Oral (poly)peptide delivery: On the emulsifying properties of inverted lipid phases under gastrointestinal conditions

Abstract

Introduction

This study explores the emulsification behavior and oral delivery performance of dry and wet inverted lipid phases (ILP_dry and ILP_wet) with and without emulsifying agents. A central aim was to assess whether reverse micelle-based lipid systems enable sufficient self-emulsification in the gastrointestinal (GI) tract under physiological bile salt conditions to facilitate systemic absorption of polypeptides.

Highlights

Dry ILP exhibit enhanced structural stability and bile salt resistance.
se-ILP enable complete self-emulsification across gastric and intestinal media.
Oral HRP bioavailability markedly increased with se-ILP: 12.10 % (dry) and 9.24 % (wet).
Emulsification capacity identified as key determinant for systemic protein uptake.

Methods

ILP_dry and ILP_wet formulations containing reverse micelles, as well as corresponding self-emulsifying systems (se-ILP_dry and se-ILP_wet) incorporating a non-ionic surfactant, were developed. Emulsification capacity was evaluated via turbidity measurements in bile salt-containing media (5–20 mM). Emulsification kinetics of se-ILP were assessed in water, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF). In vivo performance was evaluated in rats using horseradish peroxidase (HRP) as a model polypeptide.

Results

ILP_dry and ILP_wet exhibited limited emulsification and poor oral bioavailability (1.54 % and 0.89 %, respectively). In contrast, se-ILP showed rapid and complete emulsification across all media and significantly enhanced bioavailability (12.10 % for se-ILP_dry and 9.24 % for se-ILP_wet). ILP_dry demonstrated superior bile salt stability compared to ILP_wet.

Conclusion

Reverse micelle-based ILP require emulsifying excipients for efficient GI emulsification and peptide transport. ILP_dry and se-ILP_dry outperformed wet systems, likely due to reduced water uptake and improved structural integrity.

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Materials

Sorbitan monooleate (Span80®, for synthesis), isopropyl myristate (≥92 %, IPM), monobasic potassium phosphate, and sodium chloride were purchased from Carl Roth, Germany. Methanol (100 %), acetonitrile (≥99.95 %), hydrochloric acid (37 %), horseradish peroxidase (HRP), QuantaRed™ Enhanced Chemifluorescent HRP Substrate Kit, and resazurin sodium salt were purchased from Thermo Fisher Scientific (Waltham, MA, USA). Further, medium-chain triglycerides (MCT, Miglyol®812) were obtained from IOI Oleo GmbH (Germany), and human erythrocyte concentrate was generously supplied by Tirol Kliniken GmbH. Minimum Essential Medium (MEM), penicillin/streptomycin solution, phosphate-buffered saline (PBS), and Triton X-100 were purchased from Merck (Tutzing, Germany). Polyoxyl 40 hydrogenated castor oil (Kolliphor RH40) was supplied by BASF (Ludwigshafen, Germany). Fetal bovine serum (FBS), 7,7,8,8-tetracyanoquinodimethane (TCNQ), trifluoroacetic acid 99.9 %, Safranin O, and bile salts for microbiology were all obtained from Sigma Aldrich (Vienna, Austria).

Melanie Lena Ebert, Annika Postina, Marlene Ramona Schmidt, Flavia Laffleur, Gergely Kali, Andreas Bernkop-Schnürch, Oral (poly)peptide delivery: On the emulsifying properties of inverted lipid phases under gastrointestinal conditions, Journal of Controlled Release, Volume 390, 2026, 114508, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2025.114508.

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Oral (poly)peptide delivery: On the emulsifying properties of inverted lipid phases under gastrointestinal conditions

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