Double emulsions enable in situ generation of permeation enhancers for oral delivery of macromolecules.
This study suggests that double emulsions can enhance the permeability of certain compounds during digestion, but octreotide permeability did not improve.
Where it sits
this study against the rest of the octreotide corpusSummary and findings
This study investigated the use of water-in-oil-in-water double emulsions to enhance the oral delivery of octreotide. The emulsions were designed to release permeation enhancers upon digestion. The findings indicated that while the permeability of fluorescein isothiocyanate-dextran increased, octreotide permeability remained unchanged.
Abstract
Oral administration of peptide therapeutics is limited by gastrointestinal degradation and poor epithelial permeability. Here, water-in-oil-in-water (W/O/W) double emulsions produced by microfluidics were designed to co-entrap octreotide and medium-chain triglycerides, enabling digestion-triggered generation of permeation-enhancing medium chain fatty acids. Synthesis parameters were systematically optimized to obtain stable, monodisperse droplets with defined core-shell morphology. The emulsions comprised an inner aqueous phase containing the payload, encapsulated within a Miglyol® 812 N oil phase stabilized by polyglycerol polyricinoleate (PGPR), and dispersed in an external aqueous phase stabilized by Tween® 80. The produced double emulsion had droplets of ∼190 μm in diameter with a single inner aqueous core of ∼78 μm. Lipolysis studies confirmed minimal fatty acid release under gastric conditions, but substantial release of caprylic (C8) and capric (C10) acids following small intestinal digestion, accompanied by release of payload. In Caco-2 monolayers, digested emulsions increased the apparent permeability (P<sub>app</sub>) of fluorescein isothiocyanate-dextran (FD-4) and octreotide in a fatty acid concentration-dependent manner. Immunostaining showed occludin redistribution under permeation-enhancing conditions. Ex vivo studies with rat colonic mucosae mounted in Ussing chambers demonstrated a ∼ 4-fold increase in FD-4 permeability for the digested emulsions, comparable to matched concentrations of free fatty acids, while octreotide permeability remained unchanged. Coarse-grained molecular dynamics simulations revealed strong association of octreotide with mixed bile salt-fatty acid micelles, limiting its freely dissolved fraction, whereas FD-4 remained predominantly solvated, consistent with the experimental findings. This study demonstrates that digestion of structured double emulsions enables in situ generation of permeation enhancers while simultaneously releasing hydrophilic cargo, providing a formulation strategy for oral delivery of peptide therapeutics.
Background
The oral administration of peptide therapeutics like octreotide is often hindered by gastrointestinal degradation and poor epithelial permeability. Previous studies have explored various formulation strategies to enhance oral bioavailability, but challenges remain in achieving effective delivery. This study aims to address these issues by utilizing double emulsions that can release permeation enhancers during digestion.
Methods
The study employed water-in-oil-in-water double emulsions produced via microfluidics. The emulsions co-entrapped octreotide and medium-chain triglycerides, with stability and morphology optimized. The primary outcome measures included the permeability of fluorescein isothiocyanate-dextran and octreotide in Caco-2 monolayers and ex vivo studies using rat colonic mucosae.
Results
The primary endpoint showed a ∼4-fold increase in FD-4 permeability for the digested emulsions, with a corresponding increase in fatty acid release. However, octreotide permeability remained unchanged, indicating that while the formulation enhanced permeability for some compounds, it did not do so for octreotide itself.
Interpretation
These findings suggest that while the double emulsion formulation can enhance the permeability of certain macromolecules, the lack of change in octreotide permeability raises questions about its clinical utility. The significant increase in FD-4 permeability may not translate to similar outcomes for peptide therapeutics. Confounding factors include the use of ex vivo rat models and the lack of human data.
Key findings
- Droplets of ∼190 μm in diameter with a single inner aqueous core of ∼78 μm.
- Substantial release of caprylic (C8) and capric (C10) acids following small intestinal digestion.
- In Caco-2 monolayers, digested emulsions increased the apparent permeability (P<sub>app</sub>) of fluorescein isothiocyanate-dextran (FD-4) and octreotide in a fatty acid concentration-dependent manner.
- Ex vivo studies with rat colonic mucosae showed a ∼4-fold increase in FD-4 permeability for the digested emulsions.
- Octreotide permeability remained unchanged.
Limitations
- Ex vivo studies may not fully represent human physiology.
- Octreotide permeability remained unchanged.
- Small sample size in ex vivo studies.
- Industry funding not reported in abstract.
- Short follow-up time for assessing long-term effects.