RESUMO
PURPOSE: To obtain and characterize reverse hexagonal phase nanodispersions of monoolein and oleic acid, and to evaluate the ability of such system to improve the skin penetration of a model peptide (cyclosporin A, CysA) without causing skin irritation. METHODS: The nanodispersion was prepared by mixing monoolein, oleic acid, poloxamer, and water. CysA was added to the lipid mixture to obtain a final concentration of 0.6% (w/w). The nanodispersion was characterized; the skin penetration of CysA was assessed in vitro (using porcine ear skin mounted in a Franz diffusion cell) and in vivo (using hairless mice). RESULTS: The obtainment of the hexagonal phase nanodispersion was demonstrated by polarized light microscopy, cryo-TEM and small angle X-ray diffraction. Particle diameter was 181.77 +/- 1.08 nm. At 0.6%, CysA did not change the liquid crystalline structure of the particles. The nanodispersion promoted the skin penetration of CysA both in vitro and in vivo. In vitro, the maximal concentrations (after 12 h) of CysA obtained in the stratum corneum (SC) and in the epidermis without stratum corneum (E) + dermis (D) were approximately 2 fold higher when CysA was incorporated in the nanodispersion than when it was incorporated in the control formulation (olive oil). In vivo, 1.5- and 2.8-times higher concentrations were achieved in the SC and [E+D], respectively, when the nanodispersion was employed. No histopathological alterations were observed in the skin of animals treated with the nanodispersion. CONCLUSION: These results demonstrate that the hexagonal phase nanodispersion is effective in improving the topical delivery of peptides without causing skin irritation.
Assuntos
Ciclosporina/metabolismo , Fármacos Dermatológicos/metabolismo , Portadores de Fármacos/química , Glicerídeos/química , Nanopartículas , Ácido Oleico/química , Absorção Cutânea , Administração Tópica , Animais , Química Farmacêutica , Ciclosporina/administração & dosagem , Ciclosporina/química , Fármacos Dermatológicos/administração & dosagem , Cultura em Câmaras de Difusão , Portadores de Fármacos/administração & dosagem , Fluoresceína-5-Isotiocianato , Corantes Fluorescentes , Cristais Líquidos , Masculino , Camundongos , Camundongos Pelados , Pele/efeitos dos fármacos , Pele/metabolismo , Suínos , Tecnologia Farmacêutica/métodosRESUMO
Reverse cubic and hexagonal phases of monoolein have been studied as drug delivery systems. The present study was aimed at investigating whether these systems enhance the cutaneous penetration of cyclosporin A (CysA) in vitro (using porcine ear skin) and in vivo (using hairless mice). Different mesophases were obtained depending on CysA concentration. CysA at 4% allowed the formation of reverse cubic and hexagonal phases in a temperature range of 25-40 degrees C. At 8%, CysA induced the formation of other phases, which might be due to an interaction between the polar groups of the peptide and monoolein. In vitro, the cubic phase increased the penetration of CysA in the stratum corneum (SC) and epidermis plus dermis ([E+D]) at 12 h post-application. The reverse hexagonal phase increased CysA penetration in [E+D] at 6 h and percutaneous delivery at 7.5 h post-application. In vivo, both liquid crystalline phases increased CysA skin penetration. Topical application of these systems, though, induced skin irritation after a 3-day exposure. These results demonstrate that liquid crystalline systems of monoolein are effective in optimizing the delivery of peptides to the skin. The skin irritation observed after topical application of cubic and hexagonal phases should be minimized for their safe use as topical delivery systems.