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Hydrophilic albumin microspheres are proposed as a new delivery system for amphotericin B (AMB; AMB microspheres). The acute toxicity of AMB microspheres was lower than that of the AMB-deoxycholate (AMBDoc) reference formulation in hamsters. Lethal doses in healthy and infected animals were improved at least eight times. Intravenous bolus administration of doses of AMB microspheres up to 40 mg/kg of body weight did not produce acute symptoms of toxicity. The efficacy of this new formulation was tested against Leishmania infantum-infected hamsters at doses of 2, 10, 20, and 40 mg/kg. With the 2-mg/kg dose, the activity of AMB, as assessed through the parasite load reductions in the liver and spleen and the evolution of antibody levels, was also improved (P < 0.05) by use of the AMB microsphere system. At the higher doses of 10, 20, and 40 mg/kg, reductions in parasite levels of more than 99% were achieved in the liver and spleen after the administration of AMB microspheres. A pharmacokinetic study was performed to study the serum, liver, and spleen AMB concentrations after administration of AMB microspheres and the reference formulation. Interestingly, a significant accumulation of AMB in the spleen and liver was observed after AMB microsphere administration. Our results suggest that this new formulation is a promising alternative to the conventional AMB-Doc formulation for the treatment of visceral leishmaniasis.

An in vivo study has been performed in order to determine the influence of amphotericin B (AMB) molecular organization on the toxicity and activity of this drug in the treatment of experimental visceral leishmaniasis. Three formulations with similar composition but different drug molecular self-association in aqueous media were prepared. Acute toxicity was evaluated by injecting them in healthy hamsters. Sub-acute toxicity and efficacy were studied administering them to animals previously infected with Leishmania infantum. The preparation with drug molecules completely dissolved into monomers (formulation "C") and produced the highest acute toxicity. The formulation whose AMB molecules were disposed as non-water-soluble multi-aggregates (formulation "B") proved to provide the lowest acute toxicity. This formula also showed an improved activity, mainly in the liver, if compared with the third tested formulation containing AMB molecules disposed as smaller dimerical "water-soluble" aggregates (formulation "A"). As a conclusion, molecular aggregation in biological media should be an important factor to consider when researching or optimizing medicines containing AMB. The liberation of molecules as large dispersed non-water-soluble multi-aggregates seems to improve the narrow therapeutic margin attached to the use of this drug.

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This study investigated the combination of different proportions of cationic chitosan and anionic carboxymethyl cellulose (CMC) for the development of polyelectrolyte complexes to be used as a carrier in a sustained-release system. Analysis via scanning electron microscopy (SEM) Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) confirmed ionic interactions occur between the chitosan and carboxymethyl cellulose chains, which increases drug entrapment. The results of the dissolution study in acetate buffer (pH 4.2) showed significant increases in the kinetic profiles of clarithromycin for low proportions of chitosan/carboxymethyl cellulose tablets, while the tablets containing only chitosan had high relaxation of chitosan chains and disintegrated rapidly. The Korsmeyer–Peppas kinetic model for the different interpolymer complexes demonstrated that the clarithromycin transport mechanism was controlled by Fickian diffusion. These results suggest that the matrix tablets with different proportions of chitosan/carboxymethyl cellulose enhanced the ionic interaction and enabled the prolonged release of clarithromycin.