The Effect of Counterions in Hydrophobic Ion Pairs on Oral Bioavailability of Exenatide.

The aim of this study was to evaluate the potential of n-octadecyl sulfate (SOS) as a counterion for hydrophobic ion pairing (HIP) with exenatide-a potent glucagon-like peptide-1 (GLP-1) analogue in the treatment of diabetes mellitus-to improve its oral bioavailability. Exenatide was ion-paired with SOS and docusate (DOC) serving as the gold standard followed by the incorporation in a self-emulsifying drug delivery system (SEDDS) comprising Capmul MCM EP, Captex 355, Kolliphor RH40, and propylene glycol at a mass ratio of 41:15:40:4. The hydrophobicity of exenatide-SOS and exenatide-DOC was characterized by determining the butanol-water partition coefficient (log Pbutanol/water). Droplet size and zeta potential of the ion pair-loaded SEDDS were characterized followed by intestinal membrane permeability determination on freshly excised rat intestines compared to exenatide solution. Furthermore, the oral bioavailability of exenatide-SOS- and exenatide-DOC-loaded SEDDS was also evaluated in vivo in healthy male Sprague-Dawley rats. Hydrophobic ion pairing increased the log Pbutanol/water of exenatide from -1.9 to 2.0 for exenatide-SOS and to 1.2 for exenatide-DOC. SEDDSs loaded with 0.26% (m/m) exenatide-SOS and 0.17% (m/m) exenatide-DOC had mean droplet size less than 30 nm and negative zeta potential. Ex vivo permeation experiments revealed 3.5-fold and 6.4-fold improvement in membrane permeability of the exenatide-SOS-loaded SEDDS vs. the exenatide-DOC-loaded SEDDS and exenatide solution, respectively. The orally administered exenatide-SOS-loaded SEDDS and exenatide-DOC-loaded SEDDS resulted in relative oral bioavailability vs. subcutaneous injection (SC) of 19.6 and 15.2%, respectively. Within this study, the key role of counterions for oral peptide delivery via HIP could be confirmed, and SOS was identified as a promising surfactant for this purpose.