JP3869949B2 - Skin external preparation suitable for whitening - Google Patents

Description

【０００７】
【発明の実施の形態】
（１）本発明のメラニン産生抑制剤
本発明のメラニン産生抑制剤は、上記一般式（Ｉ）に表される化合物からなる。一般式（Ｉ）に表される化合物は様々な立体異性体が存在するが、これらの中では、化学構造式１に表されるアリストロンが特に好ましい。これは優れたメラニン産生抑制作用を有するからである。この様な構造を有する化合物は、天然物として植物体などに多く含まれているので、植物体の抽出物を精製して得ることもできる。例えば、化学構造式１に表される化合物であれば、ウマノスズクサやマルバウマノスズクサ等のウマノスズクサ科の植物体中に多く含まれていることを、本発明者らは見いだしている。これらの植物体にメタノールなどの溶媒を加え、室温であれば数日、沸点付近の温度であれば数時間浸漬し、濾過した後濃縮し、シリカゲルカラムクロマトグラフィー等の方法で精製すれば得ることが出来る。本発明では、これら何れの方法で製造された一般式（Ｉ）に表される化合物であってもメラニン産生抑制剤として使用できる。これらの化合物は何れも優れた安全性とメラニン産生抑制作用とを有する。
【０００８】
＜製造例１＞
ウマノスズクサの植物体５００ｇに１００％メタノールを５ｌ加えて、３時間加熱還流し、冷却後減圧濃縮し、水５ｌとｎ−ヘキサン５ｌを加え、液液抽出を行い、ｎ−ヘキサン層を取り、濃縮した後、シリカゲルカラムクロマトグラフィー（溶出溶媒；ノルマルヘキサン：酢酸エチル＝１００：０→５０：５０）で精製し、メタノールから再結晶して、アリストロン（化学構造式１）を得た。
【０００９】
【化５】

【００１１】
（２）本発明の皮膚外用剤
本発明の皮膚外用剤は、上記一般式（Ｉ）に表される化合物から選ばれる１種乃至は２種以上を含有することを特徴とする。上記一般式（Ｉ）に表される化合物は優れた安全性とメラニン産生抑制作用を有しているため、本発明の皮膚外用剤は、化粧料として好適であり、中でも美白用の化粧料として特に好適である。ここで、本発明で言う皮膚外用剤とは、皮膚上に投与する形態の組成物の総称であって、皮膚外用医薬組成物、医薬部外品、化粧料、皮膚洗浄料、浴用剤などを総括して意味する言葉である。本発明の皮膚外用剤において、一般式（Ｉ）に表される化合物の好ましい含有量は、総量で０．０１〜１０重量％であり、更に好ましくは０．０５〜１重量％である。一般式（Ｉ）に表される化合物で、本発明の皮膚外用剤に特に好ましく含有されるものは、アリストロン（化学構造式１）である。
【００１２】
本発明では、上記必須成分以外に、通常皮膚外用剤で使用される、任意成分を含有することが出来る。かかる任意成分としては、ワセリンやマイクロクリスタリンワックス等のような炭化水素類、ホホバ油やゲイロウ等のエステル類、牛脂、オリーブ油等のトリグリセライド類、セタノール、オレイルアルコール等の高級アルコール類、ステアリン酸、オレイン酸等の脂肪酸、グリセリンや１，３−ブタンジオール等の多価アルコール類、非イオン界面活性剤、アニオン界面活性剤、カチオン界面活性剤、両性界面活性剤、エタノール、カーボポール等の増粘剤、防腐剤、紫外線吸収剤、抗酸化剤、色素、粉体類等が好ましく例示できる。勿論、既にメラニン産生抑制作用が知られている、ビタンミンＣとその誘導体、ハイドロキノンとその誘導体、レゾルシノールとその誘導体等を含有することも可能である。本発明の皮膚外用剤は上記必須成分と任意成分とを常法に従って処理することにより得ることが出来る。
【００１３】
【実施例】
以下に、実施例を挙げて、本発明について更に詳細に説明を加えるが、本発明がこれら実施例にのみ限定を受けないことは言うまでもない。
【００１４】
＜実施例１＞
メラニン産生抑制作用
上記アリストロン１について、メラニン産生抑制作用をマウスメラノーマＢ−１６Ｆ１細胞を用いて、メラニン産生抑制作用を調べた。即ち、プラスチック培養フラスコ（２５ｃｍ²）内の１０％ＦＢＳ加ＲＰＭＩ−１６４０培地に２×１０⁵個のマウスメラノーマＢ−１６ Ｆ１細胞を播種し、５％炭酸ガス加気流中３７℃で培養した。播種２４時間後、最終濃度１×１０^-3（Ｗ／Ｖ）％となるように、上記メラニン産生抑制剤をＤＭＳＯに溶解させて加え、更に２日間培養した。この際、ＤＭＳＯは最終濃度で０．２％を越えないように注意した。培養終了後、培地を除き、燐酸緩衝生理食塩水液で洗浄後、トリプシン処理し細胞を剥離させ、遠心分離により細胞を回収し、細胞数より細胞毒性を、細胞の色よりメラニン産生抑制作用を判定した。判定基準は細胞毒性が、＋＋：検体無添加（対照）に比し著しく少ない、＋：対照に比し明らかに少ない、±：対照に比しやや少ない、−：対照に比し同程度であり、メラニン産生抑制作用は、＋＋：対照に比し著しく白い、＋：対照に比し明らかに白い、±：対照に比しやや白い、−：対照同程度に黒いであった。結果を表１に示す。これより、本発明のメラニン産生抑制剤は細胞毒性が低いにもかかわらずメラニン産生抑制作用に優れることがわかる。
【００１５】
【表１】

【００１６】
＜実施例２＞
以下に示す処方に従って、本発明の化粧料を作成した。即ち、処方成分を室温で攪拌溶解し、本発明の化粧料である化粧水を得た。
アリストロン １ 重量部
ポリオキシエチレン（６０）硬化ヒマシ油 ０．５重量部
エタノール １０ 重量部
グリセリン ５ 重量部
水 ８３．５重量部
【００１７】
＜実施例３＞
以下に示す処方に従って、本発明の化粧料を作成した。即ち、処方成分を室温で攪拌溶解し、本発明の化粧料である化粧水を得た。
アリストロン ０．１重量部
ポリオキシエチレン（６０）硬化ヒマシ油 ０．５重量部
エタノール １０ 重量部
グリセリン ５ 重量部
水 ８４．４重量部
【００１８】
＜実施例４＞
以下に示す処方に従って、本発明の化粧料を作成した。即ち、処方成分を室温で攪拌溶解し、本発明の化粧料である化粧水を得た。
アリストロン ０．０１重量部
ポリオキシエチレン（６０）硬化ヒマシ油 ０．５重量部
エタノール １０ 重量部
グリセリン ５ 重量部
水 ８４．３９重量部
【００１９】
＜実施例５＞
以下に示す処方に従って、本発明のクリームを作成した。即ち、イの成分を良く混練りした後、８０℃に加熱し、ロ、ハを予め８０℃に予熱しておき、イにロを加え希釈し、これにハを徐々に加え乳化し、攪拌冷却しクリームを得た。
イ
トリグリセリンジイソステアレート ５ 重量部
マルチトール７０％水溶液 ５ 重量部
グリセリン ３ 重量部
１，３−ブタンジオール ５ 重量部
アリストロン ０．７重量部
メチルパラベン ０．２重量部
ブチルパラベン ０．１重量部
ロ
流動パラフィン １５ 重量部
マイクロクリスタリンワックス ３ 重量部
ネオペンチルグリコールジイソオクタネート ５ 重量部
カルナウバワックス ２ 重量部
ハ
水 ５６ 重量部
【００２０】
＜実施例６＞
上記実施例２〜５の各化粧料を被験者１名の上腕内側部の１ｃｍ×１ｃｍの部位に塗布した後、１時間後にふき取り、予め測定した最小紅斑照射量の２倍の線量の紫外線（線源ＢＬＢランプ及びＳＥランプ）を照射し、照射後１週間に黒化度を＋＋：対照に比し著しく白い、＋：対照に比し明らかに白い、±：対照に比しやや白いの基準で判定した。尚、対照はサンプルを投与せずに紫外線照射のみを行った。結果を表２に示す。これより本発明の皮膚外用剤である化粧料は、美白作用の内、肌が黒くなるのを予防する作用に優れることがわかる。
【００２１】
【表２】

【００２２】
＜実施例７＞
上記実施例３の化粧水を用いて、実使用試験を行い美白効果を確かめた。即ち、色黒に悩むパネラー１群１０名、４群計４０名を用い、実施例３の化粧水、実施例３の化粧水の化学構造式１の化合物をビタミンＣナトリウム塩に置換した比較例１、実施例３の化粧水の化学構造式１の化合物をアルブチンに置換した比較例２、実施例３の化粧水の化学構造式１の化合物を水に置換した対照例の４群で、朝晩１日２回、２カ月連続使用してもらい、色黒の改善の印象を＋＋：すばらしい改善、＋：明らかな改善、±：やや改善、−：改善せずのランクに分けてアンケートで答えてもらった。結果を表３に出現例数として示す。これより、本発明の化粧料は美白作用に優れることがわかる。
【００２３】
【表３】

【００２４】
＜実施例８＞
下記に示す処方に従って、色素異常症の治療用の軟膏を作成した。即ち、処方成分を良く混練りし、軟膏を得た。
白色ワセリン ９０ 重量部
アリストロン １０ 重量部
【００２５】
＜実施例９＞
下記に示す処方に従って、美白用の浴用剤を作成した。即ち、処方成分を良くヘンシェルミキサーで混合した後、０．９ｍｍ丸穴スクリーンを装着したパルベラーザーで粉砕し、浴用剤を得た。
硫酸ナトリウム ９０ 重量部
アリストロン １０ 重量部
【００２６】
【発明の効果】
本発明によれば、新規のメラニン産生抑制作用を有する化粧料などの皮膚外用剤を提供することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a skin external preparation suitable for cosmetics and the like.
[0002]
[Prior art]
Fair-skinned beautiful skin has been desired by all since ancient times, and many efforts have been made to obtain such skin. In this, it was clarified that the cause of the whiteness of color, in other words, the blackness of color, is melanin produced in melanocytes. It has also been clarified that the skin color becomes black or white depending on the amount of melanin. It is already known that proteins called tyrosinase and tyrosinase-related proteins are involved in the biosynthesis of melanin. In addition, materials and cosmetics have been developed to inhibit the action of such enzymes and the like to realize fairness, and it has become possible to whiten the color to a considerable extent. However, there are still unexplained factors regarding the relationship between the color black and melanin biosynthesis, and the factors related to the biosynthesis of melanin differ depending on the type of color black. It has become known. However, it is already well known that there are people who do not exhibit the effects of melanin production inhibitors that have been considered to have a relatively high effect. The reason for this is that there are many factors involved in melanin production, and it is considered that the melanin production inhibitor may or may not be effective due to the difference. It cannot be said that such factors and the mechanism of melanin production have been elucidated. Therefore, it is necessary to say that the present situation is that it is desired to find various kinds of novel melanin production inhibitors.
[0003]
On the other hand, the compounds represented by the general formula (I) to be described later are compounds already known in the literature. However, these compounds may be contained in an external preparation for skin, or these compounds may have a melanin production inhibitory action. It was not known at all.
[0004]
[Problems to be solved by the invention]
An object of the present invention is to find a novel melanin production inhibitor and to provide a skin external preparation such as a cosmetic having a melanin production inhibitory action.
[0005]
[Means for solving problems]
In view of such a situation, the present inventors have sought for a novel melanin production inhibitor and, as a result of intensive research, have found such an action in the compound represented by the general formula (I) described below. Furthermore, as a result of repeated application studies to external preparations for skin, it was found that an external preparation for skin containing such a compound has a whitening effect due to a melanin production inhibitory action, and has led to the completion of the invention. Hereinafter, the present invention will be described in detail with a focus on embodiments.
[0006]
[Chemical 3]

[0007]
DETAILED DESCRIPTION OF THE INVENTION
(1) Melanin production inhibitor of this invention The melanin production inhibitor of this invention consists of a compound represented by the said general formula (I) . The compound represented by the general formula (I) has various stereoisomers, and among these, the aristrone represented by the chemical structural formula 1 is particularly preferable. This is because it has an excellent melanin production inhibitory action. Since many compounds having such a structure are contained in plants as natural products, they can be obtained by purifying extracts of plants. For example, the present inventors have found that a compound represented by the chemical structural formula 1 is contained in a large number of plants of the family Uminosufactaceae such as Umanosuzuma and Malbaumanosuzusa. It can be obtained by adding a solvent such as methanol to these plants, immersing them for several days at room temperature, immersing for several hours at temperatures near the boiling point, filtering, concentrating, and purifying by a method such as silica gel column chromatography. I can do it. In the present invention, the compound represented by the general formula (I) produced by any of these methods can be used as a melanin production inhibitor. These compounds all have excellent safety and melanin production-suppressing action.
[0008]
<Production Example 1>
Add 5 liters of 100% methanol to 500 g of Umanosuzu plant, heat and reflux for 3 hours, cool and concentrate under reduced pressure, add 5 liters of water and 5 liters of n-hexane, perform liquid-liquid extraction, take n-hexane layer, concentrate Then, it was purified by silica gel column chromatography (elution solvent; normal hexane: ethyl acetate = 100: 0 → 50: 50) and recrystallized from methanol to obtain aristolone (chemical structural formula 1).
[0009]
[Chemical formula 5]

[0011]
(2) External preparation for skin of the present invention The external preparation for skin of the present invention is characterized by containing one or more selected from the compounds represented by the general formula (I). Since the compound represented by the general formula (I) has excellent safety and melanin production inhibitory action, the external preparation for skin of the present invention is suitable as a cosmetic, and among others, as a cosmetic for whitening. Particularly preferred. Here, the external preparation for skin referred to in the present invention is a general term for a composition in a form to be administered on the skin, and includes an external pharmaceutical composition for skin, quasi-drug, cosmetic, skin cleansing agent, bath preparation and the like. These are words that collectively mean. In the external preparation for skin of the present invention, the total content of the compound represented by the general formula (I) is preferably 0.01 to 10% by weight, more preferably 0.05 to 1% by weight. Of the compounds represented by the general formula (I), Aristrone (chemical structural formula 1) is particularly preferably contained in the external preparation for skin of the present invention.
[0012]
In this invention, in addition to the said essential component, the arbitrary component normally used with a skin external preparation can be contained. Such optional components include hydrocarbons such as petrolatum and microcrystalline wax, esters such as jojoba oil and gallow, triglycerides such as beef tallow and olive oil, higher alcohols such as cetanol and oleyl alcohol, stearic acid, olein Fatty acids such as acids, polyhydric alcohols such as glycerin and 1,3-butanediol, nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, thickeners such as ethanol and carbopol Preservatives, ultraviolet absorbers, antioxidants, pigments, powders and the like can be preferably exemplified. Of course, it is also possible to contain bitumin C and its derivatives, hydroquinone and its derivatives, resorcinol and its derivatives, etc., which are already known to inhibit melanin production. The skin external preparation of this invention can be obtained by processing the said essential component and arbitrary components in accordance with a conventional method.
[0013]
【Example】
Hereinafter, the present invention will be described in more detail with reference to examples, but it goes without saying that the present invention is not limited only to these examples.
[0014]
<Example 1>
For melanin production inhibitory effect said Alice Tron 1, the melanin production inhibitory effect using mouse melanoma B-16f1 cells was examined melanin production inhibitory effect. Specifically, 2 × 10 ⁵ mouse melanoma B-16 F1 cells were seeded in RPMI-1640 medium supplemented with 10% FBS in a plastic culture flask (25 cm ² ) and cultured at 37 ° C. in a 5% carbon dioxide gas stream. 24 hours after sowing, the above melanin production inhibitor was dissolved in DMSO and added to a final concentration of 1 × 10 ⁻³ (W / V)%, and further cultured for 2 days. At this time, care was taken not to exceed 0.2% of DMSO at the final concentration. After completion of the culture, remove the medium, wash with phosphate buffered saline, trypsinize, peel off the cells, collect the cells by centrifugation, cytotoxicity from the number of cells, and melanin production inhibitory action from the color of the cells. Judged. Criteria are cytotoxicity ++: significantly less than no sample added (control), +: apparently less than control, ±: slightly less than control, −: comparable to control The melanin production inhibitory action was ++: markedly white compared to the control, +: clearly white compared to the control, ±: slightly white compared to the control, −: black as much as the control. The results are shown in Table 1. From this, it can be seen that the melanin production inhibitor of the present invention is excellent in melanin production inhibitory action despite its low cytotoxicity.
[0015]
[Table 1]

[0016]
<Example 2>
The cosmetic of the present invention was prepared according to the formulation shown below. That is, the prescription ingredients were stirred and dissolved at room temperature to obtain a lotion that is the cosmetic of the present invention.
Aristron 1 part by weight polyoxyethylene (60) hydrogenated castor oil 0.5 part by weight ethanol 10 parts by weight glycerin 5 parts by weight water 83.5 parts by weight
<Example 3>
The cosmetic of the present invention was prepared according to the formulation shown below. That is, the prescription ingredients were stirred and dissolved at room temperature to obtain a lotion that is the cosmetic of the present invention.
Aristolon 0.1 parts by weight Polyoxyethylene (60) hydrogenated castor oil 0.5 parts by weight Ethanol 10 parts by weight Glycerin 5 parts by weight Water 84.4 parts by weight
<Example 4>
The cosmetic of the present invention was prepared according to the formulation shown below. That is, the prescription ingredients were stirred and dissolved at room temperature to obtain a lotion that is the cosmetic of the present invention.
Aristron 0.01 parts by weight Polyoxyethylene (60) hydrogenated castor oil 0.5 parts by weight Ethanol 10 parts by weight Glycerin 5 parts by weight Water 84.39 parts by weight
<Example 5>
The cream of the present invention was prepared according to the formulation shown below. That is, after knead | mixing the component of (a) well, it heats to 80 degreeC, pre-heats (b) and (c) beforehand to 80 degreeC, dilutes by adding (b) to (b), and emulsifies, stirs and adds it gradually. Cooled to obtain a cream.
Itoliglycerin diisostearate 5 parts by weight Maltitol 70% aqueous solution 5 parts by weight Glycerin 3 parts by weight 1,3-butanediol 5 parts by weight Aristrone 0.7 part by weight Methylparaben 0.2 part by weight Butylparaben 0.1 part by weight B Liquid paraffin 15 parts by weight Microcrystalline wax 3 parts by weight Neopentyl glycol diisooctanoate 5 parts by weight Carnauba wax 2 parts by weight C water 56 parts by weight
<Example 6>
After applying each cosmetic of Examples 2 to 5 to a 1 cm × 1 cm site on the inner side of the upper arm of one subject, it was wiped off after 1 hour, and ultraviolet rays (line) twice the minimum erythema dose measured in advance. Source: BLB lamp and SE lamp), and the degree of blackening within one week after irradiation is ++: markedly white compared to the control, +: clearly white compared to the control, ±: slightly white compared to the control Judged. As a control, only the ultraviolet irradiation was performed without administering the sample. The results are shown in Table 2. From this, it can be seen that the cosmetic which is an external preparation for skin according to the present invention is excellent in the effect of preventing the skin from becoming dark in the whitening effect.
[0021]
[Table 2]

[0022]
<Example 7>
Using the lotion of Example 3 above, an actual use test was conducted to confirm the whitening effect. That is, the comparative example which substituted the compound of Chemical Formula 1 of the lotion of Example 3 and the lotion of Example 3 with vitamin C sodium salt using the panel 1 group 10 persons and 4 groups total 40 persons who suffer from darkness. 1. Comparative group 2 in which the compound of formula 1 of the lotion of Example 3 was substituted with arbutin, and 4 groups of control examples in which the compound of formula 1 of the lotion of Example 3 was substituted with water. Use twice a day for two consecutive months, and give impressions of improvement in darkness ++: Great improvement, +: Clear improvement, ±: Slight improvement,-: No improvement received. The results are shown in Table 3 as the number of appearance examples. This shows that the cosmetic of the present invention is excellent in whitening action.
[0023]
[Table 3]

[0024]
<Example 8>
An ointment for treating dyschromia was prepared according to the prescription shown below. That is, the formulation components were well kneaded to obtain an ointment.
White petrolatum 90 parts by weight Aristolon 10 parts by weight [0025]
<Example 9>
A whitening bath agent was prepared according to the formulation shown below. That is, the prescription ingredients were well mixed with a Henschel mixer and then pulverized with a pulverizer equipped with a 0.9 mm round hole screen to obtain a bath preparation.
Sodium sulfate 90 parts by weight Aristolone 10 parts by weight
【The invention's effect】
ADVANTAGE OF THE INVENTION According to this invention, skin external preparations, such as cosmetics which have a novel melanin production inhibitory effect, can be provided.

Claims (2)

A melanin production inhibitor comprising a compound represented by formula (I).

Formula (I) The melanin production inhibitor of Claim 1 whose compound represented by general formula (I) is aristrone (Aristolone; Chemical structural formula 1).

Chemical structural formula 1