In Vitro and In Vivo Efficacy and Tolerability of a Non-Hydroquinone, Multi-Action Skin Tone Correcting Cream

July 2019 | Volume 18 | Issue 7 | Original Article | 642 | Copyright © July 2019

Pearl E. Grimes MD,a David H. McDaniel MD,b Mitchell Wortzman PhD,c Diane Nelson RN MPHc

aVitiligo & Pigmentation Institute of Southern California, Los Angeles, CA

bMcDaniel Institute of Anti-Aging Research, Virginia Beach, VA

cskinbetter science LLC, Phoenix, AZ 

modalities in addition to rigorous sun protection and avoidance.12 Topical therapies are a consistent and core component of treatment strategies; when needed, additional interventions may include lights and lasers, chemical peels, and systemic approaches, as well as a combination of treatments.11 Optimal treatment approaches reduce hyperpigmentation without causing hypopigmentation or irritation.13
Hydroquinone (HQ) has been the standard treatment for hyperpigmentation for more than 50 years and exerts its effect on melanin primarily by inhibiting activation of melanocytes.14,15 HQ inhibits tyrosinase, reducing conversion of DOPA to melanin; studies have shown that HQ has melanocyte-specific cell toxicity.16 Potential side effects of HQ include erythema, irritant and allergic contact dermatitis and in rare cases, ochronosis. Given the concerns regarding side effects, HQ has been banned in some countries. There is a global need for effective, tolerable skin lightening agents.

In an effort to address safety concerns and provide alternatives for patients, a new, non-HQ, non-retinol, multi-action skin tone correcting cream (ETCS) has been developed to comprehensively target and inhibit melanin production throughout the cell signaling pathways that affect skin pigmentation without the accompanying adverse effects of melanocyte toxicity.8 ETCS was developed based on a balanced ratio of ingredients designed to address multiple concerns in the overall appearance of skin, including visibly reducing brown patches associated with hyperpigmentation, reducing redness and age-related yellowing of skin tone, and brightening and evening skin tone while supporting the overall quality of skin across a variety of skin types.

An initial study was conducted to quantify melanin and the effects of ETCS relative to 4% hydroquinone (HQ) following 14-days of topical exposure in a reconstructed skin model consisting of human-derived keratinocytes and melanocytes from African American donor cells. Initial pre-toxicity screening revealed that 4% HQ at the standard amount tested in this model, 10μL, resulted in <90% viability of the donor cell model. Consequently, it was determined that 2μL was the maximum tolerable amount of 4% HQ that did not result in toxicity to the skin model. In an effort to make relative comparisons, ETCS tissue samples were topically treated with the lower adjusted amount (2μL) as well as the standard amount (10μL), as viability of the skin model was not an issue using the standard amount of ETCS. ETCS demonstrated 55% (10 μL) and 22% (2μL) reductions in melanin versus negative control (P<0.05). Reduction in melanin with 4% HQ (2 μL) was 17% versus negative control (P<0.05).

Following initial testing, we clinically evaluated twice daily use of this formulation. Additionally, we postulated that a regimen that included use of a potent, non-irritating retinoid/alpha hydroxy acid cream (AHA-Ret) in the evening would further reduce pigmentation and contribute to additional improvements in the quality of skin tone and texture.17

Study Objectives
This open-label trial conducted across two dermatology research practices evaluated the efficacy and tolerability of twice-daily use of ETCS over 12 weeks in subjects with mild to severe facial dyschromia or hyperpigmentation. Additionally, efficacy and tolerability of ETCS in combination with AHA-Ret was evaluated in a separate group of subjects.

Study Design
Study Population
Women, 30 to 65 years of age, were eligible to participate in the study if they exhibited evidence of mild to severe dyschromia or hyperpigmentation, had no known medical conditions that may interfere with study participation, and agreed to minimize sun exposure, including the consistent use of sunscreen when outdoors and total avoidance of tanning beds. Exclusion criteria included any dermatologic disorder that may interfere with evaluation of facial skin (i.e. severe acne vulgaris, any active inflammatory skin condition), pregnant or lactating women, hypersensitivity to any of the ingredients contained in the study products, current or prior use of any cosmetic skin care product that, in the investigator’s opinion, may interfere with the study including prescription products such as HQ and retinoids (12- week wash-out period) and non-prescription products (up to 4-week wash-out period).

Study Product(s)
The study product was provided in identical individual containers labelled only with lot and batch numbers. Additionally, AHA-Ret was provided for use in the evening (Treatment Group 2). A basic, gentle, commercially available cleanser, moisturizer (as needed), and a sunscreen (SPF 50) were also supplied.

Study Procedures
Subjects at each site were randomly assigned to ETCS only (Treatment Group 1) or ETCS + AHA-Ret (Treatment Group 2). ETCS was applied twice daily to clean skin, with subjects in Treatment Group 2 applying ETCS (AM/PM) and AHA-Ret (PM only, following ETCS) for a period of 12 weeks. Digital images of subjects were obtained at baseline, 4, 8, and 12 weeks (VISIA® CR, Canfield Scientific, Inc., NJ) on clean, washed skin. Evaluations occurred at each timepoint and assessed changes in five categories using a 6-point grading scale (0=None, 1=Minimal, 2=Mild, 3=Moderate, 4=Moderately Severe, 5=Severe) for dyschromia, erythema, fine lines/ wrinkles, pore size, and skin texture. Global improvement was assessed using a 5-point grading scale (0=None, 1=Minimal Immodalities