Desenvolvimento e caracterização físico-química e biofarmacêutica de nano e microemulsões lipídicas de uso intravenoso contendo metildiidrojasmonato

• Autor(a) principal: Silva, Gisela Bevilacqua Rolfsen Ferreira da [UNESP]
• Data de Publicação: 2013
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Repositório Institucional da UNESP
• Texto Completo: http://hdl.handle.net/11449/108421
• topic: Agentes antineoplasicos; Fármacos; Reologia; Microscopia de polarização; Cancer; Rheology

The jasmonates are a new family of anti-cancer agents, natural and semi-synthetic, with proven efficacy against several tumor growth. These compounds exhibit a selective cytotoxic for tumor cells. Colloidal nanocarriers as micro (ME) and nanoemulsions (NE), provide drug release at the desired site of action while minimizing the side effects that often follow the use of conventional drugs. The methyl dihydro jasmonate (MJ) was added in order to obtain nanostructured systems with antineoplastic activity. Three phase diagrams were developed, one of them without drug, the second with drug and the third with MJ replacing the oil phase. Based on the phase diagrams 32 formulations were selected by varying the percentage of the oily phase (soya oil), of the surfactants (fatty acids salts, soya phosphatidylcholine and glycerol) and of the MJ. The formulations were analyzed by their physico-chemical characterization. With the technique of light scattering it was observed that the diameter of the droplets increased with the incorporation of the drug and with the increase of the MJ percentage. By increasing the surfactants percentage, the droplet diameter decreased in formulations without MJ and increased in formulations with the drug. With the oil phase increase the droplet diameter was reduced in formulations with and without MJ. The rheology evaluation syudied revealed that the flow behavior of the formulations ranged as newtonian, pseudoplastic, thixotropic, anti-thixotropic and reopetic. Based on the polarized light microscopy it was observed that the formulations, with and without MJ showed dark field with rare presence of Maltese cross. In the formulations where MJ was used as the oil phase, the presence of microscopic oil droplets was observed. The majority of the formulations exhibit characteristics of crystalline structures by X-ray diffraction. The SAXS curves show that, in the formulations without MJ, structural organization occurred when the oil phase was increased, the percentage of surfactants and the percentage of drug increased. A disruption has occurred when MJ was incorporated in the formulations. The zeta potential decreased in module when MJ was incorporated in the formulations and when the percentage of the drug increased. However, the zeta potential increased in module, in the formulations having MJ as the oil phase, as the percentage of oil phase and surfactant increased. In the in vitro release assay the ME and NE systems behaved as reservoirs delaying the release of MJ. Through the analysis of antitumor activity in vivo it can be observed that the percentage inhibition of tumor volume of MJ micellar solution exceeded the positive control, doxorubicin. As the concentration of MJ-ME increasing the percentage of tumor inhibition remained almost constant. The angiogenesis degree was lower for doxorubicin and micellar solution compared to the saline and the formulation without MJ. However, the groups treated with MJ-ME revealed a high degree of angiogenesis. The average weight of the tumors was higher in the groups treated with saline and with the formulation without MJ and lower for those treated with doxorubicin and MJ micellar solution. As for the groups treated with MJME there was reduction of the weight tumors as the MJ concentration increased on the ME. It was possible to obtain sustained release systems, micro and nanoemulsions, able to carry and direct the MJ in order to reach tumor cells allowing intravenous administration.