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

Pollyanna Álvaro Spósito,1 Ana Lia Mazzeti,1,2 Caroline de Oliveira Faria,1 Julio A Urbina,3 Gwenaelle Pound-Lana,1 Maria Terezinha Bahia,2 Vanessa Furtado Mosqueira1 1Laboratory of Pharmaceutics and Nanotechnology Research, Pharmacy Department, School of Pharmacy, Universidad...

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Autores principales:	Spósito PA, Mazzeti AL, de Oliveira Faria C, Urbina JA, Pound-Lana G, Bahia MT, Mosqueira VF
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	ravuconazole self-emulsifying drug delivery flow field flow fractionation Trypanosoma cruzi Chagas disease in vitro activity Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/1cc94e244de445e0acfe79c2367a7d2d
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spelling	oai:doaj.org-article:1cc94e244de445e0acfe79c2367a7d2d2021-12-02T07:13:45ZRavuconazole self-emulsifying delivery system: in vitro activity against Trypanosoma cruzi amastigotes and in vivo toxicity1178-2013https://doaj.org/article/1cc94e244de445e0acfe79c2367a7d2d2017-05-01T00:00:00Zhttps://www.dovepress.com/ravuconazole-self-emulsifying-delivery-system-in-vitro-activity-agains-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Pollyanna Álvaro Spósito,1 Ana Lia Mazzeti,1,2 Caroline de Oliveira Faria,1 Julio A Urbina,3 Gwenaelle Pound-Lana,1 Maria Terezinha Bahia,2 Vanessa Furtado Mosqueira1 1Laboratory of Pharmaceutics and Nanotechnology Research, Pharmacy Department, School of Pharmacy, Universidade Federal de Ouro Preto, Minas Gerais, Brazil; 2Parasite Diseases Research Laboratory, NUPEB, Medical School, Universidade Federal de Ouro Preto, MG, Brazil; 3Venezuelan Institute for Scientific Research, Apartado, Caracas, Venezuela 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® 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% (IC50 and IC90), 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. Keywords: ravuconazole, self-emulsifying drug delivery, asymmetric flow field-flow fractionation, Trypanosoma cruzi, Chagas disease, in vitro activitySpósito PAMazzeti ALde Oliveira Faria CUrbina JAPound-Lana GBahia MTMosqueira VFDove Medical Pressarticleravuconazoleself-emulsifying drug deliveryflow field flow fractionationTrypanosoma cruziChagas diseasein vitro activityMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 3785-3799 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	ravuconazole self-emulsifying drug delivery flow field flow fractionation Trypanosoma cruzi Chagas disease in vitro activity Medicine (General) R5-920
spellingShingle	ravuconazole self-emulsifying drug delivery flow field flow fractionation Trypanosoma cruzi Chagas disease in vitro activity Medicine (General) R5-920 Spósito PA Mazzeti AL de Oliveira Faria C Urbina JA Pound-Lana G Bahia MT Mosqueira VF Ravuconazole self-emulsifying delivery system: in vitro activity against Trypanosoma cruzi amastigotes and in vivo toxicity
description	Pollyanna Álvaro Spósito,1 Ana Lia Mazzeti,1,2 Caroline de Oliveira Faria,1 Julio A Urbina,3 Gwenaelle Pound-Lana,1 Maria Terezinha Bahia,2 Vanessa Furtado Mosqueira1 1Laboratory of Pharmaceutics and Nanotechnology Research, Pharmacy Department, School of Pharmacy, Universidade Federal de Ouro Preto, Minas Gerais, Brazil; 2Parasite Diseases Research Laboratory, NUPEB, Medical School, Universidade Federal de Ouro Preto, MG, Brazil; 3Venezuelan Institute for Scientific Research, Apartado, Caracas, Venezuela 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® 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% (IC50 and IC90), 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. Keywords: ravuconazole, self-emulsifying drug delivery, asymmetric flow field-flow fractionation, Trypanosoma cruzi, Chagas disease, in vitro activity
format	article
author	Spósito PA Mazzeti AL de Oliveira Faria C Urbina JA Pound-Lana G Bahia MT Mosqueira VF
author_facet	Spósito PA Mazzeti AL de Oliveira Faria C Urbina JA Pound-Lana G Bahia MT Mosqueira VF
author_sort	Spósito PA
title	Ravuconazole self-emulsifying delivery system: in vitro activity against Trypanosoma cruzi amastigotes and in vivo toxicity
title_short	Ravuconazole self-emulsifying delivery system: in vitro activity against Trypanosoma cruzi amastigotes and in vivo toxicity
title_full	Ravuconazole self-emulsifying delivery system: in vitro activity against Trypanosoma cruzi amastigotes and in vivo toxicity
title_fullStr	Ravuconazole self-emulsifying delivery system: in vitro activity against Trypanosoma cruzi amastigotes and in vivo toxicity
title_full_unstemmed	Ravuconazole self-emulsifying delivery system: in vitro activity against Trypanosoma cruzi amastigotes and in vivo toxicity
title_sort	ravuconazole self-emulsifying delivery system: in vitro activity against trypanosoma cruzi amastigotes and in vivo toxicity
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/1cc94e244de445e0acfe79c2367a7d2d
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Ravuconazole self-emulsifying delivery system: in vitro activity against Trypanosoma cruzi amastigotes and in vivo toxicity

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