Ravuconazole self-emulsifying delivery system: in vitro activity against Trypanosoma cruzi amastigotes and in vivo toxicity

• Published in: International journal of nanomedicine Vol. 12; pp. 3785 - 3799
• Main Authors: Spósito, Pollyanna Álvaro, Mazzeti, Ana Lia, de Oliveira Faria, Caroline, Urbina, Julio A, Pound-Lana, Gwenaelle, Bahia, Maria Terezinha, Mosqueira, Vanessa Furtado
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2017; Taylor & Francis Ltd; Dove Medical Press
• Subjects: Administration, Oral; Animals; Antifungal agents; Bioavailability; Chagas disease; Chagas Disease - drug therapy; Chagas Disease - parasitology; Chromatography; Disease; Drug delivery systems; Drug Delivery Systems - methods; Drug therapy; Drugs; Emulsions - administration & dosage; Emulsions - chemistry; Emulsions - pharmacology; Excipients - chemistry; Female; flow field flow fractionation; Glycerides - chemistry; in vitro activity; Influence; Lipids; Lipids - chemistry; Male; Mice; Nanoparticles; Original Research; Parasites; Pharmacy; Physiological aspects; Polyethylene glycol; Properties; ravuconazole; self-emulsifying drug delivery; Solubility; Surface-Active Agents - chemistry; Surfactants; Thiazoles - administration & dosage; Thiazoles - chemistry; Thiazoles - toxicity; Triazoles - administration & dosage; Triazoles - chemistry; Triazoles - toxicity; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - pathogenicity; Trypanosomiasis; Brazil; Chagas disease; ravuconazole; in vitro activity; self-emulsifying drug delivery; asymmetric flow field-flow fractionation; Trypanosoma cruzi
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S133708

Self-emulsifying drug delivery systems (SEDDSs) are lipid-based anhydrous formulations composed of an isotropic mixture of oil, surfactant, and cosurfactants usually presented in gelatin capsules. Ravuconazole (Biopharmaceutics Classification System [BCS] Class II) is a poorly water-soluble drug, and a SEDDS type IIIA was designed to deliver it in a predissolved state, improving dissolution in gastrointestinal fluids. After emulsification, the droplets had mean hydrodynamic diameters <250 nm, zeta potential values in the range of -45 mV to -57 mV, and showed no signs of ravuconazole precipitation. Asymmetric flow field-flow fractionation with dynamic and multiangle laser light scattering was used to characterize these formulations in terms of size distribution and homogeneity. The fractograms obtained at 37°C showed a polydisperse profile for all blank and ravuconazole-SEDDS formulations but no large aggregates. SEDDS increased ravuconazole in vitro dissolution extent and rate (20%) compared to free drug (3%) in 6 h. The in vivo toxicity of blank SEDDS comprising Labrasol surfactant in different concentrations and preliminary safety tests in repeated-dose oral administration (20 days) showed a dose-dependent Labrasol toxicity in healthy mice. Ravuconazole-SEDDS at low surfactant content (10%, v/v) in -infected mice was safe during the 20-day treatment. The anti- activity of free ravuconazole, ravuconazole-SEDDS and each excipient were evaluated in vitro at equivalent ravuconazole concentrations needed to inhibit 50% or 90% (IC and IC ), respectively of the intracellular amastigote form of the parasite in a cardiomyocyte cell line. The results showed a clear improvement of the ravuconazole anti- activity when associated with SEDDS. Based on our results, the repurposing of ravuconazole in SEDDS dosage form is a strategy that deserves further in vivo investigation in preclinical studies for the treatment of human infections.