title: Novel solid dispersions of benznidazole: preparation, dissolution profile and biological evaluation as alternative antichagasic drug delivery system.
abstract: 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 µM, IC₅₀ amastigotes = 0.40 ± 0.05 µM and LC₅₀ = 183.87 ± 12.30 µM) replacing NaDC by L-HPC, which achieved the fastest dissolution profile. This fact, together with the safety this carrier ensures (LC₅₀ > 256 µM), 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.
authors.affiliation: CEI Campus Moncloa, UCM-UPM & CSIC, Madrid, Spain; Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Pza. Ramón y Cajal s/n, Madrid 28040, Spain. Electronic address: crfonseca@pdi.ucm.es.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fonseca-Berzal
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid, Pza. Ramón y Cajal s/n, Madrid 28040, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Palmeiro-Roldán
authors.affiliation: CEI Campus Moncloa, UCM-UPM & CSIC, Madrid, Spain; Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Pza. Ramón y Cajal s/n, Madrid 28040, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Escario
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid, Pza. Ramón y Cajal s/n, Madrid 28040, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Torrado
authors.affiliation: CEI Campus Moncloa, UCM-UPM & CSIC, Madrid, Spain; Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), c/ Juan de la Cierva 3, Madrid 28006, Spain.
authors.forename: Vicente J
authors.initials: VJ
authors.lastname: Arán
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid, Pza. Ramón y Cajal s/n, Madrid 28040, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Torrado-Santiago
authors.affiliation: CEI Campus Moncloa, UCM-UPM & CSIC, Madrid, Spain; Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Pza. Ramón y Cajal s/n, Madrid 28040, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Gómez-Barrio
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002482:Cellulose / Q000031:analogs & derivatives / Q000737:chemistry; D014355:Chagas Disease / Q000188:drug therapy*; D002756:Cholagogues and Choleretics / Q000737:chemistry; D003840:Deoxycholic Acid / Q000737:chemistry; D004339:Drug Compounding; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000469:parasitology; D005612:Freeze Drying; D006801:Humans; D020128:Inhibitory Concentration 50; D007928:Lethal Dose 50; D051379:Mice; D009593:Nitroimidazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D014344:Trypanocidal Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D002756:Cholagogues and Choleretics; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; D003840:Deoxycholic Acid; D002482:Cellulose; C008079:hydroxypropylcellulose; C009999:benzonidazole
keywords: Benznidazole; Dissolution rate; Low-substituted hydroxypropylcellullose; Sodium deoxycholate; Solid dispersions; Trypanocidal activity