ENHANCED PERCUTANEOUS-ABSORPTION OF A NOVEL TOPICAL CYCLOSPORINE-A FORMULATION AND ASSESSMENT OF ITS IMMUNOSUPPRESSIVE ACTIVITY

No clinically successful topical cyclosporin A (CyA) formulation has been produced, mainly due to the apparent lack of drug penetration. This study has produced the first in vitro kinetic data on CyA penetration across human cadaver stratum corneum and has shown that addition of the penetration enhancers (PE) Azone and propylene glycol to the CyA vehicle significantly enhanced drug permeation across the skin barrier. Using flow-through permeability cells with 5% w/v CyA (Sandimmun®) alone (CyA) or with PE (CyA + PE) in olive oil in the donor chamber, the penetration rate (mean ± SD μg/cm2/h) into receptor fluid was 53 ± 43 (n = 13) for CyA and 660 ± 175 (n = 7) for CyA + PE. The in vivo efficacy of this formulation was assessed in guinea-pigs undergoing delayed-type hypersensitivity (DTH) reactions to dinitrofluorobenzene (DNFB). CyA was applied topically at the time of challenge and twice daily thereafter. At 24 h, skin reactions revealed that compared with appropriate drug vehicles, concentrations of 0.25, 0.5 and 5% CyA ± PE had a significant inhibitory effect upon the erythema response and this corresponded with significant reductions in T-cell infiltrates (0.5 and 5% CyA). No statistically significant reductions in erythema were demonstrated with 0.05% CyA ± PE, but there was a reduction in the number of infiltrating lymphocytes in site receiving 0.05% CyA + PE compared with vehicle-treated sites (P < 0.01). This suggests that PE permitted some penetration of an otherwise non-immunosuppressive concentration of CyA through the skin.