101 J. Cosmet. Sci., 74, 101–131 (March/April 2023) Address all correspondence to Zaida Maria Faria de Freitas, zaida@pharma.ufrj.br Clinical Application of Kojic Acid in the Treatment of Melasma: A Scope Review RAYANE VIEIRA BRAZIL, JENIFER BRASIL DOS SANTOS, VÂNIA EMERICH BUCCO DE CAMPOS, ELISABETE PEREIRA DOS SANTOS AND ZAIDA MARIA FARIA DE FREITAS Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil (R.V.B., J.B.S, V.E.B.C, E.P.S., Z.M.F.F.) Accepted for publication July 01, 2023. Synopsis Melasma is a pigmentary system failure marked by macules or symmetrically distributed irregular spots in sun-exposed areas, particularly on the forehead, lips, cheeks, and chin. With its ability to inhibit the tyrosinase enzyme, which is in charge of producing melanin, kojic acid (KA) is one of the depigmenting substances frequently employed in the topical treatment of melasma. This systematic scoping review followed the recommendations of Joanna Briggs and the PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation to map the therapeutic application of KA in treating melasma. The following databases, searched without regard to year or language through December 2022, were used: MEDLINE (PubMed), Embase, VHL, Scopus, Cochrane, Web of Science, and the grey literature. The search found 2,104 records in the databases. Eventually, 24 studies were added since they matched the requirements for eligibility. The outcomes and occurrences of adverse effects are influenced by variables such as the pharmaceutical form, concentration, frequency, period of treatments, and therapeutic associations. In the therapy of melasma, KA, whether isolated or associated, has substantial effects. INTRODUCTION Melasma, also known as acquired and chronic symmetrical cutaneous hyper melanosis, is a malfunction of the pigmentary system. It is recognized by macules or irregular spots on sun-exposed skin that range in tone from light brown to dark brown. It is distributed symmetrically, mostly throughout the parts of the face that include the chin, cheeks, lips, and forehead. Other body parts such as the neck and chest may be affected less frequently (1). Melasma may develop due to exposure to ultraviolet radiation (UVA and UVB), sunlight, exposure to visible light, genetic predisposition, pregnancy, and exogenous hormone use. The use of various drugs such as anticonvulsants photosensitizing cosmetics nutritional inadequacy and ovarian and thyroid dysfunction are other variables that may contribute to the development of melasma. Women with darker skin and those from Asian, Latin American, Middle Eastern, and African regions with higher sun exposure are most affected

102 JOURNAL OF COSMETIC SCIENCE by this dysfunction. In addition, it significantly impacts the quality of life, resulting in psychological problems including depression and low self-esteem (2,3). Histologically, melasma is characterized by an increase in melanin in the epidermis and dermis. Unfortunately, melasma’s clinical course is sometimes lengthy, resistant to treatment, and typically recurs once treatment is stopped or with increasing sun exposure (3). Current treatments include topical and systemic agents, chemical peels, laser, and light- based therapies. The goals of the treatment should be to improve existing lesions and avoid recurrences. Topical therapies include ultraviolet (UV) backlight protection, depigmenting agents, retinoids, corticosteroids, tranexamic acid (TXA), and combinations of these. Depigmenting or keratolytic topical medications include hydroquinone (HQ), tretinoin, azelaic acid, kojic acid (KA), niacinamide, and TXA, among a wide range of others. Glycolic acid (GA), salicylic acid (SA), and trichloroacetic acid (TCA) are three commonly utilized chemical peels. Intense pulsed light, Q-Switched ND YAG Laser (ADSS, Beijing, China), and fractional laser are a few examples of laser/light-based therapies. TXA and natural supplements are recent systemic medications. Melasma can be improved by combination therapy, which typically yields superior results (2,4). Among the depigmenting substances commonly used in the topical treatment of melasma is KA, which may be applied alone or in combination with other substances or therapies. Also known as 5-hydroxy-2-hydroxymethyl-4-pyrone (International Union of Pure and Applied Chemistry, IUPAC), KA is a naturally occurring chemical produced when fungi such as Aspergillus and Penicillium ferment carbohydrates. Its function is to lighten the skin by inhibiting the tyrosinase enzyme, which is responsible for melanin production. Tyrosinase contains copper ions that regulate melanin synthesis by a two-step reaction. In the first stage, tyrosinase catalyzes tyrosine hydroxylation in L-3,4-dihydroxyphenylalanine (L-DOPA) and oxidation of DOPA in dopaquinone. In the second stage, dopaquinone converts into melanin. So, when tyrosinase is inhibited, melanin production is blocked, which leads to a decrease in pigment formation (5). Due to its mechanism of action, KA has wide application in the cosmetic industry. With the growth of this industry, its supply and demand are increasing considerably, and clinical studies are essential for designing and developing new products based on KA (6,7). However, there needs to be more literature regarding the use of KA as a depigmenting agent in treating melasma. Publications of systematic and scoping reviews or other methodologies that gather primary studies on this asset were not found to evaluate the safety and efficacy alone or in association with other therapies. This systematic scoping review aims to map the clinical application of KA in treating melasma by mapping the literature that is currently available. These publications provide a descriptive view of the pharmaceutical forms of KA as well as delivery, concentration, treatment duration, frequency of application, and associations. In addition, these publications summarize the evidence found on efficacy and safety, if available, regarding reducing the severity of melasma spots, improving the quality of life of carriers, and adverse effects reported. METHODS STUDY DESIGN This scoping review was carried out following the guidelines of the Joanna Briggs Institute to map, describe, and categorize the available information on the clinical use of KA in the treatment of melasma (8).