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)