Comparative Analysis of PEG‐Free and PEG‐Based Self‐Emulsifying Drug Delivery Systems for Enhanced Oral Bioavailability of Therapeutic (Poly) Peptides

• Published in: Small (Weinheim an der Bergstrasse, Germany) Germany), 2024-07, Vol.20 (27), p.e2307618-n/a
• Main Authors: Haddadzadegan, Soheil, To, Dennis, Matteo Jörgensen, Arne, Wibel, Richard, Laffleur, Flavia, Bernkop‐Schnürch, Andreas
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Bioavailability; Biological Availability; Diabetes; Drug delivery systems; Drug Delivery Systems - methods; Emulsions - chemistry; Glycerol - analogs & derivatives; Glycerol - chemistry; Hydrophobic ion pairing; Insulin; Ion pairs; Lipid‐based formulation; Male; Octanol; oral peptide delivery; Peptides; Peptides - chemistry; Peptides - pharmacokinetics; Polyethylene glycol; Polyethylene Glycols - chemistry; Polyglycerols; Rats; Rats, Sprague-Dawley; Response surface methodology; Sulfosuccinates; Surface-Active Agents - chemistry; Surfactants
• ISSN: 1613-6810; 1613-6829; 1613-6829
• DOI: 10.1002/smll.202307618

This study aims to compare the potential of Polyethylene glycol (PEG‐free and PEG‐based self‐emulsifying drug delivery systems (SEDDS) for the oral administration of insulin glargine (IG). Hydrophobic ion pairs (HIPs) of IG are formed using various counterions. HIPs are assessed for log P octanol/water and dissociation behavior. They are incorporated into SEDDS based on polyglycerol (PG) and zwitterionic surfactant (ZW) using response surface methodology and compared to conventional PEG‐SEDDS in size, stability, and log D SEDDS/release medium. Oral IG bioavailability in PG/ZW‐SEDDS and PEG‐SEDDS is evaluated in rats. Among the various counterions studied, IG‐BIS (bis(isotridecyl)sulfosuccinate) HIPs demonstrated the highest log P and an improved dissociation profile. PG/ZW‐SEDDS and PEG‐SEDDS have similar ≈40 nm sizes and are stable over 24 h. Both formulations have log D > 4 in water and >2 in 50 mM phosphate buffer pH 6.8. PG/ZW‐SEDDS yielded an oral bioavailability of 2.13 ± 0.66% for IG, while the employment of PEG‐SEDDS resulted in an oral bioavailability of 1.15 ± 0.35%. This study highlights the prospective utilization of PEG‐free SEDDS involving the concurrent application of PG and ZW surfactants, an alternative to conventional PEG surfactants, for improved oral therapeutic (poly) peptide delivery. This study presents a novel strategy to boost oral bioavailability of insulin glargine (IG) using polyglycerol/zwitterion‐based self‐emulsifying drug delivery systems (PG/ZW‐SEDDS) as an alternative to polyethylene glycol‐based SEDDS (PEG‐SEDDS). Research focuses on optimizing hydrophobic ion pairing (HIP) complexation, developing a PEG‐free SEDDS, and evaluating its oral IG bioavailability versus PEG‐based SEDDS in rats, advancing diabetes therapeutics.