208 JOURNAL OF COSMETIC SCIENCE A COMPARISON OF SKIN LIGHTENING AGENTS Evelyn G. Su, Ph.D. Sino Lion (USA) Ltd., New York, NY 10048 INTRODUCTION: Skin lightening products have become increasingly popular in the Asian-pacific countries as well as in the African and South American countries. Europe and America have also seen increased interests in skin lightening agents. For Asian and Black skin, the main purpose for skin lightening products is to lighten or whiten the skin as well as to even-tone and brighten the skin while for Caucasian white skin the focus is on even-toning and brightening the skin. For all skin types, the skin lightening agents can be used to treat pigmentation disorders such as freckles, pregnancy masks and age spots. The purpose of this paper is to compare the various aspects of the four popular skin lightening agents, i.e., kojic acid, kojic dipalmitate, arbutin and magnesium ascorbyl phosphate (MAP), as well as hydroquinone. SKIN COLOR AND MELANIN: Skin color is mainly determined by the amount of melanin present in the skin. Melanin is synthesized in melanocytes which are normally found in the epidermal basal layer. Within the melanocytes melanin is bound to a protein matrix to form melanosomes. In the melanosomes, tyrosinase converts tyrosine to eumelanin or pheomelanin. Fig. 1 illustrates the pathways of melanin biosynthesis in the melanocytes. By blocking at the various points of the pathways, skin lightening agents can inhibit or even reverse melanin biosynthesis, and are thus useful in whitening or lightening the human skin. Skin lightening agents can also be used to treat local hyperpigmention or spots which are caused by a local increase in melanin synthesis or uneven distribution. SKIN LIGHTENING AGENTS: A. Mechanism of Action: Arbutin, kojic acid, kojic dipalmitate, MAP are all tyrosinase inhibitors. Arbutin reportedly works by competing with DOPA at its receptor site on tyrosinase, • while kojic acid inactivates tyrosinase by chelating with its vital copper ion and suppressing the tautomerization from dopachrome to DHICA) L-ascorbic acid and its derivatives, which include MAP, are believed to act as reducing agents on melanin intermediates, thus blocking the oxidation chain reaction at various points from tyrosine/DOPA to melanin) Kojic dipalmitate is a tyrosinase inhibitor, but the exact mechanism of action is unclear. Hydroquinone is also a tyrosinase inhibitor. n' s In addition, hydroquinone has cytotoxic effect on melanocytes, which causes high toxicity to the skin. B. Ease of Formulation and Stability: Kojic Acid, arbutin and MAP are all water-soluble, and can be easily incorporated into the formulation. On the other hand, kojic dipalmitate is oil-soluble, and can be easily melted into oil phase at 75-85øC, followed with immediate emulsification. However, kojic acid, hydroquinone and arbutin have color stability problems, which impose various difficulties on formulation. Kojic acid usually tums yellowish brown with time in the finished product. The reasons for this instability are mainly two-fold: a) kojic acid chelates with many metal ions, especially for iron (Fe3+), to produce colored complex (yellow color for iron) b) kojic acid can oxidize slowly in contact with air, and this process accelerates at high temperature. Hydroquinone solution becomes brown on exposure to air as a result of oxidation and must be stabilized. Arbutin has by far higher stability than hydroquinone, 6 but still has potential instability in formulation. MAP is stable in formulation. Kojic dipalmitate is stable to heat, light, pH and oxidation. Compared with kojic acid, kojic dipalmitate neither chelate with metal ions and nor oxidize in air. As a result, kojic dipalmitate has excellent stability in formulation. C. Safety and Efficacy: Kojic acid is non-toxic and has minimal irritation. 7 Kojic acid has been used in Japan since 1988 and has extended to other parts of the world. The human patch test on kojic dipalmitate showed that it is completely non-irritating. 8 There are no known safety issues associated with the use of kojic dipalmitate. Hydroquinone can be irritating and cause redness and burning. More importantly, it has been shown to cause exogenous ochronosis, 9' •0 which has resulted in a ban on its use in South Africa, Thailand and other countries. Arbutin has far higher safety than hydroquinone, has no irritation and virtually no sensitization) • MAP is a vitamin C derivative, has an excellent safety record. Figure 2 shows the comparison of tyrosinase inhibitory effects among kojic acid, hydroquinone and the blank (water). The y-axis is absorbency at 475 nm which measures the coloration of various melanin

PREPRINTS OF THE 1998 ANNUAL SCIENTIFIC SEMINAR 209 intermediates, and thus tyrosinase activity. The x-axis is the lapse of time starting from the addition of tyrosinase into the culture medium. Figure 2 exhibits that the effect of kojic acid is much milder than hydroquinone while kojic acid has substantial inhibitory effects on tyrosinase activity compared with blank. Figure 3 shows the inhibitory effects of kojic acid and its esters on tyrosinase activity, and reveals that the kojic acid esters have far better inhibitory effects than kojic acid, while kojic acid showed substantial inhibitory effects on tyrosinase activity compared with blank (water). It is clear from Fig. 2 and 3 that kojic esters have comparable or better inhibitory effects on tyrosinase activity than hydroquinone, which in turn has stronger inhibitory effects than kojic acid. In clinical trials on patients with pigmentary disorders, a 55% effective rate was obtained for MAP, •2 while 60-95% and 80% effective rates were obtained for kojic acid ? and kojic dipalmitate, •3 respectively. It should be noted that both the active skin lightening agent and the formulation itself affect the efficacy or effectiveness of the final p•:oduct. D. Functionality and Compatibility: Apart from being a skin lightener, kojic acid is used as an anti-microbial agent to preserve vegetables, kojic dipalmitate is an emollient while MAP is an anti-oxidant. MAP also works synergistically with vitamin E. On the other hand, hydroquinone, kojic acid, arbutin and MAP may not be compatible with some organic sun screens and preservatives due to potential hydrogen bonding, while kojic dipalmitate is fully compatible with all sunscreens and preservatives. CONCLUSIONS: The various aspects of the skin lightening agents can be summarized in Table 1 below. It is clear that the use of hydroquinone is no longer desirable, due to its safety concerns. Among the other four skin lightening agents, kojic dipalmitate is the latest development and offers the best overall performance. It is therefore considered the "active of choice" for use in cosmetic formulations for skin lightening purposes. ./ ',...:-= 1,4ueM)O fAd•.eee DHI• Dor• M q..b....• K•41dmdm MmlO iF_ 4 ß O I 4 O I le 111 11 I•11 II as Fig. 1. Mclanin biosynthcsis pathways. Fig.2. Kojic acid and hydroquinone Fig. 3. Kojic acid and its csters Table 1. Comparison of Skin Lightening Agerib Agent Hydmquinone Arbutin Kojic Acid Kojic Dipalmitate MAP Functionality Skin Lightening Skin Lightening Skin Lightening, Skin Lighten/rig, Skin Lightening, Anti- Antimicrobial Emollient Oxidant Mechanism of Acdo• Tymsinase inhibitor Tyrosinase inhibitor Tyrosinase inhibitor Tyrosinase inhibitor Tymsinase inhibitor ELle of Formulig•on + -I-I-t- • .:',::: : | ', ', ',q Stability 4-• • • ::::: ::::: !mtmon • 4+ + -/+ E•cl• ::::: :::', :::: :',::: Safety + :::: :::: ::::: ::::: Cost + ::::: 4-i- .I-l-i- ::::: indicates the highest value "4+"minimal and "-"negative, ' G. imokawa ct al, JSoc Costa Chetn Jpn 17 0), 149 1993. 2 G. imokawa ct al., Jlnv Derm 91, 106, 1988. • Y Ohmoff ½t al, JSoc Costa Chem Jpn 18 (4), 215, 1994. 4 C.R. Denton ½t al., J- Invest. Dermatoi., 18, 119, 1952. s S. lijima ½t al., J. Invest. Dermatoi., 28, 1,1957. 6 Japanese Patent, Publication No. 60016906, Publication Date: 850128, "External Drug for S, kin" ? Y.F. Yang, China Surfactant Detergent and Cosmetics (DaO• Chemical Industry), No. 1, p28, 1995 ß C.F. Liu, X. L. Yc, Unpublished Data, 1995. 9 H.F. Jordaan, D.G. Van Nickcrk, ,4m JDermatopathoi 13(4), 418-424, 1991. lO j. 1. Phillips, C. issacson, H. Cannan,,4mJDermatopathol, 8(1), 14-21, 1986. n Japanese Patent, Publication No. 60056912, Publication Date 850402, "External Use Preparation for Skin". • 2 K. Kamcyamn ctal., J ,4m ,4cad Dermatoi 34(1 ): 29-33, 1996. n S. Nagai T. lzumi, US Patent 4•78,656, July. 14, 1981.