_SKIN_~1
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Theory on Theory on Skin PigmentationSkin Pigmentation
Melanin Balance
Basal layer
KeratinocytesKeratinocytes
Melanocytes
Desquamation
Stratum corneum
Balance of melanin synthesis and Transportation (excretion) is essential
Normal human keratinocytes Normal human melanocytes
Actual human cells (cultivated)
Maturation of melanosome
Melanocyte
NucleusPremelanosome
Melanin is accumulated in melanosomes
Melanosome
Melanogenesis pathway
Eumelanin Pheomelanin
HO
COOH
NH2 HO
COOH
NH2
HO O
O
COOH
NH2
NCOOH
HO
HO
N H
COOH
O
O
N
HO
HO
N H
O
O
HNS
COOH
NH2
HO
HOOC
Tyrosine
LeucoDOPAchromeDOPAchrome
DOPAchrome tautomerase (Tyrosinase Related Protein-2; TRP-2)
DHICA
Indole-5,6-quinone-2-calboxilic acid
CO2
DOPA
Tyrosinase
DOPAquinone
DHI
DHICA oxidase (Tyrosinase Related Protein-1; TRP-1)
Indole-5,6-quinone
Cysteine
Dihydrobenzothiazone
NH
HO
HOCOOH
NCOOH
HO
O
Tyrosinase
HO
HOS
COOH
NH2
HN2 COOH
5-Cysteinyldopa
Three melanin-generating enzymes
1. Tyrosinase
2. DOPAchrome tautomerase(Tyrosinase Related Protein-2; TRP-2)
3. DHICAoxidase(Tyrosinase Related Protein-1; TRP-1)
Tyrosine DOPA DOPAquinone
Tyrosinase
DOPAchrome
Eu-Melanin DHICA
Indole-5,6-quinone-2-carboxylic acid
TRP-2
TRP-1
DHIIndole-5,6-quinone
Reaction involving three enzymes
Factors which upsetmelanin balance
Factors which upsetmelanin balance
Causes of skin pigmentation
• DNA• Hormone balance• Stress• External factors• UV
Types of light
Ozone layer
190 400 780 1000 nm290 320
UV visible Infra-red
ABC
Skin penetration of different types of light
UV Visible Infra-red
ABC
Epidermis
Dermis
Fattylayer
Changes in epidermis caused by UV
KeratinocyteSun burn (apotosis)
canceration
Overgrowth
Melanocyte MelanogenesisLangerhans cell
Damage
UV
DNA damageDNA damage
Immunosuppression
Cytokine
Role of melanin
-Cell-Damage
UV
ΧΧ ΧΧ
UV
-Melanin-UV absorption
↓ ↓
-Cell-Damage is prevented
ΧΧ ΧΧ
UV If melanin was prepared in time and cell is protected
Tan
UVIf cell is damaged anyway
↓
Redness = Redness = inflammationinflammation
Role of melanin
The system of information transfer tomelanocytes
Basal layer
Keratinocytes
Melanocyte
Stratum corneum
UV
Cytokine
Cytokines
Generic name for substance involved in intercellular information exchange (hormones and neurotransmitters)
Information carrier = “letter” from cell to cell
How cytokines work?
UV↓
Synthesis / release from keratinocytes↓
Act on melanocyte↓
Activation of melanocyte
•Tyrosinase activation•Increase of number of melanocytes
Main cytokines involved in pigmentation
Alpha-Melanocyte Stimulating Hormone (Alpha-MSH)
• Endothelin-1
Alpha-MSH
α-MSH gets in contact with MSH receptor in melanocyte, thus increasing the amount of cyclic AMP in the cells.
Melanogenesis + cell growth
Alpha-MSH: mechanism of action
ATP cyclic AMP
α-MSH α-MSHReceptorGs Gi
Adenylate cyclase
Protein kinase A
Protein-P
Cell responseMelanogenesis, Proliferation
Endothelin-1Endothelin-1 is secreted in keratinocytes after UV irradiation. E-1 gets in contact with E-1 receptor on melanocyte’s cell membrane, thus stimulating Protein KinaseC activation in the cells.
Melanogenesis + cell growth
Endothelin-1: mechanism of action
Endothelin-1Receptor
Gi/oPhospholipase C
Protein-PCell response
Melanogenesis, Proliferation
Endothelin-1
PIP2
1,2-diacyl glycerol1,4,5-IP3
Protein kinase CER
CaCaM
CaM kinase
Effective blocking of alpha-MSH and Endothelin-1
Prevention of pigmentation induced by UV
New concept in skin lightening
How to prevent pigmentation?
1. Protect skin from UV (UV filters).2. Control melanogenesis (lightening
agents).3. Promote fast desquamation of melanin
(metabolism improving agents).
Mass marketMass marketShiseido FiTit, KaneboCosmett, KHP, Kose
Cosmeport, Pola DC, Nippon Lever, Lion, Kissme, Juju,
Sana
CatalogueCatalogue
DHC, Fancl, Dr. C-Labo
DoorDoor--toto--doordoor
Pola, Noevir, Avon, Menard, Amway, Naris, Ivy, Foulveil
Counseling Counseling Shiseido, Kanebo, Kose, Kao,
Albion, L’Oreal, EsteeLauder, Max Factor, Clinique, Dior, Chanel, Guerlain, YSL
Classification of Skin Care Brands in Japan
• Pigmentation associated with aging and exposure to sunlight
• Freckles (genetic); spots; blemish• Chloasma (caused mainly by hormone
disorder)• Post-inflammatory pigmentation
Targets of Lightening / Whitening Products
Period Evolution of whitening skincare in Japan Year Products / Brands1960s First whitening powders 1966 Soie de Reine (Kanebo) etc
1971 Real beauty (Kanebo)1971 Natural Shine (Albion)1976 Freshure (Shiseido)1980 Lumiera (Pola)1984 Faircrea (Kanebo)1985 UV White (Shiseido), Sekkisei (Kose)1986 Swiss Whitening (Estee Lauder)1988 Sur White (Kose)1989 Kanebo Blanchir (Kanebo)
Start of skin lightening boom 1990 Whitess Essence (Shiseido)1993 Whitea (Shiseido FiTit)1994 Freshel White C (Kanebo Cosmetto)1995 Sofina Medicated Whitening (Kao)1997 Shokubutsu Monogatari Medicated Whitening (Lion)1997 Fair Crea Power of Clear (Kanebo)1997 Eau de Blanc (Shiseido)1998 Seikisho (Kose)1998 Lumiera Whitissimo White Shot (Pola)1998 Blanchir Whitening Clear Conditioner (Kanebo)1998 Ponds Double White (Nippon Lever)
1970s
1980s
1990s
First whitening product series
Development of new skin lighteningingredients
Shift from powder form products toessences.
Popularity of mass market brands
General reduction of prices of skinlightening products. Further expansion ofskin lightening among young people.
"Easy skin lightening": appearance of newtypes of products: wipe-off lotion-type,soap-type products for cleansing /removing of old keratinocytes.
Evolution of Skin Lightening Market in Japan
Year Evolution of whitening skincare in Japan Products / Brands
2000Development of new skin lighteningingredients Rutina Pure White (Kose), Cle de Peau (Shiseido)
Whitist (Kose Cosmenience)ArbuWhite (Pola DC)White Balance (Kose Cosmeport)Grand de Neu Superior White (Kose)Blanchir Powercon DC (Kanebo)Issyma Perfect White (Guerlain)
Kojic acid is no longer usedBeaute de Kose (Kose)SK-II Whitening Source (Max Factor)Exia White AL (Albion)Dior Snow Dual (Christian Dior)Active White Lab Solutions (Clinique), Clarite (YSL)SK-II Whitening Source Clear Spots Sheet (Max Factor)Whitess Spots Rule A (Shiseido)White Shot W (Pola)Sofina Medicated Whitening Deep Science (Kao)Sekkisei Essence Excellent (Kose)
2005 New lightening mechanisms Shiseido, Kanebo, Kose
2002
2003
Growth of mass market sector
Lightening + anti-wrinkle (multifunctionalproducts)
Renewal of many lightening brands
Development of new skin lighteningmechanisms
New product types: stick type pointtreatments, masks, packs etc.
Evolution of Skin Lightening Market in Japan (2)
Share of skin lightening products in Japanesecosm etic m arket (%; sales)
27.5
72.5
Skin lightening products (%) O thers (%)
Share of skin lightening products in Japanesecosm etic m arket (%; sales)
79.4
20.6
C ounseling M ass m arket
Structure of Japanese skin lightening m arket (%; sales)
21.2
14.2
8.6
8.06.34.2
3.8
3.2
30.5
Shiseido
Kanebo
Kose
Pola
Kao Sofina
Shiseido FiTit
Albion
Nippon Lever
O thers
Structure of Japanese skin lightening m arket:m ajor brands (%; sales)
9.7
7.3
6.4
6.3
6.1
4.74.2
4.23.33.2
44.6
UV W hite (Shiseido)
Kanebo Blanchir
Fair C rea (Kanebo)
Sofina (Kao)
W hitess (Shiseido)
W hitissim o (Pola)
W hitea (Shiseido FiTit)
M edicated Sekkisei (Kose)
Lum iera W hitissim o (Pola)
Ponds Double W hite (Lever)
O thers
Product type share of lightening counseling brands (%; sales)
50.4
20.7
9.5
8.2
3.73.83.8 Essence (%)
Lotion (%)
M ilky lotion (%)
C leansing / m akeup rem oving (%)
C ream (%)
U V care (%)
M asks etc (%)
Product type share of lightening m ass m arket brands (%; sales)
34.9
27.2
15.4
9.9
4.83.5
4.8Lotion (%)
Essence (%)
C leansing / m akeup rem oving (%)
M ilky lotion (%)
C ream (%)
U V care (%)
M asks etc (%)
3.1 11.7 34.6 32.1 8.6 9.9 0
2.36 38.6 30.3 6.9 12 4
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
2002
2004
Price range of Japanese skin lightening products(counseling brands)
< JPY 1000 JPY 1000 - 2999 JPY 3000 - 4999 JPY 5000 - 7999 JPY 8000 - 9999 > JPY 10000 open price
28 45.2 14.9 3 8.1
34.1 38.7 8.1
1.2
17.9
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
2002
2004
Price range of Japanese skin lightening products(m ass m arket brands)
< JPY 1000 JPY 1000 - 1499 JPY 1500 - 1999 > JPY 2000 open price
Major Japanese Major Japanese Lightening BrandsLightening Brands
ShiseidoShiseido’’s UV White still s UV White still leads the marketleads the market
A popular quasi-drug whitening series with UV protection effect (day / night collection).
Active ingredients: vitamin C derivatives (skin lightening); sakuraextract, rumpuyan (Indonesian ginger) extract (moisturizing) etc.
Price range: JPY 3500 – 6000 ($ 30 – 55)
Mask Medicamente EXQuasi-drug60 pieces JPY 4,000 ($ 37)
Whitening Revitalizer Quasi-drug 30g JPY 5,000 ($ 45)
Whitening Powder Quasi-drug30 pieces JPY 5,000 ($ 45)
UV Cut & WhiteQuasi-drug. 35ml JPY 3,500 ($ 30) SPF25・PA++
KANEBO“BLANCHIR”
WHITENING NIGHT CONDITIONER(Quasi Drug)
KANEBOKANEBO““BLANCHIRBLANCHIR””
WHITENING NIGHT CONDITIONERWHITENING NIGHT CONDITIONER(Quasi Drug)(Quasi Drug)
Concept:Brightening during sleeping.
Main Ingredients:DIPOTASSIUM GLYCYRRHIZINATE,SAXIFRAGE EXTRACT, COIX SEED EXTRACT, REHMANNIA EXTRACT, Vitamin C derivative
Retail Price in Japan:Essence: ¥4,800/40g (approx. $40)
KANEBO“FAIRCREA”
Whitening Spots EX(Quasi Drug)
KANEBOKANEBO““FAIRCREAFAIRCREA””
Whitening Spots EXWhitening Spots EX(Quasi Drug)(Quasi Drug)
Concept:After care of the exposure to UV-rays.
Whitening complex which enhances fairer and clearer complexion with radiance.
Main Ingredients:STEARYL GLYCYRRHETINATE, POLYOL SOLUBLE LICORICE EXTRACT P-T(40)Raspberry Extract, Nandina Extract, Vitamin C derivative
Retail Price in Japan:Essence: ¥8,000/30ml (approx. $65)
KANEBO“FAIRCREA”
Whitening Daily Veil(Quasi Drug)
KANEBOKANEBO““FAIRCREAFAIRCREA””
Whitening Daily VeilWhitening Daily Veil(Quasi Drug)(Quasi Drug)
Concept:Prevention from UV damage. Prevention of melanogenesis.
Main Ingredients:STEARYL GLYCYRRHETINATE, POLYOL SOLUBLE LICORICE EXTRACT P-T(40) (Glabridin),PEONY ROOT EXTRACT, Vitamin C derivative
Retail Price in Japan:Foundation: ¥4,300/25g (approx.$35)
KAO“SOFINA”
Whitening Deep White(Quasi drug)
KAOKAO““SOFINASOFINA””
Whitening Deep WhiteWhitening Deep White(Quasi drug)(Quasi drug)
Concept:“Chamomile ET”, the new brightening ingredient, intercepts the primary stepsof melanogenesis.
Main Ingredients:CHAMOMILE EXTRACT, STEARYL GLYCYRRHETINATE, BURNET EXTRACT
Retail Price in Japan:Stick: ¥5,000/ 3.7g (approx.$46)
The central product of Shiseido Whitessseries is Whitess EX, whitening cream for eye area with arbutin and ethyl ester of vitamin C. “For effective care of visible and invisible spots. Prevention of melanin formation in deep layers of dermis and close to skin surface”.
Quasi-drug40 g.JPY 12,000 ($ 100)
Prevents spots caused by sun exposure by inhibiting skin inflammation and consequently, excessive melanogenesis, based on the newly discovered inflammatory condition of the spotted skin.
Dr. Ci:Labo
PHOTO-WHITE-C 80 Point Stick
4 g, JPY 4200
Whitening stick with 80% vitamin C derivative.
IngredientsAscorbylAscorbyl tetraisopalmitatetetraisopalmitate (80%)(80%)
DHCQ10 Stick Foundation9.5 g.; 1900 yen
Ultra strong coverage and matte effect.Long lasting.
Ingredients: Ubiquinone (Coenzyme Q10), AscorbylAscorbyl TetraisopalmitateTetraisopalmitate..
Skin Lightening Skin Lightening Active Ingredients in Active Ingredients in
JapanJapan
Skin Lightening Skin Lightening Mechanisms:Mechanisms:
Different Different ApproachesApproaches
SunUVStress; unorganized
lifestyle
Pollution; chemical substances
(A) Free radicals (active oxygen etc)(A) Free radicals (active oxygen etc)
(B) Information Carrying Substances ((B) Information Carrying Substances (endothelinendothelin etc.)etc.)
(G) Desquamation(G) DesquamationSpots;
frecklesEpidermisEpidermis
DermisDermis
Tyrosine DOPA DOPA-quinone (E) Melanin(E) Melanin
(C)(C) Formation (H) DecompositionFormation (H) Decomposition
(D)(D) Activation (I) MaturationActivation (I) Maturation
MelanosomeMelanosome
(F) Blood Vessels(F) Blood Vessels
Sun
UVStress; unorganized
lifestyle
Pollution; chemical
substances
Free radicals (active oxygen etc) and UVB Free radicals (active oxygen etc) and UVB induced inflammationinduced inflammationSpots;
freckles
EpidermisEpidermis
Approach 1Approach 1
Free radicals (active oxygen etc) : Free radicals (active oxygen etc) : Green tea extract,Green tea extract, White White grape grape polyphenolspolyphenols, Gentian extract etc, Gentian extract etc
UVB induced inflammation : UVB induced inflammation : DipotassiumDipotassium GlycyrrhizinateGlycyrrhizinate,,Chamomile extract, Chamomile extract, MukurossiMukurossi extract, Mulberry extract, extract, Mulberry extract, ScutellariaScutellaria Root extractRoot extract
Information Carrying Substances (activators of Information Carrying Substances (activators of tyrosinasetyrosinase))
Approach 2Approach 2
EndothelinEndothelin : : Chamomile ET (quasiChamomile ET (quasi--drug)drug)
MelanocyteMelanocyte Stimulating Hormones (MSH) : Stimulating Hormones (MSH) : Zinc Zinc GlycinateGlycinate(promotion of (promotion of tyrosinasetyrosinase regulating enzyme regulating enzyme metallothioneinmetallothionein))
Black Tea extract, Black Tea extract, SophoraSophora Root extractRoot extract
PGE2: PGE2: tt--AMCHA (quasiAMCHA (quasi--drug)drug)
Nitric Oxide : Nitric Oxide : Raspberry ketone glucoside
Histamine : Histamine : Sambucus extract, Kakyoku (Chinese Rose) Extract
Tyrosine DOPA DOPA-quinone
ActivationActivation
MelanosomeMelanosome
Approach 3Approach 3
Melanin synthesisMelanin synthesisSuppression of Suppression of tyrosinasetyrosinase activation and melanin synthesis activation and melanin synthesis suppression : suppression :
RucinolRucinol, , EllagicEllagic acid, Vitamin C derivatives, acid, Vitamin C derivatives, KojicKojic acid, Placenta acid, Placenta extract, extract, ArbutinArbutin (all quasi(all quasi--drugs)drugs) , ,
Licorice extract (Licorice extract (GlabridinGlabridin),), AscorbylAscorbyl TetraisopalmitateTetraisopalmitate,,Mulberry extract, Turmeric extract, Arnica extract, Indian DatesMulberry extract, Turmeric extract, Arnica extract, Indian Datesextractextract
Approach 4Approach 4
MelanocyteMelanocyte
Cut !Cut !Cut !Cut !
Prevention of melanin release into epidermis : Prevention of melanin release into epidermis : White wine White wine yeast extract, soybeans extract, Vitamin B3 yeast extract, soybeans extract, Vitamin B3
Reduction of Reduction of melanocytemelanocyte dendricitydendricity : : SwertiaSwertia extractextract
DermisDermis
Blood Circulation Improvement Blood Circulation Improvement (brightening (brightening effect due to better blood flow, healthier skin color)effect due to better blood flow, healthier skin color)
Approach 5Approach 5
Blood vesselsBlood vessels
Ginkgo extract,Ginkgo extract, Iris Root extract, Iris Root extract, CnidiumCnidium extract, extract, Arnica Extract, Japanese Angelica extract, Arnica Extract, Japanese Angelica extract,
SwertiaSwertia Herb extractHerb extract
Turnover and Turnover and desquamation promotion desquamation promotion
(brightening effect due to faster (brightening effect due to faster removal of old removal of old keratynocyteskeratynocytes))
Approach 6Approach 6
AHAAHA
Citrus Extract Citrus Extract Complex BGComplex BG
Approach 7Approach 7
Prevention of Prevention of
formationformation
RooibosRooibos extract; extract; Zinc Zinc GlycinateGlycinate
(promotion of (promotion of tyrosinasetyrosinase regulating regulating enzyme enzyme metallothioneinmetallothionein))
Approach 8Approach 8
Promotion of Promotion of
decompositiondecomposition
LinoleicLinoleic acid acid (Quasi(Quasi--drug)drug)
NEWNEWApproach 9Approach 9
Prevention of Prevention of
maturationmaturation
Magnolignan Magnolignan (Quasi(Quasi--drug; drug; KaneboKanebo) )
(5,5-dipropyl-biphenyl-2,2-diol)
Whitening ConclusionQuasi-drug; 40 mL
\11,550-From March 16, 2006
Kanebo: New Approach to Whitening
(Prevention of tyrosinasematuration)
Magnolignan Magnolignan (Quasi(Quasi--drug) drug)
(5,5-dipropyl-biphenyl-2,2-diol)
Skin Lightening Ingredients with Quasi-drug Status in Japan
1. Arbutin (Shiseido / Pola)
2. Kojic acid
3. Rucinol (Pola)
4. Placenta extract
5. Vitamin C derivatives (e.g. MAP 3%)
6. Ellagic acid (Lion)
7. Chamomile ET (Kao)
8. t-AMCHA (trans-4-(aminomethyl) cyclohexanecarboxylic acid) (Shiseido; 2002)
9. Linoleic acid (Sunstar; 2002)
10. Magnolignan (Kanebo; 2005) (5,5-dipropyl-biphenyl-2,2-diol)
Suppression of tyrosinase activity; melanin synthesis suppression
Blocks Endothelin (activator of melanin synthesis) before melanocyte
Blocks Prostaglandin (activator of tyrocinase); suppresses Plasmin (cause of rough skin and acne)
Promotes decomposition of tyrosinase
Prevents maturation of tyrosinase
Skin Lightening Ingredients with Quasi-drug Status in Japan
1. Arbutin (Shiseido / Pola)
2. Kojic acid
3. Rucinol (Pola)
4. Placenta extract
5. Vitamin C derivatives (e.g. MAP 3%)
6. Ellagic acid (Lion)
7. Chamomile ET (Kao)
8. t-AMCHA (trans-4-(aminomethyl) cyclohexanecarboxylic acid) (Shiseido; 2002)
9. Linoleic acid (Sunstar; 2002)
10. Magnolignan (Kanebo; 2005)
After BSE problem in 2001, Pola DC, KoseCosmeport, Nippon Lever removed Placenta Extract from all products. (Kose Group does not use animal derived ingredients from 2003)
In 2003 many companies replaced KojicAcid due to alleged safety issues.
Besides quasi-drug approved materials, Japanese companies develop original skin lightening ingredients (indicated as
“moisturizing” or “skin refreshing” ingredients.
• Dioscorea Composita (Chinese potato) (Kanebo) : strong tyrosinasesuppression (up to 10,000 times); melanin synthesis suppression.
• Clove extract (Kao): suppression of SCF (stem cell factor, one of melanin synthesis factors); prevention of growth of endothelin receptors.
• Chinese Tea extract (Kose): suppression of alpha-MSH (Alpha-MelanocyteStimulating Hormone).
•Hydroquinone was approved for use in Japan after deregulation in 2001 and can be seen in various dermo-cosmetic brands. However, safety issue still remains.
Other Skin Lightening Ingredients in Japan (not quasi-drugs)
1. Bio-SOD (KOSE)
2. S.N.O.W. X2 (Dior)
3. Iris Root extract (Kose Cosmenience)
4. AHA; fruit acids
5. “Easy skin lightening” (wipe-off type essences, soaps etc) (since 1997)
Blocks free radicals (active oxygen)
Prevents formation of melanin at DNA level
Promotes blood circulation to improve face skin color
Promote desquamation of old keratinocytes
M ajor skin lightening ingredients in Japan(num ber of brands)
8
51
22
1111
Arbutin
Vitam in C deriv.
C ham om ile ET
Rucinol
Elagic acid
t-AM C H A
others
Major Quasi-drug Ingredients in Japan (by number of brands)