ESTRADIOL PERMEATION THROUGH HUMAN SKIN AND SILASTIC MEMBRANE - EFFECTS OF PROPYLENE-GLYCOL AND SUPERSATURATION

One approach to transdermal permeation enhancement investigated in this paper is to increase the thermodynamic activity of a drug in the transdermal delivery system to supersaturation levels. Saturated solubilities of the model drug oestradiol (OE) in different concentrations of propylene glycol/water (PG/W) co-solvent systems were determined. Utilising the saturated solubility curve, a series of OE supersaturated solutions at different multiples of saturation in PG/W systems was prepared using a mixed co-solvents method. Antinucleating polymers including hydroxypropylmethylcelluose (HPMC), hydroxypropylcelluose (HPC), polyvinyl alcohol (PVA), polyvinylpynolidone (PVP) and polyethylene glycols, 4000 and 8000 (PEG 4000 and PEG 8000), were used to stabilise the supersaturated solutions. All but the PEGs were able to retard the crystallisation of OE and polyvinylpyrrolidone (MW 40 000) was the most efficient. Mass transport characteristics of OE from saturated and supersaturated solutions through human skin and silastic membranes were then examined using an automated diffusion apparatus. OE flux was enhanced from saturated solutions with increased PG concentration. This increase was attributed to increased OE solubility in the membrane. Also, uptake of OE by human stratum corneum and silastic membrane from supersaturated solution was determined. The results were compared with those from saturated solutions having the same PG/W co-solvent compositions. Generally, both the uptake and flux of OE through both human skin and silastic membrane increased with increasing degree of saturation. Stratum corneum showed an 18.8 +/- 4.88 times increase in uptake from a supersaturated solution of 18 times saturation. OE flux through human skin from a solution of 18 times saturation increased about 13-fold during the 12 h experiment when compared with the flux from saturated solution.