Skin Lightening Agents - a4m.com · 2013-01-20 · vera plant • Tyrosinase inhibitor • Limited...

©Sharon McQuillan, MD. All rights reserved. 1

Skin Lightening Agents

Sharon McQuillan, MD

Draelos ZD, ed. Procedures in Cosmetic Dermatology: Cosmeceuticals. Philadelphia, Elsevier Saunders, 2005.

Acquired Hyperpigmentation

•  Skin diseases and conditions –  Melasma –  Riehl’s melanosis –  Poikiloderma of Civatte –  Erythromelanosis follicularis –  Linea fusca –  Post inflammatory hyperpigmentation



•  Exogenous Causes –  Ultraviolet exposure –  Photosensitizing agents –  Drugs –  Cosmetics




•  Other causes –  Pregnancy –  Liver disease –  Addison’s disease –  Hemochromatosis –  Pituitary tumors

Melanin Synthesis Pathways

Skin Lightening Agents

•  Act at various points during cycle of melanin production and degradation –  Transcription and activation of tyrosinase,

tyrosinase-related protein-1 (TRP-1), tyrosinase-related protein-2 (TRP-2), peroxidase

–  Uptake and distribution of melanosomes in recipient keratinocytes

–  Melanin and melanosome degradation and turnover of “pigmented” keratinocytes


Depigmenting Agents & Mechanism of Action

Tyrosinase Inhibition

•  Hydroquinone •  4-hydroxy-anisole •  Arbutin •  Aloesin •  Azelaic acid •  Kojic acid

Tyronsinase Transcription & Glycosylation

•  Tretinoin •  Glucosamine •  Retinol •  N-acetyl glucosamine •  retinaldehyde


Tyrosinase Degradation

•  Ellagic acid •  Resveratol •  Oxyresveratol

Inhibition of Melanosome Transfer

•  Linoleic acid

Anti-Inflammatory

•  Niacinamide •  Soybean/milk extracts


Reactive Oxygen Species Scavengers

•  Topical steroids •  Glycyrrhetinic acid

Increased Epidermal Turnover •  Vitamin C •  Vitamin E •  Thiotic acid •  Retinoids •  Lactic acid •  Glycolic acid •  Salicylic acid •  Liquirtin

Depolymerization of Melanin

•  Lignin peroxidase


Tyrosinase Inhibitors

•  Do not destroy melanin in skin •  Inhibit tyrosinase and oxidative reactions

affecting tyrosine in melanogenesis •  Do not produce rapid results as they need to

penetrate skin and change metabolism of melanocytes

•  Takes 4-6 weeks to see affect

Hydroquinone

•  Gold standard for treatment of hyperpigmentation

•  Closely related to phenol in structure

•  Inhibits conversion of tyrosine to melanin

•  Degrades melanosomes

Hydroquinone

•  Available over the counter in strengths up to 2% •  Available by prescription in strengths up to 4% •  Is often combined with other agents to enhance

penetration –  Glycolic acid –  Vitamin C –  Retinol, hydroquinone, corticosteroid (Triluma®)


Hydroquinone

•  Causes structural change in melanocyte organelles –  Decreases formation of melanosomes –  Increases degradation of melanosomes

•  Hydroquinone only prevents formation of new melanin

Hydroquinone Side Effects

•  Skin irritation •  Contact dermatitis •  Ochronosis

–  Blue-black patch –  Usually appears in skin types IV-VI when

hydroquinone is used at high concentrations or if a low concentration is used for extended time periods

FDA and Hydroquinone

•  Has been withdrawn from European and Japanese markets

•  In 2006, FDA proposed ruling to ban OTC skin products containing hydroquinone

•  Based on studies showing carcinogenicity and rats and evidence of ochronosis in lower concentrations

•  Evidence based on African studies where high levels of hydroquinone were used for extended periods of time


FDA and Hydroquinone

•  Dermatology Section of the National Medical Association and ASDS made written requests that the FDA do the following before instituting the ban: –  Consider cases of exogenous ochronosis reported in US,

not Africa –  Review available pharmacology/toxicology data on

hydroquinone –  Use resources to obtain epidemiologic human data to

answer safety questions •  To date, the FDA has not imposed the ban

Hydroquinone Studies Grimes, PE. An efficacy study of three commercially available

hydroquinone 4% treatments for melasma. Cutis 2007 Dec; 80(6) 497-502.

•  12 week split face study •  Three creams evaluated

•  Cream A (microencapsulated hydroquinone 4%, retinol 0.15% with antioxidants)

•  Cream B (hydroquinone 4%, retinol 0.3%, with antioxidants •  Cream C (fluocinolone acetonide 0.01%, hydroquinone, tretinoin

0.05%) •  Cream A showed statistically significant improvement

Melasma Study Salem A et al. Melasma: Treatment evaluation. Cosmet Laser Ther. 2009

Apr 1:1-5. •  45 patients skin types IV-V with moderate to severe melasma •  Treated melasma three ways

–  Topical hydroquinone 4% –  30% TCA chemical peel –  Q-switched Nd:YAG

•  Evaluated by MASI (melasma area severity score index) •  Improvement score significantly higher in topically treated

group.


Hydroquinone Results

Mequinol

•  4-hydroxyanisole; hydroquione derivative

•  Effective in improving appearance of solar lentigines and hyperpigmented lesions with 2% formulation combined with 0.01% tretinoin

Fleischer AS et al. The combination of 2% 4-hydroxyanisole (mequinol) and 0.01% tretinoin is

effective in improving the appearance of solar lentigines and related hyperpigmented lesions. J

Am Acad Dermatol.2000;42:459-67.

Retinol

•  Retinol induces changes in skin similar to those of tretinoin without the irritation of retinoic acid –  Lower potency than retinoic acid –  Requires 10 times the concentration to produce

similar effects


Retinoids

•  Used directly or indirectly as pigment lightening agents

•  Tretinoin and tazarotene improve skin pigmentation by normalizing the irregular grouping and melanocyte activation

Tazarotene

•  Synthetic retinoid •  Double-blind,

randomized, vehicle-controlled study 74 acne patients of dark ethnic groups

•  Tazarotene cream 0.01% reduced hyperpigmentation vs. control within 18 weeks Grimes P, Callender V. Tazarotene cream for

postinflammatory hyperpigmentation and acne vulgaris in darker skin. Cutis. 2006; 77:45-50.

Adapalene

•  Synthetic retinoid •  65 African patients with

acne associated PIH •  At baseline, 20% has

severe PIH •  Significant

improvement in degree of PIH at 4, 8, 12 weeks

Jacyk WK, Mpofu P. Adapalene gel 0.01% for topical treatment of acne vulgaris in African

patients. Cutis. 2004; 68(suppl); 485-7.


Retinoids

•  Indirectly lighten pigmentation •  Used as penetration enhancers •  Side effects: erythema, dryness, scaling

Kojic Acid

•  Tyrosinase inhibitor derived from Aspergillus, Acetobacter, and Pencillium

•  Possesses antibacterial properties

•  Reduces production of free radicals

Kojic Acid

•  Used in concentrations of 1-4% •  Best results when combined with other

ingredients (glycolic acid, vitamin C, licorice extract) to enhance penetration


Deprez P. Textbook of Chemical Peels: Superficial, Medium, and Deep Peels in Cosmetic Practice. United Kingdom, Informa UK Ltd.

2007.

Kojic Acid Side Effects

•  Irritant contact dermatitis •  Studies in mice showed oral administration

produced thyroid follicular adenomas

Kojic Acid Study

•  Study of patients with epidermal melasma •  Products used:

–  0.05% hydroquinone, 10% glycolic acid, 2% kojic acid

–  2% hydroquinone, 10% glycolic •  Kojic acid preparation superior in

performance Lim JT. Treatment of melasma using kojic acid in gel containing

hydroquinone and glycolic acid. Dermatol Surg 1999; 25:282-4.

Azelaic Acid •  Dicarboxylic acid

derived from Pityrosporum ovale

•  Possesses antibacterial properties

•  Tyrosinase inhibitor at doses of 20%

•  Inhibits mitochondrial oxidoreductase activation, DNA synthesis


Mingrone G et al. Toxicity of azelaic acid. Drugs under experimental and clinical research. 1983;9(6):447-55.

Azelaic Acid

•  Useful for treating melasma or PIH •  Slow acting; takes several months for effect •  Best when used in combination with other

ingredients to enhance penetration (AHA, retinoid)

•  Animal testing shows that azelaic acid is not cytotoxic, mutagenic, tetragenic

Azelaic Acid Side Effects

•  Transient erythema •  Skin irritation; scaling, itching, burning

Azelaic Acid Clinical Studies

•  Studies with ethnic populations compare efficacy with hydroquinone

Filton A,Goa KL. Azelaic acid: a review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary skin disorders. Drugs 1991; 5:780-798.

Balina LM, Graupe K. The treatment of melasma 20% azelaic acid versus 4% hydroquinone cream. Int J Dermatol 1991; 30(12):893-5.


Vitamin C

•  Has tyrosinase inhibiting and antioxidative effect

•  Interferes by interacting with copper ions and reducing dopaquinone

Vitamin C

•  Effective for dyspigmentation in stable form, magnesium L-ascorbic acid-2-phosphate (MAP)

Holloway VL. Ethnic Cosmetic products. Dermatol Clin 2003; 21: 743-9.

Glabridin

•  Licorice extract •  Derived from root of

Glycyrrhiza glabra linneva •  Offers 50% inhibition of

tyrosinase activity with no cytotoxicity

•  16 times more efficacious than hydroquinone


Glabridin

•  Active ingredients: licochalcone A, liquirtin

•  Have anti-inflammatory and anticarcinogenic effects; inhibit melanogenesis

Glabridin Clinical Study

•  20 subjects with melasma who applied 1 gm cream/day for 4 weeks showed 70% reduced pigmentation compared with control patients

Amer M, Metwalli M. Topical liquirtin improved melasma. Int J Dermatol 2000;39:299-301.


Glabradin

•  Best used in combination with other ingredients –  Arbutin –  Hyaluronic acid –  Hydrating agents –  Kojic acid –  Mulberry extract –  Tyrosine peptides –  Vitamin C –  Vitamin E


Arbutin (Bearberry)

•  Hydroquinone labeled to glucose

•  Inhibits tyrosinase activity rather than suppression of tyrosinase synthesis

Arbutin

•  Most effective cosmeceutical active for pigment lightening

•  Synthetic form deoxyarbutin has greater tyrosinase inhibition than natural form

Boissy RE et al. Deoxyarbutin: a novel tryosinase reversible tyrosinase inhibitor with effective in vivo skin lightening potency. Exp Dermatol 2005;14(8):

601.

Paper Mulberry

•  Extracted from mulberry leaves

•  Inhibits tyrosinase activity in the conversion of dopa into dopachrome


Jang IJ et al. Melanogenesis Inhibitor from Paper Mulberry. Cosm Toil 112(3) 59-62, 1997.

Paper Mulberry

•  Tyrosinase activity of paper mulberry measured 4.5 times more powerful than kojic acid

•  Patch tests with 1% paper mulberry extract showed no skin irritation at 24-28 hours

Soy

•  Contains Bowman-Birk inhibitor and soybean trypsin inhibitor

•  Reduces pigmentation by limiting phagocytes of melanosomes, reducing the transfer of melanin

•  Only present in fresh soy milk

Soy

•  Can inhibit pigment after three weeks •  Not as pronounced pigment lightening since

melanin production is not inhibited Paine C et al. An alternative approach to depigmentation by

soybean extracts via inhibition of the PAR-Q pathway. J Invest Dermatol 2006;116:387-395.


Aleosin •  Glycoprotein from aloe

vera plant •  Tyrosinase inhibitor •  Limited ability to penetrate

skin due to hydrophilic nature

•  Commonly used in combination with arbutin or deoxyarbutin to decrease tyrosinase activity via multiple mechanisms

Ando S et al. Tyrosinase gene transcription and its control by melanogenic inhibitors. J Invest Dermatol 1993; 100:1505-55.

Glycolic Acid

•  Inhibits tyrosinase activity

•  Faster dispersing of pigment due to increased desquamation

•  Melanogenesis-inhibiting properties shown in treatment of melasma and PIH

Melatonin

•  Hormone secreted by pineal gland in response to sunlight

•  Affects tyrosinase activity •  Inhibits cAMP processes in

pigment cells •  Effective dosing has not

been established for depigmentation


N-Acetyl Glucosamine

•  Amino monosaccharide produced by body by adding amino group to glucose

•  Substrate for hyarluronic acid, heparin sulfate, proteoglycans

•  Inhibits glycosylation of tyrosinase, enzyme necessary for melanin production

Niacinamide

•  Vitamin B3 •  Physiologically active

form of niacin •  Inhibits melanosome

transfer •  3.5% niacinamide

combined with retinyl palmitate effective in treatment of hyperpigmentation

Niacinamide Study

•  18 Asian subjects with hyperpigmentation •  5% niacinamide moisturizer caused

significant decrease in facial hyperpigmentation

Hakozaki T et al. The efect of niacinamide on reducing cutaneous pigmentation and suppression

of melanosome transfer. Br J Dermatol 2002;47:20-31.


Lignin Peroxidase

•  Natural ingredient derived from mushroom that grows on Phanerochaete chrysosporium trees

Lignin Peroxidase

•  Decomposes and fades melanin in its final structure after it is transported to upper layer of skin

•  Needs to be activated by hydrogen peroxide •  Effect is seen after short time and easily maintained

with repeated use •  Does not cause side effects seen with many

lightening agents •  Marketed by Syneron/Candela as Elure skin system

Clinical Studies

•  When used twice per day for 28 days –  82% subjects

demonstrated significant decrease in melanin

–  91% subjects showed overall improvement in fairness and skin tone

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Skin Lightening Agents - a4m.com · 2013-01-20 · vera plant • Tyrosinase inhibitor • Limited...

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