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Life sciences · Journal article
Pharmaceutics · October 31, 2026
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Background: Type 2 diabetes is a chronic metabolic disease increasingly treated with peptide therapeutics, yet their clinical use remains largely dependent on subcutaneous injection, compromising adherence and causing injection-related complications. Here, we developed a novel formulation to enhance oral semaglutide delivery and its penetration into skin tissue. Methods: This novel system was composed of betaine, glycerol, and sodium salcaprozate (SNAC) and was termed BGS, forming a deep eutectic solvent. Results: The BGS drug delivery system markedly suppressed semaglutide aggregation, shifting the peak particle size from 125.9 nm in phosphate-buffered saline (PBS) to 51.7 nm. It also enhanced semaglutide transport across Caco-2 monolayers, increasing the apparent permeability by 4.22-fold relative to PBS. In ex vivo porcine skin, BGS enhanced semaglutide penetration and accumulation, with the amount retained in skin reaching 86.34 ± 6.12 μg/cm2 at 24 h, approximately 4.51 times that with PBS. Following oral administration, BGS-formulated semaglutide achieved 1.02 ± 0.05% bioavailability, 14.57 times that of oral semaglutide. Compared with commercial formulation, oral semaglutide reached similar bioavailability, with a 74.5% SNAC decrease helping the formation of BGS via supramolecular interactions. In obese and diabetic mice, BGS effectively suppressed body weight gain and ameliorated hyperglycemia. BGS also showed favorable biocompatibility, with 0.25 ± 0.29% hemolysis and cell viability above 83% at 500 μg/mL. Conclusions: Overall, these findings demonstrate that BGS combines peptide stabilization, enhanced intestinal transport, and improved semaglutide accumulation within skin tissue, highlighting its potential for peptide delivery.