Impact of macrophages on the dissolution of LAI suspension prodrugs

Abstract

Long-acting injectable (LAI) suspensions are often designed to provide sustained drug release by exploiting the low aqueous solubility of poorly soluble drugs or prodrugs. While particle size remains the foundational determinant of drug release from crystalline suspensions, emerging evidence indicates that physiological processes such as macrophage uptake and intracellular handling of particles, which themselves are influenced by particle size represent an additional layer of complexity that can further shape in vivo dissolution and pharmacokinetics. However, the formulation-dependent relationship between LAI suspension attributes (e.g., particle size and aggregation state) and macrophage association, intracellular dissolution, and conversion remains insufficiently defined. In this study, we investigated the role of macrophages in the dissolution and metabolic conversion of two clinically approved LAI prodrugs aripiprazole lauroxil (Aristada®) and paliperidone palmitate (Invega Trinza®) and their qualitatively and quantitatively (Q1Q2) equivalent formulations. RAW 264.7 macrophages were incubated with marketed and in-house suspensions of varying particle size, and drug uptake, dissolution, and metabolite formation were assessed using LC/MS, microscopy, and TEM imaging. The LAI particles were actively internalized by the macrophages, as confirmed by TEM and elemental mapping, and the prodrugs were converted into their active forms, with metabolite detection confirmed by MS/MS fragmentation. Drug solubilization was cell density dependent, with higher macrophage confluency leading to enhanced dissolution. Particle size further influenced uptake and metabolic conversion, with particles of optimum size showing greater solubilization. Importantly, ELISA assays demonstrated that macrophage interaction with LAI suspensions did not trigger measurable inflammatory cytokine release under study conditions. Together, these findings suggest that macrophages complement the particle-size-dependent dissolution process by further modulating the dissolution and metabolic handling of LAI suspension prodrugs. This work provides new mechanistic insight into macrophage-mediated drug disposition at the injection site and has important implications for the design and performance prediction of LAI formulations.