Safety concerns over the use of intestinal permeation enhancers: A mini-review

Abstract

Intestinal permeation enhancers (PEs) are key components in »12 oral peptide formulations in clinical trials for a range of molecules, primarily insulin and glucagon-like-peptide 1 (GLP-1) analogs. The main PEs comprise medium chain fatty acid-based systems (sodium caprate, sodium caprylate, and N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC)), bile salts, acyl carnitines, and EDTA. Their mechanism of action is complex with subtle differences between the different molecules. With the exception of SNAC and EDTA, most PEs fluidize the plasma membrane causing plasma membrane perturbation, as well as enzymatic and intracellular mediator changes that lead to alteration of intestinal epithelial tight junction protein expression. The question arises as to whether PEs can cause irreversible epithelial damage and tight junction openings sufficient to permit co-absorption of payloads with bystander pathogens, lipopolysaccharides and its fragment, or exo-and endotoxins that may be associated with sepsis, inflammation and autoimmune conditions. Most PEs seem to cause membrane perturbation to varying extents that is rapidly reversible, and overall evidence of pathogen co-absorption is generally lacking. It is unknown however, whether the intestinal epithelial damage-repair cycle is sustained during repeat-dosing regimens for chronic therapy.

Oral aktive Peptide: Gibt es ein Patentrezept?

“…[82] Die Ussing-Kammer erlaubt zudem die Erforschung des elektrischen Potentialunterschieds zwischen den beiden Seiten des intestinalen Gewebes auf die Permeabilitätsrate. [90] [87] Obwohl der genaue Mechanismus immer noch unklar ist, wird berichtet, dass SNAC die Bioverfügbarkeit des parazellulären und des transzellulären Mechanismus erhçht.…”

Orally Active Peptides: Is There a Magic Bullet?

“…[83] Coadministration of the anticoagulant heparin (a non-peptide macromolecule) along with SNAC leads to noncovalent interaction with the heparin that neutralizes the negative ionic charge of am olecule to render it more lipophilic,t hus allowing transcellular absorption. [90] [88] Thep rotein semaglutide (a GLP-1 analogue for treatment of type 2diabetes) has shown promising results in clinical trials in an oral formulation with SNAC.S emaglutide has been reported to cause alocalized increase in the pH value that enables higher solubility and provides protection from enzymatic degradation of the peptide.…”

Diet, food components and the intestinal barrier

“…Food‐grade emulsifiers and surfactants increase paracellular permeability, with the majority of research suggesting a transient and temporary effect (McCartney et al . ). Sucrose monoester fatty acids, a food‐grade surfactant, decreased TEER across Caco‐2 monolayers, reorganised TJ proteins while increasing the permeability of ovomucoid, an egg white allergen (Mine & Zhang ).…”

“…This barrier is often perturbed due to exposure of alcohol, fatty acids, pharmaceuticals such as non‐steroidal anti‐inflammatory drugs (NSAIDs) and bile salts (Perrier & Corthesy ; Peterson & Artis ; McCartney et al . ). Due to this, apoptotic epithelial cells are regularly shed from the tip of jejunal or ileal villi and replaced to maintain the integrity of the intestinal barrier, and this is essential for tissue homoeostasis (Williams et al .…”