In Vitro, Ex Vivo and In Vivo Evaluation of Microcontainers for Oral Delivery of Insulin

Abstract

Enhancing the oral bioavailability of peptides has received a lot of attention for decades but remains challenging, partly due to low intestinal membrane permeability. Combining a permeation enhancer (PE) with unidirectionally releasing microcontainers (MCs) has previously been shown to increase insulin permeation across Caco-2 cell monolayers. In the present work, this setup was further employed to compare three common PEs—sodium caprate (C10), sodium dodecyl sulfate (SDS), and lauroyl carnitine. The concept was also studied using porcine intestinal tissue with the inclusion of 70 kDa fluorescein isothiocyanate-dextran (FD70) as a pathogen marker. Moreover, a combined proteolysis and Caco-2 cell permeation setup was developed to investigate the effect of soybean trypsin inhibitor (STI) in the MCs. Lastly, in vivo performance of the MCs was tested in an oral gavage study in rats by monitoring blood glucose and insulin absorption. SDS proved to be the most potent PE without increasing the ex vivo uptake of FD70, while the implementation of STI further improved insulin permeation in the combined proteolysis Caco-2 cell setup. However, no insulin absorption in rats was observed upon oral gavage of MCs loaded with insulin, PE and STI. Post-mortem microscopic examination of their gastrointestinal tract indicated lack of intestinal retention and optimal orientation by the MCs, possibly precluding the potential advantage of unidirectional release.

Design of a self-unfolding delivery concept for oral administration of macromolecules

“…Insulin release in the gastric environment can be prevented by enteric coating, but ensuring optimal unidirectional release in close proximity to the intestinal epithelium has proven challenging to attain in vivo [17]. Moreover, it has proven problematic to conduct in vivo studies of enteric coated capsules in rats, due to long-term gastric retention of such dosage forms [18].…”

pH-Responsive and Mucoadhesive Nanoparticles for Enhanced Oral Insulin Delivery: The Effect of Hyaluronic Acid with Different Molecular Weights

“…Caco-2 cells were used for assessment of the cytotoxicity and transintestinal epithelium delivery due to their morphological and functional similarity to the intestinal epithelium [ 44 ].…”

Insulin: evolution of insulin formulations and their application in clinical practice over 100 years

“…For example, the attractive potential of oral insulin is limited by the fact that insulin is a peptide hormone, and as such is destroyed by gastric acids and pancreatic enzymes, and suffers from low permeability through the intestinal membrane. Employing polymer coatings, protease inhibitors and permeability enhancers to protect insulin from gastric acids and improve absorption through the intestinal membrane show promising results [99][100][101][102], although much larger doses of insulin may be required compared with subcutaneous injection and there are concerns about the absorption of potentially toxic excipient molecules [103,104]. An additional limitation with the oral route of insulin delivery is of course the large variability in absorption depending on the presence of food in the intestine.…”