Abstract
Oral peptide delivery is trending again. Among the possible reasons are the recent approvals of two oral peptide formulations, which represent a huge stride in the field. For the first time, gastrointestinal (GI) permeation enhancers (PEs) are leveraged to overcome the main limitation of oral peptide delivery-low permeability through the intestinal epithelium. Despite some success, the application of current PEs, such as salcaprozate sodium (SNAC), sodium caprylate (C8), and sodium caprate (C10), is generally resulting in relatively low oral bioavailabilities (BAs)-even for carefully selected therapeutics. With several hundred peptide-based drugs presently in the pipeline, there is a huge unmet need for more effective PEs. Aiming to provide useful insights for the development of novel PEs, this review summarizes the biological hurdles to oral peptide delivery with special emphasis on the epithelial barrier. It describes the concepts and action modes of PEs and mentions possible new targets. It further states the benchmark that is set by current PEs, while critically assessing and evaluating emerging PEs regarding translatability, safety, and efficacy. Additionally, examples of novel PEs under preclinical and clinical evaluation and future directions are discussed.