A structure-enhancement relationship and mechanistic study of chemical enhancers on human epidermal membrane based on maximum enhancement effect (Emax)

Transdermal pharmaceutical formulations, in most cases, contain chemical penetration enhancers. To properly select efficient chemical enhancers, an understanding of their mechanism(s) of action is essential. This dissertation evaluated the enhancement effects of known topical or cosmetic ingredients on human epidermal membrane (HEM) permeation. Permeation enhancement effect, Emax, was identified as enhancement effect induced by the enhancer on HEM permeation as the enhancer approaches the thermodynamic activity of its pure state in equilibrium with HEM. A structure enhancement relationship was established for the chemical enhancers studied. Emax was shown to be dependent of the lipophilicities. A guideline for the selection of chemical enhancers based on efficiency and duration of enhancement was determined based on octanol/water partition coefficient and calculated n-octanol solubility. This dissertation also studied topical formulations consisting of a volatile carrier system containing the chemical enhancers. To fully understand the enhancer induced permeation enhancement mechanism, the transport domain of skin i.e., the stratum corneum (SC) lipid domain was probed. This involved the determination of both enhancer and permeant uptake into the lipid domain of SC following enhancer treatment. It was concluded that the permeation enhancement mechanism is attributed to the enhancement of permeant partitioning into the transport rate limiting domain. Liposomes formulated from extracted human stratum corneum lipids (EHSCLL) were characterized and used to directly study this domain. The uptake of the chemical enhancers within the EHSCLL was determined and the results suggested a quantitative relationship between enhancer uptake in EHSCLL and enhancer efficiency. DSC and ATRFTIR studies using enhancer treated intact SC supported that the mechanism of chemical enhancers is via their fluidization and perturbation of the SC lipid bilayer. This finding suggests that the enhancers induce both a polarity shift in the SC lipid domain and a decrease in lipid microviscosity through lipid fluidization in the SC.