fold higher compared to unmodified particles. Accordingly, preactivated thiolated NPs providing a prolonged residence time on mucosal membranes could be a promising dosage form for various applications.