Interaction between Permeation Enhancers and Lipid Bilayers

Area of Science:

• Biophysics
• Computational Chemistry
• Pharmacology

Background:

• Permeation enhancers (PEs) transiently increase epithelial membrane permeability.
• The precise mechanism of action for PEs remains largely unknown.
• Understanding PE-membrane interactions is crucial for drug delivery.

Purpose of the Study:

• To investigate the interaction between salcaprozate sodium (SNAC) and sodium caprate (C10) with lipid membranes.
• To elucidate the mechanism by which PEs influence membrane permeability at a molecular level.

Main Methods:

• Extensive all-atom molecular dynamics (MD) simulations were employed.
• Free energy calculations were used to assess PE-membrane association.
• Equilibrium distribution and aggregation propensity of PEs were analyzed.

Main Results:

• Neutral PEs show favorable free energy association with membranes.
• PE aggregation is more pronounced in aqueous solution than within lipid bilayers.
• PEs distribute rapidly within membranes, forming no pores or membrane disruptions.
• Micelle formation in solution does not lead to membrane rupture under simulated conditions.

Conclusions:

• PEs insert into lipid membranes through an equilibrium or near-equilibrium process.
• This study provides a foundation for understanding how PEs affect the permeation free energy of coformulated drugs.
• Findings challenge the notion of PEs acting via membrane disruption.