Skin-Lightening Active Ingredients in Japan: History
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Japanese pharmaceutical cosmetics, often referred to as quasi-drugs, contain skin-lightening active ingredients formulated to prevent sun-induced pigment spots and freckles. Their mechanisms of action include suppressing melanin production in melanocytes and promoting epidermal growth to eliminate melanin more rapidly. For example, arbutin and rucinol are representative skin-lightening active ingredients that inhibit melanin production, and disodium adenosine monophosphate and dexpanthenol are skin-lightening active ingredients that inhibit melanin accumulation in the epidermis. In contrast, oral administration of vitamin C and tranexamic acid in pharmaceutical products can lighten freckles and melasma, and these products are more effective than quasi-drugs. On the basis of their clinical effectiveness, skin-lightening active ingredients can be divided into four categories according to their effectiveness and adverse effects.

  • skin-lightening
  • pharmaceutical cosmetics
  • quasi-drug
  • ingredient
  • melasma: pigment spots

1. Development of Skin-Lightening Active Ingredients

Japanese pharmaceutical cosmetics are required to have one of the following purposes of use: (1) cleansing, (2) beautifying, (3) increasing attractiveness, (4) changing appearance, and (5) maintaining healthy skin or hair. Whether or not the product has the above purpose of use should be clarified by the efficacy or effectiveness, usage, and dosage of the product. If a product is determined not to meet the specified purpose of use on these bases of its efficacy or effectiveness, usage, and dosage, it is considered a “drug.” Examples of indications include “spots, freckles, pigmentation due to sunburn, etc.” (internal use), “spots, freckles, pigmentation due to sunburn/rash” (internal use), “skin pigmentation, senile pigmentation” (external use), “spots” (internal use), “Riehl melanosis, post-inflammatory hyperpigmentation” (for injection), and “melasma, freckles, post-inflammatory hyperpigmentation” (for internal use and injection). If the product has only the above efficacy or effectiveness, usage, and dosage, it cannot be considered a pharmaceutical cosmetic (quasi-drug).
In Japan, the efficacy for pharmaceutical cosmetics was changed in 2019 from “prevents sun spots and freckles” to “prevents sun spots and freckles by suppressing melanin production.” In 2004, the action of the ingredients in the formulation was changed to “prevents spots and freckles,” and, on the basis of the mechanism of action of the ingredients in the formula, the indication of “suppressing the accumulation of melanin and preventing spots and freckles” was approved. Thus, it is possible to apply for approval of pharmaceutical cosmetics for new efficacy within the scope of quasi-drug efficacy, on the basis of a clear scientific rationale.
The Japanese skincare market can be divided into the following functional categories: moisturizing, skin-lightening, anti-aging, sensitive skin, and pore and acne care. Lightening of the skin accounts for approximately 30% of the market and is the category with the most rapid growth over the past 35 years, particularly in terms of research and development [1]. Approximately twenty active ingredients have been developed for lightening-related quasi-drugs, including chemical substances and plant extracts with excellent inhibitory effects on tyrosinase activity and melanin production. A chronology of the development of skin-lightening active ingredients is presented in Table 1. The chemical structures of skin-lightening active ingredients in Japan are presented in Figure 1. Recent research on anti-aging skin-lightening has revealed new mechanisms and methods for the treatment of skin lightening. This section introduces the history of the skin-lightening ingredients developed in Japan.
Figure 1. Chemical structure of skin-lightening active ingredients in Japan.
Table 1. List of skin-lightening active ingredients approved in Japan.
Approved Year Generic Name Development Company Chemical Name/Substance Name Main Mechanism of Action
  placenta extract      
1983 magnesium ascorbyl phosphate (APM) Takeda Pharmaceutical Co., Ltd. magnesium L-ascorbyl-2-phosphate tyrosinase inhibition
1988 kojic acid Sansho Seiyaku Co., Ltd. kojic acid tyrosinase inhibition
1989 arbutin Shiseido Co., Ltd. hydroquinone-β-D-glucopyranoside tyrosinase inhibition
1994 ascorbyl glucoside (AA-2G) Hayashibara Co., Ltd., Kaminomoto Co., Ltd., Shiseido Co., Ltd. L- ascorbic acid 2-O-α-glucoside tyrosinase inhibition
1997 ellagic acid Lion Corporation ellagic acid tyrosinase inhibition
1998 Rucinol® Kurarey Co., Ltd.
POLA Chemical industries, Inc.
4-n-butylresorcinol tyrosinase inhibition
1999 Chamomile ET Kao Corporation Matricaria chamomilla L Extract endothelin blocker
2001 linoleic acid S Sunstar Inc. linoleic acid tyrosinase degradation, stimulation of epidermal turn over
2002 tranexamic acid
Shiseido Co., Ltd. trans-4-aminocyclohexane carboxylic acid inhibition of prostaglandin E2 production by anti-plasmin
2003 4MSK Shiseido Co., Ltd. potassium 4-methoxysalicylate tyrosinase inhibition
2004 Vitamin C ethyl Nippon Hypox Laboratories, Inc. 3-O-ethyl ascorbic acid tyrosinase inhibition
2004 Energy signal AMP® Otsuka Pharmaceutical Co., Ltd. adenosine mono phosphate stimulation of epidermal turnover
2005 Magnolignan® Kanebo Cosmetics Inc. 5,5-dipropyl-biphenyl-2,2-diol inhibition of tyrosinase maturation, cytotoxicity to melanocytes
2007 D-Melano (niacinamide W) P&G Maxfactor niacinamide suppression of melanosome transfer
2008 Rhododenol® Kanebo Cosmetics Inc. 4-(4-hydroxyphenyl)-2-butanol, Rhododendrol tyrosinase inhibition, cytotoxicity of melanocytes
2008 TXC CHANEL tranexamic acid cetyl ester hydrochloride inhibition of prostaglandin E2 production
2009 ascorbyl tetraisopalmitate Nikko Chemicals Co., Ltd. ascorbyl tetra-2-hexyldecanoate tyrosinase inhibition
2018 dexpanthenol W (PCE–DP) POLA ORBIS Holdings Inc. dexpanthenol enhance energy production of epidermal cells

2. Report on the Effectiveness of a Formulation Containing a Lightening Agent and a Spot Remedy for Senile Pigmented Lesions

This entry is adapted from the peer-reviewed paper 10.3390/molecules27154774


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