Objectives

To demonstrate the synergistic effect of 4-hexylresorcinol (4-HR) with niacinamide in boosting anti-melanogenic efficacy in-vitro and establish the in-vivo efficacy and safety of the combination in a human trial.

Methods

Primary human epidermal melanocytes and 3D pigmented skin equivalents were treated with 4-HR, niacinamide, and their combinations for their effect on pigmentation. This was followed by a randomized double-blind, split-face clinical study in Chinese subjects, and effects on skin tone, hyperpigmentation, fine lines and wrinkles, hydration, and skin firmness were measured for a 12-week study period.

Results

In-vitro tyrosinase enzyme activity studies showed that 4-HR is one of the most potent tyrosinase inhibitors. The combination of 4-HR and niacinamide showed a synergistic reduction in melanin production in cultured melanocytes and lightened the 3D skin equivalent model. In-vitro as well as in the human trial, the combination of 4-HR and niacinamide showed significantly improved efficacy over niacinamide alone on hyperpigmentation spots as measured by L*, the visual appearance of fine lines and wrinkles in crow’s feet and perioral area and, skin firmness, with no product-related adverse events.

Conclusions

A formulation containing a combination of 4-HR and niacinamide delivered superior skin tone and anti-ageing benefits significantly better than niacinamide alone with no adverse events. This study demonstrates that a product designed to affect multiple pathways of melanogenesis, inflammation, and ageing may provide an additional treatment option, beyond hydroquinone and retinoids, for hyperpigmentation and ageing.