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
acetate) also result in reduced efficacy.
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
function, immunomodulation, regulation of skin cell
hydroxy acid (or BHA), is one of five FDA cleared OTC
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
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.
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
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.
Comparison of Percent Improvement in Acne Lesion Count, Baseline to Week 8
SUBJECT 18: day 0 vs 8 Weeks
Acne Lesion Percent Change, Baseline to Week 8
The three product regimen (AHA-RC plus SA) was shown to be safe and
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.
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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.
BOLETÍN OFICIAL DEL ESTADO Núm. 317 Jueves 30 de diciembre de 2010 Sec. I. Pág. 108827 I. DISPOSICIONES GENERALES MINISTERIO DE LA PRESIDENCIA Resolución de 23 de diciembre de 2010, de la Presidencia del Consejo Superior de Deportes, por la que se aprueba la lista de sustancias y métodos prohibidos
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