Development of parenteral formulations and evaluation of the biological activity of the trypanocide drug benznidazole.
Chagas disease, caused by Trypanosoma cruzi, is a major public health problem in Latin America. According to the World Health Organization, around 20 million people are infected and another 40 million are at risk of acquiring the disease. One of the drugs most frequently used for the treatment of Chagas disease is benznidazole (BZL). It is practically insoluble in water (0.4 mg/ml), which precludes the preparation of liquid dosage forms, in particular, parenteral formulations. Thus, the aim of this work was to investigate the solubilization of BZL at two pH values using various cosolvents such as ethyl alcohol, propylene glycol, polyethylene glycol 400, benzyl alcohol, diethylene glycol monoethyl ether (Transcutol) and surfactants such as polysorbates (Tween) 40 and 80, and sodium dioctyl sulfosuccinate (AOT). Solvent systems based on PEG 400, with the addition ethyl alcohol and/or potassium biphthalate buffer solution, increased the BZL solubility up to 10 mg/ml. These alcoholic vehicles showed no toxicity against parasite when assayed at 1%. Physical and chemical stability studies showed that the formulations were stable for at least 1.5 years. In agreement with the biological activity results, the selected formulations are suitable for further clinical studies. Moreover, increasing the aqueous solubility of BZL reduced the problems in vitro testing techniques and bioassays leading to more reliable results and/or reproducibility.
Lamas
María C
MC
Area Tecnología Farmacéutica, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina.
Villaggi
Luciano
L
Nocito
Isabel
I
Bassani
Georgina
G
Leonardi
Darío
D
Pascutti
Fernanda
F
Serra
Esteban
E
Salomón
Claudio J
CJ
D000818:Animals; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D004143:Dioctyl Sulfosuccinic Acid / Q000737:chemistry; D004355:Drug Stability; D000431:Ethanol / Q000737:chemistry; D009593:Nitroimidazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D021261:Parasitic Sensitivity Tests; D010795:Phthalic Acids / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011136:Polysorbates / Q000737:chemistry; D012997:Solvents / Q000737:chemistry*; D013501:Surface-Active Agents / Q000737:chemistry; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development
D009593:Nitroimidazoles; D010795:Phthalic Acids; D011136:Polysorbates; D012997:Solvents; D013501:Surface-Active Agents; D014344:Trypanocidal Agents; D004143:Dioctyl Sulfosuccinic Acid; D000431:Ethanol; D011092:Polyethylene Glycols; C009999:benzonidazole