Dose response effect of chemical surface concentration on percutaneous penetration in human: In vivo + in vitro

The concentration of a formulation, defined as the mass of applied chemical per unit of skin surface area, is a key variable of skin absorption. Often only one concentration is available in the literature, hence a general evidence-based theory could allow prediction of how altering the concentration would produce a linear, increased, or decreased relative permeation. Here, we group topical chemicals into groups of how they permeate the skin when we increase or decrease their concentrations per unit area and discuss why we would like to predict their permeability in ranges of studied concentrations.

Our research question is: How, if at all, do changes in surface chemical concentration affect percutaneous penetration/absorption in man? Specifically, as the drug concentration is relatively increased, is the rate or extent of absorption proportionally affected? And if so, how?

We searched PubMed, Google Scholar, the United States Food and Drug Administration, Scientific Committee on Consumer Safety, and the European Food Safety Authority for approved transdermal delivery systems from January 1965 to October 2020. Search terms included combinations of the following words: topical + [absorption/penetration] + cm + [human/man].

Of the nineteen chemicals identified, five (testosterone, hydrocortisone, benzoic acid, fluazifop-butyl and lindane) showed decreased percent absorbed with increased dose, one (2-butoxyethanol) showed decreased flux with increased concentration, and thirteen (Basic Brown 17, benzene in gasoline, benzophenone-3, benzoyl peroxide, boric acid, caffeine, climbazole, diclofenac, ethanolamines, ibuprofen, N-octylamine, 2-phenoxyethanol, 2-pyrrolidone) showed increased flux with increasing concentrations.

Dermal absorption depends on the interaction between the characteristics of the substance, the vehicle, and the skin. Without experiments investigating these characteristics, we cannot accurately predict the percent absorbed or flux of a formulation without in vitro or in vivo data. More experimental data, especially in vivo, is mandated before a highly efficient prediction model will be reached for validation.