Intravenous liposomal benznidazole as trypanocidal agent: increasing drug delivery to liver is not enough

Abstract

With the aim of investigating if delivery of benznidazole (BNZ) to liver could be increased by incorporating the drug in multilamellar liposomes, single bolus of free BNZ or liposomal BNZ formulations (MLV-BNZ) composed of HSPC:DSPG:Chol 2:1:2 (mol/mol/mol) at 0.7% (w/w) drug/total lipid ratio, were injected by intramuscular (i.m.), subcutaneous (s.c.) and intravenous (i.v.) routes, at 0.2 mg BNZ/kg, in rats. The resulting blood concentrations were followed along 9 h post-injection (p.i.) and drug accumulation in liver was determined after 4 and 9 h p.i. Only upon i.v. injection of MLV-BNZ, a threefold higher BNZ accumulation in liver was obtained, together with blood BNZ concentrations of 1.1 g/ml (30% lower than the blood BNZ concentration achieved upon i.v. administration of free drug) occurred 4 h p.i. However, such increased liver uptake of BNZ, raised twice a week had no effect on parasitaemia levels of mice infected with the RA strain of Trypanosoma cruzi. Our results indicate that the relationship between increased selectivity for an infected tissue and therapeutic effect is not always straightforward, at least for the MLV-BNZ regimen used in the present study.

Benznidazole vs benznidazole in multilamellar liposomes: how different they interact with blood components?

“…Free or released BNZ can diffuse through the membrane from S to B, while liposomes, due to their size (nearly 1-3 µm) are retained (Morilla et al 2004). Before and after incubation under agitation for 1 h at 37°C, BNZ in compartment S was quantified as described in the previous item.…”

“…The drug was quantified in both fractions. The BNZ mass/plasma volume ratio used in the assays was 3.3 µg BNZ/ml plasma, resulting in 40-fold dilution of MLV-BNZ and corresponding to the concentration of MLV-BNZ injected by iv in rats (Morilla et al 2004).…”

“…The CL corresponding to MLV-BNZ was biphasic, initially fast and ending up at the same rate than that corresponding to free BNZ. The faster rate could be ascribed to the removal of liposomes from blood circulation, exhibiting a t 1/2 of 3.2 h, the same order than that required to achieve maximal accumulation in liver upon injection of a single bolus of MLV-BNZ (Morilla et al 2004). The lower rate corresponds to removal of released BNZ.…”

Improving the solubility of the antichagasic drug benznidazole through formation of inclusion complexes with cyclodextrins

“…Several techniques, such as solid dispersion, 4 sol-emulsion, 5 inclusion complexation and conjugation with water-soluble polymer or cyclodextrin have been developed to enhance the solubility of various drugs. [6][7][8][9][10][11] The potential use of natural cyclodextrins (CDs) and their synthetic derivatives has been extensively studied as a way of improving certain drug properties, such as solubility, stability and/or bioavailability.…”

“…12,13 As yet few researchers have adopted technical approaches that aim to optimize the biopharmaceutical properties of BNZ and none of these have considered the development of a solid pharmaceutical form. Alternatives to a parenteral solution of BNZ found in the literature include the development of liposomes 2,4 and obtention of a ruthenium complex, trans-[Ru(Bz)(NH3) 4 SO 2 ](CF 3 SO 3 ) 2, 14 which alters the solubility of the compound and increases the effectiveness of the drug. However, no study involving BNZ has placed the drug in an inclusion complex, an approach that may hold promise for the development of a solid dosage form that is more appropriate than the one currently available.…”