Modulated dissolution rate from the inclusion complex of antichagasic benznidazole and cyclodextrin using hydrophilic polymer

Abstract

Benznidazole (BNZ) is the primary chemotherapeutic agent for treating Chagas' disease; however, its poor water solubility and irregular oral absorption lead to the treatment failure in the chronic phase. The aim of this work was to investigate the utility of the polymer hydroxypropyl methylcellulose (HPMC) in controlling the release of BNZ from solid inclusion complexes with cyclodextrin to overcome the problem of its bioavailability. Preliminary studies of solubility were conducted in solution using selected β-cyclodextrin derivatives according to an experimental mixture design. The best cyclodextrin composition was used to produce solid-state systems by kneading in the presence or absence of HPMC. The formulations were characterized by different physico-chemical techniques, including the dissolution rate. Hydroxypropyl-β-cyclodextrin (HPβCD) produced the greatest improvement in drug solubility and was selected for the development of solid systems. Assays confirmed the production of true inclusion complexes between BNZ and HPβCD. The dissolution rate of the BNZ-HPβCD system was markedly increased, while the presence of HPMC retarded drug release. An optimal formulation obtained by the combination of kneading systems developed in appropriate ratios could be a promising drug delivery system with a prolonged therapeutic effect coupled with more balanced bioavailability. The produced systems present interesting perspectives for Chagas' therapy.

Combining Cellulose and Cyclodextrins: Fascinating Designs for Materials and Pharmaceutics

“…Macromolecules such as CD immobilized polysaccharides (Yang and Yang, 2013 ), obtained from covalent and non-covalent binding strategies, encompass important features, including an excellent biocompatibility (Du et al, 2012 ; Boztas et al, 2013 ; Liu et al, 2015a ), nontoxicity (Krukiewicz and Zak, 2016 ), thermal and chemical stability (Wintgens et al, 2012 ; Iohara et al, 2017 ), high hydrophilicity (Lin and Dufresne, 2013 ; Sá-Barreto et al, 2013 ; Zhang et al, 2013 ), and biodegradability of the polysaccharides, as well as the unique amphiphilic and transport properties (Guo et al, 2013 ; Yang and Yang, 2013 ), and the ability for inclusion (Zhang et al, 2012 ; Guo et al, 2013 ; Liu et al, 2014 ; Nardello-Rataj and Leclercq, 2014 ; Higashi et al, 2016 ; Muankaew et al, 2017 ), size specificity (Higashi et al, 2016 ; Cova et al, 2018 ) and controlled release of CDs (Blanchemain et al, 2012 ; Lavoine et al, 2014b ; Han et al, 2017 ). These latter, presented in Figure 1 , are cyclic oligosaccharides with hydrophobic cavities and hydrophilic outer surfaces, which have been recognized as useful matrices.…”

“…HPMC has been the basis for guiding the release of such agents from solid CD-based host-guest complexes, ensuring the drug bioavailability. In turn, HP-β-CD produced a significant improvement in drug solubility being often selected for the development of solid systems (Sá-Barreto et al, 2013 ). New solid dosage forms with improved physicochemical properties and oral bioavailability have been developed, containing HP-β-CD and hydrophilic additives, obtained from supercritical antisolvent processes.…”

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

“…Controlled BZ release would reduce its adverse effects by avoiding high plasmatic BZ concentration (close to 20 mg/L), which are related to a greater risk of toxicity (Soy et al, 2015) and would allow a reduction in its frequency of administration, by maintaining effective concentrations (in the range of 3-6 mg/L) (Soy et al, 2015) for a longer period of time. Moreover, BZ is very slightly soluble in water (García et al, 2015;Kasim et al, 2004) which may have a direct impact on its bioavailability (Sá-Barreto et al, 2013).…”

Effects of benznidazole:cyclodextrin complexes on the drug bioavailability upon oral administration to rats

“…In particular, BZL is the drug of choice in the majority of the American countries and Europe and recommended for the acute and recent chronic phases, as well as, for congenital infection [4]. As already described, it is poorly soluble in water [5,6] which may have a direct impact into its bioavailability [7,8]. Thus, the improvement of BZL dissolution rate becomes crucial for achieving improved pharmacokinetic parameters.…”