Salcaprozate Sodium as a Permeation Enhancer—Mechanism, Applications and Unresolved Questions

Oral absorption remains challenging for peptides, proteins, and other drug substances with limited stability or permeability. Sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC), also known as salcaprozate sodium, is an oral permeation enhancer used in approved drug products. This review summarizes the physicochemical properties and mechanisms of action of SNAC and evaluates its clinical and emerging preclinical applications. A structured literature search was conducted in PubMed and Scopus, supplemented as needed with ClinicalTrials.gov and regulatory documents. The search covered 2015–2026, with earlier key publications included where necessary for historical context. After screening, 71 sources were included in the narrative synthesis. The review examines the proposed mechanisms of SNAC-mediated permeation enhancement, including local pH modulation, membrane-mediated effects, peptide self-association, and context-dependent effects on epithelial permeability. Clinical evidence is summarized for oral semaglutide, cyanocobalamin, unfractionated heparin, ibandronate, and investigational peptide products. Emerging applications beyond metabolic diseases are discussed together with formulation strategies and safety considerations. Recent preclinical findings suggesting changes in gut microbiota and inflammatory markers are critically evaluated in the context of the available clinical safety experience, while their relevance to humans remains unconfirmed. Overall, SNAC reliably enhances permeation in vitro and in vivo, yet the resulting oral bioavailability remains low and variable and is strongly dependent on payload, formulation, and gastrointestinal conditions. Long-term safety and the clinical relevance of recent preclinical microbiome findings remain important areas for future investigation.