Self-Emulsifying Drug Delivery Systems (SEDDS) Containing Reverse Micelles: Advanced Oral Formulations for Therapeutic Peptides

Alternative methods to hydrophobic ion pairing for the formation of lipophilic complexes of peptide drugs to incorporate them in lipid-based nanocarriers such as self-emulsifying drug delivery systems (SEDDS) for oral administration are highly on demand. Such an alternative might be reverse micelles. Within this study, SEDDS containing dry reverse micelles (dRMs_PMB ) formed with an anionic (sodium docusate; AOT), cationic (dimethyl-dioctadecyl-ammonium bromide; DODAB), amphoteric (soy lecithin; SL), or non-ionic (polysorbate 85; P85) surfactant loaded with the model peptide drug polymyxin B (PMB) are developed. They are characterized regarding size, payload, release kinetics, cellular uptake, and peptide activity. SEDDS exhibit sizes from 22.2 ± 1.7 (AOT-SEDDS-dRMs_PMB ) to 61.7 ± 3.2 nm (P85-SEDDS-dRMs_PMB ) with payloads up to 2% that are approximately sevenfold higher than those obtained via hydrophobic ion pairing. Within 6 h P85-SEDDS-dRMs_PMB and AOT-SEDDS-dRMs_PMB show no release of PMB in aqueous medium, whereas DODAB-SEDDS-dRMs_PMB and SL-SEDDS-dRMs_PMB show a sustained release. DODAB-SEDDS-dRMs_PMB improves uptake by Caco-2 cells most efficiently reaching even ≈100% within 4 h followed by AOT-SEDDS-dRMs_PMB with ≈20% and P85-/SL-SEDDS-dRMs_PMB with ≈5%. The peptide drug maintains its antimicrobial activity in all SEDDS-dRMs_PMB . According to these results, SEDDS containing dRMs might be a game changing strategy for oral peptide drug delivery.