Dynamic Dialysis Method for Characterizing Ammonia-Driven Drug Release from Liposomal Doxorubicin: Applicability and Kinetic Modeling

Abstract

Characterizing the complex drug release profiles of nanoparticle-based pharmaceuticals is essential to ensure their efficacy and safety. In this study, we investigated the drug release of a representative liposomal drug, Doxil, to explore the applicability of the dynamic dialysis method (DDM), which offers the advantage of simple implementation. The DDM demonstrated considerable doxorubicin release from Doxil in response to increased ammonia concentration, supporting the hypothesis of ammonia-driven drug release from Doxil in tumor environments. To analyze the drug release of liposomal doxorubicin, we developed a mathematical model that (i) does not require strict sink conditions and (ii) avoids introducing numerous kinetic parameters. This model consolidates the complexities of drug partitioning into the liposomal membrane into a single apparent permeability constant. The release profiles of Doxil at 25°C and a physiological temperature of 40°C were successfully reproduced by the kinetic model, yielding reasonable permeability coefficients of 1.4 × 10⁻¹⁰ and 2.1 × 10⁻¹⁰ cm/s, respectively. Our model described the release behavior of the generic product Lipodox, yielding a permeability coefficient of 2.1 × 10⁻¹⁰ cm/s at 40°C, thereby confirming the utility of the DDM across products. Our results demonstrate that, with optimized conditions, the DDM can assess the drug release kinetics of liposomal doxorubicin. Furthermore, we believe that our study provides a valuable framework for evaluating and optimizing drug release phenomena in liposomal formulations.