1697-P: Oral Delivery of Semaglutide, Tirzepatide, and Retatrutide Formulated in Polymerized Ursodeoxycholic Acid (pUDCA) Nanoparticles (NP)

Introduction and Objective: Injection of peptide drugs for the treatment type 2 diabetes remains a significant barrier for long-term medication compliance. While oral formulations of some peptide drugs and orally delivered small molecule receptor agonists are becoming available, the bioavailability and/or efficacy of these approaches does not reach the same level as the injected peptides. Newer formulations are needed that can deliver peptide drugs with improved oral bioavailability. We hypothesized that pUDCA NP, formulated using polymers of naturally occurring ursodeoxycholic acid, may protect therapeutic peptides passing through the GI tract and promote intestinal uptake into the circulation. Methods: We report an oral delivery method for therapeutic peptides using an economical and scalable fluidics manufacturing process. Representative characteristics for NP include: peptide loading 30% wt/wt; size 100 nm; charge -40 mV; burst release <30%; batch reproducibility +/- 5%. Results: We administered tablets containing pUDCA NP encapsulating either semaglutide, tirzepatide, or retatrutide (1 to 5 mg) to beagles. Over 50 studies were conducted to optimize exposure, meal effect, and inter-day variability. Exposure of each peptide was measured in plasma over a four-day period following the final dose. Normalized Cmax (80 ng/mL) and AUC were approximately 5-10X higher than an orally administered commercial semaglutide formulation containing salcaprozate sodium. Relative bioavailability was estimated at 7% of encapsulated API. Meal effect on bioavailability was less than +/-20%. Conclusion: In conclusion, peptide drugs formulated in pUDCA NP were successfully taken into systemic circulation following oral dosing. Our approach may provide a promising strategy for economical oral delivery of peptide therapeutics for the long-term treatment of type 2 diabetes. Disclosure G.W. Rea: None. J. Lee: None. E.J. Bastyr III: Consultant; Current; Housey Pharma. A. Aayush: None. M. Arul: None. T. Wagner: None. A. Glasebrook: Stock/Shareholder; Current; Eli Lilly and Company. M.D. Michael: None.