Transdermal delivery of levonorgestrel. V. Preparation of devices and evaluation in vitro

Transdermal devices were prepared and evaluated for their ability to codeliver levonorgestrel and the permeation enhancers ethyl acetate and ethanol in vitro. The 24-hr devices were prepared with membranes composed of ethylene vinyl acetate (EVAc) copolymers. The vinyl acetate (VAc) content of the membranes (50 +/- 10 or 100 +/- 10 microns thick) was varied from 12 to 25% to give a range of permeabilities toward the enhancers. The reservoir used was ethyl acetate/ethanol (7:3, v/v; 0.5 ml) containing excess solid levonorgestrel and gelled with 2% hydroxypropyl cellulose. The higher VAc content membranes (18 and 25%) exhibited relatively high release rates of EtAc and EtOH leading to depletion of ethyl acetate and ethanol from the reservoir by the end of 24 hr. As a result, the transdermal flux of levonorgestrel, evaluated using rat skin, reached a maximum at about 8 hr and thereafter diminished to zero by 24 hr. The less permeable membranes (12 and 15% VAc content) led to a more sustained release of enhancers, but due to lower solvent delivery to the skin, levonorgestrel flux was substantially lower. There was a direct relationship between drug delivery through skin and the amount of solvent delivered until release of the enhancers had diminished. The potential use of ethyl acetate in transdermal drug delivery is also discussed.