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Artículo

Preclinical pharmacokinetics of benznidazole-loaded interpolyelectrolyte complex-based delivery systems

García, Mónica CristinaIcon ; Guzman, Maria LauraIcon ; Himelfarb, Martin Alejandro; Litterio, Nicolas Javier; Olivera, Maria EugeniaIcon ; Jimenez Kairuz, Alvaro FedericoIcon
Fecha de publicación: 09/2018
Editorial: Elsevier Science
Revista: European Journal Of Pharmaceutical Sciences
ISSN: 0928-0987
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Enfermedades Infecciosas

Resumen

Benznidazole (BZ), first-line drug for Chagas treatment, is available as immediate-release tablets. High frequency of administration, long-term therapy, and side effects of BZ conspire against treatment adherence, and negatively impact in therapeutic success. We have developed BZ-loaded interpolyelectrolyte complexes (IPECs) composed of polymethacrylates (EE-EL-BZ) or polysaccharides (Ch-AA-BZ) for controlled BZ release. This work aimed to evaluate their preclinical pharmacokinetics compared to Abarax® (reference treatment) and to correlate them with the in vitro BZ release. A randomization schedule with a 3 × 2 cross-over design was used. Each healthy dog received a single oral dose of 100 mg of BZ from EE-EL-BZ, Ch-AA-BZ or Abarax®. BZ quantification was performed in plasma by a validated HPLC-UV method. Moreover, in silico simulations using the pharmacokinetic software PK Solutions 2.0™ were calculated for the multiple-dose administration at two dose regimens: 100 mg of BZ administered every 12 and 24 h. Also, the relationship between in vitro dissolution and in vivo plasma BZ concentration profiles in a single step was model for IVIVC analysis. BZ was rapidly absorbed from all formulations. The Cmax value for Ch-AA-BZ was 32% higher than reference (p < 0.05) and an earlier Tmax (4.2 h) was observed as compared to EE-EL-BZ (6.0 h). For both IPECs, the Tmax values were higher (p < 0.05) and the areas under the curve were 25% greater than those of Abarax® (p < 0.01). Despite these variations in pharmacokinetics parameters, simulations of once or twice daily dosing showed that all formulations reached a steady-state range concentration above of the minimum therapeutic dose while avoiding high BZ concentrations related to increased side effects. A linear level A IVIVC model was established using plasma concentration profiles and dissolved data obtained. Thus, BZ-loaded IPECs prolonged drug release and formulated as capsules showed improved in vivo performance, in terms of bioavailability and Tmax values, which were significantly higher compared to Abarax®. These BZ carrier systems would be useful for oral administration in the treatment of Chagas disease.
Palabras clave: BENZNIDAZOLE , CHAGAS DISEASE , DRUG DELIVERY , POLYELECTROLYTE COMPLEXES , PRECLINICAL PHARMACOKINETIC
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Atribución-NoComercial-SinDerivadas 2.5 Argentina (CC BY-NC-ND 2.5 AR)
Identificadores
URI: http://hdl.handle.net/11336/91222
URL: https://linkinghub.elsevier.com/retrieve/pii/S0928098718303038
DOI: https://doi.org/10.1016/j.ejps.2018.07.005
Colecciones
Articulos(UNITEFA)
Articulos de UNIDAD DE INVESTIGACION Y DESARROLLO EN TECNOLOGIA FARMACEUTICA
Citación
García, Mónica Cristina; Guzman, Maria Laura; Himelfarb, Martin Alejandro; Litterio, Nicolas Javier; Olivera, Maria Eugenia; et al.; Preclinical pharmacokinetics of benznidazole-loaded interpolyelectrolyte complex-based delivery systems; Elsevier Science; European Journal Of Pharmaceutical Sciences; 122; 9-2018; 281-291
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