日本香粧品学会誌

Vol.
Effect40, ofNo.
Layered4, pp. Application
259–261（2016）of Different Cosmeceutical Formulations Containing Rhododendrol

259〈Communication〉

Effect of Layered Application of Different Cosmeceutical
Formulations Containing Rhododendrol
Kenji SUGIBAYASHI*, Hiroaki TODO, Ayaka ODA(Accepted: October, 31, 2016)

Abstract
We determined the skin permeation of rhododendrol (RD) after ﬁnite doses of layered application of RD-containing
cosmeceutical products. It was believed that the layered application increased the skin permeation of RD, causing the development of white blotches and depigmentation in various parts of the face and the body. The present results, however, clearly
indicated that the layered application of products decreased the skin permeation of RD, although the increase in application
volume may be a reason for the high skin permeation of RD.
Key words:

1.

ﬁnite dose, layered application, rhododendrol, skin permeation, transdermal delivery.

Introduction

It was revealed in Japan in July 2013 that, instead of lightening the skin tone as pseudo drug products (cosmeceuticals)
containing a tyrosinase inhibitor, 4-(4-hydroxyphenyl)-2-butanol (rhododendrol; RD), many users developed symptoms
such as white blotches and depigmentation on various parts ofthe face and body. As a result, all 26 available products werevoluntarily recalled1). Thereafter, many researches started toexamine this effect, with the intention of preventing the recurrence of white blotches caused by whitening agents. It has already been reported that the white blotches were caused by
the elimination of melanin and the destruction of melanocytes2), 3). However, large variations were observed in the generation of white spots, and detailed research is still in progress.
Together with determining the mechanism of the occurrence of white blotches, it was similarly important to observe
the concentration proﬁles of chemicals in the action sites aspart of safety assessments. For the evaluation of the usefulness and safety of therapeutic drugs, blood concentration proﬁles were evaluated in animal and clinical studies and TDM(Therapeutic Drug Monitoring) as well. In cases of topicallyapplied products on the skin, it is also important to follow theskin permeation and concentration proﬁles4), 5)．
It was thought that the layered application of RD whitening
products (i.e., second applications of lotion, milk, essence, orcream on the same region after the ﬁrst application of lotion)
may be a reason for many cases of white skin blotches. However, it might be reasonable from a pharmaceutical point ofview that both pharmaceutical systems in the products appliedﬁrst and second can be destroyed by the layered application,and that the skin permeation and concentration of RD may be* Corresponding author

Faculty of Pharmaceutical Sciences, Josai University (1–1 Keyakidai, Sakado, Saitama 350–0295, Japan)
E-mail: sugib@josai.ac.jp

lower than with each single application.
We then planned to determine the skin permeation of RD
after layered application of actual doses, of which the RD
amount on the skin decreases with the passage of time, a socalled ﬁnite dose system, whereas inﬁnite dose systems arebroadly used in the fundamental evaluation of topical or transdermal drug delivery systems.
2.

Experimental

Test samples of 2％ RD products (lotion, essence, milk, andcream from Kanebo Cosmetics Inc., Tokyo, Japan) and 1％RD aq. solution (1％ was used because 2％ did not dissolve inwater) were used, and an in vitro permeation experiment wasperformed using excised porcine ear skin (Central Institute forFeed and Livestock, JA Zen-Noh, Tsukuba, Japan) which hasa similar permeation proﬁle to human skin. The molecularweight (M.W.), pKa, and logarithm of n-octanol–water partition coefﬁcient (log Ko/w) of RD were 166.22 Da, 6.2 and 1.40,
respectively, and Table 1 summarizes the primary componentsof the RD products.
Porcine ear skin was kept at −30℃ after purchase andthawed on the experimental day using warm water at 32℃.
Then, the skin was rinsed with puriﬁed water, hairs wereTable 1.

Primary ingredients in the RD products.

Ingredient
1,3-Butylene glycol
Dipropylene glycol
Glycerin
70％ Sorbitol solution
Propylene glycol isostearate
Water

Lotion

MilkEssence

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