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NOVEL RETINOID ESTER IN COMBINATION WITH SALICYLIC ACID FOR THE TREATMENT OF ACNE PRIMARY AUTHOR: Zoe Draelos MD CO-AUTHORS: Joseph Lewis BS; Laura McHugh MS; Arthur Pellegrino BS; Lavinia Popescu MS, MBA combining the RC induced normalization of cellular differentiation, AHA induced exfoliation in hydrophilic Retinoids (RC), alpha hydroxy acids (AHA), and salicylic acid (SA) have therapeutic benefit in acne treatment areas, and SA induced exfoliation in lipophilic areas.
through differing mechanisms of action. It is theorized that optimal acne improvement could be achieved by Unfortunately, therapeutic doses of topically applied combining the RC induced normalization of cellular differentiation, AHA induced exfoliation in hydrophilic areas, retinoids frequently cause skin irritations that interfere and SA induced exfoliation in lipophilic areas. The AHA and RC compounds have been combined in a biologically with treatment. Figure 1 shows the relationship between designed molecule, known as an AHA Retinoid Conjugate (AHA-RC; chemically known as ethyl lactyl retinoate), commonly used retinoids and general irritation level, delivering both lactic acid (AHA) and RC in a time-released hydrolytic manner designed to reduce retinoid and the process by which they are converted from associated irritation. A 27 subject 8-week clinical trial in subjects with mild to moderate acne was conducted one form to another. Esters are molecules made by using a 3-product regimen consisting of a twice daily cleanser (7.8% l-lactic acid, 2% SA), a twice daily acne serum reacting an organic carboxylic acid and an alcohol (0.1% AHA-RC, 2% salicylic acid & 10.4% l-lactic acid) and a broad spectrum SPF 50+ sunscreen as needed. through a condensation reaction, and typically provide Investigator counts of total inflammatory (papules, pustules) and non-inflammatory (open comedones, closed increased stability and reduced irritation over the parent comedones) lesions revealed a statistically significant reduction in inflammatory lesion counts (p=0.006) and compounds. Attempts to reduce retinoid irritation by non-inflammatory lesion counts (p=0.015) after 4 weeks of use. Improvement continued into week 8 with highly statistically significant (p<0.001) reductions in inflammatory and non-inflammatory lesions. Thus, the combination esterifying Vitamin A with fatty acids or other common of lactic acid, SA and the novel AHA-RC produced acne improvement after 4 weeks with continuing cumulative organic acids such as palmitic acid or acetic acid to improvement at 8 weeks. AHA-RC represents a new molecule combining several mechanisms of action to achieve produce ‘retinyl' esters (e.g. retinyl palmitate and retinyl acne improvement.
acetate) also result in reduced efficacy. Figure 1. Vitamin A Derivatives, Method of Conversion and Irritation Potential
normalize cell differentiation and inhibit key immunity RETINOIC ACID (VITAMIN A ACID) Topical therapies serve as the frontline treatment in all factors.6 Associated irritation makes topical use somewhat but the most severe cases of acne vulgaris due to their problematic as it may affect compliance.7 Alpha hydroxy relatively low cost and ease of use. Compliance is often acids (AHA) are nontoxic, organic acids (e.g. glycolic acid, an issue with topical acne therapies,1 especially those lactic acid, malic acid, etc.) consisting of a carboxylic with associated unpleasant side effects such as stinging acid functional group with a hydroxyl group (alcohol) on and burning, redness, or drying and flaking of skin.
the adjacent (alpha) carbon atom; some, such as lactic Retinoid compounds (RC; vitamin A and its derivatives) acid, are present within the body.8 Harnessed effects are heavily studied and used but still not well include moisturization, exfoliation, and dermatologic understood; they are commonly used to treat acne, indications involving abnormal keratinization. Their photodamage, and other skin conditions due to the safety, moisturization, and exfoliant properties make range of biological effects (normalization of melanocyte them ideal for topical use. Salicylic acid (SA), a beta Retinyl Palmitate Ethyl Lactyl Retinoate Retinyl Linoleate function, immunomodulation, regulation of skin cell hydroxy acid (or BHA), is one of five FDA cleared OTC Double Conjugate) metabolism and cellular turnover, thickening of the therapies for acne and present in numerous topical epidermis, increases in dermal fibroblast production formulations. Bacteriostatic and kerolytic properties as Vitamin A Derivatives, Method of Conversion and activity, stimulation of neocollagenesis, and an well as correction of abnormal shedding of cells have and Irritation Potential increase in the height of rete ridges and the number of been noted9 but require continuous use; SA does not dermal papillae2–5). When treating acne they serve to affect sebum production or kill bacteria. It is theorized that optimal acne improvement could be achieved by A NEW AHA-RETINOID DOUBLE CONJUGATE MOLECULE eye makeup for 7 to 10 days prior to beginning the The primary clinical endpoint was the comprehensive Although technically considered carboxylic acids and study ("washout" period). Pre-screening was reviewed lesion count with comparisons made at the week 4 alcohols, reactions where AHAs are reacted as "alcohols" at baseline (day 0) with re-assessment of initial endpoint and week 8 visits against baseline evaluations. Similar are not common. Retinoate esters can be engineered evaluations including a comprehensive lesion count comparison was made for secondary endpoints. Data by combining AHA (as the alcohol) with vitamin A acid. (inflammatory lesions, non-inflammatory lesions, papules, were analyzed via Mann-Whitney test using the cutoff of Beneficial results include increased stability and reduced pustules, open comedones and closed comedones). p<0.05, with p<0.001 denoting high significance. irritation when compared to the parent compound, Baseline digital photographs were obtained. Product was but esterification often detrimentally affects efficacy. dispensed with clear instructions for proper use. A bioengineered retinoid ester, ethyl lactyl retinoate The three-product regimen included cleanser (7.8% Of enrolled subjects (n=27), 24 completed the study. Two (AHA retinoid conjugate, or AHA-RC), is the first double l-lactic acid, 2% BHA), active topical (0.1% AHA-RC, subjects discontinued the study due to irritation adverse conjugate retinoid to deliver both AHA and RC to skin on 10.4% l-lactic acid, 2% BHA), and broad-spectrum events; there were no serious adverse events, and one a hydrolysis-based time released mechanism biologically sunscreen (SPF 50+); subjects were to apply the topical subject was lost to follow up. designed to be efficient and minimally irritating to after cleansing in the morning and evening. Sunscreen There was a statistically significant reduction in patients. A molecular model of this novel ester is was to be applied after morning application of product inflammatory and non-inflammatory lesion counts at week presented in Figure 2.
and as needed throughout the day. Subject diaries were 4, with highly statistically significant reduction seen by included to promote compliance and obtain subject week 8. Specifically, there was a statistically significant Figure 2. Molecular diagram of AHA retinoid conjugate (AHA-RC).
commentary or observations. reduction in papules (p<0.001) and closed comedones Digital photography and visual expert grading of (p<0.001) at week 8. Table 1 shows percentage of endpoints were performed at week 4 and week 8 follow- improvement with corresponding p values; up; acne was evaluated via comprehensive lesion count Figure 3 graphically demonstrates study results. Data (inflammatory lesions, non-inflammatory lesions, papules, indicates strong, significant improvement in acne with pustules, open comedones and closed comedones). proper use of the AHA-RC plus SA topical. Reductions in Secondary endpoints of Dryness/Flaking, Fine Lines/ lesion counts across the board were notable and, for the Molecular diagram of AHA retinoid conjugate, Wrinkles, Dyschromia, Stinging/Burning, and Erythema/ most part, highly significant. or AHA-RC. Redness were evaluated by the investigator on a 0-5 scale For secondary endpoints, statistically significant (0=none, 1=minimal, 2=mild, 3=moderate, 4=moderately increase in facial stinging seen at week 4 subsided to severe, 5=severe). Global improvement was measured on statistical insignificance by week 8; statistically significant The purpose of this 8 week, prospective pilot study was a 0-4 scale (0=no improvement, 1=minimal improvement, improvement (29% on average) was noted in fine lines, to evaluate efficacy and tolerability of a twice daily, three 2=mild improvement, 3=moderate improvement, and improvement in global appearance (average 57%) was product skincare regimen using the bioengineered AHA 4=marked improvement). Adverse events were recorded more profound. This is particularly important in treating retinoid conjugate ester plus SA in patients with acne.
along with any concomitant medication information adult female acne, one of the most prevalent forms of as well. Subject diaries were collected (and new ones acne. Statistically significant increases were not observed dispensed) at week 4; at week 8 (Day 56) subject diaries in dryness or erythema, further attesting to the tolerability Women (n=27) aged 40–65 years (mean 52±6.20) and any remaining product were collected.
of the acne treatment. Figures 4 & 5 demonstrate typical presenting with a minimum of 15 inflammatory acne visible results demonstrated in the study.
lesions and a minimum of 15 non-inflammatory lesions Table 1: Acne Lesion Percent Improvement, Baseline to Week 8
were enrolled. The study was conducted under current Good Clinical Practices (cGCP) guidelines using an independent investigational review board (IIRB) -approved protocol. After initial screening (Days -10 to -7) during which informed consent, medical history, inclusion/exclusion criteria review, initial endpoint assessment, and other pre-screening activities were performed, *p<0.05 denoted statistical significance, p<0.001 denoted high statistical significance enrolled subjects were instructed to discontinue use of †Open comedones were only present in two patients, which may explain the lack of statistical significance despite an obviously facial products excepting dry mineral foundation and large percentage of improvement.
Figure 3. Comparison of Percent Improvement in Acne Lesion Count, Baseline to Week 8
Figure 4. SUBJECT 18: day 0 vs 8 Weeks
Table 1: Acne Lesion Percent Change, Baseline to Week 8
The three product regimen (AHA-RC plus SA) was shown to be safe and Figure 5. SUBJECT 21: day 0 vs 8 Weeks
effective for treatment of acne; statistically significant reductions in both inflammatory and non-inflammatory acne lesion counts were noted.
Significant improvement to overall skin quality was also observed.
1. Bartlett KB, Davis SA, Feldman SR. Topical antimicrobial acne treatment tolerability: a meaningful factor in treatment adherence? J Am Acad Dermatol. 2014 Sep; 71(3):581-582.e2.
2. Kligman AM, Grove GL, Hirose R, Leyden JJ. Topical tretinoin for photoaged skin. J Am Acad Dermatol. 1986 Oct; 15(4 Pt 2):836-59.
3. Kang S. Photoaging and tretinoin. Clin Dermatol. 1998; 16(2):357-364 4. Kligman LH. Topical retinoic acid enhances repair of ultraviolet damaged dermal connective tissue. Connect Tissue Res. 1984; 12(2):139-50.
5. Zelickson AS. J Cut Aging Cosmet Dermatol. 1988: 1:41-47.
6. Wolf JE Jr. Potential anti-inflammatory effects of topical retinoids and retinoid analogues. Adv Ther. 2002 May-Jun; 19(3):109-18.
7. Rolewski SL. Clinical review: topical retinoids. Dermatol Nurs. 2003 Oct; 15(5):447-50, 459-65.
8. Yu RJ, Van Scott E. Alpha-hydroxy acids: science and therapeutic use. Cosmet Dermatol. 1994; 7(10S):12-20. 9. Madan RK, Levitt J. A review of toxicity from topical salicylic acid preparations. J Am Acad Dermatol. 2014 Apr; 70(4):788-92. This study was sponsored by US CosmeceuTechs, LLC and conducted on their behalf by Dr. Draelos. Lewis and McHugh are employees of US CosmeceuTechs, LLC. Pellegrino and Popescu are employees of Elizabeth Arden; Elizabeth Arden has an equity investment in US CosmeceuTechs, LLC.

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Disposición 20069 del boe núm. 317 de 2010

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