Naltrexone Hydrochloride Loaded W/O Microemulsions: Preparation, Characterization and Exploring the Anti-leishmanial Activity

<strong>Background and Aims:</strong> This study investigated the potential of naltrexone hydrochloride (NH) loaded water-in-oil (W/O) microemulsions (ME) as an alternative treatment strategy for cutaneous leishmaniasis caused by <em>Leishmania tropica</em>. This study aims to provide a topical alternative to the treatment of leishmaniasis, while also identifying a new therapeutic use of naltrexone other than its use in opioid addiction. <strong>Methods: </strong>Stable water-in-oil microemulsion formulations were developed using linseed oil, Span 60®, and polyethylene glycol 400. Microemulsions were prepared using triangle phase diagrams and optimization was performed by determining the droplet size, viscosity, pH, conductivity, and zeta potential values. The antileishmanial activity of the optimized microemulsion formulation was tested under in vitro conditions. <strong>Results:</strong> The optimized formulation (ME-2) demonstrated favorable physicochemical properties, including a droplet size of 99.86 nm, low polydispersity index (0.242), and high zeta potential (-42.9 mV), ensuring stability and homogeneity. In vitro release studies indicated first-order kinetics, suggesting the controlled release of NH. The antileishmanial activity of ME-2 was evaluated against<em> L. tropica </em>promastigote, revealing a 50% inhibition at an IC50 concentration of 5.17 µM. While amphotericin B, the gold standard, exhibited superior efficacy (IC50 = 0.063 µM), NH demonstrated a dose-dependent reduction in promastigote viability. This suggests its potential as a supplementary treatment, particularly in cases where amphotericin B's toxicity is a concern. <strong>Conclusion:</strong> Future studies focusing on structural optimization, mechanism elucidation, and in vivo validation could enhance NH’s efficacy, offering a promising alternative for leishmaniasis management. This work establishes a foundational basis for leveraging NH microemulsions in parasitic disease therapy.