Enhanced bioavailability and anthelmintic efficacy of mebendazole in redispersible microparticles with low-substituted hydroxypropylcellulose

Abstract

Paloma Marina de la Torre-Iglesias,1,2 Juan José García-Rodriguez,3 Guillermo Torrado,4 Susana Torrado,1,2 Santiago Torrado-Santiago,1,5 Francisco Bolás-Fernández3 1Department of Pharmaceutical Technology, Faculty of Pharmacy, Complutense University, Madrid, Spain; 2Institute of Industrial Pharmacy, Complutense University, Madrid, Spain; 3Department of Parasitology, Faculty of Pharmacy, Complutense University, Madrid, Spain; 4Department of Pharmaceutical Technology, Faculty of Pharmacy, Alcala University, Alcala de Henares (Madrid), Spain; 5Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain Background: Mebendazole (MBZ) is an extremely insoluble and therefore poorly absorbed drug and the variable clinical results may correlate with blood concentrations. The necessity of a prolonged high dose treatment of this drug increases the risk of adverse effects. Methods: In the present study we prepared redispersible microparticles (RDM) containing MBZ, an oral, poorly water-soluble drug, in different proportions of low-substituted hydroxypropylcellulose (L-HPC). We investigated the microparticulate structures that emerge spontaneously upon dispersion of an RDM in aqueous medium and elucidated their influence on dissolution, and also on their oral bioavailability and therapeutic efficiency using a murine model of infection with the nematode parasite Trichinella spiralis.Results: Elevated percentages of dissolved drug were obtained with RDM at 1:2.5 and 1:5 ratios of MBZ: L-HPC. Thermal analysis showed an amorphization of MBZ in the RDM by the absence of a clear MBZ melting peak in formulations. The rapid dissolution behavior could be due to the decreased drug crystallinity, the fast dissolution time of carriers as L-HPC, together with its superior dispersibility and excellent wetting properties. RDM-1:2.5 and RDM-1:5 resulted in increased maximum plasma concentration and area(s) under the curve (AUC)0–∞ values. Likewise, after oral administration of the RDM-1:2.5 and RDM-1:5 the AUC0–∞ were 2.67- and 2.97-fold higher, respectively, compared to those of pure MBZ. Therapeutic activity, assessed on the Trichinella spiralis life cycle, showed that RDM-1:5 was the most effective in reducing the number of parasites (4.56-fold) as compared to pure MBZ, on the encysted stage.Conclusion: The MBZ: L-HPC RDM might be an effective way of improving oral bioavailability and therapeutic activity using low doses of MBZ (5 mg/kg), which implies a low degree of toxicity for humans. Keywords: benzimidazole carbamates, redispersible microparticles, in vitro dissolution, pharmacokinetics, anthelmintic activity, Trichinella spiralis