DESENVOLVIMENTO E AVALIAÇÃO BIOLÓGICA DE FORMULAÇÕES DE NANOCÁPSULAS PARA TRATAMENTO DA DOENÇA DE CHAGAS EM MODELO MURINO

AUTOR(ES)
DATA DE PUBLICAÇÃO

2007

RESUMO

In the present work, the pharmaceutical development and physicochemical characterization of nanostructured formulations containing different anti-Trypanosoma cruzi drugs, such as the imidazole and azole derivatives were undertaken. The biological evaluation of these new formulations were also studied in vitro, in epimastigotes cultures of T. cruzi, and in vivo, in a murine model infected with different strains of T. cruzi, in both phases of disease development, acute and chronic. The main objective of this work was the evaluation of the activity and efficacy of the different formulations, by different routes and posologic regimens. Formulations containing benznidazole, miconazole, ketoconazole, itraconazole and also a new triazole derivative, albaconazole (UR-9825), were developed. The physicochemical characterisation was also undertaken by means of the atomic force microscopy, photon correlation spectroscopy and laser doppler anemometry. Among the drugs used in the biological tests of efficacy, albaconazole was the drug that presented the best results concerning parasitaemia reduction. Thus, physicochemical and structural features of the albaconazole formulations were analyzed in detail. In the present work, a new assay method of albaconazole based in UV spectroscopy was developed and used for the determination of the loading yield, loading efficiency and release kinetic of the drug from poli-e-caprolactone nanocapsules. The results showed that albaconazole was efficiently entrapped in nanocapsules with high yielding (100%), indicating that the drug has high affinity for the nanocapsules. The release kinetic was biphasic, with an initial release lower than 40% after 2h and an incomplete and slow release after 10 hours of incubation. A burst effect was observed in the first 2 hours that was clearly related to the release of ABZ associated to NC surface, evidenced also by the zeta potential alterations with the increasing of drug concentration in NC formulation. Different routes of administration, and dose regimens were used in this work, especially with ABZ. The ability of drug retention in the inner core of nanocapsules was observed in vivo, especially by the subcutaneous route, since the nanocapsules were able to prolong the time for parasitaemia reactivation after treatment and increase the number of animals with negative parasitological exams, even after 120 days after treatment, when compared with the free drug. The efficacy data suggests that free albaconazole is promptly released from tissue to the blood circulation, while nanocapsules probably retain the albaconazole in tissues for a longer time, reducing the available concentration in blood and the absorption rate, being in this case less active in the same doses. On the other hand, at higher doses (120mg/Kg) the free fraction of ABZ rapidly released by NC was enough to decrease parasitemia, while the fraction retained by NC produce the sustained effect of parasitemia reduction at longer times. This hypothesis could explain why lower doses (20mg/Kg) failed to efficiently reduce parasitemia. In this way, a profile of drug distribution in the body seems to be modified by using nanocapsules, at the same time that a significant reduction in general toxicity was observed with albaconazole associated to nanocapsules formulation. A sustained effect and lower incidence of toxic side effects were observed especially when albaconazole was administered at higher doses by subcutaneous route. From our results, the vectorization of imidazole and triazole drugs in NC was considered interesting, because the pharmacokinetics profile was altered producing the parasitemia reduction.

ASSUNTO(S)

imunobiologia de protozoários imunologia modelo murino doenÇa de chagas nanobiotecnologia nanocÁpsulas

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