Current Research in Cosmeceuticals

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Current Research in Cosmeceuticals

• R. Randall Wickett, Ph.D.
• James L. Winkle College of Pharmacy
• randy.wickett_at_uc.edu

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What is a Cosmeceutical?

• 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 Reeds 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
  199310837-8.

Albert Kligman
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What is a Cosmeceutical?

• According the US Food and Drug Administration
  Office of Cosmetics and Colors
• The FDC 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.

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Some Cosmeceuticals Gau et. Al. (2008) Clinics
in Dermatology 26 367-374
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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
  anti-aging

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Retinol and metabolites
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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

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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

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RETINOIDS

(A) Pretreatment appearance (B) Appearance at
week 24 of TEC
(A) Pretreatment appearance (B) Appearance at
week 24 of TEC
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RETINOIDS

• TEC 0.05 significant difference from the
  vehicle in reducing the overall severity of
  photo- damage from baseline to the end of the
  therapy.

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RETINOIDS

• Mottled pigmentation, fine wrinkling and
  roughness decreased to a greater extent after
  TEC 0.05 therapy compared to vehicle.

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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.

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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.

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Retinol a cosmetic anti-aging active or
cosmeceutical
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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, 435445
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Scott reported that retinol and AHA retinol
were effective against photodamged skin on
forearms
Scott, proceedings of the 22nd IFSCC conference,
Edinburgh 2002
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In a face study retinoic acid was clearly
superior to AHARetinol
Scott, proceedings of the 22nd IFSCC conference,
Edinburgh 2002
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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
• LOreal Plentitude
• May interfere with transfer of pigment granules
  from pigment producing cells(melanocytes) to
  keratinocytes.

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Niacinamide (Nicotinamide)
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5 Niacinamide reduced hyperpigmentation in human
clinical trial.
Hakozaki et al.(2002) Brit. J. Derm. 47 20-31
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5 Niacinamide over 8 weeks of treatment
Week 0
Week 8
Week 4
Greatens et al Experimental Dermatol 14 498-508
(2005)
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Niacinamide does not lighten human melanocytes in
culture
Greatens, Wickett and Boissy, unpublished data
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Flow Cytometry Analysis

• assay used to determine mean fluorescence
• two dyes used- CFDA and PE
• outcome indicates the inhibition of melanosome
  transfer

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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)
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The effect of niacinamide on pigmentation in vivo
is reversible
Greatens et al Experimental Dermatol 14 498-508
(2005)
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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
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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.

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Effects of Niacinamide and Kinetin on facial
wrinkles
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ANTIOXIDANTS

• Free radical scavengers or chemicals that
  intercept and neutralize free radicals.
• Skin - Target organ of environmental photo-
  oxidative 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.

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Vitamin C
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Topical vitamin C has been reported to improve
photoaging
Fitzpatric and Rostan(2002) Dermatol Surg
28231-236
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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
28231-236
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Vitamin C and photoaging

• Raschke et. Al. reported that ascorbic acid in an
  oil-in-water 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

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Decrease in rq (root mean square roughness) with
treatment
Data replotted from Raschke et. Al. (2004)
Vertical axis is reduction in rq as measured by
PRIMOS result at 12 weeks is statistically
significant.
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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.

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Lipoic acid

• 6-8 dithiooctanoic acid
• Reported to be effective for treating photoaging

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Effect of 3 month treatment with 5 LA
Beitner Brit. J. Dermatol. 149 841-849 (2003)
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Laser profilometry indicated a significant
improvement in wrinkles
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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
  lysine-threonine-threonine-lysine-serine (KTTKS)
  found on type I procollagen.
• See Lupo and Cole (2007) Cosmeceutical Peptides
  Dermatologic Therapy 20343-349 for a review.

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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
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Improvement of wrinkle grades by pal-KTTKS
Robinson et. Al(2005) Int. J. Cosmet. Sci 27
155-160
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Image analysis also showed directional improvement
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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.

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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,
  435445

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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,
435445
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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

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The Affymetrix gene chip
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Gene expression before and after UV exposure from
microarray analysis
Enk et. Al. Photodermatol Photoimmunol Photomed
2004 20 129137
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Verification of specific genes by rt-PCR
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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?

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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.