Permeation enhancers like SNAC (used in oral semaglutide) promote release of hydrophobic peptides but inhibit water-soluble peptides — meaning oral formulations must be carefully matched to each drug.
Opposite effectsSNAC and sodium caprate promote hydrophobic peptide release but inhibit water-soluble peptide release — the same enhancer can help or hinder depending on the drug
What the researchers found
Two permeation enhancers — sodium caprate and SNAC (the technology behind oral semaglutide) — have opposite effects on different types of peptide drugs depending on the peptide's water solubility. In the presence of intestinal bile salts, both enhancers promoted the release of hydrophobic (fat-loving) peptides but inhibited the release of water-soluble peptides from molecular aggregates.
SNAC caused insulin to form more beta-sheet structures, while sodium caprate preserved insulin's alpha-helical and random coil structures. These structural changes matter because they affect whether the peptide drug is active or aggregated when it reaches the intestinal wall. The findings suggest that permeation enhancer selection must be matched to each specific peptide's physical properties.
Why it matters
SNAC is the absorption enhancer that makes oral semaglutide (Rybelsus) possible — the first oral GLP-1 drug. Understanding exactly how SNAC and other enhancers interact with peptide drugs at the molecular level is critical for designing the next generation of oral peptide pills. This study reveals that the same enhancer can help or hinder absorption depending on the peptide's properties, which has major implications for oral formulation development.
The numbers in context
2 permeation enhancers (SNAC + sodium caprate) · 4 peptides (octreotide, hexarelin, degarelix, insulin) · taurocholate bile salt · all-atom molecular dynamics simulations
How the study worked
All-atom molecular dynamics simulations modeling interactions between two permeation enhancers (SNAC and sodium caprate), four peptide drugs (octreotide, hexarelin, degarelix, insulin), and intestinal bile salt (taurocholate). Supplemented with experimental FTIR spectroscopy to analyze insulin secondary structure changes in the presence of enhancers.
Who was studied
Not applicable — computational simulation study with experimental spectroscopy validation
What this study cannot tell us
Computational simulations model molecular interactions but may not fully capture the complexity of the intestinal environment, including mucus layers, epithelial cells, pH gradients, and enzymatic activity. The study tested four peptides, but the principles may not generalize to all peptide drugs. Experimental validation of the predicted release profiles in biological systems would strengthen the conclusions.
How to read the evidence
This is a computational study using molecular dynamics simulations with experimental FTIR validation. While it provides valuable molecular-level insights, the findings need biological validation in intestinal absorption models to confirm clinical relevance.
When this study was published
Published in 2023 in Nanoscale. Very current, directly relevant to the ongoing race to develop oral peptide drugs building on the success of oral semaglutide.
The bigger picture
Oral semaglutide proved that peptide pills are possible, but scaling that success to other peptide drugs requires understanding why SNAC works for semaglutide specifically. This study reveals that the molecular interactions are highly peptide-specific — the same enhancer that enables oral semaglutide might not work for oral insulin or other peptide drugs. This knowledge is essential for the pharmaceutical industry's push to develop more oral peptide therapeutics.
Questions still open
- Can the molecular interaction principles identified here be used to predict which enhancer will work best for a given peptide drug?
- Does SNAC's effect on insulin's beta-sheet formation reduce or enhance insulin's biological activity?
- Could new permeation enhancers be designed that work universally across both hydrophobic and hydrophilic peptides?
Common questions
What is SNAC and why is it important for oral peptide drugs?
Why can't most peptide drugs be taken as pills?
Read the original research
Revealing the interaction between peptide drugs and permeation enhancers in the presence of intestinal bile salts.
Nanoscale, 15(47), 19180-19195
Citation
Hossain, Shakhawath; Kneiszl, Rosita; Larsson, Per. (2023). Revealing the interaction between peptide drugs and permeation enhancers in the presence of intestinal bile salts.. Nanoscale, 15(47), 19180-19195. https://doi.org/10.1039/d3nr05571j