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

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

BUENOS AIRES

Congreso; Drug Discovery for Neglected Diseases International Congress 2018 4th Scientific Meeting of ResNet NPND; 2018

Benznidazole (BZL) is the first-line treatment for Chagas Disease, caused by the protozoan parasite Trypanosoma cruzi. The 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. 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 method of fusion followed by fast cooling with liquid nitrogen, using 32% w/w BZL in P407. The effect of BZL-SD vs. BZL extracted from the commercial formulation (BZL-EX) (Abarax®)[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], as well as a the reference strain Tulahuén [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; while for BZL-SD were 10,2 ± 1,9 µM; 25,3 ± 11,3 µM y 33,1 ± 3,8 µM. The higher IC50 values in BZL-SD is explained by the presence of impurities that could not be removed, and affected the colorimetric assay. Comparisons of IC50 intra-lineage (t-test) were carried out to evaluate the trypanocidal activity of both formulations. Even though IC50 values for BZL-SD were slightly higher than BZL-EX, these differences were not statistically significant. This result suggested that the trypanocidal activity of BZL was not altered in the SD. Comparisons between lineages (ANOVA) were carried out for each formulation to determine lineage susceptibility. Statistically significant differences were found in lineages TcI and TcV vs. TcVI. These results suggested a higher susceptibly towards BZL for TcI and TcV in comparison to TcVI. In conclusion, P407 was suitable to obtain a SD that maintained the trypanocidal activity of BZL. Therefore, P407 is a promising carrier to design a BZL liquid formulation.