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Objectives The aim of this study was to evaluate the cytotoxicity of self‐emulsifying drug delivery systems (SEDDS) containing five different cationic surfactants. Methods Cationic surfactants were added in a concentration of 1% and 5% (m/m) to SEDDS comprising 30% Capmul MCM, 30% Captex 355, 30% Cremophor EL and 10% propylene glycol. The resulting formulations were characterized in terms of size, zeta potential, in‐vitro haemolytic activity and toxicity on Caco‐2 via MTT assay and lactate dehydrogenase release assay. Key findings The evaluated surfactants had in both concentrations a minor impact on the size of SEDDS ranging from 30.2 ± 0.6 to 55.4 ± 1.1 nm, whereas zeta potential changed significantly from −9.0 ± 0.3 to +28.8 ± 1.6 mV. The overall cytotoxicity of cationic surfactants followed the rank order: hexadecylpyridinium chloride > benzalkonium chloride > alkyltrimethylammonium bromide > octylamine > 1‐decyl‐3‐methylimidazolium. The haemolytic activity of the combination of cationic surfactants and SEDDS on human red blood cells was synergistic. Furthermore, cationic SEDDS exhibited higher cytotoxicity of Caco‐2 cells compared to SEDDS without cationic surfactants. Conclusions According to these results, SEDDS and cationic surfactants seem to bear an additive up to synergistic toxic risk.

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The lipophilic character of peptides can be tremendously improved by hydrophobic ion pairing (HIP) with counterions to be efficiently incorporated into lipid-based nanocarriers (NCs). Herein, HIPs of exenatide with the cationic surfactant tetraheptylammonium bromide (THA) and the anionic surfactant sodium docusate (DOC) were formed to increase its lipophilicity. These HIPs were incorporated into lipid based NCs comprising 41% Capmul MCM, 15% Captex 355, 40% Cremophor RH and 4% propylene glycol. Exenatide-THA NCs showed a log D lipophilic phase (LPh)/release medium (RM) of 2.29 and 1.92, whereas the log D LPh/RM of exenatide-DOC was 1.2 and −0.9 in simulated intestinal fluid and Hanks' balanced salts buffer (HBSS), respectively. No significant hemolytic activity was induced at a concentration of 0.25% (m/v) of both blank and loaded NCs. Exenatide-THA NCs and exenatide-DOC NCs showed a 10-fold and 3-fold enhancement in intestinal apparent membrane permeability compared to free exenatide, respectively. Furthermore, orally administered exenatide-THA and exenatide-DOC NCs in healthy rats resulted in a relative bioavailability of 27.96 ± 5.24% and 16.29 ± 6.63%, respectively, confirming the comparatively higher potential of the cationic surfactant over the anionic surfactant. Findings of this work highlight the potential of the type of counterion used for HIP as key to successful design of lipid-based NCs for oral exenatide delivery.

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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 P butanol/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 P butanol/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.

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