Novel Microsphere Formulation Developments of Long-Acting GLP-1 RA Including Exenatide, Liraglutide, and Semaglutide

Objective: Clinical applications of Glucagon-like peptide-1 receptor agonists (GLP1-RA) were greatly limited due to its short half-life. The current study aims at the formulation and characterization of sustained-release (SR)-GLP1-RAs to prolong the release profile with lag phase-free formulation technology. Methods: The long-acting drugs of those GLP1-RAs were prepared by an ultrasonic spray drying process with biodegradable PLGA polymer. Once the PLGA polymer and each API were dissolved in acetic acid, those were applied to the ultrasonic spray dryer to produce the microspheres which encapsulate the API in PLGA polymer. The pharmacokinetic profiles of long-acting SR-Exenatide, SR-Liraglutide, and SR-Semaglutide were determined by using Sprague-Dawley rats after a single injection subcutaneously. APIs were used as controls. Results: The optimized SR-Exenatide has demonstrated favorable physicochemical properties, such as mean particle size (20 ± 3 μm), percent of entrapment efficiency (90 ± 5 %), and the final drug loading (5 ± 0.5 %), with uniformly sized microspheres. Furthermore, the pharmacokinetic parameters appeared that its release profile extends up to 4 weeks without lag phase which showed 11.4 days of Tmax and 68% of relative bioavailability (BA) when 2mg/kg dose applied. Not only SR-Exenatide but also SR-Liraglutide and SR-Semaglutide showed the extended-release profile up to 1 week and 4 weeks in the rats, respectively. Conclusion: Those results showed the potentials of lag phase-free, long-acting, high productivity, and mass production. Taken together with the lag phase-free formulation and long-acting ultrasonic spray drying technologies, it will provide the rationales for the clinical development of SR-GLP1-RAs for once-weekly or -monthly formulations. As we have a GMP facility to produce long-acting drugs, we will actively and clinically investigate those SR-GLP1-RAs for antidiabetic therapy. Disclosure J. G. Jung: None.