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Skin-lightening Challenges

By: Zoe Diana Draelos, MD
Posted: January 7, 2009, from the January 2009 issue of Skin Inc. magazine.
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Retinoids, such as retinol or retinaldehyde, can also be used as penetration enhancers for other skin-lightening agents. Ingredient combinations where each ingredient affects a different portion of the skin pigmentation pathway may be more beneficial for skin-lightening than single-ingredient formulations. Because there are many steps in pigment formation, skin lighteners can interrupt melanin production and transfer at multiple sites. Formulations that have activity at multiple sites have a better chance of stopping pigment production.

Ascorbic acid. Ascorbic acid, also known as vitamin C, is used in OTC pigment-lightening formulations. It interrupts the production of melanin by interacting with copper ions to reduce dopaquinone, an important intermediate in pigment production.5 It is a potent antioxidant that is sometimes combined with hydroquinone to prevent oxidation of the hydroquinone. By itself, low-concentration ascorbic acid is a poor skin-lightening agent. In higher concentrations, ascorbic acid can be a strong skin irritant due to its low pH, but may induce pigment-lightening by providing skin peeling in lighter-skinned individuals. High concentrations of ascorbic acid must be avoided in people of color, because the irritation paradoxically will darken the skin.

Licorice extract. Licorice extracts are used in many OTC products to lighten skin. The active agents are liquiritin and isoliquertin, which are glycosides containing flavenoids.6 Liquiritin induces skin-lightening by dispersing melanin pigment and enhancing more even pigment distribution. It must be applied to the skin in a dose of 1 g/day for four weeks in order to see a clinical result. This may not be practical in OTC formulations because of the expense of such a high concentration. Because the liquiritin is an anti-inflammatory, irritation is not a side effect with licorice extract, unlike with hydroquinone, retinoids and ascorbic acid, where irritation is the dose-limiting problem.

Alpha lipoic acid. Alpha lipoic acid is found in some OTC pigment-lightening preparations. It is a disulfide derivative of octanoic acid, which is able to inhibit tyrosinase, a key enzyme in pigment production. However, its ability to lighten skin is doubtful, because it is a large molecule with questionable penetration to the level of the melanocyte where tyrosinase is present. Effective pigment-lightening agents must reach their target in order to induce the desired effect. Molecular size and molecular charge are two key considerations in pigment-lightening efficacy.

Kojic acid. Kojic acid, chemically known as 5-hydroxymethyl-4H-pyrane-4-one, is one of the most popular skin-lightening agents found globally in OTC skin-lightening creams. It is a hydrophilic fungal derivative obtained from the aspergillus and penicillium species. It frequently is employed in Asia for the treatment of melasma.7 Some studies indicate that kojic acid is equivalent to hydroquinone in pigment-lightening results.8 The activity of kojic acid is attributed to its ability to prevent tyrosinase activity by binding to copper. The problem with kojic acid is again the ability to penetrate the skin and reach its copper target. It is possible that penetration-enhancers might overcome some of this difficulty; however, damage to the skin barrier and product irritation are common side effects.