Transcript Slide 1

Current Research in
Cosmeceuticals
R. Randall Wickett, Ph.D.
James L. Winkle College of
Pharmacy
[email protected]
What is a
Cosmeceutical?
Albert Kligman
Everyone knows that the term
Cosmeceutical was coined by Albert
Kligman about 25 years ago.
Like so many things that “everyone
knows” this is incorrect.
The first known public use of
“Cosmeceutical” that I can document was
in Raymond Reed’s SCC Medal Award
Speech in December of 1961, published in
the Journal of the Society of Cosmetic
Chemists in January of 1962.
He stated that they had been using the
term in his company for many years.
Kligman began to use the term widely and
popularized it about 25 years ago.
Kligman AM. Why cosmeceuticals?
Cosmet Toilet 1993;108:37-8.
What is a Cosmeceutical?
• According the US Food and Drug Administration Office of
Cosmetics and Colors
– “The FD&C Act does not recognize and such category as
‘cosmeceuticals’. A product can be a drug, a cosmetic, or a
combination of both, but the term cosmeceutical has no meaning
under the law.”
• Since the term has no meaning under the law (at least in the US)
we are left to our own devices to define it.
• It has come to mean “active cosmetics” that have positive effects
on the skin that may go beyond cleansing or moisturization. Most
commonly it has come to refer to “actives” that have so called
“anti-aging” effects by whatever mechanism.
Some
Cosmeceuticals
Gau et. Al. (2008) Clinics in
Dermatology 26 367-374
RETINOIDS
“Gold Standard” against which all other for photo-aging
could be compared.
• Metabolites of retinol
• Best known is all trans retinoic acid or tretinoin
• Induces smoothing of skin by affecting dermis
• Clinically proven to reduce wrinkles
• It the US tretinoin is drug. Thus it is not a
cosmeceutical, it is a pharmaceutical – however
study of the mechanisms of tretinoin action may lead
to improved “cosmeceutical approaches” to antiaging
Retinol and metabolites
RETINOIDS
Olsen et.al showed the potential effectiveness
of topical tretinoin emollient cream (TEC) for
treating photo-damaged skin.
• 320 healthy, white persons with mild to moderate
facial photo-damage were selected.
• Subjects were equally randomized into 4
treatment groups,
–
–
–
–
TEC 0.05%,
TEC 0.01%,
TEC 0.001%
Vehicle.
–Olsen et al(1992) J. Amer. Acad. Dermatol 26: 215-224
RETINOIDS
• Subjects were instructed to apply the
assigned test cream to the entire face.
• Duration of treatment was 24 weeks.
• 2mm punch biopsy specimens were
obtained before therapy and after 24
weeks of treatment from adjacent areas.
–Olsen et al(1992) J. Amer. Acad. Dermatol 26: 215-224
RETINOIDS
(A) Pretreatment appearance
(A) Pretreatment appearance
(B) Appearance at week 24 of TEC(B) Appearance at week 24 of TEC
RETINOIDS
• TEC 0.05% significant difference from the
vehicle in reducing the overall severity of photodamage from baseline to the end of the therapy.
RETINOIDS
• Mottled pigmentation, fine wrinkling and
roughness decreased to a greater extent after
TEC 0.05% therapy compared to vehicle.
RETINOIDS
• There was increase in epidermal thickness and granular
layer thickness.
• The melanin content was reduced by 56% in TEC 0.05%
group and 57% in TEC 0.01% group.
RETINOIDS
CONCLUSIONS
• Many visible signs such as wrinkling and mottled
pigmentation are a result primarily from
cumulative sun exposure.
• Most notable clinical changes on treating with
TEC are reduction in fine wrinkling, roughness
and mottled pigmentation.
• Thus, TEC appears to be effective in the
treatment of photo-damaged skin.
Retinol a cosmetic anti-aging
active or “cosmeceutical”
Effects of retinol and retinyl propionate on
wrinkling and hyperpigmentation
Reduction in wrinkling and hyperpigmentation caused by retinol (ROH) and retinyl propionate (RP).
Expert graders (0-4 scale) evaluated reduction vs baseline in wrinkling and hyperpigmentation
at 4, 8, and 12 weeks (average data presented.) The low irritation of RP vs ROH permits use of higher
levels to achieve greater effects without significant negative aesthetic issues.
Bissett, Clinics in Dermatology (2009) 27, 435–445
Scott reported that retinol and AHA + retinol
were effective against photodamged skin on
forearms
Scott, proceedings of the 22nd IFSCC conference, Edinburgh 2002
In a face study retinoic acid was
clearly superior to AHA+Retinol
Scott, proceedings of the 22nd IFSCC conference, Edinburgh 2002
Niacinamide
• Water soluble form derivative of B Vitamin.
• When added to a sunscreen it lightened skin
tone.
• Promoted as an ingredient the smooths
surface texture
– Olay total effects
– L’Oreal Plentitude
• May interfere with transfer of pigment
granules from pigment producing
cells(melanocytes) to keratinocytes.
Niacinamide (Nicotinamide)
5% Niacinamide reduced hyperpigmentation in
human clinical trial.
Hakozaki et al.(2002) Brit. J. Derm. 47 20-31
5% Niacinamide over 8 weeks
of treatment
Week 0
Week 4
Week 8
Greatens et al Experimental Dermatol 14 498-508 (2005)
Niacinamide does not lighten human
melanocytes in culture
Greatens, Wickett and Boissy, unpublished data
Flow Cytometry Analysis
• assay used to determine mean
fluorescence
• two dyes used- CFDA and PE
• outcome indicates the % inhibition of
melanosome transfer
Niacinamide inhibited melansome transfer in vitro.
To demonstrate melanosome-transfer inhibition,
melanocytes were labeled with a succinimidyl
ester of CFDA and cocultured with keratinocytes.
These cocultures were assessed by confocal
microscopy for CFDA transfer in the presence or
absence of 10 mM niacinamide after 6 days of
treatment. Control cultures demonstrated brightly
fluorescing keratinocytes (arrowheads) within a
colony of keratinocytes (star) that also contain
CFDA-positive melanocytes (arrows) The
corresponding differential contrast image
demonstrates that the melanocytes were darkly
pigmented (arrows). In contrast, treatment with
niacinamide resulted in only weaklyfluorescing
keratinocytes within a colony (star) that also
contained CFDA-positive melanocytes of equal
brightness as observed in the control cultures
(arrows). The corresponding differential contrast
image demonstratedthat the melanocytes were
darkly pigmented (arrows).
Greatens et al Experimental Dermatol 14 498-508 (2005)
The effect of niacinamide on
pigmentation in vivo is reversible
Greatens et al Experimental Dermatol 14 498-508 (2005)
12 weeks of treatment with niacinamide reduced facial
wrinkles measured by image analysis more than placebo
Bissett et al (2004) Int. J. Cos. Sci. 26 231-238
Kinetin
• Kinetin is a plant growth
hormone.
• It is reported to have “anti-aging”
and “anti-oxidant effects on cells.
• Chiu et. Al. reported on the
effects of combining kinetin and
niacinamide in a human clinical
trial.
– Chiu et. Al. (2007) J. Cosmet.
Dermatol. 6 243-249
• The authors found the comination
to be effective in reducing facial
wrinkles.
Effects of Niacinamide and Kinetin on facial wrinkles
ANTIOXIDANTS
• Free radical scavengers or chemicals that
intercept and neutralize free radicals.
• Skin - Target organ of environmental photooxidative stress.
• Reactive oxygen species result in structural and
functional alterations of skin (i.e. breakdown of
type III collagen
• Thus, the use of anti-oxidants that attenuate
photo- oxidative toxicity is believed to be an
important strategy in modulating photo-aging.
Vitamin C
Topical vitamin C has been reported to
improve photoaging
Fitzpatric and Rostan(2002) Dermatol Surg 28:231-236
Improvement in wrinkle scores
C was significant over baseline but NOT
over vehicle
10% Ascorbic Acid, 7% tetrahexyldecyl ascorbate
Treatment for 12 weeks, double blind split face.
Fitzpatric and Rostan(2002) Dermatol Surg 28:231-236
Vitamin C and photoaging
• Raschke et. Al. reported that ascorbic acid in an oil-inwater emulsion was superior to its vehicle in a 12
week split face test.
– Raschke et. Al. (2004) Skin Parmacol Physiol 17: 200-206
• The authors reported reduced oxidative stress in the
skin and significant improvement in wrinkles
(roughness values by PRIMOS) compared to vehicle
Decrease in rq (root mean square roughness)
with treatment
12
10
8
3% Ascorbic
6
Placebo
4
2
0
4 weeks
8 weeks
12 weeks
-2
Data replotted from Raschke et. Al. (2004) Vertical axis is
reduction in rq as measured by PRIMOS result at 12
weeks is statistically significant.
ANTIOXIDANTS
CONCLUSIONS
• Anti – oxidants inhibit the propagation of lipid peroxidation and
should help to reduce skin damage associated with free radicals.
• Topical vitamin C treatment was reported to reduce signs of
photoaging but was not significantly better than its vehicle in one
study but did have a significant effect on fine wrinkles measured
by PRIMOS in another study.
Lipoic acid
• 6-8 dithiooctanoic acid
• Reported to be effective for treating
photoaging
Effect of 3 month treatment with 5% LA
Beitner Brit. J. Dermatol. 149 841-849 (2003)
Laser profilometry indicated a
significant improvement in wrinkles
Peptides
• Recently there has been considerable interest in the
use of short peptide sequences as cosmeceutical
actives
• Peptide sequences that can stimulate fibroblasts to
produce collagen in-vitro are used.
• The most widely studied sequence is lysinethreonine-threonine-lysine-serine (KTTKS) found on
type I procollagen.
• See Lupo and Cole (2007) Cosmeceutical Peptides
Dermatologic Therapy 20:343-349 for a review.
Robinson et al reported
that topical application of
a palmitoyl derivative of
KTTKS, PAL-KTTKS
improved signs of
photoaging.
Robinson et. Al(2005) Int. J. Cosmet. Sci 27 155-160
Improvement of wrinkle grades by palKTTKS
Robinson et. Al(2005) Int. J. Cosmet. Sci 27 155-160
Image analysis also showed
directional improvement
Results
• Expert grading of photographs did show a
significant effect versus placebo at 4 weeks
(but not at 12)
• Subjects self assessment of “age spots”
showed a significant advantage over placebo.
• The authors concluded that “Topical 3-ppm
pal-KTTKS was shown to provide a reduction
in facial lines/wrinkles in a 12 week clinical
test”.
NAG
• Glucosamine and N-acetyl glucosamine are
precursors of hyaluronic acid.
• These “sugar amines” have been investigated as both
oral and topical ingredients for improving skin
condition
• Bissett reports that 2% NAG applied topically has
been found to have positive effects on both wrinkles
and hyperpigmentation.
• Bissett, D. (Clinics in Dermatology (2009) 27, 435–
445
NAG enhanced the ability of
Niacinamide to reduce “age spots”
Computer image analysis of Caucasian facial digital images for change in spot
area fraction. More negative numbers indicate reduction in hyperpigmentation
(improvement). N, niacinamide; NAG, N-acetyl glucosamine. P is for 4% N + 2%
NAG vs 4% N.
Bissett, D. (Clinics in Dermatology (2009) 27, 435–445
Gene expression and
cosmeceutical research
• A recent trend in cosmeceutical research is
investigate the effects of treatments on gene
expression in the skin
• Studies are done either in-vitro with explants from
surgery or organotypic skin cultures such as those
from MatTek or in-vivo followed by biopsies.
• Either gene chips such as Affymetrix or rt-PCR
techniques are used investigate treatment effects on
gene expression
The Affymetrix gene chip
Gene expression before and after UV exposure from microarray analysis
Enk et. Al. Photodermatol Photoimmunol Photomed 2004; 20: 129–137
Verification of specific genes by rt-PCR
Challenges with genetic analysis and
cosmeceutical research
• Dozens or even hundreds or perhaps
thousands of genes may be changed over the
course of a treatment
• Some will be up regulated some down
regulated
• How do you decide what is a positive effect?
• Which genes are most important to a positive
interpretation?
Summary
• While cosmeceutical is not a term with legal standing in the US
we see that there are wide variety of approaches to treating skin
that may be considered “cosmeceutical”.
• We have only discussed a few of the major categories today.
• Cosmeceuticals for anti-aging treatment can reduce wrinkles and
age spots and may protect the skin from oxidative damage.
• Hot areas of research include peptides and the use of gene
analysis to investigate cosmeceutical effects on the skin.