Mechanistic study of chemical penetration enhancers for transdermal drug delivery

Incorporation of chemical permeation enhancers in transdermal drug formulations is one of the most promising methods to increase skin permeability. A quantitative description of the enhancement effect of chemical enhancers based on their physicochemical characteristics should provide principles for the rational design and use of chemical permeation enhancers.; The initial challenges and contributions of this dissertation were to develop and optimize the technique of measuring equilibrium concentrations of chemical enhancers and that for a surrogate model permeant in different domains of the stratum corneum (SC). This technique enabled us to probe the direct interactions of the permeation enhancers with the rate-limiting domains of the SC and the partitioning enhancement of permeants in the intercellular lipids under isoenhancement conditions.; Based on the developed experimental approaches, several homologous series of amphiphilic chemical enhancers were systematically studied with hairless mouse skin. It was found that the potency of the studied enhancers (based on their isoenhancement concentrations) was directly related to their hydrophobicity, which can be expressed by their octanol-water partition coefficient. The intrinsic potency of the studied enhancers (based on the equilibrium enhancer concentration in the intercellular lipids of the SC under isoenhancement conditions) was found to be independent of their molecular characteristics. Comparable partitioning enhancement of a surrogate model permeant (beta-estradiol) in the intercellular lipids of the SC for the studied enhancers under isoenhancement conditions indicated that a similar mechanism was involved for these enhancers. It was also found that 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. A good correlation between the octanol-water partition coefficient and the intercellular lipids-water partition coefficient of the studied enhancers was found, this demonstrating that the intercellular lipids "phase" of the SC can be well-mimicked by liquid n-octanol.; The mechanism of the enhancement action of chemical permeation enhancers was further studied by analysis of the transport data with one-layer and two-layer skin models. It was found that the total transport enhancement (around 11) was mainly driven by partitioning enhancement (in the range of 5∼7) of the model permeant in the transport rate-limiting domain of the SC. The consistency between the partitioning enhancement obtained from the treatment of the kinetic transport data and the equilibrium partitioning experiments indicates that the intercellular lipids "phase" is likely to be the same as the transport rate-limiting domain of the SC.