Revealing the interaction between peptide drugs and permeation enhancers in the presence of intestinal bile salts.
This study used all-atom molecular dynamics (MD) simulations, complemented by Fourier transform infrared (FTIR) spectroscopy, to investigate how two permeability enhancers (PEs) — sodium caprate and SNAC (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) — interact with four peptide drugs (octreotide, hexarelin, degarelix, and insulin) in the presence of taurocholate, an intestinal bile salt. The simulations revealed that the two PEs had distinct, peptide-dependent effects: they tended to promote release of more hydrophobic peptides while inhibiting release of more water-soluble ones. At lower peptide concentrations, peptide–peptide interactions decreased while interactions with PEs and taurocholate increased. Introducing all components together produced dynamic mixed aggregates with reduced peptide–peptide hydrogen bonding compared to peptide-only systems. FTIR analysis of insulin showed that SNAC increased β-sheet formation, while sodium caprate favored α-helical and random-coil structures. The authors suggest these molecular-level insights could guide the rational design of PE-based oral peptide formulations. Key limitations include the exclusive use of computational and in vitro/spectroscopic methods, with no cell-based, animal, or human data reported.
Why this grade: The study relies entirely on computational molecular dynamics simulations and FTIR spectroscopy with no cell, animal, or human experimental data, placing it at the in vitro/preclinical mechanistic level only.
Permeability enhancer-based formulations offer a promising approach to enhance the oral bioavailability of peptides. We used all-atom molecular dynamics simulations to investigate the interaction between two permeability enhancers (sodium caprate, and SNAC), and four different peptides (octreotide, hexarelin, degarelix, and insulin), in the presence of taurocholate, an intestinal bile salt. The permeability enhancers exhibited distinct effects on peptide release based on their properties, promoting hydrophobic peptide release while inhibiting water-soluble peptide release. Lowering peptide concentrations in the simulations reduced peptide-peptide interactions but increased their interactions with the enhancers and taurocholates. Introducing peptides randomly with enhancer and taurocholate molecules yielded dynamic molecular aggregation, and reduced peptide-peptide interactions and hydrogen bond formation compared to peptide-only systems. The simulations provided insights into molecular-level interactions, highlighting the specific contacts between peptide residues responsible for aggregation, and the interactions between peptide residues and permeability enhancers/taurocholates that are crucial within the mixed colloids. Therefore, our results can provide insights into how modifications of these critical contacts can be made to alter drug release profiles from peptide-only or mixed peptide-PE-taurocholate aggregates. To further probe the molecular nature of permeability enhancers and peptide interactions, we also analyzed insulin secondary structures using Fourier transform infrared spectroscopy. The presence of SNAC led to an increase in β-sheet formation in insulin. In contrast, both in the absence and presence of caprate, α-helices, and random structures dominated. These molecular-level insights can guide the design of improved permeability enhancer-based dosage forms, allowing for precise control of peptide release profiles near the intended absorption site.
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