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

Abstract

Transient permeation enhancers (PEs) have been widely used to improve the oral absorption of macromolecules. During pharmaceutical development, the correct selection of the macromolecule, PE, and the combination needs to be made to maximize oral bioavailability and ensure successful clinical development. Various in vitro and in vivo methods have been investigated to optimize this selection. In vitro methods are generally preferred by the pharmaceutical industry to reduce the use of animals according to the "replacement, reduction, and refinement" principle commonly termed "3Rs," and in vitro methods typically have a higher throughput. This paper compares two in vitro methods that are commonly used within the pharmaceutical industry, being Caco-2 and an Ussing chamber, to two in vivo models, being in situ intestinal instillation to rats and in vivo administration via an endoscope to pigs. All studies use solution formulation of sodium caprate, which has been widely used as a PE, and two macromolecules, being FITC−dextran 4000 Da and MEDI7219, a GLP-1 receptor agonist peptide. The paper shares our experiences of using these models and the challenges with the in vitro models in mimicking the processes occurring in vivo. The paper highlights the need to consider these differences when translating data generated using these in vitro models for evaluating macromolecules, PE, and combinations thereof for enabling oral delivery.

Head-to-Head Comparison of Caco-2 Transwell and Gut-on-a-Chip Models for Assessing Oral Peptide Formulations

“…Kasendra et al reported the basal P app of Cascade Blue-Dextran 3 kDa in a duodenal organoid Chip model as ∼1 × 10 –6 cm/s . Comparatively, the P app for FD4 in Caco-2 Transwells is typically reported as <8 × 10 –8 cm/s. ,, Here, we reported a basal P app of FD3 in Transwells as 5.3 ± 0.8 × 10 –8 cm/s in line with previous reports and P app of FD4 in Chips 3.2 ± 1.8 × 10 –7 cm/s. Tan and colleagues compared a Caco-2 Transwell and Chip model and reported an FD4 P app of ∼2.5 × 10 –7 cm/s (Chip) and <1 × 10 –7 cm/s (Transwell) .…”

“…Adding NaCap increased the P app by 7-fold and 2-fold in Transwells and Chips, while sucrose monolaurate increased the P app by 140-fold and 8-fold, respectively. The increase in permeability in the presence of PEs in the Chip model trends more appropriately with observations in ex vivo and in vivo models. , …”

“…Gleeson et al indicated that the concentration of NaCap required to double the P app of a BCS III tripeptide in Caco-2 Transwells was 5 mM while in isolated rat jejunal tissue in Ussing Chambers was 30 mM . Emeh et al investigated coincubation and coadministration of NaCap in isolated rat jejunal tissue with 25 mM NaCap to increase the P app of FD4 and a GLP1 peptide . They also found that 10 mM NaCap was the effective concentration in Caco-2 Transwells for both molecules.…”