Oral Peptide Delivery
The administration of peptide drugs by mouth, extremely challenging because digestive enzymes and poor intestinal absorption destroy most of the compound. Oral semaglutide (Rybelsus) overcame this barrier using SNAC absorption enhancer technology, though oral bioavailability remains very low at approximately 0.4-1%.
Technical Context
The oral route faces three main barriers: gastric acid/pepsin degradation (pH 1-2 denatures most peptides), intestinal protease degradation (trypsin, chymotrypsin in the lumen; brush border peptidases), and epithelial permeability (tight junctions limit paracellular transport of molecules >600 Da; transcellular transport is hindered by size, hydrophilicity, and lack of specific transporters). Oral semaglutide (Rybelsus) uses SNAC co-formulated in a tablet taken on an empty stomach with ≤120mL water. SNAC creates a localised alkaline microenvironment that protects semaglutide from pepsin, promotes monomeric peptide absorption through the gastric epithelium via transcellular transport, and is itself rapidly absorbed and eliminated. The 14mg oral dose delivers equivalent exposure to approximately 0.5-1mg SC semaglutide, reflecting ~0.4-1% oral bioavailability.