Mechanistic studies of the 1-alkyl-2-pyrrolidones as skin permeation enhancers.

The influences of 1-ethyl-, 1-butyl-, 1-hexyl-, and 1-octyl-2-pyrrolidone in their saline solutions on the transport of beta-estradiol, corticosterone, and hydrocortisone across hairless mouse skin under in vitro conditions have been investigated by the physical model approach. The experimental data were interpreted with a physical model that treats the stratum corneum as a diffusional barrier with a lipoidal pathway and a pore pathway. Enhancement factors (E values) for the lipoidal pathway were calculated from the permeability coefficients and solubility data as a function of the 1-alkyl-2-pyrrolidone concentration for all three permeants. A pattern of increasing E values with increasing 1-alkyl-2-pyrrolidone chain length was found, and the results were essentially the same for all three steroidal permeants. A nearly semilogarithmic linear relationship was also obtained between the enhancement potency and the carbon number of the alkyl chain; there was about an approximately 3.5-fold increase in the enhancement potency per 1-alkyl-2-pyrrolidone methylene group. An important outcome of this research is that the enhancement potencies of the 1-alkyl-2-pyrrolidones were essentially the same as those for the previously studied n-alkanols when compared at the same carbon numbers of the alkyl groups. This result is somewhat surprising as it suggests that the enhancer action resides (in its entirety) in the alkyl group, and the nature of the polar head group may not be intrinsically important in transdermal enhancement of the lipoidal pathway within a class of permeation enhancers.