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

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% (IC 50 and IC 90 ), 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.

Supersaturable solid self-microemulsifying drug delivery system: precipitation inhibition and bioavailability enhancement

“…1,2 A number of alternative techniques including cyclodextrin complexation, 3 particle size reduction, 4 solid dispersions, 5 and lipid-based formulations 6 have been developed to overcome this problem. Among all the formulations, lipid-based formulations, especially self-emulsifying drug delivery systems (SEDDS) have received much attention.…”

Sistemas de entrega de fármacos autoemulsificables: una plataforma de desarrollo alternativa para la industria farmacéutica colombiana

“…El SCB se basa en estos dos factores para agrupar los principios activos en cuatro categorías principales [61], como se muestra en la figura 6. Inicialmente, los SEDDS surgieron como una alternativa ante la necesidad de superar los inconvenientes en la formulación de principios activos cuya baja solubilidad acuosa conlleva a una absorción gastrointestinal limitada por la disolución y a su vez en una biodisponibilidad baja y variable [62,63]. Generalmente, estos compuestos se encuentran categorizados como clase II o clase IV en el SCB [64,65].…”

“…En ese sentido, los valores altos de HLB correspondientes a tensioactivos de naturaleza hidrofílica facilitan la disminución de la energía interfacial, lo que conduce a la formación de dispersiones más estables y de menor tamaño [63,107,111]. En general, el valor HLB para un tensioactivo hidrofílico se encuentra en el rango entre 12 y 18 [112].…”

“…Los tensioactivos no iónicos son reconocidos como más seguros y son aceptados para utilizarse en formulaciones de administración oral [107], debido a que son menos tóxicos, más compatibles con los tejidos biológicos y menos susceptibles a cambios de pH durante su paso a través del tracto gastrointestinal que los tensioactivos iónicos [112,113]. La presencia de tensioactivos en las formulaciones de SEDDS permite mejorar la absorción de los principios activos al aumentar su permeabilidad intestinal puesto que generan una desorganización o ruptura de la integridad estructural de la bicapa lipídica epitelial que afecta principalmente las uniones estrechas intercelulares [63,83,111]. Sin embargo, a altas concentraciones de tensioactivos como es habitual en los SEDDS, ocurren mayores interacciones entre las moléculas del tensioactivo y la membrana a tal punto que esta puede ser disuelta en micelas mezcladas formadas por el tensioactivo y la membrana epitelial lo que genera la presencia de efectos adversos como irritación gastrointestinal [93].…”

Enhanced oral absorption of pemetrexed by ion-pairing complex formation with deoxycholic acid derivative and multiple nanoemulsion formulations: preparation, characterization, and in vivo oral bioavailability and anticancer effect

“…Mechanistic study demonstrated that Labrasol can disrupt tight junctions at the molecular level, including the loss of junction integrity via changes in F-actin ring and redistribution of zonula occludens-1 (ZO-1), leading them to act as potential absorption enhancers of hydrophilic drugs. 54,55 Based on the results of the in vitro artificial intestinal membrane and Caco-2 cell monolayer permeability analyses, further experiments, including those on the in vivo oral absorption in rats and tumor growth suppression efficacy in mice, were carried out using HP-beta-CD/PMX/ DCK/P188-NE.…”