Unlocking the potential of microfluidic assisted formulation of exenatide-loaded solid lipid nanoparticles

Exenatide, a first-in-class GLP-1 receptor agonist, is used to control glycaemic levels in type 2 diabetes. There are two approved injectable formulations: one solution for immediate action and one dispersion for prolonged action. Oral exenatide has low bioavailability due to poor gastrointestinal stability and absorption. To address these obstacles, we designed Solid Lipid Nanoparticles (SLN) including DOTAP in the formulation to yield high exenatide encapsulation by hydrophobic ion pairing and DSPE-PEG_2kDa to convey colloidal stability and mucus diffusivity. The microfluidic production of SLN yielded 9.7 % exenatide encapsulation and 94.2 % loading efficiency. SLN exhibited solid cored-spherical morphology with sizes of about 120 nm and zeta potential of + 53 mV. The SLN surface charge was modulated by DSPE-PEG_2kDa coating; 10 and 30 w/w% DSPE-PEG_2kDa /lipid ratios yielded slightly positive and neutral zeta potentials, respectively. All SLN formulations provided exenatide protection from proteolytic enzymes. The non-PEGylated SLN resulted in a twofold increase of exenatide delivery across Caco-2 cell monolayers compared to the peptide solution. The 10 w/w% SLN PEGylation reduced the exenatide delivery compared to non-PEGylated SLN through Caco-2 cell monolayers. However, the exenatide delivery with 10 w/w% PEGylated SLN across mucus-producing Caco-2/HT29-MTX coculture layer was 2-fold higher compared to the unformulated peptide, and 1.5 higher than non-PEGylated SLN. The 30 w/w% SLN PEGylation did not improve the peptide transport neither through Caco-2 cell monolayers nor through Caco-2/HT29-MTX coculture layer.