A lipophilic drug, 17-beta-estradiol (E2), and two enhancers, Isopropyl Myristate (IPM) and Glycerol Monooleate (GO), were dissolved in an acrylic pressure sensitive adhesive (DUROTAK(R) 87-2516, DTM) to manufacture a supersaturated dissolution matrix transdermal delivery system. The analysis of variance (alpha = 0.05) on the in vitro experimental data showed that the cumulative amount of E2 penetrated from 2-6% E2 (w/w) DTM with 20%(w/w) IPM was not statistically different. When 16% (w/w) crystal inhibitor, polyvinylpyrrolidone (PVP, average M.W. ca. 10,000), was mixed in DTM, the in vitro cumulative penetration amount of E2 increased proportionally to the concentration of E2 up to 6% (w/w). The cumulative penetration amount of E2 obtained from 4% E2 (w/w) DTM with 20% IPM (w/w) and 16% PVP (w/w) reached 70.0 mug/cm(2) at 24 It, and was about 12-fold higher than that from 1% E2 (w/w) DTM. CCD micrograph and X-ray diffraction analysis demonstrated that the enhancers accelerated the crystallization process, but PVP delayed or inhibited this process and maintained the degree of saturation (DS) of E2 in an extended period. The synergistic enhancement can be attributed to the E2 supersaturated dissolution maintained by crystallization inhibitor and alter the solubility and/or diffusion coefficient of E2 in stratum corneum by the chemical enhancers.