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Randomized Controlled Trial
. 2022 Feb;44(1):103-117.
doi: 10.1111/ics.12759. Epub 2022 Feb 1.

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

Rezwan Shariff  1 , Yaping Du  2 , Maitreyee Dutta  1 , Satish Kumar 5th  1 , Sreenivasa Thimmaiah  1 , Chandraprabha Doraiswamy  1 , Annu Kumari  1 , Vaidehi Kale  1 , Nirmala Nair  1 , Shuliang Zhang  2 , Manoj Joshi  1 , Uma Santhanam  3 , Qiu Qiang  3 , Anita Damodaran  1
Affiliations
Randomized Controlled Trial

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

Rezwan Shariff et al. Int J Cosmet Sci. 2022 Feb.

Abstract
in English, French

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.

Objectifs: Démontrer l’effet synergique du 4-hexylrésorcinol (4-HR) associé au niacinamide pour stimuler in vitro l’efficacité antimélanogène, et établir l’efficacité et la sécurité d’emploi in vivo de cette association dans un essai chez l’homme. MÉTHODES: Des mélanocytes épidermiques humains primaires et des équivalents cutanés pigmentés en 3D ont été traités avec du 4-HR, du niacinamide et leurs combinaisons pour leur effet sur la pigmentation. Ceci a été suivi d’une étude clinique randomisée, en double aveugle en hémi-visage chez des sujets chinois, et les effets sur le teint, l’hyperpigmentation, les rides et ridules, l’hydratation et la fermeté de la peau ont été mesurés pendant une durée d’étude de 12 semaines. RÉSULTATS: Les études in vitro sur l’activité enzymatique de la tyrosinase ont montré que le 4-HR est l’un des inhibiteurs de la tyrosinase les plus puissants. L’association du 4-HR et du niacinamide a montré une réduction synergique de la production de mélanine dans les mélanocytes de culture et donné de la luminosité au modèle cutané 3D équivalent. Également in vitro avec l’étude chez l’homme, l’association du 4-HR et du niacinamide a fait ressortir une efficacité significativement plus élevée qu’avec le niacinamide seul sur les taches d’hyperpigmentation mesurées par L*, l’aspect visuel des rides et ridules des pattes d’oie et de la zone périorale, et la fermeté de la peau, sans événements indésirables liés au produit.

Conclusions: Une formulation contenant une association de 4-HR et de niacinamide a permis d’obtenir un teint et un effet anti-âge nettement supérieurs à ceux du niacinamide seul, sans événements indésirables. Cette étude démontre qu’un produit conçu pour toucher plusieurs voies de mélanogenèse, d’inflammation et de vieillissement peut constituer une nouvelle option thérapeutique, au-delà de l’hydroquinone et des rétinoïdes, pour l’hyperpigmentation et le vieillissement.

Keywords: cell culture; human volunteer trial; niacinamide; resorcinols; skin physiology/structure; spectroscopy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Inhibition of recombinant human tyrosinase enzyme activity by 4‐HR. Dose‐dependent inhibition of tyrosinase enzyme activity by 4‐HR was performed using synthetic recombinant human tyrosinase enzyme protein and DOPA as the substrate. The data are representative of at least three independent sets of experiments, and the values are mean ± standarad deviation (SD)
FIGURE 2
FIGURE 2
Effect of 4‐HR on melanin content in melanocytes after 72 h of treatment. The values are mean ± SD of three independent sets of experiments. *p < 0.05; statistically significant versus kojic acid, arbutin, and hydroquinone; $ p < 0.05; statistically significant versus arbutin and hydroquinone
FIGURE 3
FIGURE 3
Effect of different ratios of 4‐HR and niacinamide combination on melanin content in melanocytes after 72 h of treatment. The values are mean ± SD of three different sets of experiments. *p < 0.05; statistically significant versus control; $ p < 0.01; statistically significant versus all treatments; # p < 0.005; statistically significant versus 4‐HR (1 µM) and 4‐HR (10 µM); @ p < 0.005 statistically significant versus 4‐HR (1 µM)
FIGURE 4
FIGURE 4
Effect of 4‐HR+niacinamide on melanin content and in situ tyrosinase activity in melanocytes after 72 h of treatment. The values are mean ± SD of three different sets of experiments. *# p < 0.05; statistically significant versus 4‐HR (1 µM) for melanin and in situ tyrosinase activity
FIGURE 5
FIGURE 5
Effect of 4‐HR+niacinamide on pro‐collagen synthesis in dermal fibroblasts. The values are mean ± SD of four different sets of experiments. *p < 0.05; statistically significant versus control
FIGURE 6
FIGURE 6
(a) Effect of 4‐HR and niacinamide on melanin reduction in a 3D skin equivalent model. Data are representative of three independent sets of experiments carried out in duplicates, and the values are mean ± SD. *p < 0.05; statistically significant versus base formulation; $ p < 0.05; statistically significant versus 4‐HR (0.2%) + niacinamide (1.25%), 4‐HR (0.2%), niacinamide (1.25%); # p < 0.05 statistically significant versus niacinamide (1.25%), and 4‐HR (0.2%); @ p < 0.05 statistically significant versus niacinamide (1.25%), 4‐HR (0.2%). (b) Effect of 4‐HR and niacinamide on L* in a 3D skin equivalent model. Data are representative of three independent sets of experiments carried out in duplicates, and values are mean ± SD. *p < 0.05; statistically significant versus base formulation; $ p < 0.05; statistically significant versus 4‐HR (0.2%), niacinamide (1.25%), # p < 0.05 statistically significant versus 4‐HR (0.2%), niacinamide (1.25%) and @ p < 0.05; statistically significant versus 4‐HR (0.2%)
FIGURE 7
FIGURE 7
Effect of 4‐HR+niacinamide skin formulation on background skin colour. (a) Visual assessment on facial skin lightness. *p < 0.05, a significant improvement over baseline. (b) Spectrophotometry measurement of lightness in L* units on forehead skin. *p < 0.05, a significant improvement over baseline. *p < 0.05 a significant improvement over 3% niacinamide treatment. Effect of 4‐HR+niacinamide skin formulation on spot colour. (c) Visual assessment of overall hyperpigmentation spots. *p < 0.05, a significant improvement over baseline. (d) Spectrophotometry measurement of lightness in L* units on selected three hyperpigmentation spots. *p < 0.05, a significant improvement over baseline, and # p < 0.005 a significant improvement over 3% niacinamide treatment
FIGURE 8
FIGURE 8
(a) Effect on skin ageing parameters through visual assessment of Crow's feet fine lines and wrinkles. *p < 0.05, a significant improvement over baseline; # p < 0.05, significantly better than 3% niacinamide formulation. (b) Effect on skin ageing parameters through visual assessment of perioral fine lines and wrinkles. * p < 0.05, a significant improvement over baseline; # p < 0.05 significantly better than 3% niacinamide formulation
FIGURE 9
FIGURE 9
Effect on skin firmness parameters. (a) Cutometer measurement of skin elasticity parameter R2. *p < 0.05, a significant improvement over baseline; # p < 0.05 a significant improvement over 3% niacinamide formulation. (b) Cutometer measurement of skin elasticity parameter R7. *p < 0.05, a significant improvement over baseline; # p < 0.05 a significant improvement over 3% niacinamide formulation
FIGURE 10
FIGURE 10
(a) Effect on skin hydration and barrier parameters. Instrumental measurement on skin hydration by using a corneometer. *p < 0.05, a significant improvement over baseline, # p < 0.05 a significant improvement over 3% niacinamide treatment. (b) Effect on skin TEWL. Instrumental measurement on TEWL by AquaFlux. *p < 0.05, a significant improvement over baseline
FIGURE 11
FIGURE 11
Subject 1: 49‐year‐old woman with left side treated with 4‐HR (0.4%) + niacinamide (3%) formulation, baseline image (left), and post 12 weeks product application image (right)
FIGURE 12
FIGURE 12
Subject 1: 49‐year‐old woman with right side treated with 3% niacinamide formulation, baseline image (left), and post 12 weeks product application image (right)
See this image and copyright information in PMC

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