©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
Draelos ZD, ed. Procedures in Cosmetic Dermatology: Cosmeceuticals. Philadelphia, Elsevier Saunders, 2005.
Acquired Hyperpigmentation
• Exogenous Causes – Ultraviolet exposure – Photosensitizing agents – Drugs – Cosmetics
©Sharon McQuillan, MD. All rights reserved. 2
Draelos ZD, ed. Procedures in Cosmetic Dermatology: Cosmeceuticals. Philadelphia, Elsevier Saunders, 2005.
Acquired Hyperpigmentation
• 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
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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
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Tyrosinase Degradation
• Ellagic acid • Resveratol • Oxyresveratol
Inhibition of Melanosome Transfer
• Linoleic acid
Anti-Inflammatory
• Niacinamide • Soybean/milk extracts
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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
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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®)
©Sharon McQuillan, MD. All rights reserved. 7
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
©Sharon McQuillan, MD. All rights reserved. 8
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.
©Sharon McQuillan, MD. All rights reserved. 9
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
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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.
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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
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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
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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.
©Sharon McQuillan, MD. All rights reserved. 14
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
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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.
Draelos ZD, ed. Procedures in Cosmetic Dermatology: Cosmeceuticals. Philadelphia, Elsevier Saunders, 2005.
Glabradin
• Best used in combination with other ingredients – Arbutin – Hyaluronic acid – Hydrating agents – Kojic acid – Mulberry extract – Tyrosine peptides – Vitamin C – Vitamin E
©Sharon McQuillan, MD. All rights reserved. 16
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
©Sharon McQuillan, MD. All rights reserved. 17
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.
©Sharon McQuillan, MD. All rights reserved. 18
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
©Sharon McQuillan, MD. All rights reserved. 19
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.
©Sharon McQuillan, MD. All rights reserved. 20
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