ABS 038: Impact of macrophages on the dissolution of LAI suspension prodrugs

Nilesh Malavia ¹, Kellen Maurus ¹, Melissa Sabatella ¹, Quanying Bao ¹, Khondoker Alam ², Yan Wang ², Diane J. Burgess ¹

¹ University of Connecticut, Department of Pharmaceutical Sciences, Storrs, CT 06269 USA
² Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA

The Van Wickle Journal (2026) Volume 2, ABS038

Introduction: Long-acting injectable (LAI) suspensions are particulate-based controlled drug delivery systems often designed to provide sustained drug release over a period of time. This method of drug delivery offers several advantages over other delivery systems, including improved patient compliance due to reduced dosing frequency, and potentially enhanced therapeutic outcomes by maintaining more consistent drug levels in the body. Particle size remains the foundational determinant of drug release from crystalline suspensions, as smaller particles tend to be absorbed more quickly than larger particles. However, emerging evidence indicates that physiological processes like macrophage uptake represent an additional layer of complexity. The exact mechanism by which macrophages affect dissolution is unclear, so we investigated their role 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 equivalent formulations. RAW 264.7 macrophages were incubated with marketed and in-house suspensions of varying particle size. Drug uptake, dissolution, and metabolite formation were assessed using LC/MS, microscopy, and TEM imaging. We found that the LAI particles were actively internalized by the macrophages, as confirmed by TEM and elemental mapping. 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. Together, these findings suggest macrophages complement the particle-size–dependent dissolution process by modulating the dissolution and metabolic handling of LAI suspension prodrugs. This work provides new mechanistic insight into macrophage-mediated drug disposition and has important implications for the design and performance prediction of LAI formulations.

Methods: To investigate the impact of macrophages on the dissolution of LAI suspensions, Invega Trinza® and Aristada®, along with their Q1Q2 equivalents, were used as model formulations. Invega Trinza® and Aristada® were tested in their original forms, while the particle size of their Q1Q2 equivalents was modified using wet media milling. For each Q1Q2 equivalent, the dispersion media was prepared following the formulation provided in the respective drug’s package insert. RAW 264.7 macrophage adherent cell line were used to assess cell viability (via Cell-Counting-Kit-8), drug particle uptake (using transmission electron microscopy), metabolite conversion (using liquid chromatography–mass spectrometry) and the effects of cell density following drug treatment with both original and Q1Q2 equivalent formulations.

Results: The tested formulations were not cytotoxic, as no significant reduction in cell viability was observed across treatment groups. The results of the study confirm the presence of drug particles internalized within macrophages, as well as the presence of the active drug in substantial amounts in the extracellular compartments. Increasing cell confluency increases metabolite production, as well. Another key finding of this study is that particle size critically influences macrophage uptake and metabolic conversion.

Discussion: The results support the possibility of macrophage-mediated conversion and release of the active drug. When particle size exceeds cellular dimensions, macrophage-mediated contribution to drug disposition is limited. Notably, the in-house Aristada® formulation demonstrated markedly higher solubilization and metabolite levels, despite not being the smallest in size, suggesting the existence of an optimal particle size window for macrophage uptake. Understanding and controlling macrophage interactions through rational particle engineering could therefore reduce variability and improve predictability of LAI suspension performance. This work highlights the importance of understanding different pathways of drug release to improve formulation design and clinical performance of LAI suspensions.