Dosing Dependency on Skin Drug Delivery: Topically Applied Dose and Adhesive Coat Weight.

Abstract

The global drug delivery market value for topical and transdermal products is estimated to be $114.2 billion. Time, effort, and investments are placed towards the advancement of innovative approaches to deliver drugs. An important aspect to consider in the success of skin drug delivery is the dose of the applied drug for skin delivery. In this research, we aimed to examine factors affecting dose delivery under a) topically applied finite dose conditions and b) semi-occluded transdermal patch system. The study of the relationship between the amount of drug applied to the skin and fraction of drug absorbed can improve our understanding of finite-dose percutaneous. It has been previously shown that an increase in the dose applied to the skin leads to a decrease in the fraction of drug permeated the skin (dose-dependent effect). The first objective of this research was to examine the dose-dependent effect using permeants of varying physiochemical properties. The dose-dependent effect was studied using human epidermal membrane under finite dose conditions in Franz diffusion cell with model permeants at a range of doses. The dose-dependent effect was evident with model permeants caffeine, corticosterone, dexamethasone, and estradiol, consistent with the relationship of decreasing fraction of dose permeated the skin at increasing the applied dose. However, no significant dose-dependent effect was observed for the polar model permeants urea, mannitol, tetraethyl ammonium, and ethylene glycol, suggesting different transport mechanisms for these permeants. It was also found that, at relatively high doses, estradiol, dexamethasone, and corticosterone could increase the permeation of polar and lipophilic permeants, which could counter the dose-dependent effect under the conditions studied. The second objective was to study the effect of transdermal adhesive coat weight (patch thickness) on the rate of drug delivery. Drug-in-adhesive patches of 1.6% w/w estradiol and 1.5% w/w testosterone were fabricated at a thickness of 0.1 to 0.8 mm. To ensure the quality of the formulated patches, stability and release studies were carried out along with formulation optimization. Permeation studies were performed using human split thickness skin and Franz diffusion cells. The permeation of the drug through the skin in the permeation studies showed no significant differences in drug delivery between the 0.1, 0.4, and 0.8 mm thick patches with <10% drug permeated. The effect of lower drug loading and permeation enhancer (PE) on estradiol patches of different thickness was also investigated. A 2-fold increase in the permeation of estradiol was shown with PE treated skin using oleic acid and undecanol. There was no significant difference in skin permeation of estradiol with lower drug loading or the use of PE across different patch thickness as patch depletion did not exceed 10%. However, release studies showed a decrease in the rate of release coinciding with the patch thickness but only after >30% of the drug was released, suggesting that the patch thickness effect is due to depletion of the thinner patches. Higher penetration rates can be sustained for longer with thicker patches as they can maintain drug concentrations above 70% for extended periods of time.