Self-assembly of sodium caprate in simulated intestinal fluids and with a therapeutic peptide: A small-angle neutron scattering study.

The self-assembly behavior of sodium caprate (C10), a widely used intestinal permeation enhancer, was characterized under intestinally relevant conditions using small-angle neutron scattering (SANS) with contrast variation. Systems containing 100 mM C10, alone and in fasted-state (FaSSIF) and fed-state (FeSSIF) simulated intestinal fluid, together with 300 mM C10 in the presence of the therapeutic peptide octreotide, were investigated at pH 6.5 and 8.5. At pH 6.5, C10 alone formed coexisting ellipsoidal aggregates, vesicles, and large droplets. Addition of FaSSIF promoted co-assembled mixed structures, including large ellipsoidal aggregates, vesicles, and bilayer-like morphologies, while FeSSIF shifted the system further toward bilayer discs. The most pronounced structural reorganization occurred in the presence of octreotide, where C10 aggregates transformed into large bilayer discs with aggregation numbers approaching 18,000. At pH 8.5, all systems converge to small spherical micelles (radius 15-20 Å), with the notable exception of the C10-octreotide system, which forms prolate rod-like micelles. Contrast-dependent fitting showed that octreotide promotes axial micellar elongation without substantially altering radial packing, indicating amphiphilic cosurfactant-like behavior rather than peptide incorporation into the hydrophobic core. Coarse-grained molecular dynamics simulations supported this interpretation, showing rod-like aggregate formation in the presence of octreotide and cosurfactant-like behavior, with hydrophobic residues inserted into the micelle and hydrophilic Lys and Thr residues positioned at the interface. These findings demonstrate that intestinal fluid composition and peptide-excipient interactions are principal determinants of C10 aggregate architecture, providing a foundation for the rational design of caprate- and fatty-acid-based absorption enhancer systems for oral peptide delivery. Author keywords sodium caprate, small-angle neutron scattering, contrast variation, intestinal fluid, octreotide, cosurfactant, permeation enhancer.