Recent advances and trends in oral absorption enhancements of GLP-1 receptor agonist formulations

Abstract

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer significant clinical benefits in treating type 2 diabetes and obesity. However, owing to their peptide-based composition, GLP-1RAs have traditionally required injectable administration, which undermines patient adherence, convenience, and long-term accessibility. Recent advancements—including the approval of oral semaglutide (Rybelsus®)—have demonstrated the potential for effective oral peptide delivery, though such formulations still face significant pharmacokinetic and formulation-related challenges. Area covered: Therefore, this review aims to summarize recent strategies to address the challenges associated with the oral delivery of GLP-1RAs. Key areas include using chemical permeation enhancers—e.g., salcaprozate sodium and sodium caprate—as well as developing nanoparticle and lipid-based drug delivery systems, peptide cyclization, D-amino acid substitution, and prodrug designs. Moreover, alternative routes—such as buccal, sublingual, transdermal, and implantable delivery methods—are discussed. The review also highlights emerging technologies such as artificial intelligence (AI)-driven formulation prediction, digital twin modeling, and physiologically based pharmacokinetic (PBPK) simulations as novel tools for optimizing oral peptide absorption and systemic bioavailability. Expert opinion: Integrating pharmaceutical formulation strategies with digital modeling platforms offers a promising avenue for addressing the physiological and technical limitations associated with oral GLP-1RA delivery. While technologies such as permeation enhancers and nanoparticle-based systems have shown potential, their successful clinical translation remains constrained by challenges related to safety, scalability, and consistency. Moreover, AI and PBPK modeling could accelerate development by reducing experimental burden and supporting personalized formulation optimization. Sustained interdisciplinary collaboration will be essential to develop safe, effective, and patient-friendly oral GLP-1RA therapies.