University of Cincinnati Cincinnati, Ohio, United States
Purpose: The study of the relationship between the amount of the drug applied to the skin and fraction of drug permeated the skin can improve our understanding of finite-dose percutaneous absorption. It has been shown that an increase in the dose applied to the skin leads to a decrease in the fraction of drug permeated [1-4]. This dose dependency relationship can play an important role in the development of effective topical products, as well as risk assessment of hazardous compounds. The purpose of this research was to examine the dose dependency effect and factors that could influence it using permeants of varying physiochemical properties. Methods: The dose dependency effect of an applied topical solution on permeation through the human epidermal membrane (HEM) was studied under finite dose conditions in Franz diffusion cell. Radiolabeled urea, corticosterone, mannitol, tetraethyl ammonium bromide (TEA-Br), dexamethasone, estradiol, caffeine, and ethylene glycol were the model permeants. These permeants were prepared in ethanol at doses ranging from 0.1 -200 μg. A 72-h permeation study was conducted, and the receptor solution was sampled at predetermined time points. The amounts of permeants penetrated through the HEM were determined, and the percent penetration was calculated based on the applied dose and analyzed. A permeation enhancement study was also performed for corticosterone, dexamethasone, and estradiol that exhibited skin permeation enhancement effects at the higher doses used in this study. In the permeation enhancement study, the skin was treated with 200 μg of estradiol, corticosterone, or dexamethasone and the permeation of a radiolabeled permeant was determined. The effect of these compounds on skin permeation of polar and lipophilic permeants was analyzed. Results: The results showed a significant decrease in the percent permeated when the applied dose of estradiol, corticosterone, dexamethasone, and caffeine increased from 0.1 to 10, 50, and 200 μg (p < 0.05). However, urea, mannitol, TEA-Br, and ethyl glycol did not show a significant decrease in percent permeated between 0.1, 2.5, 50 and 200 μg doses (p > 0.05); no significant dose dependency effect was observed for these polar model permeants. In addition, while estradiol, dexamethasone, and corticosterone exhibited a dose dependency effect with increasing dose, this effect was no longer observed at the higher doses (e.g., 50 and 200 μg doses). For these permeants, it was hypothesized that skin permeability was influenced by the permeants themselves at the higher doses. To examine this hypothesis, a permeation enhancement study was conducted for the effect of estradiol, dexamethasone, and corticosterone on skin permeation. The results show an increase in skin permeation of the polar and lipophilic permeants after 72 h for all three test compounds. Particularly, dexamethasone and corticosterone were found to significantly increase skin permeation (p < 0.05), up to 2 to 3x respectively, of polar permeants at 24 h. Estradiol and corticosterone were found to significantly increase skin permeation (p < 0.05) of lipophilic permeants at 48 h. Conclusion: A finite dose study was conducted to investigate the dose dependency effect on skin permeation using permeants of different physicochemical properties. The percent of applied dose permeated the skin was determined and a dose-dependent effect was evident in the permeation of caffeine, corticosterone, dexamethasone, and estradiol. This observation was consistent with the previous dose dependency relationship, in which an increase in the dose applied to the skin generally leads to a decrease in the fraction permeated. However, this was not the case with the polar permeants urea, mannitol, TEA-Br, and ethylene glycol. At relatively high doses, estradiol, dexamethasone, and corticosterone were shown to increase polar and lipophilic compound permeation. This phenomenon can counter the dose dependency effect under the conditions studied. References: 1. Frasch, H.F., et al., Analysis of finite dose dermal absorption data: implications for dermal exposure assessment. J Expo Sci Environ Epidemiol, 2014. 24(1): p. 65-73. 2. Kasting, G.B., Kinetics of finite dose absorption through skin 1. Vanillylnonanamide. J Pharm Sci, 2001. 90(2): p. 202-12. 3. Miller, M.A., V. Bhatt, and G.B. Kasting, Dose and airflow dependence of benzyl alcohol disposition on skin. J Pharm Sci, 2006. 95(2): p. 281-91. 4. Intarakumhaeng, R., A. Wanasathop, and S.K. Li, Effects of solvents on skin absorption of nonvolatile lipophilic and polar solutes under finite dose conditions. Int J Pharm, 2018. 536(1): p. 405-413
Acknowledgments: The authors thank Dr. Kavssery Ananthapadmanabhan, Dr. Gerald Kasting and Apipa Wanasathop for their helpful suggestions. The student author gratefully acknowledges the support and funding by the Saudi Arabian Cultural Mission. Conflicts of interest: The authors declare no conflicts of interest. This research was supported in part by the Saudi Arabian Cultural Mission.
