Restoration of rat colonic epithelium after in situ intestinal instillation of the absorption promoter, sodium caprate

Background: Sodium caprate (C-10) is an oral absorption promoter that is currently in clinical trials as a component of solid dosage forms for poorly permeable small molecules and peptides. Clinical data with zoledronic acid tablets suggest that significant delivery along with acceptable safety can be achieved from a once-a-week dosing regime. C-10 has surfactant-like properties at the high doses used in vivo and therefore we examined its effects on rat intestinal epithelium following intestinal instillation. Results: Addition of 100 mM concentrations of C-10 with the paracellular flux marker, fluorescein isothiocyanate-dextran 4 kDa, permitted a bioavailability of 33% to be achieved. When C-10 was added 10, 30 and 60 min in advance of fluorescein isothiocyanate-dextran 4 kDa, enhancement still occurred, but was progressively reduced. Histology revealed that the permeability increase was likely related in part to superficial epithelial damage caused in the first few minutes of exposure, which was rapidly repaired within 3060 min. Conclusions: Design of optimized dosage forms containing C-10 should corelease the payload and promoter close to the epithelium in high concentrations. While C-10 induces some epithelial damage, its remarkable capacity for epithelial repair may render this effect insignificant in vivo.