In Vivo Mechanism of Action of Sodium Caprate for Improving the Intestinal Absorption of a GLP1/GIP Coagonist Peptide

Abstract

Sodium caprate (C10) has been widely evaluated as an intestinal permeation enhancer for the oral delivery of macromolecules. However, the effect of C10 on the intestinal absorption of peptides with different physicochemical properties and its permeation-enhancing effect in vivo remains to be understood. Here, we evaluated the effects of C10 on intestinal absorption in rats with a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GIP-GLP1) dual agonist peptide (LY) and semaglutide with different enzymatic stabilities and self-association behaviors as well as the oral exposure of the LY peptide in minipigs. Furthermore, we investigated the mechanism of action (MoA) of C10 for improving the intestinal absorption of the LY peptide in vivo via live imaging of the rat intestinal epithelium and tissue distribution of the LY peptide in minipigs. The LY peptide showed higher proteolytic stability in pancreatin and was a monomer in solution compared to that in semaglutide. C10 increased in vitro permeability in the minipig intestinal organoid monolayer to a greater extent for the LY peptide than for semaglutide. In the rat jejunal closed-loop model, C10 increased the absorption of LY peptide better than that of semaglutide, which might be attributed to higher in vitro proteolytic stability and permeability of the LY peptide. Using confocal live imaging, we observed that C10 enabled the rapid oral absorption of a model macromolecule (FD4) in the rat intestine. In the duodenum tissues of minipigs, C10 was found to qualitatively reduce the tight junction protein level and allow peptide uptake to the intestinal cells. C10 decreased the transition temperature of the artificial lipid membrane, indicating an increase in membrane fluidity, which is consistent with the above in vivo imaging results. These data indicated that the LY's favorable physicochemical properties combined with the effects of C10 on the intestinal mucosa resulted in an ∼2% relative bioavailability in minipigs.

Micro/Nanomotors for Oral Delivery of Drugs: From Design to Application

“…After utilizing confocal in vivo imaging for observation, the highest bioavailability could reach 2%. [42] It has also been noted that the bioavailability of peptides coadministered with osmotic enhancers remains low and highly variable after oral administration, and investigators have developed an enteral administration device that promotes intestinal absorption of the peptide MEDI7219 and the osmotic enhancer, sodium adipate, as an example of the use of osmotic enhancers to augment the enteral administration of peptide drugs. [43] There are also a large number of studies showing [44][45][46][47] that the effect of CS as an osmotic enhancer is potentially promising (Table 1).…”

“…In addition to its properties of permeability, nontoxicity, biocompatibility and biodegradability, CS, and its derivatives have shown good ability to enhance the permeation of drugs through mucosal absorption in recent years, making it a promising and safe mucosal osmotic enhancer. [35] Taking oral delivery of insulin as an example, a large number of studies [42,44,45,[48][49][50][51][52][53] have used a variety of osmotic enhancers in the design of insulin oral delivery systems, and from the results, unprotected insulin is still at risk of hydrolysis, but the simultaneous application of NPs and osmotic enhancers can be effective in enhancing the bioavailability of insulin for oral administration. In general, PEs exhibit notable efficacy in enhancing drug permeation, particularly for biomolecules such as peptides and proteins.…”

Experiences and Translatability of In Vitro and In Vivo Models to Evaluate Caprate as a Permeation Enhancer

“…In vitro methods range from using artificial membranes and Caco-2 cell monolayers to isolated tissue mounted in an Ussing chamber or set up as inverted sacs , The physiological similarities in the gastrointestinal tract of humans and larger animals like dogs and pigs make them good models to test and evaluate the oral absorption of such drug formulations . Nevertheless, there is an increased need in pharmaceutical research to promote the “3Rs” framework (reduce, replace, and refine the use of in vivo studies) and keep the use of in vivo studies to an acceptable minimum. , …”

“…The highest studied concentration of 300 mM mimics the scenario, where the entire dosage form dissolves in one intestinal fluid pocket, with the lowest concentration of 50 mM mimicking the scenario, where the dosage form dissolves in the total resting small-bowel volume (typical volume of 43–105 mL) . For in vitro studies presented in the manuscript, C10 solutions were formulated to 25–150 mM (or less for Caco-2 investigations to be aligned with what has previously been published). ,, …”

“…19 For in vitro studies presented in the manuscript, C10 solutions were formulated to 25−150 mM (or less for Caco-2 investigations to be aligned with what has previously been published). 12,20,21 This paper aims to share our experience and observations gained from using various in vitro and in vivo methods to evaluate C10 as a permeation enhancer in our quest to improve the oral bioavailability of macromolecules. Animal models and administration strategies that were applied in this study were endoscopic administration to the small intestine in the pig and intestinal bolus administration in the rat.…”