RESUMO
Exemestane, a novel steroidal aromatase inactivator used in the treatment of advanced breast cancer has limited bioavailability (42%) due to poor solubility, extensive first-pass metabolism, and also the absorption is dependent on formulation type and food. The present study is aimed to evaluate the feasibility of proliposomes for transdermal delivery of exemestane. The prepared proliposomes were characterized for size, zeta potential, and entrapment efficiency. The size of the vesicles was found to be between 440 and 700 nm with high entrapment efficiency for the formulation containing greater amounts of phosphatidylcholine. Differential scanning calorimetry and Fourier transform infrared studies were performed to understand the phase transition behavior and mechanism for skin permeation, respectively. The drug release across cellophane membrane follows zero-order kinetics by diffusion. Ex vivo permeation enhancement assessed from flux, permeability coefficient, and enhancement ratio were significantly higher for proliposome gels compared with control. A significant improvement in the bioavailability (2.4-fold) was observed from optimized proliposome gel compared with control (oral suspension). The stability data reveal that the formulations are more stable when stored at 4°C. In conclusion, proliposomal gels offer potential and prove to be efficient carriers for improved and sustained transdermal delivery of exemestane.
Assuntos
Androstadienos/administração & dosagem , Androstadienos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Pele/metabolismo , Administração Cutânea , Androstadienos/química , Androstadienos/toxicidade , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos , Estabilidade de Medicamentos , Géis , Técnicas In Vitro , Lipossomos , Masculino , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Permeabilidade , Transição de Fase , Ratos , Ratos Wistar , Reologia , Pele/ultraestrutura , Absorção Cutânea , Testes de Irritação da Pele , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Propriedades de SuperfícieRESUMO
Amphotericin B remains the drug of choice for the treatment of invasive fungal infections and visceral leishmaniasis. However, both the dose-dependent nephrotoxicity and the low response rates (10-80%) associated with amphotericin B limit its clinical use. The first marketed formulation of amphotericin B with deoxycholate, Fungizone, remains the "gold standard" in spite of its renal toxicity. Several investigations have been made to reduce the nephrotoxicity of amphotericin B by formulation strategies. Lipid-based formulations of amphotericin B were found to reduce toxicity and to increase tolerance and therapeutic efficacy. Three lipid formulations are now available in most countries: liposomal amphotericin B (AmBisome), amphotericin B lipid complex and amphotericin B colloidal dispersion. Amphotericin B colloidal dispersion was less nephrotoxic, but immediate reactions to this formulation were as frequent and severe as those to amphotericin B. Amphotericin B lipid complex appeared to be as effective as amphotericin B, with improved general and renal tolerability. Several comparative studies have confirmed that AmBisome has similar or superior efficacy relative to amphotericin B in various fungal infections, in visceral leishmaniasis and also in the empirical treatment of febrile neutropenia. Renal and general tolerability is excellent. A significant drawback to the newer, less toxic, commercial lipid-based formulations is their cost. There is a need to develop more affordable lipid-based formulations of amphotericin B.
