Superior even skin tone and anti‐ageing benefit of a combination of 4‐hexylresorcinol and niacinamide

Abstract

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.

The clinical benefit of a multimodal topical approach to treating skin dyspigmentation

“…Niacinamide is thought to inhibit melanosome transfer from melanocytes to keratinocytes and may also decrease collagen oxidation products improving skin sallowness. 5 A third mechanism of action to lighten facial pigment is inhibition of melanogenesis by enhancing the degradation of microphthalmiaassociated transcription factor (MITF) through activation of the extracellular signal-related protein kinase (ERK), which suppresses the expression of tryosinase (TYR) and tyrosinase-related proteins (TRP1 and TRP-2) genes. Glycerrhiza glabra (licorice) root acts in this manner with the bioactive ingredients being flavonoids and triterpene saponins.…”

Skin Pigmentation and Cosmetic Considerations for Even Skin Tone

“…As a substrate, instead of forming melanin, it gets metabolized to quinones and free radicals which cause lipid peroxidation, damaging the melanocyte membrane and leading to melanocyte cytotoxicity and depigmentation [126,127]. However, in a recent study designed to compare the effects of arbutin, HQ , and kojic acid with numerous resorcinol vis-à-vis inhibition of recombinant human tyrosinase [128,129], HQ was found to be ineffective against tyrosinase enzyme as compared to resorcinol (Figure 3). Thus, although considered to be a tyrosinase inhibitor for a long, it appears that the cytotoxic potential of HQ may largely contribute to its depigmentation effect.…”

“…It is only in recent times that more potent tyrosinase inhibitors have been identified using enzymes sourced from human melanocytes or recombinant human tyrosinase protein with superior efficacy on melanotic conditions like solar lentigines and melasma, [129,168]. The commonly used compounds in the class of tyrosinase inhibitors include hydroquinone, arbutin, kojic acid, thiols, and resorcinol and among them, resorcinol derivatives are the most potent in enzyme inhibition [128,129]. It has been shown that resorcinol is a mono-oxygenase substrate and gets oxidized to hydroxy intermediate; 3-hydroxy-ortho-quinone, which results in irreversible elimination of Cu (0) of tyrosinase enzyme leading to inactivation of the enzyme [169,170].…”

“…The availability of recombinant human tyrosinase protein [128,129] combined with new platforms that allow for structure-active site prediction based on amino acid sequence [168] will hopefully promote further investigations on tyrosinase chemistry, leading to the identification of inhibitors with greater potency and reduced safety concerns.…”

“…Shariff et al [128] successfully adopted a combinatorial approach to demonstrate the superior clinical efficacy of a cosmetic formula containing 4-hexyl resorcinol and niacinamide. Based on the in vitro evaluation, appropriate ingredients, and doses were selected to develop a formulation which was then evaluated for spot lightening and anti-aging on Chinese subjects.…”