Clinics in Dermatology (2012) 30, 345348

New treatments for restoring impaired epidermal barrier permeability: Skin barrier repair creams
Zoe Diana Draelos, MD
Department of Dermatology, Duke University School of Medicine, 2444 North Main Street, High Point, NC 27262, USA

Abstract Skin health depends on an intact barrier composed of protein-rich corneocytes surrounded by the lamellar intercellular lipids. This barrier provides waterproof protection for the body, preventing infection, regulating electrolyte balance, maintaining body temperature, and providing a mechanism for sensation. Damage to the skin barrier results in skin disease that can be treated by a variety of externally applied substances, such as ceramides, hyaluronic acid, licorice extracts, dimethicone, petrolatum, and paraffin wax. These substances are found in moisturizers that are sold as cosmetics and in prescriptions as 510(k) devices. This contribution examines the formulation and effect of skin barrier creams. 2012 Elsevier Inc. All rights reserved.

Introduction
The skin barrier is an essential element of health, separating the body from the external world. Without this barrier, human life could not exist. Protection is necessary from infectious organisms that might enter the body causing serious disease and possibly death. A means of regulating electrolyte balance, body temperature, and sensation is also part of this barrier. Although the barrier is self-maintaining, with replacement on a 14-day cycle, disease states may perturb the barrier and delay repair or alter repair kinetics. To meet this need, a variety of barrier repair products have been introduced to speed the healing of barrier-impaired skin and to maintain a healthy barrier. This article examines the construction and effect of these new barrier repair devices on skin health.

viable epidermis, the nucleated cells possess tight, gap, and adherens junctions with desmosomes and cytoskeletal elements that contribute to the barrier. Barrier repair devices attempt to mimic the intercellular lipids that are synthesized in the keratinocytes during epidermal differentiation and then extruded into the extracellular domains. These lipids are composed of ceramides, free fatty acids, and cholesterol, which covalently bind to the cornified envelope proteins. Changes in these intercellular lipids and alterations in epidermal differentiation lead to barrier defects and, ultimately, skin disease.

Barrier products
A variety of barrier repair products have been launched into the prescription marketplace. These creams are different than traditional over-the-counter (OTC) nonprescription moisturizers because the U.S. Food and Drug Administration (FDA) has approved them as a 510(k) device. The 510(k) device approval process was originally developed to ensure the safety of equipment with an on/off switch. Lasers, light devices, cardiac pacemakers, and insulin pumps represent equipment requiring this type of approval. Although creams are not traditionally thought of as devices, they received

The barrier
The skin barrier is formed by the protein rich cells of the stratum corneum with intervening intercellular lipids. In the
Corresponding author. 2444 N Main St, High Point, NC 27262. Tel.: +1 336 841 2040; fax: +1 336 841 2044. E-mail address: zdraelos@northstate.net. 0738-081X/$ see front matter 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2011.08.018

346 (501(k) approval because they induce a physical change in the skin. This physical change was documented as an increase in skin hydration resulting from a decrease in transepidermal water loss (TEWL). TEWL can be measured by an evaporimeter using two humidity meters. The humidity meters are encased in a probe with a circular orifice that is placed on the skin surface. The distance between the humidity meters and the distance the humidity meters are from the skin surface is defined. The amount of water vapor passing between the humidity meters over a given area is measured, and a computer calculates the grams of water lost per centimeter squared. Barrier repair products place a water-impervious film over the skin surface that decreases TEWL. TEWL is elevated when the skin barrier is damaged, representing the physiologic signal for barrier repair initiated by ceramide synthesis. By decreasing TEWL, barrier creams hydrate the skin and create an environment optimal for healing. A variety of different formulations that produce barrier repair by different mechanisms presently have 510(k) approval. These 510(k)-approved barrier creams are reviewed next based on their unique active ingredient.

Z.D. Draelos injection into the skin as a filler (Juvaderm Ultra and Juvaderm Ultra Plus, Allergan, Irvine, CA; Restylane and Perlane, Medicis Pharmaceutical Corp, Scottsdale, AZ) and as a barrier repair product (Atopiclair, Graceway Pharmaceuticals, Bristol, TN; Hylatopic, Onset Therapeutics, Cumberland, RI). As a component of the extracellular matrix, hyaluronic acid is believed to stimulate neutrophil migration, fibroblast proliferation, and neoangiogenesis. Research that evaluated the effect of a hyaluronic acid sodium salt in the healing of episiotomy and cesarean section surgical wounds 5 demonstrated a lower incidence of edema and decreased wound exudate in the group treated with hyaluronic acid sodium salt. Two barrier products use hyaluronic acid as the main ingredient to enhance water holding (Bionect, JSJ Pharmaceuticals, Charleston, SC; Hylatopic, Onset Therapeutics). One contains 0.2% hyaluronic acid sodium salt, which functions as a humectant, in combination with other humectants, such as glycerol and a 70% sorbitol solution (Bionect, JSJ Pharmaceuticals). In addition to humectants, occlusive ingredients are required to keep the water attracted by the humectant from evaporating into the environment. These are oily substances, such as an emulsifying wax, that physically block TEWL. Most good moisturizers use ingredients with occlusive and humectant properties to increase skin hydration. The same hyaluronic acid sodium salt is combined in a foam formulation with glycerin as an added humectant, accompanied by dimethicone and petrolatum as occlusives (Hylatopic, Onset Therapeutics, Cumberland, RI).

Ceramide
Ceramide synthesis is the first step in healing a damaged skin barrier. Nine different ceramides have been identified and many synthetically duplicated for inclusion in moisturizer formulations. 1 The ceramides are distinguished by their polar head group architecture and by their hydrocarbon chain properties. 2 A ceramide-dominant, triple-lipid barrier repair formulation (EpiCeram, Promius Pharma, Bridgewater, NJ) was designed to correct the lipid-biochemical abnormalities in atopic dermatitis. It contains capric acid, cholesterol, and conjugated linolenic acid. In addition, candelilla and petrolatum are included to decrease TEWL. EpiCeram received FDA approval in April 2006 for use as a nonsteriodal lipid barrier emulsion to manage the symptoms of dry skin associated with a variety of dermatologic diseases. 3 It was compared with fluticasone cream in 121 patients with moderate to severe atopic dermatitis for 28 days. EpiCeram reduced Scoring Atopic Dermatitis (SCORAD) scores, decreased pruritus, and improved sleep habits; however, faster improvement was seen with the topical corticosteroid at day 14. 4 The unique aspect of this cream is that the ratio of the triple-lipid combination mimics that of physiologic lipids.

Palmitoyl ethanolamide
A different approach to barrier repair is found in a 510(k)approved cream that contains a variety of moisturizers, such as olive oil, glycerin, and vegetable oil, in addition to palmitamide monoethanolamine (PEA; Mimyx, Stiefel, Research Triangle Park, NC). PEA is a fatty acid that is purported to be deficient in atopic skin. 6 It has been shown to decrease itch, perhaps because PEA may modulate the cannabinoid itch receptors in the skin. 7 In an open-label study of 2456 patients, the intensity of erythema, pruritus, excoriation, scaling, lichenification, and dryness were significantly reduced, with a combined score reduction of 58.6%. 8 There was no placebo in this noncontrolled prospective cohort study.

Licorice extract Hyaluronic acid

Another endogenous component of the skin necessary for the maintenance of hydration is hyaluronic acid, a glycosaminoglycan found in the dermis. Hyaluronic acid acts as a sponge in the skin to attract and hold water, a function known as humectancy. Hyaluronic acid is approved as a device for Other 510(k) device barrier creams contain a variety of botanical extracts. One currently marketed product contains glycyrrhetinic acid and Vitis vinifera extracts (Atopiclair, Graceway Pharmaceuticals) along with allantoin, -bisabolol, hyaluronic acid, and shea butter. Glycyrrhetinic acid is a licorice extract that was reported to be safe by the Cosmetic

Skin barrier repair creams Ingredient Review. It is able to block gap junction intracellular communication, but is cytotoxic at high concentrations. Glycyrrhetinic acid is mainly used in moisturizer formulations as an anti-inflammatory. 9 In an open-label multicenter study, the product reduced the median visual analog scale rating for itching in atopic dermatitis from 48.5 to 34.1 mm after 3 weeks of treatment, with a further reduction to 24.6 mm after 6 weeks of treatment. 10 In a second study of 142 pediatric patients ages 6 months to 12 years, the same formulation was compared with a vehicle cream and was statistically more effective in reducing the symptoms of mild to moderate atopic dermatitis. 11 It was also effective for symptomatic relief of contact dermatitis. 12 In addition to the anti-inflammatory effect of glycyrrhetinic acid, the Vitis vinifera extract, derived from grapes, and -bisabolol, derived from camomile, also serve as antioxidant, anti-inflammatory ingredients. Finally, allantoin, a heterocyclic organic compound, is a time-tested antiinflammatory, as assessed by the Cosmetic Ingredient Review. 13 The combination of various botanical antiinflammatories may be an alternative to more traditional topical corticosteroids used for the treatment of dermatoses.

347 discharges. The silicone used in topical preparations is an odorless, colorless, nontoxic liquid. Because silicone is immiscible and insoluble in water, it is used in barrier products with water-resistant capabilities. To date there is no report of toxicity from the use of topical silicone. 15 Dimethicone is the first ingredient in a foam formulated for the relief of irritation from dermatoses, such as atopic dermatitis and allergic contact dermatitis (Neosalus, Quinnova Pharmaceuticals, Newtown, PA). A combination of cyclomethicone, a cyclic higher-viscosity silicone, and dimethicone are used in barrier creams designed to prevent skin sensitization to allergens (Tetrix, Coria Laboratories, Aliso Viejo, CA). 16 The water-in-oil emulsion is also resistant to water removal. 17

Paraffin wax
Another time-tested occlusive agent to decrease TEWL is paraffin wax. Liquid paraffin combined with paraffin wax is the basis for another barrier cream designed to be used in the management of superficial wounds, dermal ulcers, donor sites, burns, and radiation dermatitis (Biafine, OrthoNeutrogena, Los Angeles, CA). The wax provides an artificial barrier until healing can occur. The formulation was chemotactic for macrophages and increased the interleukin-1/inteleukin-6 ratio in epidermal wounds in healthy human volunteers. 18 Healing effects were also noted: the wax-based formulation improving healing after the treatment of actinic keratoses. 19

Petrolatum
The oldest barrier product and the very first therapeutic moisturizer ever developed was petrolatum. Petrolatum is a semisolid mixture of hydrocarbons obtained through the dewaxing of heavy mineral oils. Pure cosmetic-grade petrolatum is practically odorless and tasteless; however, hydrocarbon contaminants in lower-quality petrolatum may account for the distinct chemical smell noted with some products. Petrolatum first appeared in the U.S. Pharmacopeia in 1880 and has been a widely used ingredient in skin care products and topical pharmaceuticals ever since. Petrolatum has never been duplicated synthetically. Some barrier repair creams contain petrolatum as their primary ingredient (Eletone, Ferndale Laboratories, Ferndale, MI). Petrolatum remains the gold standard for barrier repair ingredients because it is the substance closest to the natural intercellular lipids and it can intercalate into the intercellular spaces. 14

OTC moisturizers vs 510(k)-approved barrier devices

The use of occlusive, humectant, and anti-inflammatory ingredients in 510(k) barrier devices may provide an alternative to the more traditional topical corticosteroids used in dermatologic therapy. The barrier repair creams can be used as steroid-sparing aids or to maintain barrier health once the prescription drugs have been discontinued. The main question is whether these more expensive 510(k) barrier devices provide anything that is currently not available in the OTC moisturizing market. All of the ingredients that are used in the device creams are found in cosmetic formulations. These barrier devices are not drugs; they are simply devices that must be obtained with a prescription.

Dimethicone
A newer alternative to petrolatum as a barrier repair ingredient is dimethicone, one of a family of silicone oils. These oils are less greasy than petrolatum and possess better aesthetics, but are not as efficacious as petrolatum in reducing TEWL. Silicone originates from silica, which is found in sand, quartz, and granite. It derives its properties from the alternating silica and oxygen bonds, known as siloxane bonds, which are exceedingly strong. These strong bonds account for the tremendous thermal and oxidizing stability of silicone. Silicone is resistant to decomposition from ultraviolet radiation, acids, alkalis, ozone, and electrical

Conclusions
An intact skin barrier is essential for skin health. All dermatologic diseases are due to barrier defects, ranging from mild to severe. Barrier repair creams do not actually repair the barrier, but rather, create an environment optimal for healing. They contain occlusive ingredients to retard TEWL, humectants to attract water to the epidermis, and other assorted ingredients to decrease inflammation, reduce itching, and provide materials to simulate the intercellular

348 lipids. These barrier repair creams are termed devices because they have been approved through the 510(k) route and are available by prescription. They represent a new category in skin care products, providing both steroid sparing and skin care maintenance qualities.

Z.D. Draelos
rhizate, dipotassium glycyrrhizate, disodium glycyrrhizate, trisodium glycyrrhizate, methyl glycyrrhizate, and potassium glycyrrhizinate. Int J Toxicol 2007;267:9-112. Eberlein B, Eicke C, Reinhardt HW, Ring J. Adjuvant treatment of atopic eczema: Assessment of an Emollient Containing N-Palmitoylethanolamine (ATOPA Study). J Eur Acad Dermatol Venereol 2008;227:3-82. Veraldi S, De Micheli P, Schianchi R, Lunardon L. Treatment of pruritus in mild-to-moderate atopic dermatitis with a topical nonsteroidal agent. J Drugs Dermatol 2009;85:37-9. Boguniewicz M, Zeichner JA, Eichenfield LF, et al. MAS063DP is effective monotherapy for mild to moderate atopic dermatitis in infants and children: a multicenter, randomized, vehicle-controlled study. J Pediatr 2008;1528:54-9. Buraczewska I, Berne B, Lindberg M, Trm H, Loden M. Changes in skin barrier function following long-term treatment with moisturizers, a random controlled trial. Br J Dermatol 2007;1564:92-8. Becker LC, Bergfeld WF, Belsito DV, et al. Final report of the safety assessment of allantoin and its related complexes. Int J Toxicol 2010;298:4S-97S. Morrison DS. Petrolatum: a useful classic. Cosmet Toilet 1996;111: 59-69. Ruiz MA, Hernandez A, Llacer JM, Gallardo V. Silicone chemistry. Cosmet Toilet 1998;113:57-62. Slade HB, Fowler J, Draelos ZD, Reece BT, Cargill DI. Clinical efficacy evaluation of a novel barrier protection cream. Cutis 2008;822: 1-8. Slade HB, Fowler J, Reece BT, Cargill DI. Clinical safety evaluation of a novel barrier protection cream. Cutis 2008;821:6-20. Coulomb B, Friteau L, Dubertret L. Biafine applied on human epidermal wounds is chemotactic for macrophages and increases the IL-1/IL-6 ratio. Skin Pharmacol 1997;102:81-7. Cohen JL, Jorizzo JL, Kircik LH. Use of a topical emulsion for wound healing. J Support Oncol 2007;51:1-9.

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