Mechanistic aspects of chemical skin permeation enhancers.

Incorporation of chemical permeation enhancers in transdermal formulations has led to the potential of dermal and transdermal delivery of drugs at therapeutic rates. A great deal of work has been directed toward the search for chemicals that can be used as chemical permeation enhancers; however, knowledge of the mechanism of action of chemical permeation enhancers is still in its infancy. A fundamental understanding of the mechanism of action of chemical permeation enhancers should lead to more rational approaches in formulating transdermal drug delivery systems. The initial challenges and accomplishments of this dissertation were related to development of experimental methods that enabled quantitative permeability studies and data analysis to be performed. It was discovered that significant metabolism of the probe permeant, utilized in the permeability studies, occurred in the viable epidermis layer. Subsequent studies showed that the metabolite(s) does not alter the permeability coefficient determination of the parent compound. Computer simulations to determine the enhancer concentration as a function of distance in the stratum corneum and dermis showed that an equilibrium condition between the bulk solution and the hairless mouse skin stratum corneum was established prior to beginning a transport study. With a sound experimental methodology in hand, a series of 11 chemical permeation enhancers were studied with the aim of probing the relationship between the alkyl group chain length and polar head group on chemical permeation enhancement and probing the chemical microenvironment of the site of enhancer action. These experimental studies were designed based upon determination of an isoenhancement concentration utilizing a steady state physical model, where the rate limiting domain is the lipoidal pathway across the stratum corneum. Partitioning tendencies of each enhancer into semipolar and hydrocarbon organic solvents were determined to probe the chemical microenvironment of the site of action. The enhancer quantitative structure-activity relationships, influence of n-alkyl chain length on enhancer potency, and prediction of enhancer potency were established. Highly lipophilic chemical enhancers were studied employing the use of a micelle solubilizing agent. As described above, an isoenhancement concentration (which included solubilized enhancer and free aqueous enhancer) was determined for these enhancers. The free aqueous enhancer concentration in the micelle solution was determined using a silicone elastomer method. The enhancer quantitative structure-activity relationships and influence of n-alkyl chain length on enhancer potency were consistent with the less lipophilic enhancers previously mentioned.