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Ravuconazole self-emulsifying delivery system: in vitro activity against Trypanosoma cruzi amastigotes and in vivo toxicity.
- Source :
-
International journal of nanomedicine [Int J Nanomedicine] 2017 May 17; Vol. 12, pp. 3785-3799. Date of Electronic Publication: 2017 May 17 (Print Publication: 2017). - Publication Year :
- 2017
-
Abstract
- 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 <superscript>®</superscript> 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 Trypanosoma cruzi -infected mice was safe during the 20-day treatment. The anti- T. cruzi activity of free ravuconazole, ravuconazole-SEDDS and each excipient were evaluated in vitro at equivalent ravuconazole concentrations needed to inhibit 50% or 90% (IC <subscript>50</subscript> and IC <subscript>90</subscript> ), respectively of the intracellular amastigote form of the parasite in a cardiomyocyte cell line. The results showed a clear improvement of the ravuconazole anti- T. cruzi 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 T. cruzi infections.<br />Competing Interests: Disclosure The authors report no conflicts of interest in this work.
- Subjects :
- Administration, Oral
Animals
Chagas Disease drug therapy
Chagas Disease parasitology
Emulsions chemistry
Emulsions pharmacology
Excipients chemistry
Female
Glycerides chemistry
Lipids chemistry
Male
Mice
Solubility
Surface-Active Agents chemistry
Thiazoles chemistry
Triazoles chemistry
Trypanosoma cruzi pathogenicity
Drug Delivery Systems methods
Emulsions administration & dosage
Thiazoles administration & dosage
Thiazoles toxicity
Triazoles administration & dosage
Triazoles toxicity
Trypanosoma cruzi drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1178-2013
- Volume :
- 12
- Database :
- MEDLINE
- Journal :
- International journal of nanomedicine
- Publication Type :
- Academic Journal
- Accession number :
- 28553114
- Full Text :
- https://doi.org/10.2147/IJN.S133708