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Predicting the Percutaneous Penetration of Cosmetic Ingredients
By: Sara Farahmand, PhD, University of Cincinnati College of Pharmacy; and Howard I. Maibach, MD, PhD, University of California School of Medicine
Posted: March 30, 2010, from the April 2010 issue of Cosmetics & Toiletries.
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The main advantage that transdermal drug delivery possesses over oral dose regimens is that it avoids the variability associated with the gastrointestinal tract, which can be affected by pH, motility, transit time and food intake. Nevertheless, drug permeation through human skin at a selected skin site can vary from 46–66% among individuals.7 To study the variations, transdermal patches were chosen over volatile solvent vehicles such as acetone or semi-solids such as cream or ointment since transdermal patches offer a fixed dose and an abrupt removal, except for skin reservoirs. In addition, transdermal patches do not entail other penetration steps such as volatility (i.e., evaporation of the active) and rub removal. Further, these systems are near or at maximum thermodynamic activity (saturation).
In transdermal pharmacokinetic literature, data measured from different individuals were reported in means and standard deviation. In this study, the mean coefficient of variation (CV) of Cmax was calculated for transdermal drugs. The mean CV of values reported from several resources ranged from 26% (for nicotine) to 53% (for nitroglycerin).8 The mean CV of Cmax also was calculated for the oral dosage form of these drugs.
In Figure 1, the CV of Cmax for nicotine after smoking and for fentanyl after intravenous infusion is shown. The CV values from non-transdermal routes of administration range from 12.3% (for clonidine) to 202% (for testosterone), as seen in Figure 1. The main factors controlling the interindividual variation in transdermal drug delivery can be categorized in four groups: study design and methodology, general subject factors, TTS system design and kinetic variations of drug molecules.
Age: Among the drugs administered transdermally, the pharmacokinetics of fentanyl have been studied extensively in subjects ages 6–75 years.7 The plasma profile at steady state was similar between children ages 7–18 years and adults, although the interindividual variability in kinetics was less in children. There were no marked differences found in Cmax and the area under the time concentration curve in the elderly and adult group. However, the data suggests a longer delay and decay of fentanyl in elderly patients.7
Although the effects of aging on barrier qualities of skin affect drug permeation, the variability could also be explained by differences in cytochrome P450 3A4 activity in a population of patients covering a wide age range. Cytochrome P450 3A4 is one of the most important enzymes involved in the metabolism of xenobiotics in the body. In addition, renal function decreases with age, which could also increase interindividual variation, as was shown for some topically applied lipophilic drugs.13