Poly-ε-Caprolactone Implants for Benznidazole Prolonged Release: An Alternative to Chagas Disease Oral Treatment

Abstract

Benznidazole (BZ) tablets are the currently prescribed treatment for Chagas disease. However, BZ presents limited efficacy and a prolonged treatment regimen with dose-dependent side effects. The design and development of new BZ subcutaneous (SC) implants based on the biodegradable poly-ɛ-caprolactone (PCL) is proposed in this study for a controlled release of BZ and to improve patient compliance. The BZ–PCL implants were characterized by X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy, which indicated that BZ remains in its crystalline state dispersed in the polymer matrix with no polymorphic transitions. BZ–PCL implants, even at the highest doses, induce no alteration of the levels of hepatic enzymes in treated animals. BZ release from implants to blood was monitored in plasma during and after treatment in healthy and infected animals. Implants at equivalent oral doses increase the body’s exposure to BZ in the first days compared with oral therapy, exhibiting a safe profile and allowing sustained BZ concentrations in plasma to induce a cure of all mice in the experimental model of acute infection by the Y strain of T. cruzi. BZ–PCL implants have the same efficacy as 40 daily oral doses of BZ. Biodegradable BZ implants are a promising option to reduce failures related to poor adherence to treatment, with more comfort for patients, and with sustained BZ plasma concentration in the blood. These results are relevant for optimizing human Chagas disease treatment regimens.

Benznidazole-Loaded Polymeric Nanoparticles for Oral Chemotherapeutic Treatment of Chagas Disease

“…The lower treatment activity observed with the 24-treatment formulations compared to BZ may be attributed to the possibility of the slow release of drugs from formulations containing PEG and PCL polymeric carriers [ 52 , 84 ]. It is possible that BZ was released in concentrations insufficient to promote a reduction like that observed in treatments with free BZ at the concentrations mentioned.…”

“…Furthermore, polymeric carriers offer several advantages, including the potential to reduce adverse effects, increase drug stability, and improve the solubility and effects of the drug [ 86 , 87 ]. In this context, studies evaluating BZ dissolution in new formulations and in in vivo activity have demonstrated an increase in both dissolution and activity [ 84 , 88 , 89 , 90 ]. These findings suggest that the formulations presented in this work hold promise.…”

“…Nevertheless, the BNP1 formulation was able to reduce the number of infected cells compared to BZ at the lowest concentration, just as BNP1 and BNP2 were able to reduce the number of amastigotes at 3.90 µg/mL (Figures 7C,D and 8). The lower treatment activity observed with the 24-treatment formulations compared to BZ may be attributed to the possibility of the slow release of drugs from formulations containing PEG and PCL polymeric carriers [52,84]. It is possible that BZ was released in concentrations insufficient to promote a reduction like that observed in treatments with free BZ at the concentrations mentioned.…”

“…It is possible that BZ was released in concentrations insufficient to promote a reduction like that observed in treatments with free BZ at the concentrations mentioned. At 48 h after the treatments, in addition to the The lower treatment activity observed with the 24-treatment formulations compared to BZ may be attributed to the possibility of the slow release of drugs from formulations containing PEG and PCL polymeric carriers [52,84]. It is possible that BZ was released in concentrations insufficient to promote a reduction like that observed in treatments with free BZ at the concentrations mentioned.…”