Mechanistic study of alkyl azacycloheptanones as skin permeation enhancers by permeation and partition experiments with hairless mouse skin

In previous studies (Yoneto et al., 1995. J Pharm Sci 84:312-317; Kim et al., 1992. Int J Pharm 80:17-31; and Warner et al., 2001. J Pharm Sci 90:1143-53), the transport enhancing effects of four homologous series of enhancers-the n-alkanols, 1-alkyl-2-pyrrolidones, 1,2-alkanediols, and N,N-dimethylalkanamides - on the transport of steroidal permeants across hairless mouse skin (HMS) were investigated. Isoenhancement concentrations are defined as the aqueous concentrations for which different enhancers induce the same extent of permeant transport enhancement, E, for the lipoidal pathway of the stratum corneum (SC). Our studies have shown that the E = 10 isoenhancement concentrations of these four homologous series were nearly the same when compared at the same n-alkyl group chain length and therefore that the contribution of the polar head group toward the enhancer potency was found to be essentially constant. In the present study, we have determined the isoenhancement concentrations (E = 10) for the 1-alkyl-2-azacycloheptanone series [1-butyl-2-azacycloheptanone (BAZ), 1-hexyl-2-azacycloheptanone (HAZ), and 1-octyl-2-azacycloheptanone (OAZ)] and compared the results with those of the previously studied four homologous series. We have found that the E = 10 isoenhancement concentrations (aqueous phase concentrations) of the 1-alkyl-2-azacycloheptanones (Azs) are around 10 times lower than those for the previously studied four homologous series when compared at the same alkyl group chain length. This indicates an approximately 10 times higher potency of Azs. This finding was a point of interest because the polar group of Azs is similar to that of 1-alkyl-2-pyrrolidones (Aps). To further probe the nature of the mechanism of action of the Azs and Aps and to better understand the lower E = 10 isoenhancement concentrations found with the Azs, it was decided (a) to determine the equilibrium partitioning (uptake) of the Azs and the Aps from the aqueous phase into the HMS SC at E = 10, and (b) to determine the equilibrium partitioning (uptake) of a surrogate permeant, estradiol (E2beta), into the SC in the absence of and in the presence of Azs and Aps at E = 10. The following were the outcomes from the two partitioning studies. Firstly, at the E = 10 isoenhancement concentrations, the extent of partitioning (uptake) of the Azs and Aps into the intercellular lipids of the HMS SC was found to be approximately the same, even though the E = 10 isoenhancement concentrations (aqueous phase concentrations) of the Aps were around 10 times greater than those of the Azs. We interpret this to mean (whereas the potencies of the Azs are around ten times greater than those of the Aps when related to their aqueous concentrations) that the potencies of the two enhancer series are about the same when expressed in terms of their concentrations in the intercellular lipid phase of the SC. Another outcome of the partitioning studies has been the finding that the extent of partitioning into the intercellular lipids of the SC at E = 10 isoenhancement conditions for both the Azs and Aps is essentially independent of the n-alkyl chain length (from butyl to octyl). A third result from these experiments has been that the partitioning of E2beta (the surrogate permeant) into the HMS SC under E = 10 isoenhancement concentration conditions is approximately the same with the Aps and Azs as enhancers. For both the Aps and Azs, the E2beta SC partitioning enhancement was found to be in the range of 5-6 at E = 10. This comparable partitioning enhancement for E2beta in the presence of Aps and Azs at E = 10 suggests that the same mechanism was involved and that these enhancers act, in part but to a significant extent, by inducing a higher partitioning tendency of the permeant into the transport rate-limiting lipoidal domains of the SC. (c) 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:297-310, 2003