Design and Development of Lipid-Based In Situ Forming Long-Acting Injectables for Delivering a Highly Water-Soluble Drug at High Loading

Abstract Long-acting injectables (LAIs) have emerged as a pivotal modality for managing chronic diseases, driven by the need to improve patient adherence and overall quality of life. Most clinically established LAI products rely on either simple suspensions/solutions or polymer-based depot technologies designed for low-dose, hydrophobic active pharmaceutical ingredients (APIs). In contrast, achieving long-acting delivery for high drug loading of hydrophilic drugs remains a significant challenge and represents a clear technological gap in the field. The present work focused on the design and development of lipid-based in situ-forming LAIs as a promising approach for the controlled release of a model hydrophilic API, paracetamol. The key formulation parameters including lipid composition, solvent selection and content, and drug loading were systematically studied to understand their influence on the microstructure of the depot formed, injectability, and the release kinetics of paracetamol. The formulations demonstrated good injectability and immediate formation of the highly viscous depot upon contact with aqueous fluids. A comprehensive physicochemical characterization of the blank and compound-loaded formulations pre- and post-injection was conducted using a range of analytical techniques including powder X-ray diffraction, small-angle X-ray scattering, proton nuclear magnetic resonance, rheological analyzer, and texture analyzer as well as imaging techniques cryogenic field emission scanning electron microscopy and cross-polarized light microscopy. The characterization data demonstrated the complex structures of the gels, due to the various lyotropic liquid crystalline phases formed in situ post-injection. In vitro drug release studies revealed the long-acting effect, and the best-performing formulation showed 96.6% paracetamol released after 77 days. Preliminary in vivo results in rats after subcutaneous administration of an ethanol/benzyl benzoate (1:4, w/w) formulation showed that paracetamol plasma concentrations peaked after nine days, while drug release remained incomplete at day 24. Histopathological assessment suggested minimal to mild injection-site findings two months after administration. The compound release rates were significantly affected by both drug loading and the ratios between water-miscible and water-immiscible solvents used in the formulation. The findings of this study present new insights into optimizing the use of lipid-based materials with ordered structures as LAIs for the delivery of hydrophilic compounds.