JP3596622B2 - External preparation for preventing skin aging - Google Patents
External preparation for preventing skin aging Download PDFInfo
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- JP3596622B2 JP3596622B2 JP30353093A JP30353093A JP3596622B2 JP 3596622 B2 JP3596622 B2 JP 3596622B2 JP 30353093 A JP30353093 A JP 30353093A JP 30353093 A JP30353093 A JP 30353093A JP 3596622 B2 JP3596622 B2 JP 3596622B2
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- skin
- trihydroxybenzoic acid
- oxygen species
- ester
- external preparation
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Description
【0001】
【産業上の利用分野】
本発明は、新規な活性酸素種消去剤である3,4,5−トリヒドロキシ安息香酸の糖エステルを配合して成る、安全性及び安定性に優れる皮膚の老化防止用外用剤に関する。
【0002】
【従来の技術】
近年、太陽光の皮膚に対する影響が研究され、太陽光により皮膚内に生じる一重項酸素,ヒドロキシラジカル,スーパーオキシドといった活性酸素種が、表皮ケラチノサイトや真皮の線維芽細胞を攻撃し、これら細胞を死に至らしめ、その結果、皮膚の老化や種々の皮膚疾患を引き起こすことが明らかになってきた。それにつれて、このような活性酸素種を消去する物質のスクリーニングも行われ、ビタミンE群化合物やビタミンC、動植物由来のスーパーオキシドディスムターゼ様作用物質、さらにはスーパーオキシドディスムターゼ自体を皮膚外用剤に配合する試みがなされている。
【0003】
しかし、従来用いられていたビタミンE,ビタミンCのような活性酸素種消去剤は、細胞に対する親和性が低く、かなり多量に配合しなければ効果が生じなかった。動植物由来のスーパーオキシドディスムターゼ様作用物質も、天然起源であり、一定した作用を有するものを得るのが難しく、安定性も低く品質管理上の問題があった。さらに、スーパーオキシドディスムターゼ自体の配合も、酵素活性の安定化や皮膚感作性等の面で問題があった。
【0004】
【発明が解決しようとする課題】
本発明は、細胞親和性が高く、少量の配合で有効な活性酸素種消去作用を示し、且つ皮膚外用剤中で安定で、しかも安全性の高い活性酸素種消去剤を配合し、活性酸素種に起因する皮膚の老化防止や疾患を防止し得る皮膚外用剤を提供するものである。
【0005】
【課題を解決するための手段】
上記の課題を解決するため、細胞親和性の高い活性酸素種消去剤の検討を行ったところ、3,4,5−トリヒドロキシ安息香酸を糖エステルとすることにより、本発明の目的が達成されることを見い出した。糖としては、エステル化のしやすさや糖エステルの水溶性、感作性の出現等を考慮すると、単糖類又は二糖類〜三糖類くらいのオリゴ糖が好ましい。本発明の目的には、エリスロース,トレオース等のテトロース類、アラビノース,キシロース,リボース等のペントース類、ガラクトース,グルコース,マンノース,プシコース,フルクトース等のヘキソース類、N−アセチルガラクトサミン,N−アセチルグルコサミン,マンノサミン等のアミノ糖類、マルトース,ラクトース,ショ糖,セロビオース等の二糖類、セロトリオース等の三糖類などが好適な例として挙げることができる。
【0006】
3,4,5−トリヒドロキシ安息香酸の糖エステルは、たとえば3,4,5−トリヒドロキシ安息香酸をエステル化し、これと糖とを水酸化ナトリウム等のアルカリ触媒存在下にて反応させ、エステル交換反応等により合成することができる。なお、副生成物のアルコールを系から除去すると、反応を効率よく進ませることができる。
【0007】
3,4,5−トリヒドロキシ安息香酸の糖エステルは、エタノール等のアルコールに溶解したり、基剤中に分散したりして皮膚外用剤に配合できる。皮膚外用剤は液剤,乳剤,クリーム,軟膏など種々の形態を採ることができる。また、化粧水や乳液,皮膚用クリーム等、化粧料としても提供することができる。配合量は、皮膚外用剤中の有効濃度を考慮して、0.01〜10重量%が適当である。
【0008】
【作用】
3,4,5−トリヒドロキシ安息香酸の糖エステルの活性酸素種による細胞傷害防御作用は、ヒト線維芽細胞に活性酸素種を曝露し、その際の細胞生存率を指標として評価できる。培養したヒト線維芽細胞に、3,4,5−トリヒドロキシ安息香酸のグルコースエステル,ガラクトースエステル,ラクトースエステルをそれぞれ作用させた後、洗浄し、ヒポキサンチン−キサンチンオキシダーゼ系にて活性酸素種(スーパーオキシド及びヒドロキシラジカル)を曝露した。曝露後の細胞生存率はMTT還元法により測定した。比較のため、3,4,5−トリヒドロキシ安息香酸で同様に細胞を処理した場合についても測定した。
【0009】
MTT還元法は、細胞のミトコンドリア内に存在する脱水素酵素が基質に作用して生じる還元型ニコチンアミドアデニンジヌクレオチド(NADH)により、系に添加したMTT(2−(4,5−dimethyl−2−thiazolyl)−3,5−diphenyltetrazolium bromide)のテトラゾリウム環が開環することを利用する測定法である。テトラゾリウム環の開環により、青色のフォルマザンが生成するので、これを560nmにおける吸光度により測定して、細胞生存率を求める。
【0010】
その結果、図1に示すように、良好な細胞親和性を有する3,4,5−トリヒドロキシ安息香酸のグルコースエステル,ガラクトースエステル,ラクトースエステルの各糖エステルで処理した場合には、70〜80%の良好な細胞生存率を示した。これに対し、糖エステル化していない3,4,5−トリヒドロキシ安息香酸自体で処理した場合は、細胞親和性が低いため、細胞生存率は40%弱と低かった。
【0011】
従って、3,4,5−トリヒドロキシ安息香酸の糖エステルは、細胞膜に対し良好な親和性を示し、細胞膜表面において活性酸素種を効率良く消去することができる。その結果、非常に低濃度で活性酸素種による細胞傷害を防止し、活性酸素種の細胞傷害作用による皮膚の老化症状や疾患を有効に防止することができる。
【0012】
【実施例】
さらに、本発明について実施例により詳細に説明する。本発明の実施例として、3,4,5−トリヒドロキシ安息香酸のブドウ糖エステルを配合した乳液(実施例1)、3,4,5−トリヒドロキシ安息香酸のN−アセチルグルコサミンエステルを配合した皮膚用クリーム(実施例2)、3,4,5−トリヒドロキシ安息香酸のショ糖エステルを配合した乳剤性軟膏(実施例3)の処方を、それぞれ表1,表2,表3に示した。
【0013】
表1中、(1)〜(5)の油相成分を混合,溶解して均一とし、75℃に加熱する。一方、(8)を(7)に溶解して(6),(10),(13)の水相成分とともに75℃に加熱する。次いで、上記の水相成分に油相成分を添加して予備乳化し、これに(9)を加えた後ホモミキサーにて均一に乳化する。その後冷却し、(11)を加えてpHを調整し、50℃にて(12)を添加し、均一に混合する。
【表1】
【0014】
表2中、(1)〜(7)の油相成分を混合,溶解して均一とし、75℃に加熱する。一方、(9)を(8)に溶解して(10),(12)とともに75℃に加熱する。次いで、上記水相成分に油相成分を添加して予備乳化した後、ホモミキサーにて均一に乳化する。その後冷却し、50℃にて(11)を添加,混合する。
【表2】
【0015】
表3中、(1)〜(4)の油相成分を混合,溶解して均一とし、75℃に加熱する。一方、(8)を(7)に溶解して(5),(6),(9)とともに75℃に加熱する。次いで上記水相成分を油相成分に添加して乳化し、冷却する。
【表3】
【0016】
本発明の実施例について、実際に使用試験を行った。この際、各実施例で用いた3,4,5−トリヒドロキシ安息香酸の糖エステルの替わりに、3,4,5−トリヒドロキシ安息香酸を用いたものを比較例1,2及び3とした。使用試験は、日常戸外で作業する40〜60才代のパネラー20名を1群とし、実施例及び比較例をブラインドにて各群に5月〜7月の3カ月間使用させ、使用後の皮膚のしわ,きめ,はり、及び肌荒れの改善状況を観察し、評価した。皮膚のしわ,きめ及び肌荒れの改善状況については写真撮影による外観観察により、皮膚のはりについては皮膚弾性の測定により評価し、しわについては「軽減」,「やや軽減」,「変化なし」,「増加」、きめ及びはりについては「良好」,「やや良好」,「変化なし」,「悪化」又は「低下」、肌荒れについては「改善」,「やや改善」,「変化なし」,「悪化」の各4段階で評価した。結果は、各評価を得たパネラー数にて表4に示した。
【表4】
【0017】
表4より明らかなように、各実施例使用群ではしわの増加を認めたパネラーはなく、90%以上のパネラーにおいてしわの軽減を認めた。きめ及びはりについてはいずれも使用開始前より良好となっており、肌荒れの改善も全パネラーにおいて認められた。これに対して比較例使用群では、しわについては2〜3例において軽減傾向が認められたのみで、40〜55%のパネラーにおいてはしわの増加が認められた。きめ及びはりについても、使用開始前より良好となったパネラーは少なく、きめについては15〜20%、はりについては30〜35%のパネラーにおいて悪化又は低下したと評価された。肌荒れについてもほとんどのパネラーにおいて改善が認められなかった。
【0018】
本使用試験において各パネラーは、紫外線曝露量の多い5月〜7月にほぼ毎日戸外で作業をしており、表4の結果は、本発明の実施例が紫外線曝露により生じる活性酸素種に起因する皮膚の老化や肌荒れを有効に予防,改善し得ることを示唆するものである。
【0019】
【発明の効果】
以上詳述したように、本発明により、太陽光により生じる活性酸素種を有効に除去して、これらに起因する皮膚の老化,疾患を良好に防止し得る皮膚外用剤を提供することができた。
【図面の簡単な説明】
【図1】本発明で活性酸素種消去剤として用いる3,4,5−トリヒドロキシ安息香酸の糖エステルと、3,4,5−トリヒドロキシ安息香酸の細胞傷害防御作用を示す図である。
【符号の説明】
1 3,4,5−トリヒドロキシ安息香酸のグルコースエステル
2 3,4,5−トリヒドロキシ安息香酸のガラクトースエステル
3 3,4,5−トリヒドロキシ安息香酸のラクトースエステル
4 3,4,5−トリヒドロキシ安息香酸[0001]
[Industrial applications]
The present invention relates to an external preparation for preventing skin aging, which is excellent in safety and stability, comprising a sugar ester of 3,4,5-trihydroxybenzoic acid, which is a novel active oxygen species-eliminating agent.
[0002]
[Prior art]
In recent years, the effects of sunlight on the skin have been studied, and reactive oxygen species such as singlet oxygen, hydroxyl radicals, and superoxide generated in the skin by sunlight attack epidermal keratinocytes and dermal fibroblasts and kill these cells. As a result, it has been revealed that it causes skin aging and various skin diseases. Along with this, screening for substances that eliminate such reactive oxygen species is also carried out, and vitamin E group compounds, vitamin C, superoxide dismutase-like substances derived from animals and plants, and superoxide dismutase itself are added to a skin external preparation. Attempts have been made.
[0003]
However, conventionally used reactive oxygen species scavengers such as vitamin E and vitamin C have low affinity for cells, and have no effect unless they are added in a considerably large amount. Superoxide dismutase-like substances derived from animals and plants are also of natural origin, and it is difficult to obtain a substance having a constant action, and the stability is low and there is a problem in quality control. Furthermore, blending of superoxide dismutase itself has problems in terms of stabilization of enzyme activity and skin sensitization.
[0004]
[Problems to be solved by the invention]
The present invention has a high cell affinity, exhibits an effective reactive oxygen species scavenging action in a small amount, and incorporates a stable and highly safe active oxygen species scavenger in a skin external preparation, It is intended to provide a skin external preparation capable of preventing skin aging and diseases caused by the above.
[0005]
[Means for Solving the Problems]
In order to solve the above problems, a study was made on a reactive oxygen species scavenger having a high cell affinity, and the object of the present invention was achieved by converting 3,4,5-trihydroxybenzoic acid into a sugar ester. I found something. As the saccharide, an oligosaccharide such as a monosaccharide or a disaccharide to a trisaccharide is preferable in consideration of ease of esterification, water solubility of the sugar ester, appearance of sensitization, and the like. For the purpose of the present invention, tetroses such as erythrose and threose, pentoses such as arabinose, xylose and ribose, hexoses such as galactose, glucose, mannose, psicose and fructose, N-acetylgalactosamine, N-acetylglucosamine, Preferred examples include amino sugars such as mannosamine, disaccharides such as maltose, lactose, sucrose, and cellobiose, and trisaccharides such as cellotriose.
[0006]
The sugar ester of 3,4,5-trihydroxybenzoic acid is obtained, for example, by esterifying 3,4,5-trihydroxybenzoic acid, reacting this with sugar in the presence of an alkali catalyst such as sodium hydroxide, and the like. It can be synthesized by an exchange reaction or the like. When the alcohol by-product is removed from the system, the reaction can proceed efficiently.
[0007]
The sugar ester of 3,4,5-trihydroxybenzoic acid can be dissolved in an alcohol such as ethanol or dispersed in a base and blended into an external preparation for skin. The external preparation for skin can take various forms such as a liquid preparation, an emulsion, a cream and an ointment. In addition, it can be provided as a cosmetic such as a lotion, an emulsion, and a cream for skin. The amount is suitably 0.01 to 10% by weight in consideration of the effective concentration in the external preparation for skin.
[0008]
[Action]
The cytotoxic protective action of reactive sugar species of 3,4,5-trihydroxybenzoic acid sugar ester by reactive oxygen species can be evaluated using human fibroblasts exposed to reactive oxygen species and cell viability at that time as an index. Glucose ester, galactose ester and lactose ester of 3,4,5-trihydroxybenzoic acid were allowed to act on the cultured human fibroblasts, and then washed, and reactive oxygen species (super-oxygen) were added using a hypoxanthine-xanthine oxidase system. Oxides and hydroxy radicals). The cell viability after the exposure was measured by the MTT reduction method. For comparison, a measurement was also made for the case where the cells were similarly treated with 3,4,5-trihydroxybenzoic acid.
[0009]
In the MTT reduction method, a reduced nicotinamide adenine dinucleotide (NADH) generated by a dehydrogenase present in the mitochondria of a cell acting on a substrate is used to add MTT (2- (4,5-dimethyl-2 ) to a system. -Thiazolyl) -3,5-diphenyltetrazolium bromide). Since blue formazan is generated by the opening of the tetrazolium ring, this is measured by the absorbance at 560 nm to determine the cell viability.
[0010]
As a result, as shown in FIG. 1, when treated with glucose ester, galactose ester and lactose ester of 3,4,5-trihydroxybenzoic acid having good cell affinity, 70-80%. % Cell viability. On the other hand, when the cells were treated with 3,4,5-trihydroxybenzoic acid itself, which had not been subjected to sugar esterification, the cell viability was as low as slightly less than 40% due to low cell affinity.
[0011]
Therefore, the sugar ester of 3,4,5-trihydroxybenzoic acid has a good affinity for the cell membrane, and can efficiently eliminate active oxygen species on the cell membrane surface. As a result, cell damage due to reactive oxygen species can be prevented at a very low concentration, and aging symptoms and diseases of the skin due to the cytotoxic action of reactive oxygen species can be effectively prevented.
[0012]
【Example】
Further, the present invention will be described in detail with reference to examples. Examples of the present invention include an emulsion containing a glucose ester of 3,4,5-trihydroxybenzoic acid (Example 1) and a skin containing an N-acetylglucosamine ester of 3,4,5-trihydroxybenzoic acid. Tables 1, 2 and 3 show the formulations of the cream for use (Example 2) and the emulsion ointment containing the sucrose ester of 3,4,5-trihydroxybenzoic acid (Example 3), respectively.
[0013]
In Table 1, the oil phase components (1) to (5) are mixed and dissolved to make uniform, and heated to 75 ° C. On the other hand, (8) is dissolved in (7) and heated to 75 ° C. together with the aqueous phase components (6), (10) and (13). Next, the oil phase component is added to the aqueous phase component to perform preliminary emulsification, and (9) is added thereto, followed by uniform emulsification using a homomixer. Thereafter, the mixture is cooled, pH is adjusted by adding (11), (12) is added at 50 ° C., and the mixture is uniformly mixed.
[Table 1]
[0014]
In Table 2, the oil phase components (1) to (7) are mixed and dissolved to make uniform, and heated to 75 ° C. On the other hand, (9) is dissolved in (8) and heated to 75 ° C. together with (10) and (12). Next, the oil phase component is added to the water phase component and pre-emulsified, and then homogenized uniformly with a homomixer. Thereafter, the mixture is cooled, (11) is added and mixed at 50 ° C.
[Table 2]
[0015]
In Table 3, the oil phase components (1) to (4) are mixed and dissolved to make uniform, and heated to 75 ° C. On the other hand, (8) is dissolved in (7) and heated to 75 ° C. together with (5), (6) and (9). Next, the aqueous phase component is added to the oil phase component, emulsified, and cooled.
[Table 3]
[0016]
An actual use test was performed on the examples of the present invention. In this case, Comparative Examples 1, 2, and 3 were obtained using 3,4,5-trihydroxybenzoic acid instead of the sugar ester of 3,4,5-trihydroxybenzoic acid used in each Example. . In the use test, 20 panelists in their 40s and 60s who work outdoors outdoors were grouped as one group, and the examples and comparative examples were blindly used by each group for three months from May to July. The state of improvement of skin wrinkles, texture, abrasion, and rough skin was observed and evaluated. Improvement of skin wrinkles, texture and rough skin was evaluated by observing the appearance by photography, and skin swelling was evaluated by measurement of skin elasticity. Wrinkles were evaluated as “reduced”, “slightly reduced”, “no change”, “ “Increase”, “Good”, “Slightly good”, “No change”, “Deterioration” or “Decrease” for texture and beam, “Improvement”, “Slightly improvement”, “No change”, “Deterioration” for rough skin Of each of the four grades. The results are shown in Table 4 by the number of panelists who obtained each evaluation.
[Table 4]
[0017]
As is evident from Table 4, none of the panelists using each example showed an increase in wrinkles, and the reduction of wrinkles was observed in 90% or more of the panelists. Both the texture and the beam were better than before the start of use, and the improvement of rough skin was also observed in all panelists. On the other hand, in the group using the comparative example, wrinkles were only reduced in a few cases of wrinkles, and wrinkles increased in 40 to 55% of panelists. Regarding the texture and the beam, the number of panelists who became better than before the start of use was small, and it was evaluated that 15-20% of the texture and 30-35% of the beam deteriorated or decreased. No improvement was observed in skin roughness on most panelists.
[0018]
In this use test, each panelist worked outdoors almost every day from May to July, when the amount of UV exposure was high, and the results in Table 4 show that the examples of the present invention were caused by reactive oxygen species generated by UV exposure. This suggests that skin aging and rough skin can be effectively prevented and improved.
[0019]
【The invention's effect】
INDUSTRIAL APPLICABILITY As described above in detail, the present invention can provide a skin external preparation capable of effectively removing active oxygen species generated by sunlight and successfully preventing skin aging and diseases caused by these. .
[Brief description of the drawings]
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram showing cytotoxic protective effects of 3,4,5-trihydroxybenzoic acid sugar ester and 3,4,5-trihydroxybenzoic acid used as active oxygen species scavengers in the present invention.
[Explanation of symbols]
1 Glucose ester of 3,4,5-
Claims (1)
Priority Applications (1)
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JP30353093A JP3596622B2 (en) | 1993-11-08 | 1993-11-08 | External preparation for preventing skin aging |
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JP30353093A JP3596622B2 (en) | 1993-11-08 | 1993-11-08 | External preparation for preventing skin aging |
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JP2003290988A Division JP2004002468A (en) | 2003-08-11 | 2003-08-11 | Eliminating agent of active-oxygen species |
Publications (2)
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JPH07133218A JPH07133218A (en) | 1995-05-23 |
JP3596622B2 true JP3596622B2 (en) | 2004-12-02 |
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JP30353093A Expired - Fee Related JP3596622B2 (en) | 1993-11-08 | 1993-11-08 | External preparation for preventing skin aging |
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Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2737410B1 (en) * | 1995-07-31 | 1997-09-12 | Oreal | USE OF BENZOIC ACID DERIVATIVES TO PROMOTE SKIN DEQUAMATION OR STIMULATE THE EPIDERMAL RENEWAL PROCESS |
EP1340486A1 (en) * | 2002-03-01 | 2003-09-03 | Cognis France S.A. | Use of sugar esters |
JP6222888B2 (en) * | 2011-12-22 | 2017-11-01 | ホーユー株式会社 | Hair and skin external preparation composition and non-therapeutic cosmetic method |
JP6151542B2 (en) * | 2013-03-19 | 2017-06-21 | 上野製薬株式会社 | New salicylic acid derivatives |
CN104829659B (en) * | 2015-04-13 | 2017-10-24 | 江苏康缘药业股份有限公司 | A kind of compound and its preparation and application |
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1993
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