JP2019081726A - Elastase activity inhibitor - Google Patents
Elastase activity inhibitor Download PDFInfo
- Publication number
- JP2019081726A JP2019081726A JP2017209551A JP2017209551A JP2019081726A JP 2019081726 A JP2019081726 A JP 2019081726A JP 2017209551 A JP2017209551 A JP 2017209551A JP 2017209551 A JP2017209551 A JP 2017209551A JP 2019081726 A JP2019081726 A JP 2019081726A
- Authority
- JP
- Japan
- Prior art keywords
- ascorbic acid
- elastase
- elastase activity
- derivatives
- skin
- 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.)
- Pending
Links
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- 230000002087 whitening effect Effects 0.000 description 1
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Abstract
Description
本発明は、アスコルビン酸およびその誘導体を有効成分とするエラスターゼ活性の阻害剤に関する。 The present invention relates to inhibitors of elastase activity comprising ascorbic acid and its derivatives as active ingredients.
老化皮膚において真皮組織では、コラーゲン線維の減少と線維束の脆弱化、エラスチン線維の消失と無配向エラスチンの増加、プロテオグリカンの増加が生じ、さらに酸化タンパク質であるカルボニルタンパク質が真皮上層部に、最終糖化生成物がエラスチンに蓄積する。また、真皮内の微小循環系の変化としてはしわの重篤度に合わせて、血管、リンパ管の存在頻度の低下が観察され、真皮組織内には多くの好中球、マクロファージ、肥満細胞の浸潤が観察される（非特許文献１）。特に、皮膚におけるしわの形成は老化の兆候として広く認知されているが、しわ形成部位では皮膚の粘弾性が低下していることが報告されており、エラスチンがシワ形成に関与することが報告されている（非特許文献２）。
エラスチンの構造消失は、エラスチン分解酵素の発現亢進により説明される。このエラスチンの分解酵素エラスターゼは線維芽細胞により産生されるＭＭＰ型のエラスターゼと好中球に由来するエラスターゼの関与が報告されている（非特許文献１）。すなわち、皮膚の弾力を保ち、老化による皮膚のしわやたるみを防止するためには、これらエラスターゼの活性を阻害し、エラスチンの分解を防ぐことが重要である。
In aged skin, in dermal tissue, decrease in collagen fiber and weakening of fiber bundle, loss of elastin fiber and increase in non-oriented elastin, increase in proteoglycan occur, and further, carbonyl protein which is an oxidation protein is finally glycated in the upper dermis. Products accumulate in elastin. In addition, changes in the microcirculatory system in the dermis are observed according to the severity of the wrinkles, a decrease in the frequency of existence of blood vessels and lymph vessels is observed, and many neutrophils, macrophages, and mast cells are found in the dermis tissue. Infiltration is observed (Non-patent Document 1). In particular, although the formation of wrinkles on the skin is widely recognized as a sign of aging, it has been reported that the viscoelasticity of the skin is reduced at the site of wrinkles, and it is reported that elastin is involved in the formation of wrinkles. (Non-Patent Document 2).
The structural loss of elastin is explained by the enhanced expression of elastin degrading enzyme. The elastase degrading enzyme elastase is reported to be involved in MMP type elastase produced by fibroblasts and elastase derived from neutrophils (Non-patent Document 1). That is, in order to maintain the elasticity of the skin and to prevent the wrinkles and the sagging of the skin due to aging, it is important to inhibit the activity of these elastases and prevent the degradation of elastin.
エラスターゼの活性阻害剤としては、モモ種子抽出物（特許文献１）、ウコン、セイヨウノコギリソウ、ゼニアオイ、タイム、ヤーコン、ローズヒップ（特許文献２）、スイートピー花抽出物（特許文献３）等の植物抽出物、リンジン、ヘスペリジン、ルチン（特許文献４）、フィトエン及び／又はフィトフルエン（特許文献５）、ウロリチン類（特許文献６）等がその効果について、既にいくつかの報告がなされているが、植物抽出物は季節や産地により品質のばらつきがあり、化粧料や外用剤の品質管理が難しいなどの問題がある。さらに、抗老化剤として広く認知されているビタミンＡは光老化によるコラーゲン産生低下の改善をするほか、表皮においてヒアルロン酸産生を促進する作用によるしわの改善作用が報告されている（非特許文献２）。しかしながら、ビタミンＡもまた熱、光、酸化に対して弱く、非常に不安定な成分であることから、化粧料や外用剤への配合に対しては、安定に配合するための特殊な製剤化技術が必要であり、汎用性に乏しい現状にある。またビタミンＡは、痒疹や紅斑といった皮膚刺激等が起こりやすく、広く化粧料に配合する場合には、その安全性に問題があり、安全性及び安定性に優れた、汎用性の高いエラスターゼ活性阻害剤が求められている。
ところで、アスコルビン酸及びその誘導体については、抗酸化作用、美白作用、コラーゲン産生促進作用、ヒアルロン酸産生促進作用等の機能を持つことが知られているが、エラスターゼ活性阻害作用に関する報告はない。
As an active inhibitor of elastase, plant extracts such as peach seed extract (patent document 1), turmeric, prickly pear extract, zinnaea, thyme, yacon, rosehip (patent document 2), sweet pea flower extract (patent document 3), etc. , Lindin, hesperidin, rutin (Patent Document 4), phytoene and / or phytofluene (Patent Document 5), urolitins (Patent Document 6), etc. have already been reported some of their effects, but plants Extracts vary in quality depending on the season and production area, and there are problems such as difficulty in quality control of cosmetics and external preparations. Furthermore, vitamin A, which is widely recognized as an anti-aging agent, improves the decrease in collagen production due to photoaging, and it has also been reported that wrinkles are improved by promoting the production of hyaluronic acid in the epidermis (Non-patent Document 2) ). However, since vitamin A is also a weak, highly unstable component against heat, light and oxidation, it is a special formulation for stable incorporation into formulations for cosmetics and external preparations. Technology is required, and it is in the present situation where versatility is poor. In addition, vitamin A is susceptible to skin irritation such as herpes zoster and erythema, etc., and when it is widely incorporated in cosmetics, there is a problem with its safety, and it is highly safe and highly stable, highly versatile elastase activity inhibited An agent is required.
Ascorbic acid and derivatives thereof are known to have functions such as antioxidative action, whitening action, collagen production promoting action, and hyaluronic acid production promoting action, but there is no report on elastase inhibitory action.
本発明は、皮膚の弾力維持に重要な真皮組織マトリックス構造の構成成分であるコラーゲンやエラスチンの分解酵素であるエラスターゼの活性阻害剤を提供することにある。 The present invention is to provide an active inhibitor of elastase, which is a degradation enzyme of collagen and elastin which is a component of dermal tissue matrix structure which is important for maintaining the elasticity of skin.
本発明者らは、エラスターゼの活性阻害剤について鋭意研究した結果、アスコルビン酸およびその誘導体が、エラスターゼの活性を減少させる効果が顕著に優れることを見出し、本発明を完成するに至った。 As a result of earnest studies on elastase activity inhibitors, the present inventors have found that ascorbic acid and its derivatives have a remarkably excellent effect of reducing elastase activity, and have completed the present invention.
本発明のアスコルビン酸およびその誘導体は、エラスターゼの活性阻害作用が顕著であり、これらを配合することで、皮膚のしわ改善やたるみ防止に対して効果を発揮する化粧料や外用剤の提供が可能である。 Ascorbic acid and derivatives thereof of the present invention have remarkable elastase activity inhibitory action, and by combining them, it is possible to provide cosmetics and external preparations that exhibit an effect on wrinkles improvement and sagging prevention of the skin. It is.
以下、本発明の構成を更に詳細に説明する。
本発明は、アスコルビン酸およびその誘導体を有効成分として含有するエラスターゼ活性阻害剤である。
本発明のアスコルビン酸およびその誘導体としては、ジパルミチン酸アスコルビルやテトラヘキシルデカン酸アスコルビル等のアスコルビン酸アルキルエステル、アスコルビン酸リン酸エステル、アスコルビン酸硫酸エステル、３−Ｏ−セチルアスコルビン酸等のアスコルビン酸アルキルエーテル等が挙げられ、特に好ましくは油溶性のアスコルビン酸誘導体である。
Hereinafter, the configuration of the present invention will be described in more detail.
The present invention is an elastase activity inhibitor comprising ascorbic acid and a derivative thereof as an active ingredient.
Ascorbic acid and derivatives thereof according to the present invention, ascorbic acid alkyl esters such as ascorbyl dipalmitate and ascorbyl tetrahexyl decanoic acid, ascorbic acid phosphate, ascorbic acid sulfuric acid ester, ascorbic acid alkyl ester such as 3-O-cetylascorbic acid An ether etc. are mentioned, Especially preferably, it is an oil-soluble ascorbic acid derivative.
前記アスコルビン酸およびその誘導体の市販品としては、アスコルビン酸ナトリウム（和光純薬工業社製）、ＡＡ２Ｇ（アスコルビン酸グルコシド、林原社製）、ＮＩＫＫＯＬ ＶＣＰＭｇ（アスコルビン酸リン酸マグネシウム、日光ケミカルズ社製）、ＮＩＫＫＯＬ ＣＰ（ジパルミチン酸アスコルビル、日光ケミカルズ社製）やＮＩＫＫＯＬ ＶＣ−ＩＰ（テトラヘキシルデカン酸アスコルビル、日光ケミカルズ社製）等がありこれを用いることもできるし、特開平６−２４７９５６号公報等の方法で合成したものを用いてもよい。さらに、これらのアスコルビン酸およびその誘導体は、１種又は２種以上を組み合わせて使用することができる。これらアスコルビン酸およびその誘導体は、優れたエラスターゼ活性阻害作用を有し、エラスターゼの過剰な活性化によりもたらされるコラーゲンやエラスチンの分解を抑制し、これが原因で起こる皮膚のシワやたるみの改善に有用である。 Commercial products of ascorbic acid and derivatives thereof include sodium ascorbate (manufactured by Wako Pure Chemical Industries, Ltd.), AA2G (ascorbic acid glucoside, manufactured by Hayashibara), NIKKOL VCPMg (magnesium ascorbate phosphate, manufactured by Nikko Chemicals), There are NIKKOL CP (dipalmitate ascorbyl, manufactured by Nikko Chemicals), NIKKOL VC-IP (tetrahexyl decanoic acid ascorbyl, manufactured by Nikko Chemicals), etc., which can also be used, and methods such as JP-A-6-247956 You may use what was synthesize | combined by. Furthermore, these ascorbic acid and its derivative can be used 1 type or in combination of 2 or more types. These ascorbic acid and derivatives thereof have excellent elastase activity inhibitory action and suppress the degradation of collagen and elastin caused by excessive activation of elastase, which is useful for the improvement of skin wrinkles and sags caused thereby. is there.
本発明のエラスターゼ活性阻害剤は、外用剤として用いることが好ましい。本発明のエラスターゼ活性阻害剤の外用剤としての形態では、本発明の効果に影響のない範囲において、通常使用される外用基剤、薬効成分などを配合することができる。外用基剤としては、流動パラフィンやスクワランなどの炭化水素、植物油、ロウ類、合成エステル油、シリコーン系の油相成分、フッ素系の油相成分、高級アルコール類、脂肪酸類、増粘剤、紫外線吸収剤、粉体、顔料、色材、陰イオン性界面活性剤、陽イオン性界面活性剤、非イオン性界面活性剤、両性界面活性剤、多価アルコール、糖、高分子化合物、経皮吸収促進剤、溶媒、酸化防止剤、香料、防腐剤などを任意に配合することができる。薬効成分としては鎮痛消炎剤、殺菌消毒剤、ビタミン類、皮膚軟化剤等を適宜使用できる。本発明の外用剤の剤型は任意であり、油性基剤をベースとするもの、水中油型、油中水型の乳化系基剤をベースとするもの、水をベースとするもののいずれの剤型も任意にとることができる。また用途としては、化粧料の他、皮膚外用剤、医薬用軟こう等に好適に使用できる。その形態は、化粧水、乳液、美容液、クリーム、パック、美容オイル、オイルバーム、軟こう、固形物、ムース等のスキンケア製品、化粧下地やファンデーション、コンシーラー、アイシャドウ、チーク等のメイク製品、リップ製品、ボディ製品といった化粧料および外用剤に配合することができるが、これらに限定されるものではない。本発明のエラスターゼ活性阻害剤の外用剤への配合量は、用途、剤型、配合目的等によって異なり、特に限定されるものではないが、一般的には、アスコルビン酸およびその誘導体として、外用剤中０．０１〜１００．０質量％ が好ましく、より好ましくは０．５〜３０．０質量％である。 The elastase activity inhibitor of the present invention is preferably used as an external preparation. In the form of the elastase activity inhibitor of the present invention as an external preparation, a base for external use, a pharmaceutically effective ingredient and the like which are usually used can be blended within a range not affecting the effect of the present invention. As bases for external use, hydrocarbons such as liquid paraffin and squalane, vegetable oils, waxes, synthetic ester oils, oil phase components of silicone type, oil phase components of fluorine type, higher alcohols, fatty acids, thickeners, ultraviolet rays Absorbent, powder, pigment, coloring material, anionic surfactant, cationic surfactant, nonionic surfactant, amphoteric surfactant, polyhydric alcohol, sugar, polymer compound, transdermal absorption Accelerators, solvents, antioxidants, perfumes, preservatives and the like can be optionally blended. Analgesic anti-inflammatory agents, antiseptics, vitamins, emollients and the like can be suitably used as medicinal ingredients. The dosage form of the external preparation of the present invention is arbitrary, and it is based on an oil base, an oil-in-water type, an oil-in-water emulsion base, or a water base. The type can also be taken arbitrarily. Moreover, as a use, in addition to cosmetics, it can be suitably used for skin external preparations, pharmaceutical ointments and the like. The form is skin care product such as lotion, milky lotion, cosmetic liquid, cream, pack, cosmetic oil, oil balm, soft ointment, solid substance, mousse etc, makeup base or foundation, makeup product such as concealer, eye shadow, teak, lip Although it can be blended in cosmetics and external preparations such as products and body products, it is not limited thereto. The compounding amount of the elastase activity inhibitor of the present invention to the external preparation varies depending on the use, dosage form, purpose of combination, etc. and is not particularly limited, but generally external preparation as ascorbic acid and its derivative The content is preferably 0.01 to 100.0% by mass, more preferably 0.5 to 30.0% by mass.
１、試験の概要
アスコルビン酸およびその誘導体の真皮線維芽細胞由来エラスターゼに対する活性阻害作用を確認した。
1. Outline of Test The inhibitory effect of ascorbic acid and its derivative on dermal fibroblast-derived elastase was confirmed.
２、実験方法
正常ヒト線維芽細胞は０．５％Ｔｒｉｔｏｎ Ｘ−１００含有リン酸緩衝液で３０分間静置することで細胞を溶解し、これをエラスターゼの粗酵素溶液として用いた。エラスターゼの合成基質としてはスクシニル―Ｌ−アラニル―Ｌ−アラニル―Ｌ−アラニンｐ−ニトロアニリド（Ｓｕｃ−Ａｌａ−Ａｌａ−Ａｌａ−ｐＮＡ）を用いて、０．１ｍｏｌ／Ｌトリス塩酸緩衝液に５ｍｍｏｌ／Ｌの濃度で溶解した。４倍濃度の試験試料を含有する０．１ｍｏｌ／Ｌトリス塩酸緩衝液、粗酵素溶液、および基質溶液をそれぞれ１：１：２の割合で混合し、暗所で３７℃、２時間インキュベーションをした。合成基質がエラスターゼで切断されることにより放出されるｐ−ニトロアニリンに由来する４０５ｎｍの吸光度を測定することでエラスターゼ活性の指標とした。
解析は、陰性対象（試料無添加条件）のエラスターゼ活性を1００％とした相対値で表した。それぞれのエラスターゼ活性はＳｔｕｄｅｎｔ ｔ検定を用いて有意差検定を行い、陰性対象との差を評価した。
2. Experimental method Normal human fibroblasts were lysed by standing for 30 minutes in phosphate buffer containing 0.5% Triton X-100, and the cells were lysed and used as a crude enzyme solution of elastase. As a synthetic substrate for elastase, succinyl-L-alanyl-L-alanyl-L-alanine p-nitroanilide (Suc-Ala-Ala-Ala-pNA) is used, and 5 mmol / L in 0.1 mol / L Tris-HCl buffer It was dissolved at a concentration of L. 0.1 mol / L Tris-HCl buffer solution containing a 4-fold concentration of test sample, crude enzyme solution and substrate solution were mixed in a ratio of 1: 1: 2, respectively, and incubated at 37 ° C. for 2 hours in the dark . The absorbance at 405 nm derived from p-nitroaniline released by cleavage of the synthetic substrate with elastase was used as an indicator of elastase activity.
Analysis was expressed as a relative value with the elastase activity of a negative control (sample-free condition) as 100%. Each elastase activity was tested for significance using Student's t-test to evaluate the difference from negative subjects.
３、評価試料
比較品１：ＥＤＴＡ（シグマアルドリッチ社製）
比較品２：レチノイン酸（ビタミンＡ、東京化成工業社製）
発明品１：アスコルビン酸ナトリウム（L(+)-アスコルビン酸ナトリウム、和光純薬工業社製）
発明品２：アスコルビン酸グルコシド（ＡＡ２Ｇ、林原社製)
発明品３：アスコルビン酸リン酸マグネシウム（ＮＩＫＫＯＬ ＶＣＰＭｇ、日光ケミカルズ社製）
発明品４：テトラヘキシルデカン酸アスコルビル（ＮＩＫＫＯＬ ＶＣ−ＩＰ、日光ケミカルズ社製）
3, evaluation sample comparative product 1: EDTA (made by Sigma Aldrich)
Comparative product 2: retinoic acid (Vitamin A, manufactured by Tokyo Chemical Industry Co., Ltd.)
Invention 1: Sodium ascorbate (L (+)-sodium ascorbate, manufactured by Wako Pure Chemical Industries, Ltd.)
Invention 2: Ascorbic acid glucoside (AA2G, manufactured by Hayashibara Co., Ltd.)
Invention 3: Magnesium ascorbate phosphate (NIKKOL VCPMg, manufactured by Nikko Chemicals Co., Ltd.)
Invention 4: Ascorbyl tetrahexyldecanoate (NIKKOL VC-IP, manufactured by Nikko Chemicals Co., Ltd.)
４、結果
結果を表１に示した。アスコルビン酸およびその誘導体の処理により、エラスターゼ活性は有意な減少が認められた。アスコルビン酸およびその誘導体のなかでも、テトラヘキシルデカン酸アスコルビルが同モル濃度の他の試験試料と比較して、最も強いエラスターゼ活性の減少作用が確認された。
4. Results The results are shown in Table 1. Treatment with ascorbic acid and its derivatives resulted in a significant decrease in elastase activity. Among ascorbic acid and derivatives thereof, ascorbyl tetrahexyldecanoate was found to have the strongest reduction effect of elastase activity as compared with other test samples of the same molar concentration.
アスコルビン酸及びその誘導体がエラスターゼに対して有意な活性阻害作用を示したので、これをエラスターゼ活性阻害剤として使用することで、皮膚の弾力を保ち、加齢によるしわやたるみを防ぐための化粧品ならびに外用剤の提供が可能となる。 Ascorbic acid and its derivatives exhibited a significant activity inhibitory action on elastase, and by using them as an elastase activity inhibitor, a cosmetic for maintaining elasticity of the skin and preventing wrinkles and sag due to aging, and It becomes possible to provide an external preparation.
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