Enhanced buccal mucosal retention and reduced buccal permeability of estradiol in the presence of padimate O and Azone: a mechanistic study.

In previous experiments, it was suggested that the reduction in estradiol (E2) buccal permeability after pretreatment with some skin penetration enhancers was attributed to enhanced membrane storage. To verify this, further in vitro permeability experiments were performed and the kinetics of E2 buccal mucosal uptake and permeability was assessed. Porcine buccal mucosa was pretreated with the skin penetration enhancers octisalate, padimate O (PO), or Azone (AZ) and placed in modified Ussing chambers. The disappearance of E2 from the donor chamber and appearance of E2 in the receptor chamber was then monitored over 4 h. The final concentration of E2 associated with the buccal mucosa and donor chamber walls in the presence of each enhancer was also determined. The rate of E2 disappearance from the donor chamber was 3.1-fold greater than the rate of E2 appearance in the receptor chamber, indicating significant membrane storage of E2. Pretreatment with PO and AZ significantly increased the rate of E2 disappearance and reduced the rate of E2 appearance in the receptor chamber. The corresponding enhancement in E2 tissue concentration after PO and AZ pretreatment was 1.7- and 3-fold, respectively. However, PO and AZ also increased the amount of E2 adsorbed to the walls of the donor chamber, which contributed to the reduction in E2 flux through the buccal mucosa.