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

Figures

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  Figure 1. Experimental design of in vivo experiments of efficacy and determination of benznidazole plasma concentration–time profiles during treatment with the different benznidazole formulations (oral doses and subcutaneous implants).

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  Figure 2. X-ray diffractogram of implants. (A) BZ–PCL implants. (B) BZ–PCL implants (green) and benznidazole (red). Red arrows indicate peaks that cannot be attributed to the pure drug. (C) BZ–PCL implants (green) and PCL implants (black). Red arrows indicate peaks that can be attributed to the diffraction profile of the implant without BZ.

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  Figure 3. Scanning electron microphotographs of benznidazole: (A) 90× magnification; (B) magnification of 220×. PCL implants without drug: (C) 45× magnification; (D) 150× magnification. BZ–PCL implants at magnifications: (E) 65×; (F) 150×; (G) 220×; (H) 240×; (I) 270×. The red arrows indicate BZ crystals.

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  Figure 4. Differential scanning calorimetry (DSC) curves of BZ–PCL3 implant (ratio 1:1.33) (red), blank-PCL implant (black) and pure benznidazole (blue), physical mixture of PCL + benznidazole (1:1.33) (green) and PCL polymer (purple).

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  Figure 5. Thermo-optic analysis of benznidazole (A–F) and analysis of the physical mixture of PCL and benznidazole (G–L). The red arrows indicate particles of the PCL polymer.

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  Figure 6. Levels of liver enzymes in the serum of animals treated with benznidazole. Levels of AST (aspartate aminotransferase) and ALT (alanine aminotransferase) detected in the serum of animals infected by strain Y, treated for 20 or 40 days with benznidazole. The samples were collected on the last day of treatment. The AST and ALT levels in untreated animals were measured on the 15th day of infection. a = significant difference from infected untreated; b = significant difference from uninfected untreated control.

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  Figure 7. Benznidazole plasma concentration–time profiles upon administration of BZ–PCL implants (upper graph) and crushed tablet coarse suspension administered by gavage (lower graph), in healthy and T. cruzi-infected mice. Bars are standard deviations (n = 3 per group). Pharmacokinetic parameters were calculated and are shown in Table 4.