Microemulsões biocompatíveis de anfotericina B para administração oral: estudo estrutural, liberação in vitro e farmacocinética pré-clínica
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Data
2009-08-20
Autores
Pestana, Kelly Chrystina [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Anfotericina B (AmB) é o fármaco de escolha para o tratamento das infecções fúngicas invasivas, importante causa de morbidade e mortalidade em pacientes imunodeprimidos. A toxicidade da AmB na forma convencional tem estimulado o desenvolvimento de novas formulações para a administração do fármaco. Neste trabalho foram estudadas microemulsões óleo/água, contendo fosfatidilcolina de soja/tween 20 como agentes tensoativos, CaptexTM 200 como fase oleosa e tampão fosfato 50mM pH 7,2 como fase aquosa, com o objetivo de reduzir a toxicidade e aumentar a absorção oral da AmB. Os sistemas obtidos com diferentes proporções dos componentes foram descritos através de um diagrama de fase pseudo-ternário. As microestruturas foram caracterizadas por espalhamento dinâmico de luz (DLS), reologia, microscopia de luz polarizada e espalhamento de raios X a baixo ângulo (SAXS). Foi desenvolvido e validado um método por CLAE para a determinação de AmB em plasma para aplicação em estudo do perfil farmacocinético do fármaco veiculado na ME em ratos. A nefrotoxicidade da AmB foi avaliada pela determinação da creatinina plasmática dos ratos após administração oral da nova formulação desenvolvida (50 mg/kg), e comparada à administração da formulação convencional na mesma dose. Foi observado que o tamanho das gotículas das microemulsões aumenta quando a AmB é incorporada ao sistema. As amostras apresentaram comportamento Newtoniano e, dependendo da composição do sistema, antitixotropia foi observada. Também foi observado que a viscosidade aumenta com o aumento da fase oleosa assim como a formação de estruturas lamelares ordenadas que são desfavorecidas com a adição do fármaco. A incorporação do fármaco depende das proporções de fase oleosa e tensoativo. As interações da AmB...
Amphotericin B (AmB) is the drug of choice for therapy of invasive fungal infections, an important cause of morbidity and mortality among immunodeficient patients. The high toxicity of AmB in its conventional formulation have induced the development of innovative formulations for the drug administration. In this work, oil-in-water microemulsions containing soya phosphatidylcholine/Tween® 20 (1:1) as surfactant, captexTM 200 as oil phase, and phosphate buffer 50mM, pH 7.2 as aqueous phase were studied in order to reduce AmB toxicity and increase its oral absorption. Systems obtained with different proportions of the components were described by pseudoternary phase diagram. The microstructures of the system were characterized by dynamic light scattering (DLS), rheological behavior, polarized light microscopy and small angle X-ray scattering (SAXS). Was developed and validated a fast and selective HPLC method to determine AmB for application to study of pharmacokinetic profile of drug in rats. The nephrotoxicity of AmB was assessed by determining of rat plasma creatinine after oral administration of the novel formulation (50 mg/kg) and comparing with it a conventional formulation in the same dose. It was observed that the oil droplets size increase when AmB is incorporated into the system. The samples presented Newtonian behavior depending on the system composition. An anti-thixotropic behavior was found, as well, the viscosity increases withthe oil phase. The data showed the formation of ordered structures with lamellar arrangements in the drug unloaded systems and that order decrease with the drug incorporation. The AmB incorporation into the system was dependent on both the oil phase and surfactant. The interactions of AmB with the systems can control both the drug solubility and release... (Complete abstract click electronic access below)
Amphotericin B (AmB) is the drug of choice for therapy of invasive fungal infections, an important cause of morbidity and mortality among immunodeficient patients. The high toxicity of AmB in its conventional formulation have induced the development of innovative formulations for the drug administration. In this work, oil-in-water microemulsions containing soya phosphatidylcholine/Tween® 20 (1:1) as surfactant, captexTM 200 as oil phase, and phosphate buffer 50mM, pH 7.2 as aqueous phase were studied in order to reduce AmB toxicity and increase its oral absorption. Systems obtained with different proportions of the components were described by pseudoternary phase diagram. The microstructures of the system were characterized by dynamic light scattering (DLS), rheological behavior, polarized light microscopy and small angle X-ray scattering (SAXS). Was developed and validated a fast and selective HPLC method to determine AmB for application to study of pharmacokinetic profile of drug in rats. The nephrotoxicity of AmB was assessed by determining of rat plasma creatinine after oral administration of the novel formulation (50 mg/kg) and comparing with it a conventional formulation in the same dose. It was observed that the oil droplets size increase when AmB is incorporated into the system. The samples presented Newtonian behavior depending on the system composition. An anti-thixotropic behavior was found, as well, the viscosity increases withthe oil phase. The data showed the formation of ordered structures with lamellar arrangements in the drug unloaded systems and that order decrease with the drug incorporation. The AmB incorporation into the system was dependent on both the oil phase and surfactant. The interactions of AmB with the systems can control both the drug solubility and release... (Complete abstract click electronic access below)
Descrição
Palavras-chave
Anfotericina B, Farmacocinetica, Liberação de fármacos - Sistemas, Drug delivery systems, Microemulsion, Amphotericin B, Pharmacokinetics
Como citar
PESTANA, Kelly Chrystina. Microemulsões biocompatíveis de anfotericina B para administração oral: estudo estrutural, liberação in vitro e farmacocinética pré-clínica. 2009. 108 f. Tese (doutorado) - Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas, 2009.