COSMELAN 1 & 2COSMELAN 1 & 2

Depigmenting Topical Treatment

Dr. F. GarcDr. F. Garcíía a

AprilApril 20072007

Scheme of PresentationScheme of Presentation

I. Melanins Metabolism

II. Skin Melanics Abnormalities

III. Topical Depigmenting Strategies

IV. Cosmelan 1 & 2

V. Application Protocol

VI. Results

I. Melanins MetabolismA. Melanogenesis

••MelanocytesMelanocytes:

–Epidermal dendritics cells set up in the basal epidermis adjacent to keratinocytes and Langhergans cells. The melanocytes are producing melanins by means of specific subcellular intracitoplasmaticstructures named melanosomes, the real factories of melanines.

••MelanodermicMelanodermic FunctionalFunctional UnityUnity::

–A functional set constituted by one melanocyte plus 30 or 40 nearkeratinocytes.

–Through the dendritics branches of the melanocyte, the melosomescontaining melanins are injected into keratinocytes the melanosomescontaining melanins.

I. Melanins MetabolismA. Melanogenesis

CellularCellular EpidermalEpidermal KineticsKinetics::

The keratinocytes show a process of proliferation and differenciation verywell regulated which lead its transformation into a corneocytes.

The Melanosomes injected into the keratinocytes, release the melaninsinside them and remain there till its transformation into cormeocytes.

At the end of this kinetic cellular process, the corneocytes containingkeratine and melanins appear conjointly with ceramides and other lipids, forming the stratum corneum of the epidermis.

In this way, the corneocytes containing melanins work as a skinprotector cloak in the outer part of skin

MelanogenesisMelanogenesis

Common metabolic pathway:

• The key step is the oxidation of tyrosine by the enzyme tyrosinase, to produce dihydroxyphenylalanine (DOPA).

• The second one is the oxidation of DOPA to dopaquinone by tyrosinase.

• Subsequently, dopaquinone is converted to dopachrome throughauto-oxidation process.

Eumelanins metabolic pathway:

• Dopachrome is enzymatically (dopachrome tautomerase & DHICA oxidase) transformed into dihydroxyndole (DHI) or dihydroxyndole-2-carboxylic acid (DHICA).

• Through complex polymerization reactions above intermediateproduct, are converted in eumelanins.

I. Melanins MetabolismA. Melanogenesis – Melanins Biosynthesis

Feomelanins metabolic pathway:

• Dopaquinone, in presence of cysteine or glutatione, is converted tocysteinyl DOPA or glutatione DOPA

• Through complex polymerization reactions above intermediateproduct, are converted in feomelanins.

I. Melanins MetabolismA. Melanogenesis – Melanins Biosynthesis

• Skin photoprotection. They are the main responsables of the skin, eyes and hair colour.

• Are strong absorber of UV radiation and, less, of the visible light ofthe spectra.

• Work as stable free radical, neutralizing ROS.

• Inhibit the lipidic peroxidation of the cells membranes.

• Protect the skin against photoaging and photocarcinogenesis.

• Protect cellular DNA from actinic injuries.

• They have high chemically stability.

I. Melanins MetabolismB. Melanogenesis – Melanins Functions

•• FeomelaninsFeomelanins:

Yellow and reddish biopolymers containing high amount of sulfur. They givethe skin pigmentation to white and redhead people.

Scarce photoprotection capability.

Unlike eumelanins, they solve in alkaline solutions. By intensive UV radiation, suffer decomposition forming free radicals.

•• EumelaninsEumelanins:

Black and brown biopolymers without sulfur. They have high amount ofnitrogen.

They have an excellent photoprotection capability, and chemical stability.

WhatWhat amountamount ofof melaninsmelanins existexist in in thethe skinskin??

– Fitzpatrick I < 1% (They suffer sun burn easily, high skin cancer risk)

– Fitzpatrick II y III: Between 1 & 3%

– Fitzpatrick IV > 3% (They do not suffer sun burn, low skin cancer risk)

I. Melanins MetabolismC. Melanogenesis – Melanins Types

• The main and stronger factor to produce melanins is the UV radiation(UV-A, UV-B), and less visible light.

• This answer is a protective mechanism of the skin.

• Another indirect stimulus are DNA fragment produced by the injuries ofUV radiation.

• The melanogenesis regulation is an local, complex and little knownmechanism related to endocrine, paracrine and autocrine processthrough the action of several citokines between keratinocytes andmelanocytes.

• One hormone involved in the regulation process is alpha-MSH producednon only in the hypophisis but also is produced in skin cells(autocrine&paracrine regulation).

I. Melanins MetabolismD. Melanogenesis – Regulation

• The physiological way for eliminating the human skin melanins is thenatural exfoliation process of the corneocytes from the stratumcorneum.

• This process is depending on the speed of proliferation and madurationof the epidermal keratinocytes.

• Everyday a part of the corneocytes of the stratum corneum is lost andwith them their amount of melanins. These lost corneocytes are replaced with new ones.

• The rapidity of this process, may be accelerated or braking for severalinternal and external stimulus.

• An alternative way to eliminate melanins consists in the work ofmacrophagic cells (monocytes), basically to eliminate the abnomallocation of melanins in dermal areas.

I. Melanins MetabolismE. Melanogenesis – Elimination

UV

AM

L-TIROSINA

(fenilalanina)

DOPA

(3-4-dihidroxifenilalanina)

DOPA QUINONA

LEUCODOPACROMO Cisteinil - DOPA

DOPA CROMO

1 - 4 - Benzotiazinilalanina DHI 5-6-Dihidroxi Indol

DHICA Ácido 5-6-Dihidroxiindol-2-carboxílico

INDOL-5,6-QUINONA DHICA ÁCIDO INDOL-5-6-QUINONA CARBOXÍLICO

DHI - MELANINAS DHICA - MELANINAS

EUMELANINAS FEOMELANINAS

TIROSINASA (Cu2+, Fe3+, Zn2+)

TIROSINASA (Cu2+, Fe3+, Zn2+)

GLUTATION o CISTEINA

Ácido Ascórbico

TPR2 ó

Tirosinasa Protein-2 Related ó Dopa cromo-tautomerasa

TPR-1 ó

Tirosinasa Protein-1 Related ó DHICA

Pigmento negro o marrón oscuroalcali insoluble

Pigmento amarillo- marrón

Alcalisolubles (pelirrojos)

Ácido Ascórbico

MELANOCITOS & GRÁNULOS MELANINA

MELANOSOMAS

a_melan WHITENING

AGENTES

DESPIGMENTANTES

II. Skin Melanic Abnormalities: hyperpigmentation

• Hyperpigmentation is the increase of the natural colour of the skin.

• Darkened spots on the skin, have two main causes non acquired andacquired:

– Non acquired:

• Related with genetic or hereditary predisposition.

– Acquired:

• Several factors promote melanogenesis in a localizated shape, leading to appearance of melanic spots in the epidermis and/or dermis, with more intensity and frequency in skin areassun exposed (face, neck and hands), or stressed by enviromental factors.

• The spots are produced by:

– Excesive melanins prodution by melanocytes in a locatedshape.

– Hypertrophy of located melanocytes which leads to more melanin production.

A. Melanocytes hyperactivity:

a. Melasma and cloasma: frequently in skin phototype I, II & III. Located change of melanocytes producing feomelanins to produce amounts of eumelanins due to sun injuries.

b. Freckles: normal melanocytes producing a big amount of melanins. They are stimulated by the sun radiation. Appear in clear skins.

B. Melanocytes hyperproliferation:

a. Lentiges (actinic)

b. Lentiges (aging)

C. Phototoxicity: due to interaction of sun radiation with the skin plus furocumarins.

D. Post-inflamatory process: produced by mechanical, physical or chemical injuries on the skin which evoke an inflamatory state after leading a skin hyperpigmentation (acne, laser, wounds, etc.)

II. Skin Melanic Abnormalities: hyperpigmentationClassification

• Determining the cause of hyperpigmentation is important in selecting the best approach for treatment. Based on the history and the clinical findings of the patient, the etiology of the hyperpigmentation may include postinflammatoryhyperpigmentation, drugs, photosensitizing agents, UV light, pregnancy, skin aging, acne, peeling, laser, photoageing, etc.

• Skin exam under Wood Light

II. Skin Melanic Abnormalities: hyperpigmentationDiagnostic

• Emits UV radiation near to the maximum absortion of melanins.

• Based on the quenching effect, the spots may be classified according to its localization:

– Epidermal location: has a good contrast and are very well detectable. They answer well and fast with topical depigmenting agents.

– Dermal location: the contrast is lower. It answers slowly with topical depigmenting agents.

– Mixed: shows spots located in epidermis and dermis.

– Nonvisible: characteristic in skin photo type V, VI. It is not detected with Wood Lamp.

II. Skin Melanic Abnormalities: hyperpigmentationDiagnostic – Wood Lamp

• The skin application of depigmentant substances have the objective of:

– Eliminate the darkened spots

– Skin clarifying

– Skin embellishment

• Mechanisms of depigmentation:

– All depigmentant substances work inhibiting the enzymatic process involve in the melanogenesis. The key enzyme is tyrosinase, responsible of the first part of melanins biosynthesis. Besides the inhibition of the other oxidases enzymes increases the depigmentant action. The enzymatic inhibition is reversible, that means, works meanwhile the depigmenting agents are applied on the skin.

– The target of the depigmenting substances is the melanosomes.

– The lightening agents do not operate on the melanins spots. Its elimination depending on the natural mechanism of melanins clearance (skin exfoliation, phagocytosis by macrophages & skin cells).

III. Topical Depigmentation Strategies

• This special mechanism implies that the elimination of the spots is a slow process (weeks, months).

• The way of the depigmenting agents to reach the melanosomes is by passive diffusion process through stratum corneum. So, they are limited by the very low permeability of it.

• The negative stimulus produced by UV radiation must be abolish using sun filter.

• Due to the reversible inhibition of tyrosinase, the application on the skin of the depigmenting products must be made very frequently and for a long period.

• Would be more rational to use substances working on the spot by dissolution, complexation, mobilization, etc., but till today does not exists any safety product acting in this way, probably due to the high chemical stability of the melanins.

• According the above described mechanism, it seems that it is impossible to eliminate the dermal spots. However the activity of macrophagic cells (scavenger) gets mobilize slowly these abnormal amount of melanins in dermal areas.

III. Topical Depigmentation Strategies

IV. Cosmelan 1 & Cosmelan 2

• Legal Status: Cosmetic Product

• Commercial Presentation: Pack

– Cosmelan 1: Mask – Jar containing 10 g

– Cosmelan 2: Maintenance cream – Jar containing 30 g

– Degreasing Solution: Bottle containing 10 ml

• Cosmetic Preparation: Emulsions type O/W (mask & cream).

• Properties:

– Skin depigmentation

– Skin lightening

– Skin embellishment

• Complementary products:

– Moisturizing: ms Hydravital Factor K

– Sunscreen: ms Pantalla Total Hidratante (SPF 30)

• The same qualitative composition in functional cosmetic ingredients.

• Higher concentration of depigmenting agents in mask.

• They are applied on the skin in different ways.

• In both cosmetic products:

– More than 50% of the formula are formed by functional cosmetic ingredients.

– This high concentration has the purpose to create an elevated gradient of depigmenting agents in the stratum corneum as a good driving force to improve the passive diffusion of active ingredients.

– This effect will be leaded to have an effective concentration ofdepigmenting agents inside melanocytes and a critical and effective concentration inside melanosomes.

IV. Cosmelan 1 & Cosmelan 2Description

A. SUN FILTERS: Abolish the melanogenesis UV strong stimulus

a. Organic Filters:

i. Protection against UVB radiation (290 – 320 nm)

ii. Protection against UVA radiation (320 – 400 nm)

b. Inorganic Filter:Protection against UVB/A radiation (290 –400 nm).

i. Incorporate a new non-whitening inorganic filter with broad sepectrumUVA/UVB producing minimal free-radiacalsgeneration (TiO2/Mn). Enhance photostability of organic filter.

c. Sun Protection Factor (SPF) = 20 (UVA+++)

IV. Cosmelan 1 & Cosmelan 2Functional Composition

A. .

B. NON-CYTOTOXICS REVERSIBLE TYROSINASE INHIBITORS:

• Azelaic Acid:

Competitive inhibitor of tyrosinase. Bacteriostatic against aerobic & anaerobic microorganisms. Competitive inhibitor of 5-alpha reductase reducing cutaneous sebum production.

• Kojic Acid:

Competitive inhibitor of tyrosinase. Antioxidant. Scavenges ROS. Bacteriostatic.

• Alpha-arbutine:

Competitive inhibitor of tyrosinase. Enantiomer of natural beta-arbutin (ten times more potent and chemically more stable).

• Rumex Canadiensis Extract:

Competitive inhibitor of tyrosinase. Skin anti-erythema.

IV. Cosmelan 1 & Cosmelan 2Functional Composition

A. .

B. NON-CYTOTOXICS REVERSIBLE TYROSINASE INHIBITORS:

• Tyrosinol Complex:

Competitive inhibitor of tyrosinase.

• Aloesine (Aloe Barbadensis):

Competitive inhibitor of tyrosinase.

• Glabridin (Licorice Extract):

Competitive inhibitor of tyrosinase. Skin lightening.

• Sodium Ascorbyl Phosphate:

Stable derivative of Ascorbic Acid. Avoids melanin formation by reducing o-quinones. Skin lightening.

IV. Cosmelan 1 & Cosmelan 2Functional Composition

A. .

C. OTHER EFFECTS ON MELANOGENESIS PROCESS:

• Azelaic Acid:

Antiproliferative and cytotoxic effects on hyperplasic melanocites.

• Niacinamide:

Stops melanosomas transfer to keratinocytes.

• Aminoethylphosphinic Acid:

Specific DOPA-tautomerase inhibitor.

• Tyrosinol Complex:

Tyrosine Related Protein (TPR1) inhibitor (eumelanins metabolic pathway).

• Nonapeptide-1:

Biomimetic peptide specific antagonist of the alpha-MSH, due to its high affinity for cell melanotropin receptor (MC-1R) producing reversible inhibition. Inhibit the UV / alpha-MSH induced melaninsbiosynthesis.

IV. Cosmelan 1 & Cosmelan 2Functional Composition

A. .

D. SKIN BEAUTY AGENTS:

• Retinol:

Promotes fibroblastic activities. Antioxidant. Stimulates the epidermal kinetic. Prevents wrinkles and free radicals formation.

• Tocopherol:

Antioxidant. Protects cell membranes from lipidic peroxidation. Avoids collagen crosslinked and protein glycation (antiagingeffect).

• Ascorbic Acid:

Stimulates collagen formation and increases the fibroblastic activity.

Free radicals neutralizer.

• Aloe Barbadensis:

Moisturizing and skin revitalizer.

IV. Cosmelan 1 & Cosmelan 2Functional Composition

A. .

E. SKIN PENETRATION ENHANCERS:

• Bisabolol & Ethoxydiglycol:

Promotes the stratum corneum permeability to functional ingredients, improving its passive diffusion and higher epidermal concentration.

F. MELANINS ELIMINATION ACCELERATOR.

• Salicylic Acid:

Exfoliant agents that promotes the turnover of korneocytes.

IV. Cosmelan 1 & Cosmelan 2Functional Composition

A. .

1. Proffessional Treatment (Beauticien):

• Cleaning the skin surface with Degreasing Solution.

Soak in a gauze the solution and rub the skin surface to treat gently trying to leave the skin very well clean.

• Apply the content of the jar Cosmelan 1 in face and neck like a mask.

• Standard period of action: let the product acting for 8 hours on the skin. Depending of the skin type, this period may be expand to 12 hours

2. In House Treatment:

• Apply on the skin to treat Cosmelan 2 (cream) twice per day during 8 weeks.

� Morning: keep it minimum 3 hours

� Night: keep it all the night

� 9th week in advance: one time during night

• This standard treatment protocol may be reinforced depending on the results of the “skin reading” during treatment.

V. Application Protocol

A. .

1. Due to the depigmenting effect is depending on the concentration of active ingredients on melanosomes, the amount of the cosmetic product applied on the skin matters in the effectiveness.

2. Suitable doses is about 2 mg of cream per cm2 of skin. That means, for face, the minimal dose should be about 0,5 g of cream per application.

3. The enzymatic tyrosinase inhibition is a reversible process. So, the treatment must be maintained without interruptions even with skin erythema.

4. In some cases is advisable to apply a mask session (Cosmelan 1) each month.

V. Application ProtocolComments

A. .

1. Significant attenuation, diminution or disappearance of melanic spot at the third or fourth week of treatment.

2. Renovation and embellishment of the skin at the second week of treatment.

3. Stimulation of capillary circulation giving an effect of the new skin luminous, pink , smooth and shining.

VI. Results

VI. Results - Pictures

Group Body_esthetic LaboratoriesGroup Body_esthetic Laboratories

Thanks a lot for your attentionThanks a lot for your attention