Mechanistic study of chemical skin permeation enhancers with different polar and lipophilic functional groups

In a previous study, the enhancement effects on the transport of a steroidal permeant along the hairless mouse skin (HMS) stratum corneum (SC) lipoidal pathway were investigated for two homologous series of chemical enhancers: the 1‐alkyl‐2‐pyrrolidones and the 1‐alkyl‐2‐azacycloheptanones. The objective of the present study was to extend this investigation to a broader range of enhancers in order that generalizations with regard to the mechanistic aspects of enhancer function might be established. Specific questions to be addressed included: (a) what is the nature of the microenvironment of the enhancer site of action? (b) what is the extent of the equilibrium uptake of the enhancer from its E = 10 aqueous enhancer solution (the aqueous concentration for which the enhancer induces a tenfold transport enhancement) into the HMS SC intercellular lipid “phase”? and (c) are the microenvironment of the enhancer site of action and that for the equilibrium enhancer uptake at E = 10 relatively independent of the molecular characteristics of the enhancers (as suggested by the earlier study)? Enhancers selected for this study included: a wide range of polar head group size and polarity; n ‐alkyl group chain lengths from C 4 to C 12 ; and enhancers in which a double bond is substituted for a single bond in the hydrocarbon chain (3‐alkenols) from C 5 to C 9 . In addition to the main study, an ancillary set of experiments were to be conducted on the partitioning of a surrogate permeant (estradiol) into the intercellular lipid “phase” under E = 10 isoenhancement conditions to assess the extent to which the permeant partition coefficient may contribute to the permeation enhancement. The following were the principal findings of this research. First, there was very good correlation between the E = 10 isoenhancement aqueous enhancer concentrations and K octanol/water for all the studied enhancers. Second, the partitioning of the enhancer from the E = 10 aqueous enhancer solution into the HMS SC intercellular lipid “phase” was found to be relatively independent of the molecular characteristics for all studied enhancers, and the partition coefficients also correlated well with K octanol/water . These results may have the following meanings: both the microenvironment of the enhancer site of action and the SC intercellular lipid “phase” involved in the enhancer partitioning experiments are well mimicked by liquid n ‐octanol, and the “intrinsic” potencies (as assessed by the equilibrium enhancer concentration in the microenvironment at the site of action) of the enhancers are relatively independent of the molecular characteristics of the studied enhancers. Finally, the estradiol partitioning experiments suggest the permeant partitioning into the HMS SC intercellular lipid “phase” is enhanced around five‐ to seven‐fold when permeation is enhanced ten‐fold for most of the studied enhancers; therefore, the enhancement of the permeant partition coefficient rather than the permeant diffusion coefficient seems to be more important in permeation enhancement of the SC barrier lipoidal pathway. © 2004 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1415–1430, 2004