Permeation Enhancers SDS and Caprate Fail to Improve Intestinal Absorption of the Peptide Hexarelin in Rats
Background
The oral delivery of peptide drugs like hexarelin is a major challenge due to their low intestinal permeability. Larger peptides are particularly difficult to get into systemic circulation from the gut. Chemical permeation enhancers, such as sodium dodecyl sulfate (SDS) and caprate, are one strategy being explored to overcome this barrier. These compounds work by transiently opening the tight junctions between intestinal cells, allowing molecules to pass through. While effective for smaller peptides like enalaprilat, their utility for larger, more complex peptides like hexarelin remains poorly understood, representing a significant hurdle in developing orally available peptide therapeutics.
Study Design
This study used an in vivo single-pass intestinal perfusion model in rats to investigate the effects of two permeation enhancers on peptide absorption. Researchers perfused the small intestine with solutions containing either enalaprilat (349 Da) or hexarelin (887 Da). The enhancers tested were sodium dodecyl sulfate (SDS) at 5 mg/mL and caprate at multiple concentrations (5, 10, and 20 mg/mL). The caprate solutions were also tested at two different luminal pH levels, pH 6.5 and pH 7.4, to evaluate the impact of pH on the concentration of free, dissolved caprate. The primary endpoint was the change in intestinal permeability of the two peptides.
Results
The permeation enhancers significantly increased the absorption of the smaller peptide, enalaprilat, but had no effect on the larger peptide, hexarelin. Specifically, SDS at 5 mg/mL increased enalaprilat permeability by 8-fold. Caprate was also effective for enalaprilat, but only under specific conditions. At pH 7.4, where the free dissolved caprate concentration was higher (5 mg/mL), caprate at 10 mg/mL and 20 mg/mL increased enalaprilat permeability by 9-fold. However, at pH 6.5 (free caprate 2 mg/mL), there was no enhancement.
Crucially, neither SDS nor caprate at any tested concentration or pH managed to enhance the intestinal absorption of the larger peptide hexarelin.
The results suggest that for caprate to be effective, it requires doses above its saturation concentration to create a reservoir, as the dissolved form is absorbed rapidly itself.
Key Findings
- SDS (5 mg/mL) increased the intestinal permeability of the small peptide enalaprilat by 8-fold.
- Caprate (10 and 20 mg/mL) increased enalaprilat permeability by 9-fold, but only at pH 7.4.
- Neither SDS nor caprate at any tested concentration enhanced the absorption of the larger peptide hexarelin.
- The effectiveness of caprate was pH-dependent, correlating with higher concentrations of its free, dissolved form at pH 7.4.
- Caprate likely requires a suspension reservoir (doses above saturation) to be effective, as the dissolved form is rapidly absorbed.
Why It Matters
This research highlights a critical limitation of common permeation enhancers for oral peptide delivery. The finding that enhancers effective for small peptides completely fail for a larger peptide like hexarelin suggests that size is a major limiting factor that these specific agents cannot overcome. This implies that simply adding enhancers like SDS or caprate to an oral hexarelin formulation is unlikely to improve its bioavailability. The study underscores why many oral peptide delivery systems that show promise in vitro fail to translate into effective products. For users or researchers interested in oral peptides, this reinforces the need for more advanced delivery strategies beyond simple enhancers, such as encapsulation, nanotechnology, or structural modifications of the peptides themselves. The failure observed here may explain the slow progress in developing approved oral peptide drugs.
hexarelin
enalaprilat
permeation enhancer
oral peptide delivery
bioavailability
animal study
