3D printed S-protected mucoadhesive lidocaine-based orodispersible films for immediate and sustained release of the drug in paediatric therapies

This study describes a solvent-free, one-step Direct Powder Extrusion (DPE) approach to 3D-print paediatric orodispersible films (ODFs) delivering lidocaine (LID) with tunable performance. Five matrices were prepared at a fixed drug load (3 % w/w): a VA64/PEO formulation for immediate release and PEO/HPMC backbones containing chitosan (CS), thiolated chitosan (CS-SH), or S-protected chitosan (CS-MNA) for controlled performance. This is the first report of both first- and second-generation thiomers (CS-SH and CS-MNA) processed by DPE. Printing preserved drug and excipient integrity; DSC/PXRD supported formation of an amorphous LID state in the films. Drug release was adjustable from immediate (VA64/PEO; disintegration ≤ 5 min) to sustained with thiomer films (CS-SH/CS-MNA; disintegration up to 40 min). Texture analysis showed a clear mucoadhesion ranking (Form 1 ≈ Form 2 < Form 3 < Form 5 < Form 4), with thiomer matrices exhibiting the highest detachment force and work of adhesion. On ex vivo oral mucosa, thiomer films increased residence and modulated permeation versus non-thiomer controls; notably, the S-protected system Form 5 provided higher permeation than CS-SH (Form 4) while maintaining slower release and strong mucoadhesion. Overall, this work establishes a solvent-free DPE platform to produce mucoadhesive paediatric ODFs with immediate to sustained release, enhanced mucosal retention, and controllable permeation, supporting patient-centric paediatric pain management and expanding the formulation toolbox for small-batch or point-of-care manufacturing.