Influence of Hydrophobic Ion Pairing on Formulation Performance of Liraglutide in PLGA Microspheres

The Food and Drug Administration of the United States (USFDA) and the European Medicines Agency (EMA) have approved peptide-based long-acting formulations to manage chronic diseases. However, the formulation of long-acting injectables for hydrophilic drug molecules and peptides remains a persistent challenge due to poor encapsulation and high initial burst release, which increases the complexity of the formulation. In the present research, we formulated long-acting injectable microspheres for liraglutide, a peptide used for managing type 2 DM (Diabetes Mellitus), utilizing a modified solid-oil-water (S/O/W) method. The method includes a hydrophobic ion pairing (HIP) strategy to improve the hydrophobicity of native molecules using various hydrophobic ion-pairing agents. Further, the PLGA microspheres prepared by the modified S/O/W method were compared with the traditional water-oil-water (W/O/W) double emulsion method. The modified S/O/W method (batch F2) demonstrated a significant improvement in encapsulation efficiency, increasing from 56.15% to 85.45%, and a minimal burst release of 3.58%. A comprehensive characterization of microspheres was performed using modern analytical techniques. The developed microspheres were spherical with a mean particle size of 43.97 µm and exhibited sustained drug release over 55 days. The S/O/W method demonstrated a promising approach for the encapsulation of hydrophilic peptide molecules.