DRUG THERAPY TOPICS Impact of Order of Application of Moisturizers on Percutaneous Absorption Kinetics: Evaluation of Sequential Application of Moisturizer Lotions and Azelaic Acid Gel 15% Using a Human Skin Model James Q. Del Rosso, DO; Paul A. Lehman, MSc; Sam G. Raney, PhD The medical management of rosacea increasingly osacea is a common facial skin disorder esti- has involved not only the appropriate selection of mated to affect at least 14 million people in topical medication but also patient education and Rthe United States. Adults are predominantly specific recommendations regarding appropriate affected, with most cases diagnosed before the skin care. The recognition that epidermal barrier age of 50 years.1 The papulopustular subtype of dysfunction and transepidermal water loss (TEWL) rosacea generally is characterized by facial inflam- play a pathophysiologic role in rosacea and that matory lesions (papules, pustules), erythema, and skin moisturization may help to mitigate signs telangiectases, and many patients are affected and symptoms of the disease has led to a deeper by symptoms such as burning and stinging. In appreciation of the importance of proper skin care most cases of rosacea, periods of spontaneous in the treatment of rosacea. Data from a percutane- remission may alternate with periods of exacer- ous penetration study performed using human skin bation.1,2 Current medical treatment strategies suggest that any of the tested moisturizer lotions include using topical therapies, such as sodium may be applied either before or after azelaic acid sulfacetamide–sulfur, metronidazole, and azelaic gel 15% without a major change in the percutane- acid, or oral therapies, such as tetracycline deriva- ous absorption profile of azelaic acid. tives, to control signs and symptoms of rosacea Cutis. 2009;83:119-124. and mitigate flares.1-3 It has become increasingly recognized that epidermal barrier dysfunction Accepted for publication June 17, 2008. predominantly affecting central facial skin is a Dr. Del Rosso is from Valley Hospital Medical Center, Las Vegas, contributing factor related to signs and symptoms Nevada. Mr. Lehman and Dr. Raney are from PRACS–Cetero 4-7 Research, Fargo, North Dakota. of rosacea. As a result, optimal medical manage- Dr. Del Rosso is a consultant, researcher, and speaker for Allergan, ment of rosacea incorporates appropriate selection Inc; Coria Laboratories, Ltd; Galderma Laboratories, LP; Graceway of topical medication, patient education, and use Pharmaceuticals, LLC; Intendis, Inc; Medicis Pharmaceutical of an appropriate skin care regimen.3-5 Physical Corporation; Onset Therapeutics; OrthoNeutrogena; Quinnova modalities such as intense pulsed light and appro- Pharmaceuticals, Inc; Ranbaxy Laboratories Ltd; SkinMedica, Inc; Stiefel Laboratories, Inc; Triax Pharmaceuticals, LLC; Unilever; and priately selected lasers may be used for treatment Warner Chilcott. Mr. Lehman and Dr. Raney report no conflict of interest. of persistent diffuse erythema, telangiectases, and Correspondence not available. phymatous changes.3 VOLUME 83, MARCH 2009 119 Drug Therapy Topics How does moisturizer use provide therapeutic How was the impact of order of application of impact when incorporated into the treatment a moisturizer on the percutaneous absorption regimen for rosacea? kinetics of azelaic acid evaluated using the in vitro Some reports have suggested that the use of moistur- human ex vivo skin model? izers can have a beneficial effect on skin disorders An in vitro human skin penetration study was per- such as rosacea, acne vulgaris, and atopic dermatitis formed to determine the percutaneous absorption phar- by improving the signs and symptoms associated with macokinetics of azelaic acid gel 15% that incorporated epidermal barrier dysfunction and enhancing hydra- radiolabeled azelaic acid (14C-azelaic acid) applied before tion of the stratum corneum, which leads to barrier and after 3 different commonly recommended moistur- repair.4-9 Epidermal barrier dysfunction, characterized izer lotions (Cetaphil® Moisturizing Lotion, Dove® by increased transepidermal water loss (TEWL), is an Lotion, CeraVe™ Moisturizing Lotion). Azelaic acid integral feature of rosacea and may explain the sensi- gel 15% contains azelaic acid, a naturally occurring tive facial skin characteristic of the disorder.10 Well- saturated dicarboxylic acid. Chemically, azelaic acid is formulated moisturizers, particularly those moisturizers 1,7-heptanedicarboxylic acid, with a molecular weight combined in the appropriate application sequence of 188.22. It is approved by the US Food and Drug with certain active topical formulations, may help to Administration for the topical treatment of inflamma- minimize the effects of epidermal barrier dysfunction tory papules and pustules of mild to moderate rosacea.14 and increased TEWL, thereby reducing signs and The single-center, open-label, within-donor, human symptoms of cutaneous irritation and facilitating epi- skin study evaluated azelaic acid gel 15% applied before dermal barrier repair.5 Moisturizers replenish depleted and after the 3 different moisturizer lotions. The primary lipids within intercellular lipid membranes of the test formulation was azelaic acid gel 15%. Application of epidermis and thus restore the ability of the stratum this formulation to the skin was conducted before and corneum to retain moisture.4-9 A properly selected skin after the application of Cetaphil Moisturizing Lotion, care regimen inclusive of a moisturizer used in com- Dove Lotion, or CeraVe Moisturizing Lotion. Each for- bination with a topical medication also may reduce mulation was tested on skin from 3 different donors using potential tolerability reactions that can be associated the Franz finite dose model (see Study Procedures). with topical therapy and may enhance percutaneous For the primary test formulation, matched sets of skin delivery of the active agent.6-11 However, there are no sections were either predosed with a lotion formulation prior data available evaluating how the order of mois- before the application of azelaic acid or postdosed with a turizer application affects percutaneous absorption of lotion formulation after the application of azelaic acid. All the active ingredient when the moisturizer is applied dose applications were 5 µL/cm2 and were spread through- sequentially with topical medications for rosacea. out the skin section. Fifteen minutes separated the first and second dosing applications to each skin section. Calculated parameters included the amount absorbed What measures can be used to assess the (total penetration into the reservoir solution over potential impact of moisturizer application 48 hours), rate of penetration (flux), and mass distri- on the percutaneous absorption kinetics of bution (epidermal and dermal contents). Replicate topical medications? skin sections within donors were averaged to provide The in vitro human ex vivo skin model has proven to a within-donor mean, which was used to calculate an be a valuable tool for the study of percutaneous absorp- across-donor population mean. Differences between the tion and the determination of the pharmacokinetics groups applying azelaic acid gel 15% before and after of topically applied drugs.11 The model uses human the lotion were evaluated using the Student t test. All ex vivo skin mounted in specially designed diffusion conduct and data entry was reviewed and verified by chambers that allow the skin to be maintained at a quality control and quality assurance personnel as per temperature and humidity matching typical in vivo the standard operating procedures of the testing facility. conditions.10,11 A finite dose (eg, 4–7 mg/cm2) of a formulation, which may include both the therapeutic agent and a moisturizer, is applied to the outer surface What were the outcomes of the percutaneous of the skin and drug absorption is measured by monitor- absorption kinetics study evaluating moisturizer ing its rate of appearance in the reservoir solution that application with azelaic acid gel 15%? bathes the inner surface of the skin.11 Data defining The penetration profile observed for azelaic acid dis- total absorption, rate of absorption, and skin content played a characteristic finite dose absorption profile can be accurately determined in this model.11,12 The with a rise to a peak rate of penetration followed by method has a historic precedent for accurately predict- a slow but steady decline (Figure 1). The penetration ing in vivo percutaneous absorption kinetics.12,13 profile for azelaic acid did not appreciably change 120 CUTIS® Drug Therapy Topics Study Procedures Reagents and Source of Standards All reagents used in this study were of analytical reagent grade or better. Radiolabeled azelaic acid, [1-14C], was concentrated and mixed into the azelaic acid formulation to achieve a final specific activity of approximately 0.1 µCi per applied dose. Diffusion Cell and Skin Preparation Donated human trunk skin without obvious signs of skin disease was used in this study. At collection, skin samples were dermatomed, cryopreserved, sealed in a water-impermeable plastic bag, and stored at the appropriate temperature (approximately 2708C) until the day of the study. Skin sections were mounted onto 1.0-cm2 static Franz diffusion cells. The dermal reservoir solution was phosphate-buffered isotonic saline (pH, 7.460.1), and the epidermal chamber was left open to ambient laboratory environment. The cells were stirred magnetically at