Background: The objective of this study was to develop and evaluate a more effective mucoadhesive thiomer for buccal drug-delivery systems. Methods: 2-iminothiolane was covalently attached to a chitosan backbone. A preactivation step followed, mediated by 6,6´dithionicotinamide, thiol groups were modified by disulfide bonds formation. Mucoadhesion studies were performed on buccal mucosa. In addition, water-uptake capacity, disintegration, release and cytotoxicity studies were completed. Results: The obtained chitosan–thiobutylamidine conjugate displayed 647.4 ± 85.23 µmol/g immobilized thiol groups. Due to the preactivation, approximately 60% of thiol groups were modified by formation of disulfide bonds. Chitosan–thiobutylamidine–mercaptonicotinamide displayed 1.8-fold higher stability and 1.6-fold higher mucoadhesive properties, respectively. The release study demonstrated a 1.4-fold more prolonged drug release compared with corresponding thiomers. Conclusion: According to these results, preactivated thiomers demonstrate an improved stability and increased mucoadhesive properties. Therefore, they seem to be advantageous for buccal administration over corresponding thiomers and chitosan.