Bioinspired pullulan-based adhesive coacervate films for targeted buccal delivery of peptides

abstract

Mussel-inspired coacervation offers a powerful strategy for underwater adhesion; however, translating this chemistry into scalable drug delivery platforms remains challenging. Here, we present a bioinspired adhesive coacervate, integrating catechol/gallol-mediated adhesion with mucoadhesion principles to produce a manufacturable, patient-friendly film for buccal peptide delivery. Using tannic acid (TA) and pullulan-methacrylate (PUL-MA), adhesive coacervates were formulated and processed by slot-die coating into dual-layer films consisting of (i) an active mucoadhesive layer (ML) containing a GLP-1 receptor agonist (GLP-1-RA) and a permeation enhancer, sodium glycodeoxycholate (GDC), and (ii) a cellulose-based backing layer (BL). Slot-die processing enabled uniform film fabrication while preserving GLP-1-RA peptide structural integrity. By tuning PUL methacrylation degree (MD), material properties including film swelling, cohesion, and adhesion were optimized. PUL at a 3% MD level exhibited ~ five-fold higher adhesion (102.6 ± 14.2 J/m2) than conventional buccal films. In ex vivo assays, the same formulation also achieved the highest peptide permeation, indicating that stronger mucoadhesion enhances tissue residence and facilitates transbuccal transport. Overall, this study demonstrates for the first time the successful integration of mussel-inspired coacervation with mucoadhesive film engineering, enabling a scalable and non-invasive platform for buccal administration of poorly permeable peptides, bridging bioinspired chemistry and drug delivery.

authors

Margarida M. A. Sacramento, Nazanin Z. Ezazi, Eleftheria Pantazoglou, Philip Mark Lund, Marco van de Weert, Zhongyang Zhang, Rui Vitorino, Floriane Bahuon, Ragna Berthelsen, Stephen T. Buckley, Gavrielle R. Untracht, Peter Eskil Andersen, David J. Brayden, Ana S. Silva , João M.M. Rodrigues, João F. Mano, Line Hagner Nielsen

Groups

G5 - Biomimetic, Biological and Living Materials

Projects

Development of a multifunctional biomaterial patch for buccal delivery of peptide-analogue treatments (BUCCAL-PEP)

CICECO-Aveiro Institute of Materials R&D Unit Pluriannual Funding (CICECO-Aveiro Institute of Materials)

Associated Laboratory CICECO-Aveiro Institute of Materials (LA/P/0006/2020)

PRR CICECO - Instituto de Materiais de Aveiro (Equipar+ CICECO)

(J)

acknowledgements

This work was supported by the European Union's Horizon Europe research and innovation program, 101091765 single bond BUCCAL-PEP single bond HORIZON-CL4–2022-RESILIENCE-01. This work was also funded by the project CICECO-Aveiro Institute of Materials, UID/50011/2025 (DOI 10.54499/UID/50011/2025) & LA/P/0006/2020 (DOI 10.54499/LA/P/0006/2020) & UID/PRR/50011/2025 (DOI 10.54499/UID/PRR/50011/2025), financed by national funds through the FCT/MCTES (PIDDAC). M.M.A.S, A.S.S., and J.M.M.R. gratefully acknowledge the Portuguese Foundation for Science and Technology (FCT) for funding through the individual PhD grant 2020.07156.BD (DOI 10.54499/2020.07156.BD) awarded to M.M.A.S., and individual Assistant Researcher contracts 2021.02196.CEECIND (DOI 10.54499/2021.02196.CEECIND/CP1659/CT0002) awarded to A.S.S. and 2023.07239.CEECIND (DOI 10.54499/2023.07239.CEECIND/CP2840/CT0004) awarded to J.M.M.R., under the Scientific Employment Stimulus, respectively. We would like to thank Dr. Sahil Malhotra of University College Dublin for his work on establishing the ex vivo porcine tissue dissection protocol, as well as Mr. Sandeep Karki and Dr. Muhammad Ijaz of University College Dublin for establishing and sharing their work on the 3D-printed custom-made permeable support devices, as well as providing the TR146 cells.