JP3583158B2 - Cosmetics - Google Patents

Description

本発明はＮ^Ｇ−モノメチル−Ｌ−アルギニンを含有することを特徴とする化粧料および美白剤である。本発明で用いられるＮ^Ｇ−モノメチル−Ｌ−アルギニンは市販品を利用することが出来る。
【０００５】
Ｎ^Ｇ−モノメチル−Ｌ−アルギニンは、本発明化粧料あるいは美白剤の全量中、０．００１〜１０重量％、好ましくは、０．０１〜１．０重量％配合することができる。０．０００１％以下の濃度では充分な効果が得られず、１０重量％以上の濃度では効果の増強が認められず不経済である。本発明の化粧料および美白剤にはＮ^Ｇ−モノメチル−Ｌ−アルギニンの効果を損なわない範囲内で、化粧料や医薬などに使用される油脂類、ロウ類、炭化水素類、脂肪酸類、アルコール類、エステル類、界面活性剤などの原料を配合することができる。本発明の化粧料は、クリーム、ローション、乳液、パックなどの基礎化粧料、ファンデーション、リップスティックなどのメイクアップ化粧料、浴用剤、石鹸などの剤型を採用することができる。また、本発明の美白剤の剤型は、散剤、丸剤、錠剤、注射剤、坐剤、外用剤などとされ、通常の製剤化技術に従って製造される。一日の投与量は、１０ｍｇ〜２００ｍｇ好ましくは２０ｍｇ〜１００ｍｇで、２〜３回に分けて投与することができる。
マウスを用いた急性毒性試験では、経口投与において、１，０００ｍｇ／ｋｇで死亡例は認められなかった。また、剖検所見においても、全ての臓器で異常は認められなかった。
【０００６】
【実施例】
次に本発明を詳細に説明するため実施例を挙げるが、本発明はこれに限定されるものではない。実施例に示す配合量の部とは重量部を示す。
【０００７】
実施例−１ 化粧水

製造方法：成分１〜５および成分６〜１０をそれぞれ均一に溶解し、混合し濾過して 製品とする。
【０００８】
比較例−１ 従来の化粧水
実施例−１において、Ｎ^Ｇ−モノメチル−Ｌ−アルギニンを精製水に置き換えたものを従来の化粧水とした。
【０００９】
実施例−２ クリーム

製造方法：油相成分１〜７および水相成分８〜１２をそれぞれ７０〜７５℃に加熱溶解し た後、油相成分１〜７に水相成分８〜１２を加えて乳化し、冷却途上で成分１３を加え て混合し、３０℃まで冷却して製品とする。
【００１０】
実施例−３ 乳液

製造方法：油相成分１〜６および水相成分７〜１０をそれぞれ７０〜７５℃に加熱溶解し た後、油相成分１〜６に水相成分７〜１０を加えて乳化し、冷却途上で成分１１を加え て混合し、３０℃まで冷却して製品とする。
【００１１】
比較例−２ 従来の乳液
実施例−３において、Ｎ^Ｇ−モノメチル−Ｌ−アルギニンを精製水に置き換えたものを従来の乳液とした。
【００１２】
実施例−４ パック

製造方法：各成分を均一に溶解し製品とする。
【００１３】
実施例−５ ファンデーション

製造方法：成分１０〜１３および１５を７０℃に加熱しよく膨潤させる。これに成分９お よび１４を溶解し水相とする。成分１〜８を加熱溶解し、８０℃に保ち油相とする。よく混合し粉砕機に通し粉砕した成分１６〜１８を水相に加え、ホモミキサーで攪拌し７５℃に保つ。この水相に油相をかきまぜながら加え、冷却し、４５℃で成分１９を加え、攪拌しながら冷却し製品とする。
【００１４】
実施例−６ 浴剤

製造方法：各成分をよく混合し製品とする。
【００１５】
実施例−７ 軟膏剤

製造方法：各成分をよく混合して製品とする。
【００１６】
比較例−３ 従来の軟膏剤
実施例−７において、Ｎ^Ｇ−モノメチル−Ｌ−アルギニンを白色ワセリンに置き換えたものを従来の軟膏剤とした。
【００１７】
実施例−８ 錠剤

製造方法：Ｎ^Ｇ−モノメチル−Ｌ−アルギニン，トウモロコシデンプン，精製白糖，カルボキシメチルセルロースカルシウム，微結晶セルロースを混合し，次いでポリビニルピロリドンの水溶液を結合剤として加えて常法により顆粒化した．これに滑沢剤としてタルクを加えて配合した後，１錠１００ｍｇの錠剤に打錠した．
【００１８】
実施例−９ 散剤

製造方法：上記成分を混合し，常法により散剤とした．
【００１９】
実施例−１０ 注射剤

製造方法：Ｎ^Ｇ−モノメチル−Ｌ−アルギニン，Ｎｉｋｋｏｌ ＨＣＯ−６０，ゴマ油及び半量のプロピレングリコールを混合して約８０℃で加温溶解し，これにリン酸緩衝液及び塩化ナトリウムとプロピレングリコールを予め溶解した蒸留水を約８０℃に加温して加え，全量１０００ｍｌの水溶液とした．この水溶液を１ｍｌのアンプルに分注して熔閉した後，加熱滅菌した．
【００２０】
【発明の効果】
本発明の美白剤は優れたメラニン生成抑制及び美白効果を有する。次に実験例を挙げて、本発明の美白剤の効果をさらに詳しく説明する。
【００２１】
実験例−１ Ｂ１６マウスメラノーマを用いたメラニン生成抑制試験
対数増殖期にあるメラノーマをφ６０ｍｍ ｄｉｓｈに２×１０^４細胞播種し，最終濃度０．３，１及び３ｍＭになるようにＮ^Ｇ−モノメチル−Ｌ−アルギニンを含むＥａｇｌｅｓ’ ＭＥＭ（１０％ＦＣＳを含む）を加え，３７℃，５％ＣＯ_２条件下にて培養した．培養５日後に細胞をｄｉｓｈから剥離し，細胞を超音波破砕した後に，２ＮＮａＯＨを加え６０℃で２時間の処理を行い，分光光度計でＯ．Ｄ．４７５ｎｍを測定した．尚， 超音波処理後の細胞破砕液をＬｏｗｒｙの方法（Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．，１９３，２６５−２７５，１９５１）でタンパク定量し，タンパク量当りのメラニン量を比較することによって，メラニン生成抑制効果の指標とした．その結果，表１に示すとおり，Ｎ^Ｇ−モノメチル−Ｌ−アルギニンは優れたメラニン生成抑制作用を示した．
【００２２】
【表１】

【００２３】
実験例−２ 使用試験
実施例−１の化粧水、実施例−３の乳液、比較例−１の従来の化粧水および比較例−２の従来の乳液を用いて、各々女性３０人（３０〜４５才）を対象に１ヶ月間の使用試験を行った。使用後、肌のしみ、そばかす、透明感およびくすみの改善に関するアンケート調査により美白効果を判定した。その結果、Ｎ^Ｇ−モノメチル−Ｌ−アルギニンを含有することを特徴とする化粧料は優れた美白効果を示した（表２、表３、表４、表５）。
以下余白
【００２４】
【表２】

【００２５】
【表３】

以下余白
【００２６】
【表４】

【００２７】
【表５】

【００２８】
試験例−３ 臨床例
日焼け炎症後色素沈着した患者４名に対して実施例−７に示した軟膏剤を１日１回患部に塗布し、最高３カ月まで観察した。同時に比較例−３の従来の軟膏剤についても同様にして試験した。効果の判定は、−：変わらない、＋：うすくなった、＋＋：ほとんど消えた、＋＋＋：完全に消えたの４段階とした。また、副作用は全例に認められなかった。
その結果、表６に示したように、実施例−７の軟膏剤において、４例中３例に効果が認められた。それに対し、比較例−３の軟膏剤には効果が認められなかった（表７）。
【００２９】
【表６】

【００３０】
【表７】

【００３１】
実施例−２のクリーム、実施例−４のパック、実施例−５のファンデーションおよび実施例−６の浴用剤についても実験例−２と同様に使用試験を行ったところ、優れた美白効果を示した。
以上示したように、Ｎ^Ｇ−モノメチル−Ｌ−アルギニンは優れたメラニン生成抑制作用を示し、また、本発明のＮ^Ｇ−モノメチル−Ｌ−アルギニンを配合した化粧料および美白剤は優れた美白効果を示した。[0001]
[Industrial applications]
The present invention relates to a cosmetic and a whitening agent characterized by containing ^NG -monomethyl-L-arginine.
[0002]
[Prior art]
Pigmentation of the skin, which is generally observed in spots, freckles, sunburn, and the like, is caused by the melanin-producing cells present in the skin excessively producing melanin pigment. Conventionally, treatments for this pigmentation include treatments for decomposing melanin (ie, external use of hydroquinone and its derivatives) and treatments for external use of arbutin, glutathione, and ascorbic acid as tyrosinase activity inhibitors.
[0003]
[Problems to be solved by the invention]
However, the conventional ones are not enough to treat this pigmentation, and ones that treat pigmentation by a different mechanism of action are desired. The present inventors have repeatedly studied the mechanism by which melanin-producing cells produce melanin, and as a result, have discovered that the melanin-producing cell has an entirely new mechanism. That is, when arginine, one of the amino acids, is added to melanocyte-producing cells, arginine is converted to nitric oxide and citrulline by the action of nitric oxide synthase present in the melanocyte-producing cells, and this nitric oxide is converted to melanin. It has been shown to promote pigment formation. From this, it was found that nitric oxide is involved in melanin pigment production in melanin pigment producing cells. If the production of melanin pigment by nitric oxide could be inhibited, it could be a new whitening agent. However, at present, no material is effective for this mechanism.
[0004]
[Means for Solving the Problems]
Thus, the present inventors have repeatedly studied substances that inhibit nitric oxide synthase and found that ^NG -monomethyl-L-arginine represented by the following general formula (1) has an excellent whitening effect. And completed the present invention.
Embedded image

The present invention relates to a cosmetic and a whitening agent containing ^NG -monomethyl-L-arginine. As ^NG -monomethyl-L-arginine used in the present invention, commercially available products can be used.
[0005]
^NG -monomethyl-L-arginine can be added in an amount of 0.001 to 10% by weight, preferably 0.01 to 1.0% by weight, based on the total amount of the cosmetic or whitening agent of the present invention. At a concentration of 0.0001% or less, a sufficient effect cannot be obtained, and at a concentration of 10% by weight or more, no enhancement of the effect is observed, which is uneconomical. Oils and fats, waxes, hydrocarbons, fatty acids, alcohols and the like used in cosmetics and pharmaceuticals are included in the cosmetics and whitening agents of the present invention as long as the effects of ^NG -monomethyl-L-arginine are not impaired. , Esters, surfactants, and other raw materials. The cosmetic of the present invention can employ basic cosmetics such as creams, lotions, emulsions, and packs, makeup cosmetics such as foundations and lipsticks, and bath forms, soaps, and other forms. In addition, the dosage form of the whitening agent of the present invention includes powders, pills, tablets, injections, suppositories, external preparations, and the like, and is manufactured according to ordinary formulation techniques. The daily dose is 10 mg to 200 mg, preferably 20 mg to 100 mg, which can be administered in two or three divided doses.
In an acute toxicity test using mice, no death was observed at 1,000 mg / kg by oral administration. In addition, no abnormalities were found in any of the organs in the autopsy findings.
[0006]
【Example】
Next, examples will be described to explain the present invention in detail, but the present invention is not limited to these examples. The term "parts by weight" shown in Examples means parts by weight.
[0007]
Example 1 Lotion

Production method: Components 1 to 5 and components 6 to 10 are each uniformly dissolved, mixed and filtered to obtain a product.
[0008]
Comparative Example-1 Conventional lotion The same as in Example 1 except that ^NG -monomethyl-L-arginine was replaced with purified water was used as the conventional lotion.
[0009]
Example-2 Cream

Production method: After heating and dissolving oil phase components 1 to 7 and aqueous phase components 8 to 12 at 70 to 75 ° C., respectively, add water phase components 8 to 12 to oil phase components 1 to 7, emulsify, and cool down. Add component 13 with, mix and cool to 30 ° C to obtain a product.
[0010]
Example-3 Emulsion

Production method: After oil-phase components 1 to 6 and aqueous-phase components 7 to 10 are heated and dissolved at 70 to 75 ° C. respectively, water-phase components 7 to 10 are added to oil-phase components 1 to 6, and emulsified. Add component 11 and mix by cooling to 30 ° C to obtain a product.
[0011]
Comparative Example 2 Conventional Emulsion A conventional emulsion was prepared by replacing ^NG -monomethyl-L-arginine with purified water in Example-3.
[0012]
Example-4 Pack

Production method: Each component is uniformly dissolved to produce a product.
[0013]
Example-5 Foundation

Production method: Components 10 to 13 and 15 are heated to 70 ° C. to swell well. Components 9 and 14 are dissolved in this to form an aqueous phase. Components 1 to 8 are dissolved by heating and kept at 80 ° C. to form an oil phase. The components 16 to 18 obtained by mixing well and passing through a pulverizer are added to the aqueous phase, and the mixture is stirred with a homomixer and kept at 75 ° C. The oil phase is added to the aqueous phase with stirring, cooled, and the component 19 is added at 45 ° C., and cooled with stirring to obtain a product.
[0014]
Example-6 Bath agent

Production method: Each component is mixed well to produce a product.
[0015]
Example-7 Ointment

Manufacturing method: Each component is mixed well to produce a product.
[0016]
Comparative Example-3 Conventional Ointment A conventional ointment was obtained by replacing ^NG -monomethyl-L-arginine with white petrolatum in Example-7.
[0017]
Example-8 Tablet

Production method: ^NG -monomethyl-L-arginine, corn starch, purified sucrose, carboxymethylcellulose calcium, and microcrystalline cellulose were mixed, and then an aqueous solution of polyvinylpyrrolidone was added as a binder and granulated by a conventional method. After adding talc as a lubricant to the mixture, the mixture was compressed into 100 mg tablets.
[0018]
Example-9 Powder

Production method: The above components were mixed and made into a powder by a conventional method.
[0019]
Example-10 Injection

Production method: ^NG -monomethyl-L-arginine, Nikkol HCO-60, sesame oil and half of propylene glycol are mixed and heated and dissolved at about 80 ° C., and a phosphate buffer, sodium chloride and propylene glycol are added thereto in advance. Dissolved distilled water was heated to about 80 ° C. and added to make a 1000 ml aqueous solution. This aqueous solution was dispensed into 1 ml ampules, sealed, and then heat-sterilized.
[0020]
【The invention's effect】
The whitening agent of the present invention has excellent melanin production inhibition and whitening effects. Next, the effects of the whitening agent of the present invention will be described in more detail with reference to experimental examples.
[0021]
EXPERIMENTAL EXAMPLE 1 Melanin Production Inhibition Test Using B16 Mouse Melanoma Melanoma in the logarithmic growth phase was seeded at 2 × 10 ⁴ cells on a φ60 mm dish, and ^NG -monomethyl- was added to a final concentration of 0.3, 1 and 3 mM. Eagles' MEM (containing 10% FCS) containing L-arginine was added, and the mixture was cultured at 37 ° C. under 5% CO ₂ . After 5 days of culture, the cells were detached from the dish, the cells were sonicated, 2N NaOH was added, and the mixture was treated at 60 ° C. for 2 hours. D. 475 nm was measured. The cell lysate after sonication was quantified for protein by the method of Lowry (J. Biol. Chem., 193, 265-275, 1951), and by comparing the amount of melanin per protein amount, suppression of melanin production was achieved. It was used as an index of the effect. As a result, as shown in Table 1, ^NG -monomethyl-L-arginine exhibited an excellent inhibitory action on melanin production.
[0022]
[Table 1]

[0023]
EXPERIMENTAL EXAMPLE-2 Use Test Using the lotion of Example-1, the lotion of Example-3, the conventional lotion of Comparative Example-1 and the conventional lotion of Comparative Example-2, 30 women (30 to 30) each were used. A 45-year-old subject was subjected to a one-month use test. After use, the whitening effect was determined by a questionnaire survey on improvement of skin spots, freckles, transparency and dullness. As a result, cosmetics containing ^NG -monomethyl-L-arginine exhibited excellent whitening effects (Tables 2, 3, 4, and 5).
The following margins [0024]
[Table 2]

[0025]
[Table 3]

[Margin]
[Table 4]

[0027]
[Table 5]

[0028]
Test Example-3 Clinical Case The ointment shown in Example-7 was applied to the affected area once a day for four patients who had pigmentation after sunburn inflammation and observed for up to three months. At the same time, the conventional ointment of Comparative Example-3 was similarly tested. The effect was judged in four stages:-: no change, +: faint, ++: almost disappeared, +++: completely disappeared. No side effects were observed in all cases.
As a result, as shown in Table 6, in the ointment of Example-7, the effect was recognized in 3 out of 4 cases. In contrast, the ointment of Comparative Example-3 had no effect (Table 7).
[0029]
[Table 6]

[0030]
[Table 7]

[0031]
The cream of Example 2, the pack of Example 4, the foundation of Example 5, and the bath preparation of Example 6 were subjected to use tests in the same manner as in Experimental example 2, and showed excellent whitening effect. Was.
As described above, ^NG -monomethyl-L-arginine has an excellent melanin production inhibitory effect, and the cosmetic and whitening agent containing ^NG -monomethyl-L-arginine of the present invention have excellent whitening effect. showed that.

Claims (2)

A cosmetic comprising ^NG -monomethyl-L-arginine. N ^G - whitening agent is characterized by containing a monomethyl -L- arginine.