Evaluation of a Hydroquinone-Free Skin Brightening Product Using In Vitro Inhibition of Melanogenesis and Clinical Reduction of Ultraviolet-Induced Hyperpigmentation

March 2013 | Volume 12 | Issue 3 | Supplement Individual Articles | 16 | Copyright © March 2013

Elizabeth T. Makino BS CCRA MBA,a Sujatha Sonti PhD,a Monya L. Sigler PhD,b Piyush Jain PhD,c Ajay Banga PhD,c and Rahul C. Mehta PhDa

aSkinMedica, an Allergan Company, Carlsbad, CA bThomas A. Stephens and Associates, Dallas, TX cCollege of Pharmacy and Health Sciences, Mercer University, Atlanta, GA

BACKGROUND and OBJECTIVE: Skin lightening preparations are used by people all over the world for a diverse range of dermatologic indications. Hydroquinone (HQ) is the gold standard and remains the only prescription product available in the United States for the treatment of generalized facial hyperpigmentation. Irritation and the risk of exogenous ochronosis are the main adverse effects for concern. Therefore, there has been a constant search for new treatment alternatives. Understanding the molecular mechanisms involved in pigmentation has resulted in the development of a series of formulations that utilize a multimodal treatment approach. These proprietary formulas combine skin lightening agents that act via different mechanisms of action. The actives included 4-ethoxybenzaldehyde (anti-inflammatory and prostaglandin E2 suppressor), licorice extract (tyrosinase inhibitor), tetrahexyldecyl ascorbate (antioxidant), niacinamide (melanosome transport inhibitor), ethyl linoleate (tyrosinase inhibitor; enhances turnover of epidermis), hexylresorcinol (tyrosinase inhibitor), and retinol (tyrosinase transcription inhibitor; enhances turnover of epidermis).
METHODS: Select formulations were tested in several studies using the MelanoDermâ„¢ Skin Model (MatTek Corporation, Ashland, MA) to assess the ability of the product to reduce melanin production and distribution. A single-center, double-blind comparison clinical study of 18 subjects was conducted to evaluate the efficacy of the product in reducing ultraviolet-induced hyperpigmentation. Test sites were irradiated with 1.0, 1.5, 2.0, and 2.5 minimal erythema doses. After 5 days, to allow for pigmentation development, the product or 4% HQ cream was applied to the respective test sites, once daily for 4 weeks. Chroma Meter measurements (L* brightness) and standardized digital photographs were taken of the test sites twice a week.
RESULTS: The test product resulted in greater reduction in melanin as measured by melanin content and histological staining compared with the positive control in the MelanoDerm Skin Model. The product also demonstrated statistically significant reductions in pigmentation compared with baseline (all P≤.0001) at the end of the clinical study, and produced greater increases in L*, compared with 4% HQ. Results from these studies indicate that a product designed to affect multiple pathways of melanogenesis and melanin distribution may provide an additional treatment option beyond HQ for hyperpigmentation.

J Drugs Dermatol. 2013;12(3 suppl 1):s16-s20.

Hyperpigmentation disorders pose a real treatment challenge for patients all over the world. The number of people seeking treatments to alleviate the psychological distress associated with facial hyperpigmentation continues to grow rapidly. Currently, 4% hydroquinone (HQ) remains the gold standard of topical treatments and is the only prescription product available in the United States for the treatment of generalized facial hyperpigmentation. Hydroquinone has been used as a skin lightener for more than 50 years, and multiple clinical studies have documented its efficacy in various formulations.1-5 However, regulatory agencies have recently begun questioning the safety of this drug.6,7 Adverse effects, including skin irritation, contact dermatitis, and exogenous ochronosis, may occur with use of this compound. The US Food and Drug Administration (FDA) has initiated long-term studies to better understand the safety of topical HQ but has not made a final determination.8 Many user interest groups have taken the position that products containing HQ should not be used due to potential safety concerns, and both physicians and patients are now asking about product options that are free of HQ or its derivatives such as α-arbutin. As a result, there exists a large and growing market for alternative products that effectively lighten the skin.
The first objective of this study was to develop a HQ-free, arbutin-free formulation that addresses all major known biochemical pathways of skin pigmentation regulation. The second objective of this study was to determine the efficacy of such a composition using the most advanced techniques available that closely mimics the natural depigmenting effects in skin.
The control of pigmentation can be achieved by combining 4 groups of biochemical approaches summarized in Table 1: (1) prevent stimulation of melanocytes by minimizing the effect of ultraviolet (UV) exposure and activation via keratinocytes; (2) inhibit activity or decrease the levels of tyrosinase, the key enzyme responsible for the synthesis of melanin; (3) inhibit transfer of mel-