Benznidazole polymeric nanoparticles for the optimization of Chagas disease treatment

OKULIC C.; SALOMON C.; SEREMETA K.

Ciudad Autónoma de Buenos Aires

Congreso; DRUG DISCOVERY FOR NEGLECTED DISEASES INTERNATIONAL CONGRESS 2018; 2018

Nearly 6 million to 7 million people worldwide are estimated to be infected with Trypansosoma cruzi, the parasite that causes Chagas disease [1]. Benznidazole (BNZ) is the drug of choice for the treatment of this disease, however, it exhibits low aqueous solubility limiting their dissolution and oral bioavailability [2]. Thus, several strategies have been used to improve the solubility and dissolution of BNZ [3]. Therefore, the aim of this work was to enhance its dissolution rate using nanostructured systems as carriers, by formulating BNZ-loaded nanoparticles through the nanoprecipitation method. Acrylic/methacrylic copolymer and BNZ were dissolved in acetone (polymer:drug ratio 2.5:1); and Pluronic® F68 surfactant was dissolved in distilled water. The organic phase was injected on the aqueous phase at constant flow rate (20 mL/h). The resulting suspension was stirred at room temperature to allow the complete evaporation of acetone. Then, this suspension was filtered and the supernatant was frozen at -20°C and freeze-dried (48 h). The characterization of the nanoparticles was carried out by Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC) and Dynamic Light Scattering (DLS). The encapsulation efficiency (%EE) and loading capacity (%LC) were determined by UV-visible spectrophotometry. Polymer/drug interactions were analysed by attenuated total reflectance/Fourier transform-infrared spectroscopy (ATR/FT-IR). The in vitro release of BNZ from the nanoparticles was assessed by the dialysis bag method using 0.1 N HCl (pH 1.2, 37 ± 1 °C) as release medium. The dissolution profiles were compared using the dissolution efficiency (DE) at 20 min (DE20) and 120 min (DE120). Results showed that the yield (%) after freeze-drying process was high (~85%). The %EE and %LC of the nanoparticles was 96% and 18% w/w, respectively. SEM and DLS analysis showed spherical particles with submicrometer size before and after freeze-drying (201 and 242 nm respectively), low polydispersity index (0.099-0.186) and positive zeta potential (+37.4). FT-IR spectra of nanoparticles showed characteristic bands of BNZ suggesting that part of drug remained on their surface while thermal analysis revealed that the drug crystallinity after process decreased. In vitro release studies showed an increase of more than twice in the dissolution rate of drug from nanoparticles. It could be due to the reduction of size and reduced crystallinity of the drug and to that part of BNZ remained on the surface of particles. This study demonstrates that nanoprecipitation is an effective method to enhance the dissolution rate of BNZ and could be used in treatment optimization.