Development of self-emulsifying drug delivery systems (SEDDS) to improve the bioavailability of a new antileishmanial drug.

PURPOSE: Different self-emulsifying drug delivery systems (SEDDS) were developed to improve the poor oral bioavailability of the bis(pyridine-2-carboxamidine) compound JNII40, a promising new oral antileishmanial drug.

METHODS

Solubility, Particle size, transmission microscopy, precipitation, and permeability assays were used to characterize the formulations. Different pharmacokinetic parameters such as maximum concentration (Cmax), concentration at 24 h (C24h), half-life (t1/2), bioavailability and plasma concentrations above IC50 value were used to evaluate a possible relationship with the efficacy of these formulations.

RESULTS

SEDDS with hydrophilic solvents F1 showed higher solubility values (4.09 ± 0.65 mg/mL) and rapid precipitation in simulated intestinal medium. However, SEDDS with less hydrophilic solvents (F6) showed lower solubility (1.69 ± 0.07 mg/mL) but exhibited high supersaturation concentrations at pH 6.8. Permeability assays intestinal tissue demonstrated that SEDDS F6 exhibited a high increase in intestinal absorption (2.51-fold at 2 h compared to JNII40). These good results were related to the absence of transcutol® HP and a high Capryol® 90 ratio in its composition. Pharmacokinetic results for SEDDS F6 given as a single oral dose of 2 mg/kg of JNII40 showed a significant increase in the Cmax (1.28-fold), C24h (1.18-fold) and bioavailability (1.21-fold) compared to the active ingredient. The SEEDS formulation showed plasma concentrations up to 3 × IC50 against L. donovani intracellular amastigotes during 24 h.

CONCLUSIONS

The bioavailability improvement of JNII40 with SEDDS displaying high C24h and t1/2 values is relevant. Hence, these SEDDS should be considered as drug delivery system for oral administration of this antileishmanial drug.