Self-assembly of sodium caprate in simulated intestinal fluids and with a therapeutic peptide: A small-angle neutron scattering study.
Octreotide significantly alters the structure of sodium caprate aggregates, which could impact oral peptide delivery systems, though clinical relevance is not established.
Where it sits
this study against the rest of the octreotide corpusSummary and findings
The study characterized the self-assembly behavior of sodium caprate (C10) in simulated intestinal fluids with and without the therapeutic peptide octreotide. Systems were tested at pH 6.5 and 8.5, revealing that octreotide significantly influenced the structural organization of C10 aggregates. The findings suggest implications for the design of absorption enhancer systems for oral peptide delivery.
Abstract
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.
Background
This paper addresses the self-assembly behavior of sodium caprate (C10), an intestinal permeation enhancer, under conditions mimicking the intestinal environment. Previous studies have shown that the structure of aggregates can influence drug absorption. Understanding how C10 interacts with peptides like octreotide is crucial for improving oral delivery systems for therapeutic peptides.
Methods
The study utilized small-angle neutron scattering (SANS) to characterize the self-assembly of C10 at concentrations of 100 mM and 300 mM in simulated intestinal fluids (FaSSIF and FeSSIF) at pH 6.5 and 8.5. The primary outcome measures focused on the structural organization of aggregates formed in these conditions.
Results
At pH 6.5, C10 alone formed coexisting ellipsoidal aggregates, vesicles, and large droplets. The addition of octreotide resulted in the transformation of C10 aggregates into large bilayer discs with aggregation numbers approaching 18,000. At pH 8.5, all systems converged to small spherical micelles, except for the C10-octreotide system, which formed prolate rod-like micelles.
Interpretation
The findings suggest that octreotide significantly alters the structural properties of C10 aggregates, promoting larger and more complex structures. While the statistical significance of the findings is noted, the clinical relevance remains uncertain as the study does not directly assess the implications for oral peptide delivery. Limitations include the absence of human data and potential confounding factors related to the in vitro nature of the study.
Key findings
- At pH 6.5, C10 alone formed coexisting ellipsoidal aggregates, vesicles, and large droplets.
- In the presence of octreotide, C10 aggregates transformed into large bilayer discs with aggregation numbers approaching 18,000.
- At pH 8.5, the C10-octreotide system formed prolate rod-like micelles.
- Contrast-dependent fitting showed that octreotide promotes axial micellar elongation without substantially altering radial packing.
- Coarse-grained molecular dynamics simulations supported rod-like aggregate formation in the presence of octreotide.
Limitations
- Not reported in abstract.
- In vitro study, no human data.
- Small n, specific conditions tested.
- Short follow-up on structural changes.