Novel solid dispersions of benznidazole: Preparation, dissolution profile and biological evaluation as alternative antichagasic drug delivery system

摘要

Solid dispersions (SD) of benznidazole (BNZ) in sodium deoxycholate (NaDC) or low-substituted hydroxypropylcellulose (L-HPC) were developed by freeze-drying process to improve the solubility of this low water-soluble drug and consequently, its trypanocidal activity. Although the dissolution studies showed a progressive decrease in the release rate of BNZ when formulated in the presence of NaDC, the increase in the surfactant concentration resulted in a better trypanocidal profile on epimastigotes, as well as in an enhancement of the unspecific cytotoxicity. However, such an effect was not so evident on amastigotes and in vivo (blood-trypomastigotes), where high concentrations of surfactant (BNZ:NaDC >= 1:6) experimented a loss of activity, correlating this fact with the minor cession of BNZ these formulations accomplished in acidic locations (i.e., dissolution test medium). According to the in vitro results, we reformulated the promising SD-1:3 (IC50 epimastigotes = 33.92 +/- 6.41 mu M, IC50 amastigotes = 0.40 +/- 0.05 mu M and LC50 = 183.87 +/- 12.30 mu M) replacing NaDC by L-HPC, which achieved the fastest dissolution profile. This fact, together with the safety this carrier ensures (LC50 > 256 mu M), prompted us to evaluate the cellulose SD in vivo, improving the effectiveness of its NaDC equivalent (%AUPC = 96.65% and 91.93%, respectively). The results compiled in the present work suggest these solid dispersions as alternative drug delivery systems to improve the limited chemotherapy of Chagas disease. (C) 2015 Elsevier Inc. All rights reserved.