Solid dispersions based on poloxamer 407 as a strategy to improve Benznidazol bioperformance against Trypanosoma cruzi

CAROLINA DAVIES; FEDERICO RAMOS; JOSÉ MARÍA BERMUDEZ; ANALÍA SIMONAZZI; MARÍA CELIA MORA; SANTIAGO CAMPOS; LUIS ANTONIO PARADA

Ciudad Autónoma de Buenos Aires

Congreso; DRUG DISCOVERY FOR NEGLECTED DISEASES INTERNATIONAL CONGRESS 2018 - 4th Scientific Meeting of the Research Network Natural Products against Neglected Diseases; 2018

Consejo Nacional de Investigaciones Científicas y Técnicas - Facultad de Farmacia y Bioquímica - IQUIMEFA ? Universidad de Buenos Aires

Benznidazole (BZL) is the first-line treatment for Chagas Disease, caused by the protozoan parasite Trypanosoma cruzi. The complex life cycle of the parasite in the mammalian host, combined with the low solubility of BZL, require a long-term treatment at high doses for human patients. BZL is commercially available in 50 and 100 mg tablets (Abarax®). However, an area of growing interest is the development of new liquid formulations that improve BZL?s dissolution, bioavailability, and therapeutic efficacy. Poloxamer 407 (P407) is a GRAS-type polymer (Generally Recognized As Safe) according to Food and Drug Administration (USA), widely used in the pharmaceutic industry. Our aim was to evaluate P407 as a polymeric carrier in a solid dispersion of BZL (BZL-SD), and determine if P407 interfered with BZL activity in different T. cruzi lineages. BZL-SD were prepared by the fusion method followed by fast cooling with liquid nitrogen, using 32% w/w of BZL in P407. The effect of BZL-SD vs. BZL extracted from the commercial formulation (BZL-EX) [1] was compared using the inhibitory concentration 50 (IC50). To that aim, MTT assays modified for T. cruzi [2] were performed. Parasites belonging to lineages with high and low prevalence in northwest Argentina (TcV and TcI, respectively) [3], and the reference strain Tulahuén (TcVI) [4] were used. For lineages TcI, TcV, and TcVI, IC50 values for BZL-EX were 5,4 ± 0,9 µM; 8,3 ± 3,5 µM y 26,1 ± 0,9 µM, whereas; for BZL-SD were 10,2 ± 1,9 µM; 25,3 ± 11,3 µM y 33,1 ± 3,8 µM. Since SD were not prepared in sterile conditions, a low concentration of bacteria was detected at the highest SD concentration. Bacterial contaminants were diluted along with the formulation, affecting the colorimetric assay. Even though IC50 values for BZL-SD were slightly higher than BZL-EX, differences were not statistically significant. This result suggested that the trypanocidal activity of BZL was not altered in the SD (t-tests). ANOVA was performed to determine lineage susceptibilty. Statistically significant differences were found in lineages TcI and TcV vs. TcVI (p=0,001). These results indicated that TcI and TcV had a higher susceptibily towards BZL in comparison to TcVI. In conclusion, P407 was suitable to obtain a SD that maintained the trypanocidal activity of BZL. Therefore, if BZL-SD could be prepared in sterile conditions, P407 would be a promising carrier to design a BZL liquid formulation for oral use.