Layer-by-Layer Polymeric Films: A Novel Approach to Buccal GLP-1 Delivery

Buccal delivery offers a promising alternative to oral drug administration by enabling direct systemic absorption and avoiding first-pass metabolism. Multilayer polymeric films represent a promising strategy for the sequential delivery of drug and absorption enhancer in the oral cavity. Here, dual- and triple-layer films were fabricated via slot-die coating, incorporating a GLP-1 receptor agonist (GLP-1-RA) and the penetration enhancer sodium glycodeoxycholate (GDC). These were co-loaded in dual-layer films or compartmentalized in triple-layer films. Scanning electron microscopy and optical coherence tomography confirmed well-defined, distinct layers with thicknesses suitable for buccal administration (339 {+/-} 10.24 {micro}m and 487 {+/-} 36.5 {micro}m for dual- and triple-layer films, respectively). Both designs exhibited good mucoadhesion and mucosal compatibility, and preserved the secondary structure of GLP-1-RA. In vitro release studies showed rapid diffusion of GDC and GLP-1-RA from dual-layer films, whereas triple-layer films enabled sustained, sequential release of GDC and GLP-1-RA. Ex vivo porcine buccal mucosa studies showed higher GLP-1-RA and GDC flux from triple-layer films compared to dual-layer films. The films also did not compromise epithelial integrity, in contrast to the direct application of GLP-1-RA and GDC, which caused significant epithelial disruption. These results demonstrate that multilayer film architecture and spatial layering can be harnessed to control release kinetics, maximize peptide penetration, and minimize tissue stress, offering a versatile platform for safe and effective peptide delivery. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/700335v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@76858borg.highwire.dtl.DTLVardef@1397e74org.highwire.dtl.DTLVardef@19d1841org.highwire.dtl.DTLVardef@a369c5_HPS_FORMAT_FIGEXP M_FIG C_FIG