Enhancement of hydrocortisone permeation of human and hairless mouse skin by 1-dodecylazacycloheptan-2-one.

The influence of 1-dodecylazacycloheptan-2-one (Azone) on the in vitro permeation of hairless mouse skin and human epidermis by hydrocortisone was studied as a function of the amount of Azone solubilized and/or emulsified into aqueous media applied to the membranes using the infinite-dose technique. The permeability-enhancing effect of Azone increases with increasing Azone total concentrations until 0.1% is reached with mouse skin and 0.01% is reached for human epidermis. Thereafter, permeabilities for both tissues drop systematically. The maximally enhanced permeability in mouse skin approached that for mouse skin stripped of its stratum corneum. The peak permeability in human epidermis is an order of magnitude smaller than for mouse skin with the duration of Azone treatment required to achieve the full effect in human epidermis being twice that for mouse skin (approximately 20 h vs approximately 12 h). Thus, there is a profound difference in Azone's action on these two tissue types. It was also established that the affinity of an enhancer for a permeant drug can significantly offset its ability to enhance permeability. Specifically, hydrocortisone was found to partition significantly into the Azone-rich phase of the emulsion, lowering its concentration (and its thermodynamic activity) in the continuous aqueous phase and thereby reducing its flux through the skin. This physiochemical effect was profound enough to nullify the intrinsic permeability-enhancing effect of Azone as the total Azone concentration was raised to 10%.