Advances in Topical Formulation Development: Applications in Acne and Barrier Repair

Supplement to the July 2010 & AGING Advances in Topical Formulation Development: Applications in Acne and Barrier Repair 4 Advances in Formulation Technologies: Creating Highly Effective and Well-Tolerated Topical Dermatologicals Daniel A.W. Bucks, PhD Director, Skin Biology and Drug Delivery Dow Pharmacuetical Sciences, Inc. Petaluma, CA Radhakrishnan S. Pillai, PhD Associate Director, Project Management Dow Pharmaceutical Sciences, Inc. Petaluma, CA Fred McCall-Perez, PhD Senior Medical Science Liaison Valeant Pharmaceuticals North America Redwood City, CA 7 Acanya Gel: Optimized Clindamycin/Low-Concentration BPO (2.5%) Fixed Combination Julie Harper, MD Clinical Associate Professor of Dermatology University of Alabama-Birmingham Birmingham, AL 12 Atralin (Tretinoin) Gel 0.05%: Micronized Tretinoin Julie Harper, MD Clinical Associate Professor of Dermatology University of Alabama-Birmingham Birmingham, AL 15 CeraVe : Optimized to Build and Repair the Skin Matthew Zirwas, MD Assistant Professor of Dermatology Ohio State University Columbus, OH Supported by

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Advances in Topical Formulation Development: Applications in Acne and Barrier Repair INTRODUCTION Therapeutic options for acne and atopic dermatitis (AD) have evolved slowly over the years; many advances are related to improvements in topical formulations and drug delivery. For patients with acne, the use of topical retinoids, antibiotics and benzoyl peroxide (BPO), and of combination products, allows targeting of multiple pathogenetic pathways with better-tolerated, easy regimens of care. Both BPO and retinoids can cause concentration- and formulation-dependent irritation and dryness. In addition, the surfactants and alcohol used in some formulations can irritate skin. Better understanding of the physicochemical properties of active ingredients and technological advancements in excipients have allowed development of combination products that have good efficacy and tolerance profiles and exhibit improved cosmetic acceptability. The understanding of AD pathogenesis has been affected by the study of genetic defects in skin-barrier function. One useful adjunctive strategy for improving AD is targeting barrier dysfunction by using products that may both improve barrier function and replace aspects of the epidermal barrier that have been negatively affected by underlying genetic abnormalities and inflammatory disease. Novel drug delivery strategies play an important role in improving the topical delivery of anti-acne agents by enhancing their dermal localization. This timely supplement reviews the key principles of formulation optimization and shows how they were applied to several developments in the fields of acne Acanya Gel and Atralin Gel and atopic dermatitis the CeraVe product line. Lawrence F. Eichenfield, MD Chief, Pediatric and Adolescent Dermatology Professor of Pediatrics and Medicine (Dermatology) Rady Children's Hospital San Diego University of California, San Diego School of Medicine San Diego, CA Supported by Coria Laboratories is a division of Valeant Pharmaceuticals North America. Supplement to Skin & Aging July 2010 3

ADVANCES IN FORMULATION TECHNOLOGIES Advances in Formulation Technologies: Creating Highly Effective and Well-Tolerated Topical Dermatologicals Daniel A.W. Bucks, PhD; Radhakrishnan S. Pillai, PhD; Fred McCall-Perez, PhD Fixed combinations of clindamycin and benzoyl peroxide (BPO) as well as retinoids, such as tretinoin (all-transretinoic acid) are widely used in the treatment of acne. 1 4 Unfortunately, both BPO and tretinoin can cause concentration-dependent irritation and dryness, resulting in patients poor adherence to the prescribed treatment. 5 10 As a result, patients may spot-treat specific lesions, stop treatment once some improvement is achieved, or otherwise reduce use of their medications, generating sub-optimal results. 11 14 Dose-dependent Irritation and Dryness The primary limitations of BPO are concentration-dependent skin irritation and dryness that are well characterized. 15 16 It s well-known that high concentrations of BPO (> 5%) can result in skin irritation that may limit patient adherence. 17 It has been shown that two commonly used fixed-combination products containing 5% BPO and clindamycin were moderately irritating, and that there is meaningful reduction in irritation scores when BPO concentration is reduced to 2.5%. 18,19 Another study compared the effects of a fixed-combination of clindamycin phosphate 1% and BPO 5% (BenzaClin ) with a fixed-combination of clindamycin phosphate 1.2% and BPO 2.5% (Acanya Gel) on transepidermal water loss (TEWL) and stratum corneum (SC) hydration. The investigators found no relevant irritant effect or negative influence on SC hydration using a once-daily application of Acanya Gel. However, skin hydration significantly decreased with the BenzaClin, reflecting a clinically apparent drying effect. 20 Two-hundred acne patients 15 to 40 years old who were prescribed a fixed-combination product containing 5% BPO and 1% clindamycin were surveyed. They applied the product on at least 50% of their faces for at least 5 days per week. Forty-five percent of patients reported being bothered by dry-skin or irritation, and 55% made a variety of changes to treatment including spot treatment (33%), intermittent use (32%), or stopping use altogether (10%). 21 Tretinoin is also known to cause skin irritation (burning, stinging, redness, peeling and itching), especially in the first weeks of treatment. 22,23 The effect appears to be largely concentration-dependent, and somewhat formulation-dependent. 24 This irritation is a major drawback and can limit adherence to the prescribed treatment in many patients. 22,24 Various formulations and concentrations of tretinoin have been developed in an attempt to reduce irritation and allow flexible dosing. 23 What may not be as well known about inherently irritating drugs such as BPO and tretinoin is that formulation can significantly affect irritation and dryness as well as efficacy. 22,24 These limitations are best addressed through a formulationdevelopment process based on the clinical need to develop products that have less irritation and dryness, while maintaining efficacy. This approach relies on in vitro and clinical evaluation to assess the resultant new formulations. Formulation and Delivery System: Hydrogel and Micronization The modern topical formulation process is a long, often complex endeavor that has yielded some innovative products for the treatment of acne. The development of a novel aqueous gel formulation that incorporates micronized active drug, suspended in a moisturizing hydrogel vehicle, offers advances over other dosage forms (i.e., lotions, creams, pastes). It enhances stability, vehicleskin interaction and drug delivery to the pilosebacious units. In a hydrogel, hydrophobic active drugs such as BPO and tretinoin are not in a solution but a solid state, dispersed and suspended by a polymeric gelling agent. The gel is alcohol-free, contains humectants and moisturizers, and produces very little or no additional barrier disruption, making this delivery system ideal for acne. Hydrogel delivery systems, especially for irritating hydrophobic active ingredients, make it possible to create controlled release of the suspended active ingredient, with the attendant advantages. An aqueous gel formulation holds the micronized particles of the active drug in suspension. Having small particle sizes (less than 10 microns) lets the particles more easily enter the follicular openings (which are typically 11 to 66 microns) with improved efficacy when targeting acne, which is a follicular disease. There is direct uptake into sebum, potentially improving efficacy in treating acne. New Products Based on Modern Formulation Technology Two new formulations, Acanya Gel (fixed-combination of clindamycin phosphate 1.2% and BPO 2.5%) and Atralin Gel BenzaClin (clindamycin 1.0% and BPO 5%) is a registered trademark of Aventis Pharmaceuticals, Inc., and Acanya is a registered trademark of Dow Pharmaceutical Sciences, Inc. Atralin is a registered trademark of Coria Laboratories, Ltd. 4 July 2010 Supplement to Skin & Aging

ADVANCES IN FORMULATION TECHNOLOGIES Score ( ACANYA GEL Figure 1. Mean cumulative irritation score with varying BPO concentrations. (tretinoin 0.05%), were recently added to the acne treatment armamentarium. Acanya Gel was developed to minimize the irritation caused by BPO at concentrations 5% without sacrificing efficacy. Atralin Gel was developed to minimize the burst of irritation and dryness seen with most tretinoin products. Acanya Gel. The development hypothesis for Acanya Gel was that by using a combination of micronized BPO particles (delivered in a hydrogel) and a non-irritating excipient that acted both as humectant and delivery aid, efficacy would be maintained while irritability would be attenuated. Acanya Gel contains no preservatives, surfactants or alcohol, all of which are excipients known to cause irritation and dryness. 25 The aqueous gel formulation used in Acanya Gel is important for stabilizing two otherwise-incompatible active ingredients: solubilized clindamycin phosphate and a microsuspension of BPO. Low amounts of propylene glycol act as a humectant-type moisturizer and effective wetting agent for the BPO microcrystals after application to the skin, allowing good bioavailability without compromising cosmetic elegance. In addition, the uniformly distributed, suspended micronized particles further minimize irritation in comparison to solubilized BPO. Two studies were conducted to confirm that the formulation of Acanya Gel allowed for minimal irritation and optimal penetration: a 21-day cumulative irritation study in healthy volunteers, and an in vitro skin penetration study in metabolically active dermatosed human abdominal skin. 21-day cumulative irritation study. A 21-day cumulative irritation study showed that reducing the BPO concentration from 5% to 2.5% in a series of clindamycin-bpo fixed-combinations with common vehicle reduced irritation by 33%. 19 Clindamycin-BPO fixed-combination gels were evaluated in 35 healthy human volunteers assessed for cumulative irritation potential of formulations containing clindamycin phosphate 1.2% in combination with three concentrations of BPO (5%, 2.5% and 1%). To exaggerate the use, the study medication was applied under separate occlusive patches on the patients backs Duac (clindamycin 1.0% and BPO 5%) is a registered trademark of Stiefel Laboratories, Inc. Figure 2. Cumulative benzoic acid levels for Acanya Gel compared to two clindamycin-bpo 5% marketed products. three times a week for 3 weeks. Sodium lauryl sulfate 0.3% was used as a positive control. Each test application site was observed 48 hours post-application for signs of irritation or inflammation. Assessment of skin irritancy was rated on a scale of 0 (no sign of irritation) to 4 (erythema with edema and blistering). As can be seen in Figure 1, there was a marked reduction of 33% in mean irritancy score when the concentration of BPO was reduced from 5% to 2.5% (the formulation used in Acanya Gel). Further reducing BPO concentration to 1.0% provides minimal benefit. In vitro skin penetration study. Acanya Gel was shown in an in vitro percutaneous absorption study to have comparable bioavailability to other marketed fixed combinations in which the concentration of BPO was higher (5%). 26 Clinical studies confirmed efficacy and tolerability to be excellent (see Acanya Gel: Optimized Clindamycin/Low-Concentration BPO (2.5%) Fixed Combination on p. 7). An in vitro skin penetration study was undertaken to determine how the penetration of BPO from Acanya Gel compared to two commercial fixed combination formulations containing 5% BPO (BenzaClin and Duac topical gels). The penetration study was conducted over 24 hours and used metabolically active human skin. A single application of each of the test articles was applied to the skin. The skin was maintained at a constant temperature of 32 C with continuous replacement of the receptor fluid using a flow-through diffusion cell. Receptor fluid was collected at 6-hour intervals. BPO s skin penetration and subsequent metabolism appear to be relatively fast, being essentially complete within 12 hours of application. In the skin, BPO rapidly converts to benzoic acid, which readily permeates the receptor fluid phase. These results are consistent with the literature, where it has been reported that topically applied BPO rapidly metabolizes to benzoic acid in the skin. 16,17 Figure 2 shows cumulative benzoic acid levels in the receptor phase plotted against time in hours for Acanya Gel compared to the two clindamycin-bpo 5% marketed products. Acanya Gel Supplement to Skin & Aging July 2010 5

ADVANCES IN FORMULATION TECHNOLOGIES has been optimized through in vitro human skin testing to provide the same percutaneous absorption as the two commercially available products that contain twice the BPO concentration (5%). Atralin (tretinoin) Gel 0.05%. The development hypothesis for Atralin Gel was to disperse micronized particles of tretinoin in a moisturizing hydrogel vehicle, thus reducing the potential tretinoin burst to provide excellent tolerability without compromising efficacy. The Atralin Gel formulation contains excipients commonly found in skin hydration and moisturizer products (soluble collagen, sodium hyaluronate and glycerin). The first-generation tretinoin products, including all the generic copy products, have been formulated with tretinoin in solubilized form. The solubilizing agents for the tretinoin in the original Retin A products and its generics comprise significant levels of isopropyl myristate or alcohol. The use of these products is associated with a burst in tretinoin penetration when the medication is applied to the epidermis. The burst-delivery of tretinoin causes drying and peeling, and can advance to uncomfortable scaling and redness in the skin. Physicians accept that all tretinoin formulations cause some irritancy and dryness and believe that irritation is a function of drug concentration that cannot be modulated by the tretinoin s delivery vehicle. Fortunately, with the novel advancements in formulation technology, Atralin Gel minimizes the burst effect while maintaining efficacy. This has been achieved through the incorporation of micronized tretinoin in a moisturizing hydrogel formulation. In Atralin Gel, the tretinoin is in the form of a microsuspension, with 85% of the particles smaller than 10 microns. The tretinoin micro-particles can easily enter the pilosebaceous unit, concentrate in the infundibulum and slowly dissolve directly in the sebum. This sustained delivery of tretinoin, which eliminates the burst-release characteristics of most tretinoin products, allows for controlled release over time. This, coupled with the moisturizing triad of sodium hyaluronate, glycerin and hydrolyzed collagen, helps minimize tretinoin-associated irritation, dryness, scaling and redness. Conclusion Modern formulation technologies have created newer entries to the anti-acne armamentarium. Two new products Acanya Gel (clindamycin phosphate 1.2%-BPO 2.5%) and Atralin Gel (tretinoin 0.05%) were developed to address the clinical need to reduce irritation and dryness in acne vulgaris. Both employ moisturizing hydrogels that deliver micronized drug particles to the surface of the skin or directly into the infundibulum of the hair follicles. This allows for controlled release of the active which, combined with wellselected moisturizing excipients, helps to maintain hydration and attenuate irritation and dryness, and may help encourage patient adherence to the prescribed treatment regimen. Acknowledgment The authors acknowledge the support of Brian Bulley, MSc, in the development of this manuscript. Retin A is a registered trademark of Ortho-McNeil Pharmaceuticals, Inc. References 1. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA. 2004;292(6):726 735. 2. Ingram JR, Grindlay DJ, Williams HC. Management of acne vulgaris: an evidence-based update. Clin Exp Dermatol. 2009 Oct 23. [Epub ahead of print] 3. Del Rosso JQ. Combination topical therapy in the treatment of acne. Cutis. 2006;78(2 Suppl 1):S5 S12. 4. Ghali F, Kang S, Leyden J, Shalita AR, Thiboutot DM. Changing the face of acne therapy. Cutis. 2009 Feb;83(2 Suppl):S4 S15. 5. Vrijens B, Urquhart J. Patient adherence to prescribed antimicrobial drug dosing regimens. J Antimicrob Chemother. 2005;55(5):616 627. 6. Lee IA, Maibach HI. Pharmionics in dermatology: a review of topical medication adherence. Am J Clin Dermatol. 2006;7(4):231 236. 7. Hodari KT, Nanton JR, Carroll CL, Feldman SR, Balkrishnan R. Adherence in dermatology: a review of the last 20 years. J Dermatolog Treat. 2006;17(3):136 142. 8. Ali SM, Brodell RT, Balkrishnan R, Feldman SR. Poor adherence to treatments: a fundamental principle of dermatology. Arch Dermatol. 2007;143(7):912 915. 9. Jones-Caballero M, Pedrosa E, Peñas PF. Self-reported adherence to treatment and quality of life in mild to moderate acne. Dermatology. 2008;217(4):309 314. 10. Brown KK, Rehmus WE, Kimball AB. Determining the relative importance of patient motivations for nonadherence to topical corticosteroid therapy in psoriasis. J Am Acad Dermatol. 2006;55(4):607 613. 11. Jorrizo J, Ohlrogge W, Frase T, et al. A comparative, randomized, controlled, observer-blind study to assess the skin hydration and epidermal function of 2.5% and 5% benzoyl peroxide-clindamycin topical gels. [in press] 12. Yentzer BA, Alikhan A, Teuschler H, et al. An exploratory study of adherence to topical benzoyl peroxide in patients with acne vulgaris. J Am Acad Dermatol. 2009;60(5):879-80. 13. Zaghloul SS, Cunliffe WJ, Goodfield MJ. Objective assessment of compliance with treatments in acne. Br J Dermatol. 2005;152(5):1015 1021. 14. Leyden JJ. Are 2 combined antimicrobial mechanisms better than 1 for the treatment of acne vulgaris? Clinical and antimicrobial results of a topical combination product containing 1% clindamycin and 5% benzoyl peroxide. Introduction. Cutis. 2001;67(2 Suppl):S5 S7. 15. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from the alliance to improve outcomes in acne. J Am Acad Dermatol. 2003;49(Suppl):S1 S38. 16. Mills OH Jr, Kligman AM, Pochi P, Comite H. Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. Int J Dermatol. 1986;25(10):664 667. 17. Waller JM, Dreher F, Behnam S, et al. Keratolytic properties of benzoyl peroxide and retinoic acid resemble salicylic acid in man. Skin Pharmacol Physiol. 2006;19(5):283 289. 18. Dosik J. Varnvakias G. Comparative irritation potential of two combination acne products. Am J Clin Dermatol. 2008;9(5):313 333. 19. Bucks D, Sarpotdar P, Yu K, Angel A, Del Rosso J. The development and optimization of a fixed combination of clindamycin and benzoyl peroxide aqueous gel with minimal irritation and enhanced bioavailability. J Drugs Dermatol. 2009;8(7):634 638. 20. Jorrizo J, Fluhr JW, Yu K, Chen D. Effect of clindamycin phosphate (1.2%) and low concentration benzoyl peroxide (2.5%) on transepidermal water loss and stratum corneum hydration: A comparative, randomized, controlled, observer-blind study to assess the effects of a fixed combination aqueous gel formulation. Poster presented at: Fall Clinical Dermatology Meeting; Las Vegas, NV; October 16 18, 2009. 21. Feldman, SF, Chen DM, How patients experience and manage dryness and irritation from acne treatment. [in press] 22. Thielitz A, Gollnick H. Topical retinoids in acne vulgaris: update on efficacy and safety. Am J Clin Dermatol. 2008;9(6):369 381. 23. Weiss JS, Shavin JS. Topical retinoid and antibiotic combination therapy for acne management. J Drugs Dermatol. 2004;3(2):146 154. 24. Leyden JJ, Grossman R, Nighland M. Cumulative irritation potential of topical retinoid formulations. J Drugs Dermatol. 2008 Aug;7(8 Suppl):S14 S8. 25. Banke GS, Christopher TR, eds. Modern Pharmaceutics, Fourth Edition. New York, NY: Marcel Dekker, 2003. 6 July 2010 Supplement to Skin & Aging

ACANYA GEL Acanya Gel: Optimized Clindamycin/Low-Concentration BPO (2.5%) Fixed Combination Julie Harper, MD Acne vulgaris affects 40 to 50 million people in the United States. 1 Current evidence suggests it results from a combination of increased sebum production and follicular hyperkeratinization, and is compounded by host responses to the pro-inflammatory activities of Propionibacterium acnes (P. acnes). 2 Combination therapy targeting the multiple components of acne is now commonplace, providing better patient outcomes. Benzoyl Peroxide and Combination Therapy Two topical acne medications commonly used in fixedcombination are clindamycin and benzoyl peroxide (BPO). Clindamycin improves symptoms by reducing the levels of P. acnes and may decrease inflammation. 3 BPO is also safe and effective, its efficacy maintained over many years of use with the distinct advantage of not being associated with antimicrobial resistance. 2 In addition, BPO has keratolytic and anticomedogenic properties. 4,5 Many studies have shown that the clindamycin and BPO combination is superior to the individual active ingredients. 6 8 The primary limitation of BPO in certain patients is concentration-dependent (and potentially formulation-dependent) skin dryness and irritation. 2 Patients who used topical formulations containing 5% BPO concentrations experienced significantly greater frequency and severity of burning, erythema and peeling compared with those who used a 2.5% concentration. 9 Dosik et al demonstrated that two commonly used fixed-combination products containing 5% BPO and clindamycin were moderately irritating when applied under occlusion on the back. 10 In addition, a small subset of patients may respond to BPO with allergic contact dermatitis. 11 In a survey of 200 patients who had previously used fixed-combination products containing 5% BPO and clindamycin, dry skin or irritation was a common complaint, reported by up to 45% of acne patients. These side effects can be rather bothersome (55% of patients said they were bothered or extremely bothered) and patients coping mechanisms influenced their use of medication and may have decreased likelihood of achieving full treatment benefit. 12 BPO concentrations of 2.5% may be as effective as 5% or 10% concentrations in reducing the number of inflammatory lesions of acne. 9 BPO 2.5% also significantly reduced P. acnes counts after 1 week of topical application to the face. 9 One in vitro study showed that when BPO and clindamycin were combined in a ratio of 2.5 to 1, P. acnes strains resistant to clindamycin were inhibited by BPO. 13 Another in vitro study that assessed skin penetration where P. acnes resides in the skin showed no statistically significant difference between 2.5% BPO in clindamycin-bpo 2.5% and 5% BPO in clindamycin- BPO 5%. 14 In fact, the 2.5% BPO formulation had a 2 log reduction in resistant clindamycin strains, illustrating that 2.5% BPO is just as likely to kill resistant strains as a 5% formulation. Choosing a Treatment Formulation Generally, treatment should be initiated with a low concentration of BPO to minimize local side effects. 15 An effective, minimally irritating once-daily acne treatment may contribute to improved patient compliance. 16 An ideal fixed-combination acne product would be once-daily, contain a low concentration of BPO (< 5%), attack multiple pathogenic pathways, be stable and be formulated in a vehicle that enhances BPO bioavailability while minimizing irritation. Consequently, a fixed-dose, once-daily combination product containing clindamycin phosphate 1.2% (equivalent to 1% clindamycin) and a low concentration (2.5%) of BPO (Acanya Gel) was developed to effectively treat both the inflammatory and noninflammatory lesions of moderate and severe acne while minimizing the potential for skin irritation. Acanya Gel is formulated in an alcohol-free aqueous gel with humectant and solubilizing properties to enhance both delivery and bioavailability of microdispersed BPO and clindamycin phosphate into the pilosebaceous unit. Two identical Phase III clinical studies have been conducted to evaluate the efficacy, safety and cutaneous tolerability of Acanya Gel in the treatment of moderate to severe acne. Together, they represent some of the largest studies to date in the treatment of acne. In addition, data on patient satisfaction and quality of life were collected as they have important implications for overall patient outcomes in acne management. Efficacy Overview The efficacy and safety of once-daily Acanya Gel was evaluated in two identical Phase III studies in 2,813 patients with Supplement to Skin & Aging July 2010 7

ACANYA GEL Figure 1. Median percentage reduction in lesions at week 12: 64% reduction in inflammatory lesions with Acanya Gel. Figure 2.Treatment success compared to active ingredients and vehicle:35% treatment success with Acanya Gel. moderate and severe acne. 17 Twenty percent of patients studied had severe acne; the other 80% had moderate acne. Acanya Gel was compared with the individual active ingredients (clindamycin phosphate 1.2% and BPO 2.5%) and vehicle over 12 weeks. Efficacy evaluations comprised inflammatory, noninflammatory and total lesion counts, and an evaluator global severity score (EGSS) at screening, baseline, and during treatment (weeks 4, 8, and 12). The EGSS was evaluated on a static scale ranging from 0 (clear) to 5 (very severe) independent of the baseline score. A patient self-assessment (SSA) was also carried out; patients evaluated severity and degree of improvement relative to baseline on a scale ranging from 1 (clear) to 7 (worse). Patient satisfaction was assessed at baseline and week 12. At baseline, patients were given the following instructions: On a scale of 1 to 10, with 1 being the least satisfied and 10 being the most satisfied, please rate your level of satisfaction with your prior acne therapy ; and at week 12: On a scale of 1 to 10, with 1 being the least satisfied and 10 being the most satisfied, please rate your level of satisfaction with your current acne study treatment. In the post-hoc analysis, patients with a baseline score of 5 or less were considered dissatisfied with their prior acne therapy, and patients with a score 6 or more were considered satisfied with their prior acne therapy. Health-related quality of life (HRQL) was as- 8 July 2010 Supplement to Skin & Aging

ACANYA GEL Figure 3. Subject self-assessment compared to active ingredients and vehicle: 39% clear/almost clear with Acanya Gel at week 12 and superior efficacy from week 2. Figure 4. Absolute change in baseline domain scores: Acanya Gel superior to active ingredients and vehicle. sessed in the pivotal studies of Acanya Gel using a validated, acne-specific HRQL Acanya Gel demonstrated statistically superior efficacy over individual active ingredients and vehicle for all lesion types including inflammatory, noninflammatory and total lesion reduction. After 12 weeks of treatment, inflammatory lesion counts were reduced by a median of 64.1% with Acanya Gel and noninflammatory lesion counts by a median of 48.7%, compared to 54.0% and 40.3% median reductions with clindamycin phosphate gel (P<0.001), 55.2% and 43.8% with BPO 2.5% gel (P<0.001 and P=0.001, respectively), and 34.4% and 26.0% with vehicle gel (P<0.001). Total lesion counts were reduced by a median of 52% with Acanya Gel, compared to 44.5% with clindamycin gel, 46.6% with BPO 2.5% gel, and 26.9% with vehicle gel (all P<0.001) (see Figure 1). 18 Treatment success was defined as at least a two-grade improvement in EGSS. More than one-third of patients (34.9%) on Acanya Gel were judged to be treatment successes by the investigators, compared to 16.5% on vehicle gel (p<0.001) (see Figure 2). 17 Investigators judged moderate-baseline-acne patients to be clear or almost clear if they d had at least a two-grade improvement in EGSS and severe-baseline-acne patients to be clear or almost clear if they d had at least a three-grade im- Supplement to Skin & Aging July 2010 9

ACANYA GEL Figure 5. Cutaneous tolerability of Acanya Gel comparable to vehicle. provement in EGSS. At week 12, 28.6% of patients were determined to be clear or almost clear of their acne, compared to 12.6% on vehicle (P<0.001). 17 Patient Satisfaction and Quality of Life In clinical practice, patient expectation of and satisfaction with their acne therapy is an important aspect of management. Patients can often have unrealistic expectations of therapy. Previous studies have shown that patients expect to see improvements in their acne within 1 month, and that even those with severe acne expect to see improvement within 8 weeks. 19,20 A significantly greater percentage of patients on Acanya Gel (39.2%) judged their acne to be clear/almost clear at week 12, compared to 16.6% on vehicle gel (P<0.001). 17 An encouraging note about this very large study: the number of patients who reported that their acne was clear/almost clear was statistically significantly superior to vehicle as early as week 2 (P=0.002) and greater than the investigator assessment (see Figure 3). Patients were significantly more satisfied with Acanya Gel than prior acne therapies. At baseline, patients randomized to receive Acanya Gel had a mean satisfaction score of 4.2 (dissatisfied) with their prior acne therapies. At week 12, these patients had a mean score of 7.5 (satisfied), statistically significant compared to baseline (P<0.001). In addition, 81.2% of Acanya Gel patients were satisfied with the treatment at week 12. 20 Facial acne can profoundly affect HRQL, similar to levels reported by patients with other chronic diseases such as asthma, arthritis or diabetes. 21 Clinical objective assessments such as lesion counts and physician grading classifications alone don t adequately capture the impact of acne from a patient s perspective. 22 Acne treatments can differentially impact HRQL. Consequently, HRQL is an important endpoint in comparative clinical trials complementing the clinical objective assessments of efficacy. However, many studies on the impact of acne treatments on HRQL have included small numbers of patients and only patients with mild to moderate facial acne; have not fully examined changes in HRQL; and have been conducted as unblinded observational studies. 16,21,23 30 In this large study, treatment with Acanya Gel significantly improved patient perception of moderate to severe acne compared with individual active ingredients and vehicle across all the four domains of acne quality of life: acne symptoms, self perception, role-emotional and role-social (P<0.001). The absolute change from baseline to week 12 on the Acne-QoL for patients treated with Acanya Gel was 7.4 for acne symptoms, 7.3 for role-emotional, 8.9 for self-perception and 5.6 for role-social. What s more, the Acanya Gel patients had significantly greater improvements in these domains than patients treated with individual active ingredients and vehicle (P<0.001) consistent with results relating to lesion count reduction (see Figure 4). 31 Safety Overview Overall, the safety and tolerability evaluations of Acanya Gel were excellent and comparable with its active ingredients and vehicle. 20 Incidence of adverse effects (AEs) determined to be possibly, probably or definitely related to therapy was low and was similar among Acanya Gel, active ingredients and vehicle. Most of the AEs reported (97%) were mild to moderate in severity. Application site reactions in the Acanya Gel were rare (0.1%). 20 One patient reported both application-site pain and application-site irritation that resulted in treatment discontinuation. No patients in the Acanya Gel cohort reported experiencing application-site dryness. No serious AEs occurred that were considered treatment-related. 10 July 2010 Supplement to Skin & Aging

ACANYA GEL The vast majority of patients in all treatment groups did not experience local signs and symptoms during treatment and, when these occurred, they were mostly mild in severity. No patients in the Acanya Gel cohort experienced severe local signs or symptoms or discontinued study treatment because of erythema, scaling, itching, burning or stinging. Mean scores for erythema, scaling, itching, burning and stinging at each post-baseline visit were less than 1 (1 = mild) and comparable between Acanya Gel and vehicle (see Figure 5). Conclusion An ideal fixed-combination acne product would be oncedaily, contain a low concentration of BPO (< 5%), attack multiple pathogenic pathways, be stable and be formulated in a vehicle that enhances BPO bioavailability while minimizing irritation. Acanya Gel is a once-daily treatment approved for use in moderate to severe acne. It has been studied in more than 3,000 patients and shown to be effective in both inflammatory and noninflammatory lesions. Acanya Gel provides a 64% median reduction in inflammatory lesions. Thirty-nine percent of patients were clear/almost clear with superior efficacy from 2 weeks. There were significantly greater improvements in all four acne quality of life domains versus individual ingredients, and 81% of patients were satisfied with their treatments. In addition, overall efficacy and tolerability were reported as excellent, a factor likely to lead to enhanced compliance to acne therapy and, therefore, optimal patient outcomes. Acknowledgment The author acknowledges the support of Brian Bulley, MSc, in the development of this manuscript. References 1. White GM. Recent findings in the epidemiologic evidence, classification and subtypes of acne vulgaris. J Am Acad Dermatol. 1998;39(Suppl):S34 S37. 2. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: A report from the alliance to improve outcomes in acne. J Am Acad Dermatol. 2003;49(Suppl):S1 S38. 3. Webster GF, Jeyden JJ, McGinley KJ, McArthur WP. Suppression of polymorphonuclear leucocyte chemotactic factor production in Propionibacterium acnes by subminimal inhibitory concentrations of tetracycline, ampicillin, minocycline, and erythromycin. Antimicrob Agents Chemother. 1982(5);21:770 772. 4. Gupta AK, Lynde CW, Kunynetz RA, Amin S, Choi K, Goldstein E. A randomized, double-blind, multicenter, parallel group study to compare relative efficacies of the topical gels 3% erythromycin/5% benzoyl peroxide and 0.025% tretinoin/erythromycin 4% in the treatment of moderate acne vulgaris of the face. J Cutan Med Surg. 2003;7(1):31 37. 5. Waller JM, Dreher F, Behnam S, Ford C, Lee C, Tiet T, et al. Keratolytic properties of benzoyl peroxide and retinoic acid resemble salicylic acid in man. Skin Pharmacol Physiol. 2006;19(5):283 289. 6. Cunliffe WJ, Holland KT, Bojar R, Levy SF. A randomized, double-blind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris. Clin Ther. 2002;24(7):1117 1133. 7. Leyden J, Kaidby SF, Levy K. The combination formulation of clindamycin 1% plus benzoyl peroxide 5% versus 3 different formulations of topical clindamycin alone in the reduction of Propionibacterium acnes. Am J Clin Dermatol. 2001;2(4):263 266. 8. Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide and vehicle gel: Combined results of two double-blind investigations. J Am Acad Dermatol. 1997;37(4):590 595. 9. Mills OH Jr, Kligman AM, Pochi P, Comite H. Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. Int J Dermatol. 1986;25(10):664 667. 10. Dosik J. Varnvakias G. Comparative irritation potential of two combination acne products. Am J Clin Dermatol. 2008;9(5):313 333. 11. Haustein UF, Tegetmeyer L, Ziegler V. Allergic and irritant potential of benzoyl peroxide. Contact Dermatitis. 1985;13(4):252 257. 12. Patient survey [data on file]. Alison Viejo, CA: Coria Laboratories. 13. Data on file. Alison Viejo, CA: Coria Laboratories. 14. Bucks D, Sarpotdar P, Yu K, Angel A, Del Rosso J. The development and optimization of a fixed combination of clindamycin and benzoyl peroxide aqueous gel. J Drugs Dermatol. 2009;8(7):634 638. 15. Tucker R, Walton S. The role of benzoyl peroxide in the management of acne vulgaris. Pharm J. 2007;279:48 53. 16. Serup J, Lindblad AK, Maroti M, et al. To follow or not to follow dermatological treatments a review of the literature. Acta Derm Venereol. 2006;86(3):193 197. 17. Thiboutot D, Zaenglein A, Weiss J, et al. An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% for the once-daily treatment of moderate-to-severe acne vulgaris: assessment of efficacy and safety in 2,813 patients. J Am Acad Dermatol. 2008;59(5):792 800. 18. Gold MH. A new, once-daily, optimized, fixed combination of clindamycin phosphate 1.2% and low-concentration benzoyl peroxide 2.5% gel for the treatment of moderate-to-severe acne. J Clin Aesthetic Dermatol. 2009:2(5):44 48. 19. McEvoy B, Nydegger R, Williams G. Factors related to patient compliance in the treatment of acne vulgaris. Int J Dermatol. 2003;42(4):274 280. 20. Tan JK, Vasey K, Fung KY. Beliefs and perceptions of patients with acne. J Am Acad Dermatol. 2001;44:439 445. 21. Mallon E, Newton JN, Klassen A, Stewart-Brown SL, Ryan TJ, Finlay AY. The quality of life in acne: a comparison with general medical conditions using generic questionnaires. Br J Dermatol. 1999;140(4):672 676. 22. Finlay AY. Quality of life measurement in dermatology: a practical guide. Br J Dermatol. 1997;136(3):305 314. 23. Klassen AF, Newton JN, Mallon E. Measuring quality of life in people referred for specialist care of acne: comparing generic and disease-specific measures. J Am Acad Dermatol. 2000;43(2 Pt 1):229 233. 24. Girman CJ, Hartmaier S, Thiboutot D, et al. Evaluating health-related quality of life in patients with facial acne: development of a self-administered questionnaire for clinical trials. Qual Life Res. 1996;5(5):481 490. 25. Gupta MA, Johnson AM, Gupta AK. The development of an acne quality of life scale: reliability, validity, and relation to subjective acne severity in mild to moderate acne vulgaris. Acta Derm Venereol. 1998;78(6):451 456. 26. Motley RJ, Finlay AY. Practical use of a disability index in the routine management of acne. Clin Exp Dermatol. 1992;17(1):1 3. 27. Newton JN, Mallon E, Klassen A, Ryan TJ, Finlay AY. The effectiveness of acne treatment: an assessment by patients of the outcome of therapy. Br J Dermatol. 1997;137(4):563 567. 28. Kellett SC, Gawkrodger DJ. The psychological and emotional impact of acne and the effect of treatment with isotretinoin. Br J Dermatol. 1999;140(2):273 282. 29. Jones-Caballero M, Chren MM, Soler B, Pedrosa E, Penas PF. Quality of life in mild to moderate acne: relationship to clinical severity and factors influencing change with treatment. J Eur Acad Dermatol Venereol. 2007;21(2):219 226. 30. Martin AR, Lookingbill DP, Botek A, Light J, Thiboutot D, Girman CJ. Health-related quality of life among patients with facial acne assessment of a new acne-specific questionnaire. Clin Exp Dermatol. 2001;26(5):380 385. 31. Kimball AB, Thiboutot DM, Chen DM, Merikle E. Impact of a fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% on health related quality of life in 2813 patients with moderate to severe acne vulgaris. Poster presented at: Winter Clinical Dermatology Conference Hawaii; Koloa, HI; January 23 28, 2010. Supplement to Skin & Aging July 2010 11

ATRALIN GEL Atralin (Tretinoin) Gel 0.05%: Micronized Tretinoin Julie Harper, MD Topical retinoids have been used in the treatment of acne vulgaris for more than 30 years. Although treatment options for acne have expanded considerably in the past decade, the main goals of treatment continue to be reducing acne lesions while maintaining patient satisfaction and adherence to treatment. Today, topical retinoids are one of the cornerstones of acne therapy and are recommended as first-line therapy for all but the most severe forms of acne. They are used as monotherapy in mild comedonal acne. For inflammatory acne, topical retinoids are used in combination with benzoyl peroxide (BPO) and antibiotics (topical or oral) and/or hormonal therapy for females. 1 Understanding Retinoids Retinoids normalize the abnormal follicular desquamation associated with acne, which facilitates penetration of other anti-acne agents and prevents obstruction of the pilosebaceous outlet. 2,3 As a result, they are both comedolytic and anti-comedogenic and have been shown to reduce formation of microcomedones and comedones. 4 Retinoids also have direct and indirect anti-inflammatory properties, presumably from their actions on toll-like receptors and cytokine production. 5 A major drawback to retinoid therapy is its potential to irritate the treatment area, a side effect that is generally dosedependent. 6 Retinoid therapy has been associated with irritation, exfoliation, dryness and scaling, especially during the first 3 to 4 weeks of treatment. 6 Irritation can be a limiting factor for treatment adherence in many patients. 6 Factors that influence irritant reactions have been shown to include individual skin sensitivity, the particular retinoid and concentration used, and the vehicle formulation. 7 Tretinoin (all-trans-retinoic acid) was the first prescription retinoid to be approved for the treatment of acne in 1971. It normalizes keratinization, inhibits comedone formation and has anti-inflammatory properties. Like all topical retinoids, tretinoin also can cause skin irritation. 8 Since its introduction, various concentrations of tretinoin have been approved in the United States. Each of the formulations introduced has been designed to reduce irritation and provide flexibility in dosing. 9 An aqueous gel formulation containing a 0.05% concentration of tretinoin (Atralin [tretinoin] Gel 0.05%) has been developed and approved for the treatment of acne vulgaris in patients 10 years and older. Atralin Gel is uniquely formulated as micronized particles, with 85% of the particles < 10 microns in size. This is important because raw tretinoin particles are approximately 200 to 300 microns and the skin follicles have an average diameter of 11 to 66 microns. The micronized particles are stabilized in suspension in an aqueous gel for targeted, controlled release into the skin follicle to optimize tolerability and efficacy. The gel also contains ingredients commonly found in moisturizers (soluble collagen, sodium hyaluronate) and skin hydration products (glycerin). Clinical Studies Overview Two studies were recently undertaken to evaluate the efficacy and safety of Atralin Gel in mild to moderate acne. 10 These 12-week, randomized, investigator-blinded, vehicle-controlled phase 3 studies evaluated these factors in patients 10 years and older. Study No. 1 compared Atralin Gel with a higher concentration (0.1% tretinoin microsphere gel) and vehicle; study No. 2 compared Atralin Gel with vehicle. In total, 1,537 patients were included in the analysis. Patients were required to have 15 to 40 inflammatory facial lesions; 30 to 125 noninflammatory facial lesions; and a global severity score of 2 (mild), 3 (mildly moderate), or 4 (moderate) in study No. 1, and 3 (mildly moderate) or 4 (moderate) in study No. 2, which also included nasal lesions. At each study visit (weeks 1, 2, 4, 8 and 12), investigators performed counts of inflammatory (papules, pustules) and noninflammatory (open and closed comedones) lesions. Additionally, they provided a global severity score ranging from 0 (clear) to 5 (severe). Adverse events (AEs), whether observed by investigators or reported by participants, and dosing compliance, as reported by the participants and estimated from tube weights, were recorded. Efficacy Results Pooled data. The baseline global severities of patients treated with the two active comparators (Atralin Gel and 12 July 2010 Supplement to Skin & Aging

ATRALIN GEL Figure 1. Treatment success compared to tretinoin microsphere (0.1%) and vehicle: 17% treatment success with Atralin Gel (0.05% Tretinoin) at week 12. Figure 2. Median percentage change in inflammatory lesions (combined data): 47% reduction with Atralin Gel. Skin-related AEs Patients with skin-related adverse events Atralin Gel Tretinoin Vehicle gel 0.05% microsphere (n=487) (n=674) 0.1% (n=376) 208 (31%)* 196 (52%) 25 (5%) Dry skin 109 (16%) 112 (30%) 8 (2%) Peeling/scaling/flaking 78 (12%) 114 (30%) 7 (1%) Skin-burning sensation 53 (8%) 57 (15%) 8 (2%) Erythema 47 (7%) 67 (18%) 1 (<1%) Pruritus 11 (2%) 11 (3%) 3 (1%) Pain of skin 7 (1%) 3 (1%) 0 (0%) Sunburn 7 (1%) 5 (1%) 3 (1%) *P<0.001 versus tretinoin microsphere Figure 3. Median reduction in lesions (study No. 1) at week 12: 48% reduction in total lesions with Atralin Gel. Table 1. Most common skin-related adverse events. 0.1% tretinoin microsphere) in the pooled data analysis were different. More mild patients were on 0.1% tretinoin microsphere (24%) compared to Atralin Gel (14%). In addition, the dose of tretinoin microsphere was twice that of Atralin Gel. At week 12, treatment success with Atralin Gel(17%) was significantly better than with vehicle (P<0.001) (see Figure 1).The median percent change in inflammatory (see Figure 2) and noninflammatory lesion counts with Atralin Gel were 47% and 48%, respectively, at week 12 and significantly greater than with vehicle (P<0.001). Study No. 1. Treatment success defined as a global severity of clear/almost clear and a minimum change of two grades from baseline was 21% in the Atralin Gel arm, and significantly greater than with vehicle (P=0.002). Median percentage lesion count reductions in patients receiving Atralin Gel were 48% (inflammatory), 50% (noninflammatory) and 48% (total lesions) all significantly greater than with vehicle (P<0.001). (Figure 3) Study No. 2. Median percentage reductions in inflammatory lesions (41%) and noninflammatory lesions (47%) with Atralin Gel were significantly greater than with vehicle (P<0.001) at week 12. Safety Results Analyses of the combined studies demonstrated a low incidence of skin-related AEs after treatment with Atralin Gel; 70% of patients reported no skin-related AEs. The most commonly reported skin-related AE within the Atralin Gel group was dry skin (16%) (see Table 1). This is in comparison to the higher-strength 0.1% tretinoin microsphere, for which the overall incidence of skin-related adverse events was 52% (P<0.001 versus Atralin Gel) and for which dry skin occurred in 30% of patients. In addition, peeling/scaling/flaking skin was reported by 30% of patients treated with 0.1% tretinoin microsphere (compared to 12% on Atralin Gel) and erythema in 18% of patients in the 0.1% tretinoin microsphere group (compared to 7% on Atralin Gel). Skin-related AEs generally resolved within the first 4 weeks of treatment and were similar to baseline at week Supplement to Skin & Aging July 2010 13

ATRALIN GEL Tretinoin microsphere 0.1% (n=376) 30% Atralin 0.05% (n=674) Vehicle (n=487) 20% 10% 0% 1 2 3 4 5 6 7 8 9 10 11 12 Figure 4: Total skin-related adverse events: effect of treatment duration (combined data). 12 (see Figure 4). Furthermore, the incidence rates observed with Atralin Gel in the combined analysis were 50% to 75% lower than those rates reported in the literature for other marketed tretinoin formulations containing half the concentration, 0.025%, of tretinoin gel. 11,12 Conclusion The results of the combined analysis of pooled data demonstrate that Atralin Gel, when administered once daily, is an effective, safe, well-tolerated therapy for acne, exhibiting a favorable irritation profile. Overall efficacy of Atralin Gel was significantly greater than with vehicle in mild to moderate acne. Cutaneous tolerability of Atralin Gel was significantly better than that observed with 0.1% tretinoin microsphere. Treatment with topical acne medications that have proven efficacy and that are associated with fewer skin-related side effects may result in greater patient compliance and, therefore, greater overall effectiveness. In addition, safety, efficacy and adherence associated with topical retinoids are formulation-dependent. 13 The aqueous gel formulation of Atralin Gel contains a 0.05% concentration of active tretinoin, and ingredients commonly found in moisturizers (soluble collagen, sodium hyaluronate) and skin hydration products (glycerin). These moisturizing ingredients, coupled with micronized tretinoin, likely play a key role in enhancing the tolerability of Atralin Gel. Atralin Gel is an effective therapy for acne that exhibits a clinically relevant, local tolerance profile, resulting in low levels of skin irritation. Acknowledgment The author acknowledges the support of Brian Bulley, MSc, in the development of this manuscript. References 1. Ghali F, Kang S, Leyden J, Shalita AR, Thiboutot DM. Changing the face of acne therapy. Cutis. 2009 Feb;83(2 Suppl):S4 S15. 2. Yan AC. Current concepts in acne management. Adolesc Med Clin. 2006;17(3):613 637, abstract x xi. 3. Leyden JJ. A review of the use of combination therapies for the treatment of acne vulgaris. J Am Acad Dermatol. 2003;49(Suppl):S200 S210. 4. Thielitz A, Sidou F, Gollnick H. Control of microcomedone formation throughout a maintenance treatment with adapalene gel, 0.1%. J Eur Acad Dermatol Venereol. 2007;21(6):747 753. 5. Feldman S, Careccia RE, Barham KL, et al. Diagnosis and treatment of acne. Am Fam Physician. 2004;69(9): 2123 2130. 6. Leyden JJ, Grossman R, Nighland M. Cumulative irritation potential of topical retinoid formulations. J Drugs Dermatol. 2008 Aug;7(8 Suppl):S14 S18. 7. Thielitz A, Gollnick H. Topical retinoids in acne vulgaris: update on efficacy and safety. Am J Clin Dermatol. 2008;9(6):369 381 8. Weiss JS, Shavin JS. Topical retinoid and antibiotic combination therapy for acne management. J Drugs Dermatol. 2004;3(2):146 154. 9. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA. 2004;292(6):726 735. 10. Webster G, Cargill I, Quiring J, Vogelson CT, Slade HB. A combined analysis of 2 randomized clinical studies of tretinoin gel 0.05% for the treatment of acne. Cutis. 2009, 83(3);146 154. 11. Lucky AW, Cullen SI, Funicella T, et al. Double- blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris. J Am Acad Dermatol. 1998;38(Suppl): S24 S30. 12. Lucky AW, Cullen SI, Jarratt MT, et al. Comparative efficacy and safety of two 0.025% tretinoin gels: results from a multicenter double-blind, parallel study. J Am Acad Dermatol. 1998;38(Suppl):S17 S23. 13. Piacquadio D, Kligman A. The critical role of the vehicle to therapeutic efficacy and patient compliance. J Am Acad Dermatol. 1998;39(2, pt 3):S67 S73. 14 July 2010 Supplement to Skin & Aging

CERAVE CeraVe : Optimized to Build and Repair the Skin Matthew Zirwas, MD The pathogenesis of acne is frequently described as involving four primary factors: excess sebum production, Propionibacterium acnes (P. acnes) colonization, hyperkeratinization and androgens. What is often underappreciated, though, is the underlying barrier dysfunction that plays a crucial role. The Importance of Barrier Function in Acne First, androgens are implicated in the development both of microcomedones and comedones and are most frequently associated with instigating increased sebum production. However, androgens also have been shown to directly disturb barrier function, which may lead to epidermal hyperplasia that may contribute to follicular hyperkeratosis. 1 Research also shows that patients with acne have increased transepidermal water loss (TEWL), a marker of diminished barrier function, compared to controls. 2 Second, lipid bilayer deficiencies compromise the integrity of the skin barrier. 3 6 Sebum, which intuitively may be assumed to improve skin barrier function, has actually been shown to interfere with barrier function by disturbing the balance of endogenous skin lipids. With high rates of sebum production, levels of linoleate in sebaceous esters drop, leading to fatty acid deficiency. This deficiency results in follicular hyperkeratosis and comedone formation. 7 Third, acne directly affects barrier function of the stratum corneum (SC) via inflammation and the SC s impact on epidermal growth and maturation, which is evidenced by high TEWL, dryness and peeling. 8 Barrier disruption also may lead to increased absorption of topical medications and skin care products, which may be beneficial because increased penetration of active agents may be allowed; however, further increased penetration of irritating excipients would also be expected, leading to increased irritancy potential of topically applied products. 9 One of the most common chronic skin diseases, atopic dermatitis (AD), is the best-known disease in which impaired barrier function plays a major role, being directly linked to increased TEWL. 3,10,11 However, mounting evidence implicates barrier dysfunction as being present in nearly all inflammatory dermatoses, including acne vulgaris. Recognizing that barrier dysfunction is an inherent feature of acne and, probably more importantly, that common topical and systemic acne therapies may actually exacerbate barrier dysfunction, is an important reminder of the need to design treatment regimens that will help to restore and preserve the barrier and promote SC hydration, regardless of surface skin oiliness. As such, it s imperative to use gentle skin cleansers, such as CeraVe Hydrating Cleanser or other soap-free, moisturizing cleansers. In addition, there is a growing body of evidence supporting the relationship between impaired barrier function and decreased lipid content in patients with AD, psoriasis and other inflammatory dermatoses. 10 There are three types of bipolar lipids in the SC (ceramides, fatty acids and cholesterol), arranged in multiple bilayers between and around the corneocytes. Current research also suggests that abnormalities in the ratios of these skin-surface lipids impede the skin s protective function. 3 The Importance of Ceramides Ceramides consist of a base long-chain or sphingoid linked to a fatty acid via an amide bond. They are formed as the key intermediates in the biosynthesis of all the complex sphingolipids. At least nine subclasses have been identified in the human SC. These lipids have a role in the barrier properties of the skin, limiting loss of water and solutes and at the same time preventing ingress of harmful substances. Natural and synthetic ceramides are now commonly added to cosmetics and other skin care preparations. 12 Multiple lines of research support the outside-in paradigm as the primary pathogenic explanation for AD. 13 In this paradigm, a defective permeability barrier lets environmental allergens penetrate the skin, initiating the immunological reactions and inflammation crucially involved in the AD. Decreased epidermal filaggrin and decreased SC ceramide content are the two known factors that majorly contribute to the defect in permeability barrier function consistently found in AD. 13 One study shows ceramides are markedly reduced in the lesional forearm skin of affected patients compared with healthy individuals of the same age. 14 More importantly, Supplement to Skin & Aging July 2010 15

CERAVE 1. Data on file; Goldschmidt Personal Care. 2. Data on file; Centerchem, Inc. Figure 1. Barrier recovery: physiologic and nonphysiologic lipids. Figure 2. Barrier recovery: ceramides 3 and 6. non-lesional skin exhibits a similar decrease in ceramides, which shows that the ceramide decrease isn t simply a sequelae of inflammation, but rather precedes inflammation. Among the six ceramide fractions, ceramide 1 and, to some extent, ceramide 3 specifically played roles in the pathogenesis of the disease. 15 In patients with AD, cholesterol sulphate and ceramide 1 and 3 levels are significantly diminished compared with non-atopic patients. 14 In contrast, free cholesterol is higher in AD and, as a result, the ceramide-to-free-cholesterol ratio is significantly lower in patients with AD. Patients with active lesions also exhibit an inverse correlation between ceramides (particularly ceramide 3) and TEWL. This points to the relationship between impaired metabolism of ceramides and dry skin and impaired barrier function in AD. 12 Sphingomyelinase (SMase), which generates ceramides, is involved in the defective barrier function found in AD. Acid and neutral SMase (A- and N-SMase) generate ceramides with structural and signal transduction functions in epidermal proliferation and differentiation. Decreased epidermal A-SMase activity in lesional and non-lesional skin correlates with reduced SC ceramide content and disturbed barrier function. 16 N-SMase activity is reduced in non-lesional skin and more significantly in lesional skin and correlates with impaired expression of cornified envelope proteins and keratins, important for skin barrier function. 17 The SC of the skin of patients with AD is highly susceptible to colonization by various bacteria, including Staphylococcus aureus (S. aureus). Altered ceramide metabolism in AD decreases sphingosine, a potent antimicrobial agent against S. aureus (and a metabolite that may significantly affect the bacterial defense mechanisms of healthy, normal skin). This contributes to AD patients vulnerability to S. aureus colonization. 18 The best approach to barrier repair, based on the available evidence, is to use physiologic lipid- (ceramide-) based moisturizers such as CeraVe, which are mechanistically distinct from traditional moisturizers, which are based on occlusive ingredients and emollients. The traditional, non-physiologic-lipid moisturizers infiltrate the superficial extracellular space of the SC, thereby providing an artificial physical barrier to water loss. Physiologic lipid-based moisturizers traverse the SC and enter the lamellar body s secretory system, where they improve barrier function by supplementing the natural lipids delivered to the SC interstices. Barrier Recovery and Ceramides Differences in barrier recovery after various topical treatments are shown in Figure 1. In the study, the SC was acutely perturbed with application of a non-physiologic lipid (petrolatum), and three mixtures of physiologic lipids (ceramides, fatty acids, cholesterol): an incomplete mixture of physiologic lipids, a mixture that replicated the normal 1:1:1 molar ratio found in the SC, and an optimized mixture that contained an increased amount of ceramide relative to the other components. 19 Barrier function was measured at 45 minutes, and 2, 4 and 8 hours after application of each of these. With no treatment, skin barrier recovery was 55% after 8 hours. The non-physiologic, occlusive lipid improved barrier function rapidly (50% at 45 minutes), but subsequent barrier recovery was impaired; by 8 hours, the skin treated with an occlusive lipid had recovered less than skin that was not treated at all. As expected, the mixtures of physiologic lipids showed no difference compared to no treatment at 45 minutes due to the lag time to enter the lamellar secretory system. However, with the optimized physiologic lipid, a dramatic acceleration of barrier recovery followed: By 8 hours, there was 90% recovery in barrier function. Treatment with the incomplete mixture of physiologic lipids impaired barrier recovery, and use of the mixture that replicated the normal SC lipid profile had no effect on barrier recovery. Treatment with combined optimized physiologic and occlusive, non-physiologic lipids pro- 16 July 2010 Supplement to Skin & Aging

CERAVE *p<0.0001 Figure 3. Barrier recovery: effect of ceramides 1 and 3 on transepidermal water loss. Figure 4. Physiologic lipid moisturizer in atopic dermatitis. vided the benefits of rapid recovery (55% at 45 minutes) combined with the sustained acceleration in recovery (95% at 8 hours). These observations are predicted and explained by the different mechanisms of action of nonphysiologic and physiologic lipids. 18 The penetrations of ceramides into the SC, sustained benefits in skin hydration and reduced water loss have also been studied. An ex vivo study of ceramide 6 (the same as in CeraVe ) demonstrated that it was effectively incorporated into 10 stripped layers of the SC when topically applied (see Figure 2). 20,21 An in vivo study of ceramide 3 (the same as in CeraVe ) demonstrated a significant increase in hydration of the skin that was maintained even 6 days after application ceased (P<0.0006). 3 A ceramide 1+3-containing emulsion had significantly more favorable effects on TEWL when compared with a control emulsion (see Figure 3). Fifteen healthy patients were treated twice daily for 28 days with either the ceramide 1+3- containing emulsion or the identical emulsion without the ceramides (which contained typical occlusive ingredients). As would be predicted, it required at least 3 days for the ceramide-containing emulsion to demonstrate benefit over the vehicle; however, from that point, the ceramide-containing emulsion dramatically improved barrier function, demonstrating a 600% improvement in TEWL at 28 days compared to the control, occlusive-only emulsion (P<0.001). 19 Clinical Evidence for Physiologic Lipids One study looked at the benefits of a ceramide-dominant barrier repair emollient in 24 children receiving standard therapy for stubborn-to-recalcitrant AD. 5 Patients continued prior therapy (topical tacrolimus or corticosteroids), substituting the barrier-repair emollient for their prior moisturizer. Follow-up evaluations, which included severity scoring of atopic dermatitis (SCORAD) values and several biophysical measures of SC function, were performed every 3 weeks for 20 to 21 weeks. SCORAD values improved significantly in 22 of 24 patients by 3 weeks, with further improvement in all patients between 6 and 20 or 21 weeks. TEWL, which was elevated in both involved and uninvolved areas at study entry, decreased in parallel with SCORAD scores and continued to decline even after SCORAD scores plateaued. Both SC integrity (cohesion) and hydration also improved slowly but significantly during therapy (see Figure 4). The ultrastructure of the SC, treated with ceramide-dominant emollient, revealed extracellular lamellar membranes, which were largely absent in baseline SC samples. These results suggest a ceramide-dominant, barrier-repair emollient represents a safe, useful adjunct to the treatment of childhood AD. In another clinical study, a multilamellar vesicular emulsion (MVE ) ceramide-containing liquid cleanser and moisturizing cream (CeraVe Cleanser and Cream) plus fluocinonide cream 0.05% were compared with a mild syndet bar cleanser (Dove ) plus fluocinonide cream 0.05% in 60 patients with mild to moderate eczema. 22 Replacing the syndet cleanser with MVE ceramidecontaining cleanser enhanced treatment efficacy. Substitution of the cleanser combined with addition of MVE ceramide-containing moisturizer further enhanced the treatment outcome compared to substituting the cleanser alone (see Figure 5). Clearly, using ceramide-dominant skin care products had an important clinical effect on the improvement in mild to moderate eczema. Conclusion Ceramide replenishment is the therapeutic strategy with the best evidence to demonstrate clinically significant barrier repair. Substantial evidence demonstrates a major role for ceramide-dominant products in the treatment of atopic dermatitis, especially because this is the only strategy currently available that specifically targets the outside-in paradigm that has been shown to be the major pathogenic pathway in atopic dermatitis. Dove is a registered trademark of Unilever NV. Pharmaceuticals, Inc. MVE is a registered trademark of Healthpoint Limited and is used under license. Supplement to Skin & Aging July 2010 17

CERAVE Figure 5. Efficacy of physiologic lipid products on AD: effect of CeraVe. CeraVe contains three key physiologic lipids necessary for barrier repair: ceramides, fatty acids and cholesterol. The adjunctive use of CeraVe facilitates barrier repair helping patients get better, faster. Acknowledgment The author acknowledges the support of Brian Bulley, MSc, in the development of this manuscript References 1. Thune P. Evaluation of the hydration and the water-holding capacity in atopic skin and so-called dry skin. Acta Derm Venereol. 1989;144:1333 1335. 2. Bergfeld WF. The pathophysiology of acne vulgaris in children and adolescents, part 1. Cutis. 2004;74(2):92 97. 3. Huang HC, Chang TM. Ceramide 1 and ceramide 3 act synergistically on skin hydration and the transepidermal water loss of sodium lauryl sulfate-irritated skin. Int J Dermatol. 2008;47(8):812 819. 4. Yamamoto A, Takenouchi K, Ito M. Imparied water barrier function in acne vulgaris. Arch Dermatol Res. 1995;287(2):214 218. 5. Motta S, Monti M, Sesana S, et al. Abnormality of water barrier function in psoriasis. Arch Dermatol. 1994;130(4):452 456. 6. Chamlin SL, Kao J, Frieden IJ, et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: Changes in barrier function provide a sensitive indicator of disease activity. J Am AcadDermatol. 2002;47(2):198 208. 7. Goldstein AM, Abramovits W. Ceramides and the stratum corneum: Structure, function, and new methods to promote repair. Int J Dermatol. 2003;42(4):256 259. 8. Downing DT, Stewart ME, Wertz PW, et al. Skin lipids: an update. J Invest Dermatol. 1987; 8(3 Suppl):S2 S6. 9. Tanghetti EA. The importance of vehicle in acne therapy. Skin & Allergy News. 2005;(Suppl):S3 S4. 10. Pilgram GSK, Vissers DCJ, van dermeulen H, et al. Aberrant lipid organization in stratum corneum of patients with atopic dermatitis and lamellar ichthyosis. J Invest Dermatol. 2001;117(3):710 717. 11. Lebwohl M, Herrmann LG. Impaired skin barrier function in dermatologic disease and repair with moisturization. Cutis. 2005;76(Suppl 6):S7 S12. 12. Jungersted JM, Hellgren LI, Jemec GB, Agner T. Lipids and skin barrier function a clinical perspective. Contact Dermatitis. 2008 May;58(5):255 262. 13. Elias PM, Steinhoff M. Outside-to-inside (and now back to iutside ) pathogenic mecahnisms in atopic dermatitis. J Invest Dermatol. 2008:128(5):1067 1070. 14. Imokawa G, Abe A, Jin K, et al. Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol. 1991;96(4):523 526. 15. Bikowski J. The use of therapeutic moisturizers in various dermatologic disorders. Cutis. 2001;68(Suppl 5):S3 S11. 16. Di Nardo A, Wertz P, Giannetti A, Seidenari S. Ceramide and cholesterol composition of the skin of patients with atopic dermatitis. Acta Derm Venereol. 1998;78(1):27 30. 17. Jensen JM, Fölster-Holst R, Baranowsky A, et al. Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis. J Invest Dermatol. 2004;122(6):1423 1431. 18. Arikawa J, Ishibashi M, Kawashima M, et al. Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patient with atopic dermatitis to colonization by Staphylococcus aureus. J Invest Dermatol. 2002;119(2):433 439. 19. Elias PM. In: Draelos Z, ed. Procedures in Cosmetic Dermatology: Cosmeceuticals. Philadelphia, PA: Elsevier, Inc.; 2005:63 70. 20. Product information [data on file]. Essen, Germany: Goldschmidt Personal Care. 21. Product information [data on file]. Norwalk, CT: Centerchem, Inc. 22. Draelos ZD. The effect of ceramide-containing skin care products on eczema resolution duration. Cutis. 2008;81(1):87 91. 18 July 2010 Supplement to Skin & Aging

FIGURES INFORMATION AND PERMISSIONS Figures Information and Permissions Advances in Formulation Technologies: Creating Highly Effective and Well-Tolerated Topical Dermatologicals Figure 1. Reproduced with permission: Bucks D, Sarpotdar P, Yu K, Angel A, Del Rosso J. The development and optimization of a fixed combination of clindamycin and benzoyl peroxide aqueous gel. J Drugs Dermatol. 2009;8(7):634 638. Figure 2. Reproduced with permission: Bucks D, Sarpotdar P, Yu K, Angel A, Del Rosso J. The development and optimization of a fixed combination of clindamycin and benzoyl peroxide aqueous gel. J Drugs Dermatol. 2009;8(7):634 638. Acanya Gel: Optimized fixed Clindamycin/Low-Concentration BPO (2.5%) Combination Figure 1. Reproduced with permission: Gold MH. A new, once-daily, optimized, fixed combination of clindamycin phosphate 1.2% and low-concentration benzoyl peroxide 2.5% gel for the treatment of moderate-to-severe acne. J Clin Aesthetic Dermatol. 2009;2(5):44 48. Figure 2. Adapted from: Thiboutot D, Zaenglein A, Weiss J, et al. An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% for the once-daily treatment of moderate to severe acne vulgaris: Assessment of efficacy and safety in 2813 patients. J Am Acad Dermatol. 2008;59(5):792 800, with permission American Academy of Dermatology. Figure 3. Adapted from: Thiboutot D, Zaenglein A, Weiss J, et al. An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% for the once-daily treatment of moderate to severe acne vulgaris: Assessment of efficacy and safety in 2813 patients. J Am Acad Dermatol. 2008;59(5):792 800, with permission American Academy of Dermatology. Figure 4. Kimbal AB, et al. Impact of fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% on Health Related Quality of Life in 2813 patients with moderate to severe acne vulgaris. Poster presented at: Fall Clinical Dermatology; January 23 28, 2010; Kauai, HI. CORIA Laboratories, a division of Valeant Pharmaceuticals North America Figure 5. Adapted from: Thiboutot D, Zaenglein A, Weiss J, et al. An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% for the once-daily treatment of moderate to severe acne vulgaris: Assessment of efficacy and safety in 2813 patients. J Am Acad Dermatol. 2008;59(5):792 800, with permission American Academy of Dermatology. Atralin (Tretinoin) Gel 0.05%: Micronized Tretinoin Figure 1. Data on file. Figure 2. Data on file. Figure 4. Data on file. Figure 5. Data on file. Figure 3. Data on file. CeraVe : Optimized to Build and Repair the Skin Figure 1. Adapted from: Elias PM. In: Draelos Z, ed. Procedures in Cosmetic Dermatology: Cosmeceuticals. Philadelphia, PA: Elsevier, Inc; 2005:63 70. Figure 2. Data on file. Figure 3. Reproduced with permission: Huang HC, Chang TM. Ceramide 1 and ceramide 3 act synergistically on skin hydration and the transepidermal water loss of sodium lauryl sulfate-irritated skin. Int J Dermatol. 2008;47(8):812 819. Figure 4. Reproduced with permission: Chamlin SL, Kao J, Frieden IJ, et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol. 2002;47(2):198 208. Figure 5. Reproduced with permission: Draelos ZD. The effect of ceramide-containing skin care products on eczema resolution duration. Cutis. 2008;81(1):87 91.

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