Benznidazole solid dispersions: a new strategy to improve treatment of Trypanosoma cruzi infection

DAVIES, C.; SIMONAZZI, A.; RAGONE, P.; CID, A. G.; SÁNCHEZ NEGRETE, O.; MORA, M. C.; RAMOS, F.; BERMÚDEZ, J. M.; PARADA, L. A.

Buenos Aires

Otro; Reunión Conjunta de Sociedades de Biociencias; 2017

Benznidazol (BZL) and Nifurtimox are the only drugs approved to specifically treat T. cruzi infection. Both are orally administered, and can present adverse side effects or treatment failure. BZL, the first-line treatment in Argentina, is a molecule of low solubility in water, limited bioavailability, and is administered for long periods of time at high doses. One posibility to improve treatment lies in pharmaceutical formulations designed to increase water solubility of poorly soluble molecules. For that reason, a new liquid formulation based on an amphiphilic polymer (P) acting as a carrier of BZL was tested on mice models of acute and chronic T. cruzi infection. Female Swiss mice (N=57) were infected with Tulahuén strain (300 parasites/mouse for the acute phase model, and 50 parasites/mice for the chronic phase model). Treatments were given orally once a day, every day for 2 months, starting at 5 days post-infection (dpi) in the acute phase model, and 150 dpi in the chronic phase. Doses of BZL-P were: 15 mg/Kg/day, 60 mg/Kg/day, and 60 mg/Kg/day twice per week. Controls: placebo (PBS), and comercial formulation at 50 mg/Kg/day. Results showed that the effect of BZL was dose-dependent: higher doses (60 and 50 mg/Kg/day) were more effective in clearing parasites from blood and tissue than lower doses (15 mg/Kg/day). Intermittent administration of BZL (twice a week) was effective in reducing parasitaemia in blood, but it did not prevent the establishment of parasites in muscle or heart tissue. The new formulation was as effective as the commercial one at equivalent doses. Adverse effects were not detected. Being a liquid, the new formulation tested in these experiments may provide an alternative for better dosing, since commercial tablets must be divided and mashed to achieve a give dose. A liquid formulation of BZL could represent an improvement for treatment in children and adults.