A Novel, High Drug-Loading Long-Acting Injectable (LAI) Enables One Monthly Subcutaneous Administration of Tirzepatide and Retatrutide

Introduction and Objective: Transitioning from weekly to monthly administration of tirzepatide/retatrutide may substantially reduce injection burden and improve treatment adherence and convenience. Long-acting injectable(LAI) represent a robust and scalable approach for monthly Tirzepatide/Retatrutide LAIs. However, the resulting increase in total injection-volume may limit of subcutaneous administration. We therefore developed a high drug-loading LAI which is essential to enable clinically feasible 1-monthly subcutaneous administration, with the potential to improve treatment convenience. Methods: Tirzepatide/Retatrutide LAIs were prepared using biodegradable polymers via an emulsion-based fabrication process. Formulation characteristics were assessed by HPLC. To assess the pharmacokinetic of tirzepatide/retatrutide LAIs, male Sprague-Dawley(SD) rats were selected as test animals. Results: Tirzepatide/Retatrutide LAIs were prepared successfully with high-drug encapsulation efficiency. All the tirzepatide/retatrutide LAIs regardless of high-drug content have a spherical shape and smooth surface. Despite the high-drug content of tirzepatide/retatrutide, the initial release was well controlled to less than 5% during the first 24 hours after injection. In rat PK studies of tirzepatide/retatrutide LAIs after a single injection, plasma tirzepatide/retatrutide concentration was kept more than 1-month. Conclusion: The high drug-loading tirzepatide/retatrutide LAIs enables practical 1-monthly subcutaneous administration of tirzepatide/retatrutide while achieving optimal pharmacokinetic profile. The increased drug loading reduced microsphere mass compared to conventional loading levels, thereby improving injection feasibility while maintaining controlled release characteristics. This approach provides a viable pathway for tirzepatide/retatrutide LAIs therapy development with the potential to improve treatment adherence and convenience. Disclosure: J. Lee: None. E. Seol: None. H. Lee: None.