Percutaneous absorption of nafarelin acetate, an LHRH analog, through human cadaver skin and monkey skin

Abstract

The in vitro skin metabolism and skin permeability of nafarelin acetate, an LHRH analog, through human cadaver skin were investigated. No appreciable metabolic degradation of nafarelin acetate in skin homogenate at pH 5.0 was observed. On the other hand, at pH 7.4, the metabolism of nafarelin acetate by skin homogenate was observed, indicating that skin metabolism of nafarelin acetate is pH dependent. The solubilities of nafarelin acetate in the polyhydroxylated vehicles were several fold higher than those in the monohydroxylated vehicles. The permeability of nafarelin acetate through cadaver skin from various vehicle formulations was evaluated using modified Franz diffusion cells. The skin flux of nafarelin acetate from a propylene glycol (PG)/Azone® vehicle was 0.14 μg/cm 2 per h. When glyceryl monooleate (GMO) was incorporated into the PG/Azone vehicle mixture, the flux increased by a factor of 1.6. The flux of nafarelin acetate was also determined from a formulation containing ethanol/Azone/GMO (8:1:1). At several fold higher drug concentration, only a 2-fold higher flux was observed compared to the PG/Azone/GMO (8:1:1) formulation. The steady-state lag time ranged from 24 to 40 h. The flux of nafarelin acetate from two vehicle formulations through monkey skin and human cadaver skin was compared. Monkey skin was slightly more permeable than human cadaver skin.