Result of a successful collaboration published in the Science Translational Medicine

2018. november 16.

Oral administration of therapeutic peptides is hindered by poor absorption across the gastrointestinal barrier and extensive degradation by proteolytic enzymes. Here, we investigated the absorption of orally delivered semaglutide, a glucagon-like peptide-1 analog, coformulated with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC) in a tablet. In contrast to intestinal absorption usually seen with small molecules, clinical and preclinical dog studies revealed that absorption of semaglutide takes place in the stomach, is confined to an area in close proximity to the tablet surface, and requires coformulation with SNAC. SNAC protects against enzymatic degradation via local buffering actions and only transiently enhances absorption. The mechanism of absorption is shown to be compound specific, transcellular, and without any evidence of effect on tight junctions. These data have implications for understanding how highly efficacious and specific therapeutic peptides could be transformed from injectable to tablet-based oral therapies.

Stephen T. Buckley, Tine A. Bækdal, Andreas Vegge, Stine J. Maarbjerg, Charles Pyke, Jonas Ahnfelt-Rønne, Kim G. Madsen, Susanne G. Schéele, Tomas Alanentalo, Rikke K. Kirk, Betty L. Pedersen, Rikke B. Skyggebjerg, Andrew J. Benie, Holger M. Strauss, Per-Olof Wahlund, Simon Bjerregaard, Erzsébet Farkas, Csaba Fekete, Flemming L. Søndergaard, Jeanett Borregaard, Marie-Louise Hartoft-Nielsen and Lotte Bjerre Knudsen: Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Science Translational Medicine 14 Nov 2018: Vol. 10, Issue 467