RESUMEN
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. PURPOSE: 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? METHODS: 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]. RESULTS: 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. CONCLUSION: 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.
Asunto(s)
Absorción Cutánea , Piel , Administración Cutánea , Ácido Benzoico , Cafeína , Humanos , Piel/metabolismoRESUMEN
The 21-day cumulative irritation test (21-day CIT) has been widely used in dermatopharmacology and dermatotoxicology to assess the irritation potential of topical products. Since described by Lanman in 1968, it has been modified, shortened, re-evaluated, and statistically analysed by multiple groups of authors. As the assay has been recommended in FDA draft guidance, we bring subsequent experience to date. The shorter 14-day version is commonly used and may be as adequate as the 21-day application when used to discriminate between moderate to strong irritants. While previous authors stopped the test when subjects experienced an irritation score of 3 or more, the FDA suggested moving the test to another anatomical site to complete in 21 days. This approach avoids assumptions, thus may be more accurate to quantify skin irritation. As the scoring is based on visual grading, the 21-day CIT also does not account for sensory irritation. Therefore, future studies need to propose a way to evaluate the sensation objectively in dermatological product development.