Transcript Cosmetology How to reduce esthetically pigmentation*s disorders?

Cosmetology
Are there any « pharmalogical » targets in
cosmetology for pigmentation disorders?
Seminary of scientific communication 2009-2010
Sophie Compagnon, Olivia Scaccia, MélodieDebacker, Catherine Lucas
le 12/02/2010; Lille.
1
Outline
1. Definition
2. Hypopigmentation disorders
a)
b)
c)
d)
Needs
Currently solutions
Possibilities in research
Conclusion
3. Hyperpigmentation disorders
a)
b)
c)
d)
Skin bleaching needs
Currently solutions
Possibilities in research
Conclusion
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Definition
Cosmetics:
Anysubstance or preparation intended to be placed in contact with the
various external parts of the human body (epidermis, hair system,
nails, lips and external genital organs) or with the teeth and the mucous
membranes of the oral cavity with a view exclusively or mainly to
cleaning them, perfuming them, changing their appearanceand/or
correcting body odors and/or protecting them or keeping them in good
condition.
Medicines :
Any substance or combination of substances presented as having
properties for treatingor preventing disease in human beings; and any
substance or combination of substances which may be used in or
administered to human being either with a view to restoring,
correcting or modifying physiological functions by exerting a
pharmacological, immunological or metabolic action, or to making a
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medical diagnosis.
Hypopigmentation disorders
Self-tanners and
esthetics solutions for vitiligo.
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Hypopigmentation disorders
1.
Needs
2.
Currently solutions
a)
b)
3.
Covers up
Self-tanners
Possibilities in research
a)
Increase precursor of melanin
Induction of PAH
b)
Induction of tyrosinase
1. Lotus flower essential oil
2. Humanplacentalsphingolipid
c)
increaseeumelaninsynthesis
Cysteinedeprivatio
4.
Conclusion
Needs
Vitiligo affects approximately 0,5-1% of the world population
For about 50% of patients, the onset of skin disease is before
the age of 20 years
Most affected locations are the face, hands, and feet
cause of severe psychological suffering like stress with
social encounter slow self-esteem and poor body image
Treatment of vitiligo is important
May W. LinthorstHoman et al,The burden of vitiligo: Patient characteristics associated with quality of life,J AM ACAD DERMATOL 2009
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Cosmetic cover-up for vitiligo
More simple possibility
Hard and daily application, dificult for men
Example :
Avene:
Couvrance®
Vichy:
Dermablend®
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In association with cover-up
•
•
CavilonTM3M No Sting Barrier Film :
•
siliconized material
•
a long-lasting and waterproof barrier
•
applied to cover cosmetic camouflage
•
quick and easy application, safe formulation
Melasyn 100 :
•
synthetic melanin
•
soluble in water for cosmetic
formulation
•
mimickes a natural tan
daily application => with cover-up
Reflection Dermablend®
Research possibilities for penetration in epidermis
J.M. Pawelek, approaches to increasing skin melaninwith MSH analogs and syntheticsmelanins, pigment cellres14, 2001, 155-160.
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Self-tanners
Active ingredients = DHA = DiHydroxyAcétone.
Maillard reaction between DHA and AA
of the stratum corneum → skin colouring
Factors of variability : pH, hydratation
Permitted DHA content: 0,5 – 10 %
(usually: 3 - 5 %)
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The Maillard reaction
Bases de Schiff
Réarrangements d’Amadori
Aldosamines ou
Cétosamines
Dégradation
Composés odorants
(dont hétérocycles)
Polymérisation
Mélanoïdines
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• doesn't cause irritation
• doesn‘t cause allergy
• only work son dead cells → no
systemic penetration
• declared « safe » by FDA and
a study of « The EORTC
Melanoma Cooperative group »
• offensive odor
• orange color
• heterogeneous result → difficult to
apply (thickness of the stratum
corneum; scrubs, massage...)
• existence of an upper limit of the
pigmentation
• increases pigmentation
heads
of
black
• Hygroscopic → drying effect on skin
•amadori products → free radicals
• needs frequent applications
Conclusion: a safe and effective substance, but which
needs to be improved to stay longer and better color
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DHA market
First product in 1960: Man tan®
DHA market
First product in 1960: Man tan®
Now, a large offer of products:
Products associated with DHA :
•ErythruloseHOCH2 -CO-CHOH-CH2 OH
• AHA
R
• Tyrosine
More homogeneous, natural and uniform tan
1. Erythrulose 1,5%
DHA 3,5%
2. DHA 5%
=> After 14 days: more
and longer lasting skin tan
without undesired streaks,
and 30% less dry
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Source: Pentapharm
DHA and vitiligo
• Cosmetically camouflage
• Low cost
• Improves quality of life in vitiligo
• Minimum sides effects
• No homogenous
• Hard to do a perfect application => develop new formulation
Example:
(a) Before DHA
(b) After DHA
Satisfying
result
Not
acceptable
result
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Natta Rajatanavin et al, dihydroxyacetone: a safe camoufling option in vitiligo, inter journal of derm 2008, 47, 402-406
SWOT of cover up and self-tanners
Strenghts :
Weaknesses :
• no side effects
• daily application
• performing
•heterogenity of color
• strong odor
•comedogenic
• increase UV bad effects
• don’t prevent lesions extention
Opportunities :
Threats :
• possibilities of new formula: patch
• difficult to be accepted by men
• wide impact of vitiligo : 0,5 to 1% of
population world wilde = 60M potential
patients.
• saturated market
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Conclusion
To limit weaknesses and threats we should
leverage the Natural synthesis of melanin
Induce melanogenesis
• wide market
• reach male market
• homogenous and natural color
• spaced out applications
• no comedogenic
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Possibilities in cosmetic research
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Different possibilities
L-phe
PAH
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Different possibilities
L-phe
PAH
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Differentpossibilities
1) Increase local concentration of
Melanin precursor
→ Inducephenylalaninehydroxylase
2) Induction of tyrosinase
→ Lotus flower essential oil
→ Humanplacentalsphingolipid PSL
3) Expose skin to free radicals
→ Dangerous
4) Bring melanogenesis around
to EUMELANIN synthesis
→ Cysteinedeprivation
→ MC1R agonists : α-MSH analog
ACTH analog
1) Increase local concentration of melanin
precursors
Disruption of PAH mechanism in vitiligo
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Augmentation of H2O2 and ROS in vitiligo
The loss of existing skin color from the epidermis suggested the
involvement of reactive oxygen species.
Epidermal H2O2 concentrations in the 10-3 range were demonstrated.
Indeed, these patients present a decreased catalase and
gluthationperoxidase level.
H2O2 interferes with synthesis and recycling of 6-biopterin.
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Karin U. Schallreuter et al. Decreasedphenylalalineuptake and turnover in patients with vitiligo. Moleculargenetics and metabolism 86 S27, S33, 2005
Disruptation with H2O2 10-3M
melanin
K.U. Shallreuter et al, perturbed 6-tetrahydrobiopterinrecycling via decreaseddihydropteridinereductase in vitiligo : more evidence for H2O2 stress.
The journal of investigativedermatology, 2004, 122, 307-313.
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With H2O2
 Dimininution of PCD
decreasedrecycling of 6BH4
accumlation of 4αOHBH4
formation of 7BH4
 Favors formation of 7BH4
potentcompetitor of 6BH4
inhibition of PAH
decreased epidermal enzyme activities in patients with
vitiligo (n=8) compared to healthy controls (n=10) skin
phototype III (Fitz- patrick classiWcation).
K.U. Shallreuter et al, Epidermal H2O2 Accumulation Alters Tetrahydrobiopterin (6BH4) Recycling in Vitiligo: Identification of a General
Mechanism in Regulation of All 6BH4-Dependent Processes? The journal of investigative dermatologt, 2001, vol 116; 167-174
With H2O2 30μM
 Diminution of PCD
 Favors formation of 7BH4
 Diminution of DHPR
decreased recycling of 6BH4
miss cofactor of PAH and TH
The influence of H2O2 on the Vmax of DHPR activity.
Enzyme activities were determined in the presence of H2O2.
Decrease of Vmax for DHPR with H2O2 concentrations of
greater than 30 mm. The decrease of Vmax suggests
deactivation of the enzyme. N.B., Vmax without the addition
of H2O2 is 4.76 mU.
K.U. Shallreuter et al, perturbed 6-tetrahydrobiopterin recycling via decreased dihydropteridine reductase in vitiligo : more evidence for H2O2 stress.
The journal of investigative dermatology, 2004, 122, 307-313.
With H2O2
 Diminution of PCD
 Favors formation of 7BH4
 Diminution of DHPR
Diminution of PAH activity
accumulation de L-phe
augmentation of 6BH4synthesis by GTPCH1/GFRP
Consequently the short circuit to q-BH2 causes the formation
of H2O2from O2 and 6BH4.
What can we do?
Reduction of ROS : superoxide dismutase
SOD + O2- + M(n+1)+
SOD + O2 + Mn+
Reduction of H2O2 : catalase
2 H2O2
2 H2O + O2
Reduces local concentration of H2O2 and restores synthesis/recycling cycle of
6BH4 and thus restore production of tyrosine and consequently melanin too in
vitiligo.
H2O2 passes cell membrane, maybe we can use catalase for indirect action.
Reduction of extracellular H2O2 concentration is going to reduce intracellular H2O2
concentration.
Already used in Vitise® (mediderma laboratory) with melon extract.
(no study of efficiency found)
Or use a pseudo catalase like PC-KUS which passes cell membrane.
Already used in Vitix® (ACM laboratoire) which works in several studies
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2) Induction of tyrosinase
Lotus flower essential oil
Human placental shingolipid
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Lotus flower essential oil
This oil increased melanogenesis in normal human melanocytes
Stimulates melanin synthesis and tyrosinase activity in a dose
dependant manner.
More specifically with augmentation of expression of tyrosinase,
MITF and TRP 2.
Augmentation of melanin
Augmentation of tyrosinase, MITF, TRP1 and
TRP2 expression (with 10μg/ml of oil)
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Main ingredients of lotus flower essential oil (petals, stamens) :
Palmitic acid methyl ester 22,66%
Linoleic acid methyl ester 11,16%
…
Effect of ingredients on
tyrosinase expression
Effect of PA and mPA on
tyrosinase activity, melanin content
and cell viability
SongheeJeon et al, Lotus (Nelumbonuficera) flower essential oilincreasedmelanogenesis in normal humanmelanocytes, Exp. Mol. Med vol41,
2009, 517-524
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Maybe, the lotus oil can be exploited for a
cosmetic product like tan agent.
BUT miss information about :
• side effects,
• skin color after use,
• frequency of applications.
Informations important to know if oil is
better than DHA
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Human Placental Sphingolipid
SPHINGOLIPIDES
céramides, sphingomyélines, glycosphingolipides…
Ex : SPHINGOMYELINE
Sphingosine
Phosphorylcholine
AG
(acide
lignocérique)
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Sphingolipid : functions
Only:
Constituent of the plasmic membrane
Substrates for β-oxidation and Glycolisis
But also:
Major biological effects in numerous biological processes.
Ceramides, Sphingosine, Sphingosine-1-P
Cellular proliferation
Apoptosis/survival
Cellular migration
Inflammatory phenomenon
Melanogenesis
Martin Claire, Rôle de la signalisation Sphingosine kinase-1 / Sphingosine 1-Phosphate dans les interactions stroma-cellules
épithéliales au sein des métastases osseuses du cancer de la prostate, 2009. http://thesesups.ups-tlse.fr/513/1/Martin_Claire.pdf
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Human Placental Sphingolipid
A sphingolipid isolated from hydroalcoholic extract of fresh term human
placenta = Placental SphingoLipid = PSL
PSL
In vitro culture of mouse melanoma B16F10 cells
• Increase in melanin cellular content
• Induction of tyrosinase activity
•10 μg/ml = optimum dose with 24 h of
treatment as the period of stimulation.
• 10 μg/ml = optimum dose with 24 h
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of treatment as the period of
stimulation.
Human Placental Sphingolipid
On the one hand:
PSL increases tyrosinase expression:
• [tyrosinase]
• [tyrosinaseARNm]
On the other hand,
activity of the promotor of tyrosinase, after treatment with
PSL.
Conclusion : PSL up regulates tyrosinase gene expression, at transcription level,
through promoter activation.
BidishaSaha et al, Transcriptional activation of tyrosinase gene by human placental sphingolipid, DOI 10.1007/s10719-006-7931-5
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3) Expose skin to ROS
To forget: dangerous!!
Several risks: burn marks, …
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4) Bring melanogenesis around to
EUMELANIN synthesis
A) MC1R agonists:
α-MSH analogs
ACTH analog
Pharmacological
issue
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4) Bring melanogenesis around to
EUMELANIN synthesis
B) Cysteine deprivation
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4) Bring melanogenesis around to
EUMELANIN synthesis
B) Cysteine deprivation
- cysteine
EUMELANIN
Brown
pigmentation
+ cysteine
PHEOMELANIN
Red-orange
pigmentation
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4) Bring melanogenesis around to
EUMELANIN synthesis
B) Cysteine deprivation
- cysteine
EUMELANIN
Brown
pigmentation
+++
+ cysteine
PHEOMELANIN
Red-orange
pigmentation
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Decrease cysteine and GSH cellular contents
HBL = eumelanotic cells
LND1 = pheomelanotic cells
Intracellular [Cys] decreased while extracellular [Cys] was voluntary
decreased.
Intracellular [GSH] is also sensitive to cysteine deprivation.
Veronique del Marmol et al, Cysteine Deprivation promotes eumelanogenesis in Human Melanoma Cells, Society for investigative
dermatology
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Cystein deprivation promotes eumelanogenesis
HBL = eumelanotic cells
decrease in pheomelanin synthesis
increase in eumelanin synthesis
BUT
LND1 = pheomelanotic cells
increase in both melanins synthesis…
Conclusion: the results are those expected, but only in the cell lines which
preferentially product eumelanin.
However, increase in melanin (pheo+eu) synthesisis an acceptable result.
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Problem: In each scientific article about this, experiences
were conducted IN VITRO.
No cysteine in the culture medium
Expulsion of intracellular cysteine
No cysteine available for melanogenesis
Increase in eumelanin synthesis
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Problem: In each scientific article about this, experiences
were conducted IN VITRO.
No cysteine in the culture medium
Expulsion of intracellular cysteine
No cysteine available for melanogenesis
Increase in eumelanin synthesis
How is it possible to decrease intracellular
cysteine concentration IN VIVO?
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How is it possible to decrease intracellular
cysteine concentration IN VIVO?
•Alkylating agents, to make cysteine turn to R-S.
•Oxydizing agents, to make cysteine turn to S-S.
Major problem : risk to affect cysteine protease…
46
How is it possible to decrease intracellular
cysteine concentration IN VIVO?
•Alkylating agents, to make cysteine turn to R-S.
•Oxydizing agents, to make cysteine turn to S-S.
Major problem : risk to affect cysteine protease…
Decrease cysteine extracellular level, to make cells
expulse cysteine = INDIRECT ACTION
Alkylating/Oxydizing agents, but which are totally unable to
enter the epidermal/dermal cells
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Conclusion
 Several potential active substances
Only focused on four ones
In our point of view :
• lotus flower essential oil, would have a better marketing impact
than placental extract.
• pharmacological indirect mecanism concept is very hopeful
•catalase and SOD
•cysteine deprivation
It would deserve to be improved
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Last solution
 More 50% body depigmentationvitiligo induced
Total bleaching
Before
After
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Hyperpigmentation disorders
Improve of skin whitening agents
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Hyperpigmentation disorders
1. Skin bleachingneeds
2. DifferencesbetweenAsian, European and Africanmarket
3. Currently solution
a) Hydroquinone
b) Kojicacid
c) Dermocorticoid
4. Possibilities in research
a)
b)
c)
d)
Local change in pH of the skin
Inhibition of tyrosinase by SH function
Improving the stability of kojic acid
Strutural modification improved properties of Hydroquinone
5. Conclusion
Needs in whitening products
 Skin lightening products have a bright future a head of them.
 Use very wide spread in Asia, especially Japan and South Korea,
and in Africa.
 Growing preoccupation in Europe ( age spots)
52
Differences between asian, european and
african market
 Different issues : ancestral traditions (in Asia) + differences
of skin East/West.
 In Asia :
 clear skin = sophistication, innocence, woman hood and
high social level.
 asian skin : thick, becoming dull, yellowish, brown spots
from 20 years.
53
Differences between asian, european
and african market
 Precocious hyperpigmentation in comparison with wrinkles
and loss of firmness
Research of a more "transparent “ skin, with
products more "Brightening" than "Whitening".
 The lightening products represent 35% of the total market
care
54
Differences between asian, european
and african market
 European skin :
 thin skin, wrinkles and sagging skin appear before the
age spots
 main preoccupation is the fight against wrinkles, but
concern about pigment spots and radiance is growing
 recently, increased market bleaching of 15 to 20%!
55
Differences between asian, european
and african market
 African skin:
 compact, heavy, sensitive to dehydratation, large melanosomes,
more dispersed, and in greater quantity, irritation -> discoloration.
 the reasons for use included : (a) a desire to even out the skin tone,
(b) a desire to lighten the complexion, (c) a desire to improve the
appearance of the skin
Widespread use of lightening agents.
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J-J. Morand, E. Lightburne, Dermatologie des peauxgénétiquementhyperpigmentées(dites «peauxnoires»), 98-850-A-10.
Products currently on the market
• Hydroquinone : long-considered as the reference
Oxidative damage of membrane lipids and
proteins (including tyrosinase) + depletion of gluthation
Exogenous ochronosis, post inflammatory
hyperpigmentation...
57
Products currently on the market
• Kojic Acid : present in traditional Japanese
fermented food + effective for inhibiting melanin
production
Post inflammatory hyperpigmentation...
58
Products currently on the market
 Dermocorticoid : depigmenting power = secondary
effect
striae, peri-oral dermatitis, rosacea-like
cutaneous infections, ophtalmic problems...
eruption,
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Swot of skin whitening agents
Strengths :
Weaknesses :
- numerous targets for action
- treat a large number of skin’s
disorders
- positive impact on quality of life
- many side effects
- products sometimes instable
- dangerous for health
- risk of systemic transfer
Opportunities :
Threats :
- important market in development - trend effect
- demand not served
- emergence of new competing
products
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DP
 Products not irritating, not comedogenic, not allergenic, not
toxic
 Rapidly metabolized by cytochromeno systemic transfer
 Long-term use and for everyone
 Without risk when exposed to sunlight
 Skin application
 Reasonable price
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Possibilities in cosmetic research
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Possibilities in research
Local change in
pH of the skin
Kojic acid-amino
acid conjugates
To promote the formation of
phaeomelanin
Glucoside derivative of
hydroquinone :
Deoxyarbutin
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Local change in pH of the skin
 Tyrosinase activity is affected by melanosomal pH
 In melanosoms, pH is modulated by protons’ pumps and Na+/H+
exchangers
 In black skin: Tyrosinase activity high because pH of melanosoms is
neutral whereas In white skin : pH acid in melanosoms -> low
tyrosinase activity
Dustin R. Smith, Deborah T. Spaulding, The relationship between Na+/H+ exchanger expression and tyrosinase activity in human melanocytes,
Experimental Cell Research 298 (2004) 521–534
64
Local change in pH of the skin
 Objective = Increase of the acidity to decrease tyrosinase activity
➡ activation of protons’ pump or NHEs inhibitors
 ex : NHEs inhibitors : amiloride, ethyl-isopropyl amiloride (EIPA).
65
Local change in pH of the skin
• To confirm this hypothesis :
• EIPA doesn’t decrease tyrosinase abundance compared to untreated cells
•Tyrosinase activity in EIPA-treated cells is markedly reduced
66
SH functions inhibit tyrosinase?
67
SH functions inhibit tyrosinase?
Ideas :
 bring glutathione or cystein,
 bring molecules with SH functions,
 use N-acetylcystein.
68
SH functions inhibit tyrosinase?
Mechanisms of action of GSH and cysteinon melanogenesis
GSH
Cystein
69
SH functions inhibit tyrosinase?
Mechanisms of action of GSH and cystein on melanogenesis:
 reaction of the thiol groups with dopaquinone : formation of sulfhydryl-dopa conjugates and
finally sulfur-containing pigments.
 direct interaction between the sulfhydryl compounds and the tyrosinase active site.
 Cystein : inhibition of the tyrosinasehydroxylase and dopaoxidase activities of
melanoma tyrosinase.
this inhibition becoming greater as the cystein concentration increases
 GSH : - <3 mM : activation of the tyrosine hydroxylase activity.
- >3 mM : inhibition of the tyrosine hydroxylase activity.
- powerful antioxidant.
70
SH functions inhibit tyrosinase?
Bring molecules with SH functions :
 SH-containing compounds are effective inhibitors of polyphenoloxidase
 weak inhibition of o-quinone formation
 significantly inhibition of ROS generation
 positively modulation of the ratio of GSH/GSSG = GSH.
Ex: 1-Propylmercaptan
H3C - CH2– CH2 – SH
Potent candidate for cosmetic application
sickening odor : unusable!
71
SH functions inhibit tyrosinase?
Use N-acetylcystein :
• NAC is an amino acid produced by the body that stimulates
production of glutathione, a powerful antioxidant
• inhibitory effect on tyrosinase
• ➞ bleaching effect
• ex: Westerhof’s Formula: 4.7% N-acetylcystein (NAC), 2% HQ,
and 0.1% triamcinoloneacetonide
improved melasma after 4 to 8 weeks of application in a left–right,
placebo-controlled clinical study of 12 female patients
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Kojic acid
Trio D
Melanex trio
 Use of Kojic acid in cosmetics has been limited
 because of the skin irritation
 unstability during storage.
73
Derivatives of Kojic acid with improved Properties
 Acid-amino acid conjugates have increased stability during storage
 When the C-terminus was converted to the amide form stability
was further improved.
Jin-Mi Noh a, Seon-YeongKwak a, Hyo-SukSeo, Kojic acid–amino acid conjugates as tyrosinase inhibitors, Bioorganic &
Medicinal Chemistry Letters 19 (2009) 5586–5589.
74
Storage stabilities of KA and KA-F-NH2.
KA-AA-NH2 was almost stable for 3 months
75
Derivatives of Kojic acid with improved Properties
 tyrosinase inhibitory activity was also increased
76
Spectrum of mushroom tyrosinase and L-tyrosine
reaction of L-tyrosine and L-DOPA
dopachrome
77
Interactions near the tyrosinase binding site
• hydrophobic interactions between the aromatic rings of KA-AA-NH2
and the hydrophobic side chains in the tyrosinase active site.
• these interactions block the accessibility of the substrate to the
active site.
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Hydroquinone
 molecular mechanism of cytotoxicity to melanocytes :
 rapid oxidation in the extracellular milieu to generate: o-quinone
and ROS,
 Rapid oxidation by tyrosinase in the intracellular milieu to generate :
an intermediate substrate to tyrosine,
 The substitute in the para-position of phenol to confer :
 high cellular permeability,
 high susceptibility to autooxidation.
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Derivative synthesis of hydroquinone
Deoxyarbutin = 4-[(tetrahydro-2H-pyran-2-yl) oxyl] phenol
• Has synthesized by removal hydroxyls from the glucose side-chain of
arbutin :
• Increase hydrophobic property
• increase inhibition of tyrosinase activity
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Effects of D-arb on melanogenesis of
murine melanocytes
Inhibition of tyrosinase is dose-dependent.
D-arbutinis a potent melanogenic inhibitor like this HQ or arbutin.
Zhi-Ming Hua, et al. Effects of hydroquinone and its glucoside derivatives on melanogenesis and antioxidation: Biosafety as skin
whitening agents.Journalof Dermatological Science 55 (2009) 179–184
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Derivative synthesis of hydroquinone
Deoxyarbutin = 4-[(tetrahydro-2H-pyran-2-yl) oxyl] phenol
• Has synthesized by removal hydroxyls from the glucose side-chain of
arbutin :
• increase hydrophobic property
• increase inhibition of tyrosinase activity,
• is safer and less cytotoxic compared with hydroquinone.
82
Effects of D-arb on the viabilities of murinemelanocytes
with or without UVA irradiation
D-arbutin is more photo-stable against UVA-mediated oxidative
toxicity compared with arbutin.
83
Effects of D-arb on intracellular ROS level of
murinemelanocytes with or without UVA irradiation
D-arbutin exerts an anti-oxidative potential due to its resistance to
oxidation.
84
Structural modification improved properties
of Hydroquinone
 D-arb is a novel candidate to serve as a skin whitening
ingredient:




tyrosinase inhibition,
effective skin penetration,
less cytotoxicity
antioxidation.
85
Conclusion
 Strong demand, several products but dangerous.
 Our propositions are interesting but need to be
improved
 Nevertheless, the most probably:
 N-acetylcystein
 Product decreasing pH
 Deoxyarbutin
86
Are there any « pharmalogical » targets in
cosmetology for pigmentation disorders?
ANY QUESTIONS ?
Sophie Compagnon, Olivia Scaccia, MélodieDebacker, Catherine Lucas
le 12/02/2010, Lille.
87
Thank you for
your attention