HUMAN SKIN PERMEABILITY ENHANCEMENT BY LAURIC ACID UNDER EQUILIBRIUM AQUEOUS CONDITIONS

An in vitro method was developed to investigate the enhancement of hyd rocortisone transport across human stratum corneum (SC) by a model enh ancer, lauric acid, in aqueous solutions under equilibrium conditions with respect to the enhancer. In contrast to classical (i.e., nonequil ibrium) loading techniques, in which the enhancer is applied only to t he donor side of SC either in pure form or in an organic solvent while enhancer-free aqueous buffers are placed in the receptor phase, this method allowed the investigation of pH effects, concentration effects, and reversibility of both enhancer uptake and enhancement of drug tra nsport under thermodynamically well-defined conditions. The SC-buffer partition coefficients for lauric acid were linear with concentration and sigmoidal with pH, suggesting that both the neutral species and la urate anion partition into SC. Comparisons of partition coefficients i n delipidized and untreated SC as a function of pH indicated that the uptake of lauric acid in neutral form is governed primarily by the lip id domain, whereas the protein domain accounts for anion uptake. The e ffects of lauric acid on skin permeability were >80% reversible upon e xtraction of the enhancer from the membrane, However, the degree of en hancement of hydrocortisone permeability was nonlinearly dependent on the equilibrium concentration of lauric acid in either the aqueous buf fer or the membrane, exhibiting thresholds in the appearance of enhanc ement with concentration. The enhancer concentration necessary to achi eve isoenhancement of about 6-fold varied from similar to 1 x 10(-5) M at pH < pK(a) to similar to 1 x 10(-2) M at high pH (pH > 8) demonstr ating the higher influence of the free acid species. Maximum enhanceme nt, however, occurred at high pH, reflecting the significantly higher solution concentration of laurate anion attainable in saturated soluti ons at high pH.