JP3688846B2 - Skin aging preventive - Google Patents
Skin aging preventive Download PDFInfo
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- JP3688846B2 JP3688846B2 JP07170097A JP7170097A JP3688846B2 JP 3688846 B2 JP3688846 B2 JP 3688846B2 JP 07170097 A JP07170097 A JP 07170097A JP 7170097 A JP7170097 A JP 7170097A JP 3688846 B2 JP3688846 B2 JP 3688846B2
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- JP
- Japan
- Prior art keywords
- skin aging
- skin
- wrinkles
- wrinkle
- ultraviolet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- Cosmetics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【0001】
【発明の属する技術分野】
本発明は皮膚老化予防剤に関し、さらに詳細には皮膚の老化によって生じるしわ、たるみの発生やはりの減少などの外観変化を防止又は改善することのできる皮膚老化予防剤に関する。
【0002】
【従来の技術】
皮膚が老化することにより生じる外観変化の代表例としては、しわ、たるみの発生、はりの減少、色素沈着、色調変化などがある。このうち、色素沈着については、研究が進み、各種の美白剤が開発され、市販されている。
【0003】
ところで、しわ、たるみの発生、はりの減少などの皮膚の形態的変化については、充分に研究が進んでいるとはいえないのが現状である。例えばコラーゲンを配合した化粧料が用いられているが、充分なしわ発生防止効果は得られていない。
【0004】
しわなどの発生については、特に紫外線との関連性が強いとされており、紫外線照射により生じた皮膚の老化を光老化と称して、種々研究されている。しかし、未だ紫外線吸収剤又は紫外線防禦剤に代わる化粧料が開発されていないのが現状である。
【0005】
【発明が解決しようとする課題】
従って、本発明の目的はしわに代表される皮膚の老化によって生じる症状を予防又は改善することのできる薬剤又は化粧料を提供することにある。
【0006】
【課題を解決するための手段】
そこで、本発明者らは、皮膚の老化と真皮の変化、特に皮膚の老化とエラスチンとの関係に着目し、種々検討してきたところ、従来、皮膚の老化によって真皮のエラスチンは顕著に増加する〔例えば、J. Inrest. Dermatol., 82:587-590(1984)、同91:158-161(1988)、同103:182-186(1994)〕といわれていることから、エラスチンを減少させることがしわの防止につながると考えられてきた。一方、エラスチン分解酵素としては通常好中球由来のものが用いられていおり、該好中球由来エラスチン分解酵素に対する阻害剤を用いた実験では、しわの形成に対する防止効果はまったく認められなかった。そこで、この点に関し研究した結果、エラスチン分解酵素にはセリンプロテアーゼに属するものと金属プロテアーゼに属するものとがあるが、そのうち、金属依存型のエラスチン分解酵素に対する阻害剤を投与した場合にのみしわの発生が有意に防止できることを見出した。そしてさらに研究を続けた結果、下記のメルカプトプロピオンアミド誘導体が優れた金属依存型エラスチン分解酵素阻害作用を有し、かつしわやたるみなどの皮膚の老化に伴なう変化を有効に予防し得ることを見出し、本発明を完成するに至った。
【0007】
すなわち、本発明は、次の式(1)
【0008】
【化2】
【0010】
で表されるメルカプトプロピオンアミド誘導体又はその塩を有効成分とする金属依存型エラスチン分解酵素阻害剤を提供するものである。
【0011】
【発明の実施の形態】
式(1)で表されるメルカプトプロピオンアミド誘導体は、例えば特開昭57−24354号公報に記載の如く、それ自体公知の化合物であるが、これらのメルカプトプロピオン酸誘導体に哺乳類コラゲナーゼ抑制作用があることが知られているが、金属依存型エラスチン分解酵素阻害作用があることは全く知られていない。
【0018】
メルカプトプロピオンアミド誘導体(1)の塩としては塩酸塩、硫酸塩等の無機酸塩、酢酸塩等の有機酸塩が挙げられる。またメルカプトプロピオンアミド誘導体(1)は、水和物としてはも使用できる。
【0019】
これらのメルカプトプロピオンアミド誘導体(1)は、例えば特開昭57−24354号公報に記載の方法によって製造することができる。
【0020】
メルカプトプロピオンアミド誘導体(1)は、優れた金属依存型エラスチン分解酵素阻害作用を有し、皮膚老化予防剤として有用である。
【0021】
本発明の皮膚老化予防剤は、皮膚の老化により生じる形態的変化、例えばしわ、たるみの発生やはりの減少に対して予防又は改善作用を有するが、特にしわに対する予防又は改善作用が優れている。
【0022】
本発明皮膚老化予防剤の投与形態としては皮膚外用剤、経口剤などが挙げられるが、皮膚外用剤とするのが好ましい。皮膚外用剤とする場合のメルカプトプロピオンアミド誘導体(1)又はその塩の配合量は、特に制限されないが、全組成に対し0.00001〜10重量%、特に0.0001〜5重量%とするのが好ましい。
【0023】
本発明皮膚老化予防剤には、メルカプトプロピオンアミド誘導体(1)又はその塩以外に紫外線吸収剤、紫外線防禦剤、コラーゲン、保湿剤、抗炎症剤、抗酸化剤等の成分を配合することができるが、特に紫外線吸収剤及び/又は紫外線防禦剤を配合するのが好ましい。
【0024】
ここで、紫外線吸収剤としては、p−メトキシ桂皮酸2−エチルヘキシル等が挙げられる。紫外線防禦剤としては、酸化チタン、酸化亜鉛等が挙げられる。保湿剤としては、ヒアルロン酸、セラミド類等が挙げられる。また抗炎症剤としては、アラントイン、グリチルリチン等が挙げられる。
【0025】
これらの紫外線吸収剤、紫外線防禦剤、コラーゲン、保湿剤、抗炎症剤、抗酸化剤等は、本発明の皮膚老化予防剤中に0.001〜99重量%、特に0.001〜50重量%配合するのが好ましい。
【0026】
本発明の皮膚老化予防剤の具体的な剤型としては、クリーム、軟膏、ゲル、ローション、溶液、パック、ファンデーション等が挙げられ、これらの剤型とするにあたって各種油剤、界面活性剤、ゲル化剤、防腐剤、酸化防止剤、溶剤、アルコール、キレート剤、増粘剤、色素、香料、水等を配合することができる。
【0027】
【実施例】
次に実施例を挙げて本発明をさらに詳細に説明するが、本発明はこれに限定されるものではない。
【0028】
実施例1 培養ヒト線維芽細胞のエラスターゼ活性抑制試験
大日本製薬社より市販されている正常ヒト線維芽細胞は10%牛胎児血清を含むDME培地で継代培養し、本試験に供した。ラバーポリスマンを用いてシャーレからはがした細胞は、生理食塩水中に浮遊させ、低速の遠心分離器を使って細胞を集め、生理食塩水で、3回洗浄した。細胞は0.1% トリトン X−100/0.2M トリス−塩酸緩衝液(pH8.0)に浮遊させ、超音波破砕し、酵素液とした。
酵素活性測定の基質には125mM N−スクシニル Ala−Ala−Ala−p−ニトロアニリドを用い、酵素液+サンプル100μlに1μl添加し、37℃で1時間反応させ、5μlの酢酸を加えて反応を停止させた。生成したニトロアニリン量は分光光度計で、405nmにおける吸光度を測定し、求めた。
サンプル濃度を変えて、酵素活性抑制率をプロットし、50%抑制濃度(IC50)を求めた。結果を表1に示す。
【0029】
【表1】
【0030】
【化3】
【0031】
表1から明らかなように好中球由来のセリンプロテアーゼ型エラスターゼ阻害剤として知られている化合物2は、金属依存型エラスターゼであるヒト線維芽細胞由来の酵素に対しては抑制作用を示さなかった。これに対し、化合物1は金属依存型エラスターゼを強力に抑制した。
【0032】
実施例2 ヘアレスマウスによるしわ形成抑制試験
ヘアレスマウス(HR/ICR,実験開始時6週齢)の背部に、健康線用ランプ(東芝製、SE20)で、1回の照射量が1MED以下となるように調節してUV−B光の照射を行い、直後にサンプルを含む80%エタノール溶液を100μlを塗布した。この作業を20週間にわたって行った。照射エネルギー量はUV−Radiometer(TOKYOOPTICAL社製、UVR−305/365D)を用いて測定した。また、コントロールとして80%エタノールのみを塗布したものをサンプルと同様に試験した。試験終了後、形成されたしわの度数を肉眼により下記の基準(しわ指数)で評価した。結果を表2に示す。
【0033】
<しわ指数>
0:しわが無形成
1:しわがかすかに形成
2:しわが微量形成
3:しわが若干形成
4:しわが強固に形成
【0034】
【表2】
【0035】
表2から明らかなように、化合物2はしわ形成抑制作用を示さなかったが、化合物1は優れたしわ形成抑制作用を示した。
【0036】
次に、メルカプトプロピオンアミド誘導体(1)を配合した、皮膚老化防止用の外用剤の処方例を示す。
【0037】
【0038】
【0039】
【0040】
【0041】
【発明の効果】
本発明によれば、しわ、たるみの発生、はりの減少などの皮膚の老化に伴なう形態的変化を防止又は改善することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a skin aging preventive agent, and more particularly to a skin aging preventive agent capable of preventing or improving appearance changes such as wrinkles and sagging caused by skin aging.
[0002]
[Prior art]
Typical examples of changes in appearance caused by aging of the skin include wrinkles, sagging, reduction of beam, pigmentation, and color change. Among these, research on pigmentation has progressed, and various whitening agents have been developed and marketed.
[0003]
By the way, at present, research on the morphological changes of the skin such as wrinkles, sagging, and reduction of the beam is not sufficiently advanced. For example, cosmetics containing collagen are used, but a sufficient wrinkle prevention effect is not obtained.
[0004]
The occurrence of wrinkles and the like is particularly strongly related to ultraviolet rays, and various studies have been conducted on the aging of skin caused by ultraviolet irradiation as photoaging. However, the present condition is that the cosmetics which replace an ultraviolet absorber or an ultraviolet-proof agent have not been developed yet.
[0005]
[Problems to be solved by the invention]
Therefore, the objective of this invention is providing the chemical | medical agent or cosmetics which can prevent or improve the symptom which arises by skin aging represented by wrinkles.
[0006]
[Means for Solving the Problems]
Therefore, the present inventors have paid attention to the relationship between skin aging and dermis change, in particular, the relationship between skin aging and elastin, and various studies have been conducted. Conventionally, dermal elastin significantly increases due to skin aging [ For example, J. Inrest. Dermatol., 82: 587-590 (1984), 91: 158-161 (1988), 103: 182-286 (1994)]. Has been thought to lead to the prevention of wrinkles. On the other hand, elastin-degrading enzymes are usually derived from neutrophils. In experiments using inhibitors for neutrophil-derived elastin-degrading enzymes, no effect of preventing wrinkle formation was observed. Therefore, as a result of research on this point, there are elastin degrading enzymes that belong to serine proteases and those that belong to metalloproteases. Of these, wrinkles are only observed when inhibitors against metal-dependent elastin degrading enzymes are administered. It was found that the occurrence can be significantly prevented. As a result of further research, the following mercaptopropionamide derivatives have an excellent metal-dependent elastin degrading enzyme inhibitory effect and can effectively prevent changes associated with skin aging such as wrinkles and sagging. As a result, the present invention has been completed.
[0007]
That is, the present invention provides the following formula (1):
[0008]
[Chemical formula 2]
[0010]
A metal-dependent elastin degrading enzyme inhibitor comprising the mercaptopropionamide derivative represented by the formula (1) or a salt thereof as an active ingredient.
[0011]
DETAILED DESCRIPTION OF THE INVENTION
The mercaptopropionamide derivative represented by the formula (1) is a compound known per se as described in, for example, JP-A-57-24354, and these mercaptopropionic acid derivatives have a mammalian collagenase inhibitory action. However, it is not known at all that it has a metal-dependent elastinase inhibitory action.
[0018]
Examples of the salt of the mercaptopropionamide derivative (1) include inorganic acid salts such as hydrochloride and sulfate, and organic acid salts such as acetate. The mercaptopropionamide derivative (1) can also be used as a hydrate.
[0019]
These mercaptopropionamide derivatives (1) can be produced, for example, by the method described in JP-A-57-24354.
[0020]
The mercaptopropionamide derivative (1) has an excellent metal-dependent elastin degrading enzyme inhibitory action and is useful as a skin aging preventive agent.
[0021]
The skin aging preventive agent of the present invention has a preventive or ameliorating action against morphological changes caused by aging of the skin, such as wrinkles and sagging, and is particularly excellent in preventing or improving wrinkles.
[0022]
Examples of the dosage form of the skin aging preventive agent of the present invention include a skin external preparation and an oral preparation, and it is preferable to use a skin external preparation. The blending amount of the mercaptopropionamide derivative (1) or a salt thereof in the case of a skin external preparation is not particularly limited, but is 0.00001 to 10% by weight, particularly 0.0001 to 5% by weight based on the total composition. Is preferred.
[0023]
In addition to the mercaptopropionamide derivative (1) or a salt thereof, the skin aging preventive agent of the present invention may contain components such as an ultraviolet absorber, an ultraviolet antifungal agent, collagen, a moisturizer, an anti-inflammatory agent, and an antioxidant. However, it is particularly preferable to blend an ultraviolet absorber and / or an ultraviolet antifungal agent.
[0024]
Here, examples of the ultraviolet absorber include 2-ethylhexyl p-methoxycinnamate. Examples of the ultraviolet antifungal agent include titanium oxide and zinc oxide. Examples of the humectant include hyaluronic acid and ceramides. Anti-inflammatory agents include allantoin and glycyrrhizin.
[0025]
These ultraviolet absorbers, ultraviolet antifungal agents, collagen, moisturizers, anti-inflammatory agents, antioxidants and the like are 0.001 to 99% by weight, particularly 0.001 to 50% by weight, in the skin aging preventive agent of the present invention. It is preferable to mix.
[0026]
Specific dosage forms of the skin aging preventive agent of the present invention include creams, ointments, gels, lotions, solutions, packs, foundations and the like. Various oils, surfactants, gellings are used in these dosage forms. Agents, preservatives, antioxidants, solvents, alcohols, chelating agents, thickeners, dyes, fragrances, water, and the like can be blended.
[0027]
【Example】
EXAMPLES Next, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to this.
[0028]
Example 1 Inhibition test of elastase activity of cultured human fibroblasts Normal human fibroblasts commercially available from Dainippon Pharmaceutical Co., Ltd. were subcultured in a DME medium containing 10% fetal bovine serum and subjected to this test. Cells peeled from the petri dish using a rubber policeman were suspended in physiological saline, and the cells were collected using a low-speed centrifuge and washed three times with physiological saline. The cells were suspended in 0.1% Triton X-100 / 0.2M Tris-HCl buffer (pH 8.0), sonicated and used as an enzyme solution.
Use 125 mM N-succinyl Ala-Ala-Ala-p-nitroanilide as a substrate for enzyme activity measurement, add 1 μl to 100 μl of enzyme solution + sample, react for 1 hour at 37 ° C., add 5 μl acetic acid to react. Stopped. The amount of nitroaniline produced was determined by measuring the absorbance at 405 nm with a spectrophotometer.
The enzyme activity inhibition rate was plotted by changing the sample concentration, and the 50% inhibition concentration (IC 50 ) was determined. The results are shown in Table 1.
[0029]
[Table 1]
[0030]
[Chemical 3]
[0031]
As is apparent from Table 1, Compound 2 known as a neutrophil-derived serine protease-type elastase inhibitor did not exhibit an inhibitory action on an enzyme derived from human fibroblasts, which is a metal-dependent elastase. . In contrast, Compound 1 strongly suppressed metal-dependent elastase.
[0032]
Example 2 Wrinkle formation inhibition test using hairless mice On the back of hairless mice (HR / ICR, 6 weeks of age at the start of the experiment), a single irradiation dose is 1 MED or less with a lamp for health lines (SE20, manufactured by Toshiba). Then, irradiation with UV-B light was performed, and immediately after, 100 μl of an 80% ethanol solution containing the sample was applied. This operation was performed for 20 weeks. The amount of irradiation energy was measured using a UV-Radiometer (manufactured by TOKYOOPTICAL, UVR-305 / 365D). Moreover, what applied only 80% ethanol as a control was tested like the sample. After completion of the test, the degree of wrinkle formed was evaluated with the naked eye according to the following criteria (wrinkle index). The results are shown in Table 2.
[0033]
<Wrinkle index>
0: Wrinkle-free formation 1: Wrinkle faint formation 2: Wrinkle trace formation 3: Wrinkle formation slightly 4: Wrinkle formation strong
[Table 2]
[0035]
As is apparent from Table 2, Compound 2 did not show the wrinkle formation inhibitory action, but Compound 1 showed an excellent wrinkle formation inhibitory action.
[0036]
Next, the formulation example of the external preparation for skin aging prevention which mix | blended the mercaptopropionamide derivative (1) is shown.
[0037]
[0038]
[0039]
[0040]
[0041]
【The invention's effect】
ADVANTAGE OF THE INVENTION According to this invention, the morphological change accompanying skin aging, such as generation | occurrence | production of wrinkles, sagging, and a reduction | decrease, can be prevented or improved.
Claims (1)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP07170097A JP3688846B2 (en) | 1997-03-25 | 1997-03-25 | Skin aging preventive |
PCT/JP1998/001143 WO1998042308A1 (en) | 1997-03-25 | 1998-03-18 | Preventives for skin aging |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP07170097A JP3688846B2 (en) | 1997-03-25 | 1997-03-25 | Skin aging preventive |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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JP2005110561A Division JP2005206609A (en) | 2005-04-07 | 2005-04-07 | Preventive for skin aging |
Publications (2)
Publication Number | Publication Date |
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JPH10265360A JPH10265360A (en) | 1998-10-06 |
JP3688846B2 true JP3688846B2 (en) | 2005-08-31 |
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JP07170097A Expired - Fee Related JP3688846B2 (en) | 1997-03-25 | 1997-03-25 | Skin aging preventive |
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JP (1) | JP3688846B2 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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FR3026298B1 (en) * | 2014-09-30 | 2017-12-01 | Oreal | COSMETIC PROCESS FOR ATTENUATING WRINKLES |
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1997
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JPH10265360A (en) | 1998-10-06 |
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