JP2015067546A - Matrix metalloprotease-1 production inhibitor - Google Patents
Matrix metalloprotease-1 production inhibitor Download PDFInfo
- Publication number
- JP2015067546A JP2015067546A JP2013200614A JP2013200614A JP2015067546A JP 2015067546 A JP2015067546 A JP 2015067546A JP 2013200614 A JP2013200614 A JP 2013200614A JP 2013200614 A JP2013200614 A JP 2013200614A JP 2015067546 A JP2015067546 A JP 2015067546A
- Authority
- JP
- Japan
- Prior art keywords
- mmp
- production inhibitor
- extract
- production
- butanediol
- 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.)
- Granted
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Abstract
Description
本発明は、マトリックスメタロプロテアーゼ−１（以下、本明細書において「ＭＭＰ−１」と表記することがある）産生抑制剤に関する。 The present invention relates to a production inhibitor of matrix metalloproteinase-1 (hereinafter sometimes referred to as “MMP-1” in the present specification).
ＭＭＰ−１は、真皮線維芽細胞により産生され、細胞外マトリックスのＩ型コラーゲンを分解するが、加齢により、また少量の紫外線によっても、産生が促進されることが知られている。
ＭＭＰ−１産生の促進は、細胞外マトリックス成分であるＩ型コラーゲンの過剰な分解を招き、しわ、たるみ等の皮膚の老化の発現および進行を促進する。
また、ＭＭＰ−１は、皮膚の老化のみではなく、リューマチ関節症、変形性関節症等の疾患や創傷治癒に関与し、かかる病変組織や慢性的な創傷部位において産生が促進されることが報告されている（非特許文献１、２）。
MMP-1 is produced by dermal fibroblasts and degrades type I collagen in the extracellular matrix. It is known that production is promoted by aging and by a small amount of ultraviolet rays.
Promotion of MMP-1 production leads to excessive degradation of type I collagen, which is an extracellular matrix component, and promotes the development and progression of skin aging such as wrinkles and sagging.
MMP-1 is involved not only in skin aging but also in diseases such as rheumatoid arthritis and osteoarthritis and wound healing, and production is promoted in such lesion tissues and chronic wound sites. (Non-Patent Documents 1 and 2).
従って、加齢の他、紫外線、病変等の外的刺激によって惹起され、促進されるＭＭＰ−１産生を阻害または抑制する成分の探索が行われ、たとえば、キサントリゾール（特許文献１）、リグナン系化合物（特許文献２）、トルメント酸（特許文献３）、アセトゲニン（特許文献４）等が開示されている。
また、ブドウ種子抽出物（特許文献５）、イチョウ葉、ビワ葉抽出物（特許文献６）、ササクレヒトヨタケ抽出物（特許文献７）等、植物抽出物のＭＭＰ−１産生阻害または抑制活性も多く報告されている。
Therefore, in addition to aging, a search for components that inhibit or suppress MMP-1 production induced and promoted by external stimuli such as ultraviolet rays and lesions is performed. For example, xanthorizole (Patent Document 1), lignan System compounds (Patent Document 2), tormentic acid (Patent Document 3), acetogenin (Patent Document 4) and the like are disclosed.
In addition, MMP-1 production inhibition or suppression activity of plant extracts such as grape seed extract (Patent Document 5), ginkgo biloba leaf, loquat leaf extract (Patent Document 6), Sasakuhi Toyotake extract (Patent Document 7) is also large. It has been reported.
しかしながら、上記のような外的刺激により促進されるＭＭＰ−１産生、特に真皮における病的なＭＭＰ−１産生に対し、十分な抑制効果を有し、安全性、使用性等の点でも問題のないＭＭＰ−１産生抑制剤が望まれている。 However, it has a sufficient inhibitory effect on MMP-1 production promoted by external stimulation as described above, particularly pathological MMP-1 production in the dermis, and is problematic in terms of safety and usability. No MMP-1 production inhibitor is desired.
本発明は、加齢や紫外線等の外的刺激により促進されるＭＭＰ−１産生に対し優れた抑制効果を有し、特に皮膚に対する刺激性等、安全性および使用性においても問題のない、ＭＭＰ−１産生抑制剤を提供することを目的とする。 The present invention has an excellent inhibitory effect on MMP-1 production promoted by external stimuli such as aging and ultraviolet rays, and there is no problem in safety and usability, particularly irritation to skin. -1 production inhibitor is aimed at.
本発明者らは、上記課題を解決するべく、種々検討した結果、オオヤマザクラ（Cerasus sargentii (Rehder) H.Ohba）の果実の抽出物に、優れたＭＭＰ−１産生抑制活性を見出し、本発明を完成するに至った。 As a result of various studies to solve the above-mentioned problems, the present inventors have found an excellent MMP-1 production inhibitory activity in an extract of the fruit of Ceratos sargentii (Rehder) H. Ohba. It came to complete.
すなわち、本発明は、次の［１］〜［９］に関する。
［１］オオヤマザクラ（Cerasus sargentii (Rehder) H.Ohba）の果実の抽出物を含有する、マトリックスメタロプロテアーゼ−１産生抑制剤。
［２］抽出物が、エタノールまたはブタンジオールを含む抽出溶媒により抽出して得られる抽出物である、上記［１］に記載のマトリックスメタロプロテアーゼ−１産生抑制剤。
［３］抽出溶媒中のエタノールの濃度が、５０（ｖ／ｖ）％〜１００（ｖ／ｖ）％である、上記［２］に記載のマトリックスメタロプロテアーゼ−１産生抑制剤。
［４］ブタンジオールが１，３−ブタンジオールである、上記［２］に記載のマトリックスメタロプロテアーゼ−１産生抑制剤。
［５］抽出溶媒中のブタンジオールの濃度が５０（ｖ／ｖ）％〜１００（ｖ／ｖ）％である、上記［２］または［４］に記載のマトリックスメタロプロテアーゼ−１産生抑制剤。
［６］皮膚の老化の防止または改善用である、上記［１］〜［５］のいずれかに記載のマトリックスメタロプロテアーゼ−１産生抑制剤。
［７］上記［１］〜［６］のいずれかに記載のマトリックスメタロプロテアーゼ−１産生抑制剤を含有する、医薬品。
［８］上記［１］〜［６］のいずれかに記載のマトリックスメタロプロテアーゼ−１産生抑制剤を含有する、医薬部外品。
［９］上記［１］〜［６］のいずれかに記載のマトリックスメタロプロテアーゼ−１産生抑制剤を含有する、化粧品。
That is, the present invention relates to the following [1] to [9].
[1] A matrix metalloprotease-1 production inhibitor containing an extract of the fruit of Ceratos sargentii (Rehder) H. Ohba.
[2] The matrix metalloproteinase-1 production inhibitor according to [1] above, wherein the extract is an extract obtained by extraction with an extraction solvent containing ethanol or butanediol.
[3] The matrix metalloproteinase-1 production inhibitor according to [2] above, wherein the concentration of ethanol in the extraction solvent is 50 (v / v)% to 100 (v / v)%.
[4] The matrix metalloproteinase-1 production inhibitor according to [2] above, wherein the butanediol is 1,3-butanediol.
[5] The matrix metalloproteinase-1 production inhibitor according to [2] or [4] above, wherein the concentration of butanediol in the extraction solvent is 50 (v / v)% to 100 (v / v)%.
[6] The matrix metalloproteinase-1 production inhibitor according to any one of [1] to [5], which is used for preventing or improving skin aging.
[7] A pharmaceutical comprising the matrix metalloproteinase-1 production inhibitor according to any one of [1] to [6] above.
[8] A quasi-drug containing the matrix metalloproteinase-1 production inhibitor according to any one of [1] to [6] above.
[9] A cosmetic containing the matrix metalloproteinase-1 production inhibitor according to any one of [1] to [6] above.
本発明に係るＭＭＰ−１産生抑制剤は、加齢や紫外線等の外的刺激により促進されるＭＭＰ−１産生に対し優れた抑制効果を有し、特に、加齢や紫外線等の外的刺激により促進される細胞外マトリックス成分であるＩ型コラーゲンの過剰な分解を抑制して、しわ、たるみ等の皮膚の老化の発現および進行を防止または改善する効果に優れる。
また、本発明に係るＭＭＰ−１産生抑制剤において、有効成分として含有されるオオヤマザクラ（Cerasus sargentii (Rehder) H.Ohba）の果実の抽出物は、植物由来であり、低濃度で十分なＭＭＰ−１産生抑制活性を有するため、皮膚に対する刺激性等、安全性および使用性の点でも有利である。
The MMP-1 production inhibitor according to the present invention has an excellent inhibitory effect on MMP-1 production promoted by external stimuli such as aging and ultraviolet rays, and in particular, external stimuli such as aging and ultraviolet rays. It suppresses excessive degradation of type I collagen, which is an extracellular matrix component promoted by the above, and is excellent in the effect of preventing or improving the development and progression of skin aging such as wrinkles and sagging.
In addition, in the MMP-1 production inhibitor according to the present invention, the fruit extract of Ceratos sargentii (Rehder) H. Ohba, which is contained as an active ingredient, is derived from a plant and has sufficient MMP at a low concentration. -1 production inhibitory activity is advantageous in terms of safety and usability, such as irritation to the skin.
本発明の皮膚の酸化的ストレス抑制剤は、オオヤマザクラ（Cerasus sargentii (Rehder) H.Ohba）の果実より、抽出溶媒により抽出して得られる抽出物を含有する。 The skin oxidative stress inhibitor of the present invention contains an extract obtained by extracting from the fruit of Ceratos sargentii (Rehder) H. Ohba with an extraction solvent.
本発明で用いるオオヤマザクラ（Cerasus sargentii (Rehder) H.Ohba）は、バラ科（Rosaceae）に属する落葉樹であり、本発明においては、果実を用いる。
オオヤマザクラ（Cerasus sargentii (Rehder) H.Ohba）の果実は水洗し、そのまま、または細切、乾燥、粉砕等を行うことにより、スラリー状、細粒状、顆粒状または粉末状として抽出に供する。抽出溶媒としては、通常、メタノール、エタノール、プロパンジオール、ブタンジオール、グリセリン等の極性有機溶媒の１種または２種以上、または前記極性有機溶媒の１種または２種以上と水との混合溶媒が用いられるが、エタノールまたはブタンジオールを含む抽出溶媒を用いることが好ましく、５０（ｖ／ｖ）％〜１００（ｖ／ｖ）％エタノール、５０（ｖ／ｖ）％〜１００（ｖ／ｖ）％ブタンジオールがより好ましく用いられる。なお、ブタンジオールとしては、１，３−ブタンジオールが好ましく用いられる。また、エタノールを含む抽出溶媒としては、５０（ｖ／ｖ）％エタノールが特に好ましく、ブタンジオールを含む抽出溶媒としては、５０（ｖ／ｖ）％ブタンジオールが特に好ましい。
The cherry tree cherry ( Cerasus sargentii (Rehder) H. Ohba) used in the present invention is a deciduous tree belonging to the Rosaceae family. In the present invention, a fruit is used.
The fruit of Ceramus sargentii (Rehder) H.Ohba is washed with water and subjected to extraction in the form of a slurry, fine granule, granule or powder as it is, or by chopping, drying and grinding. The extraction solvent is usually one or more polar organic solvents such as methanol, ethanol, propanediol, butanediol, glycerin, or a mixed solvent of one or more polar organic solvents and water. It is preferable to use an extraction solvent containing ethanol or butanediol, 50 (v / v)% to 100 (v / v)% ethanol, 50 (v / v)% to 100 (v / v)% Butanediol is more preferably used. Note that 1,3-butanediol is preferably used as the butanediol. The extraction solvent containing ethanol is particularly preferably 50 (v / v)% ethanol, and the extraction solvent containing butanediol is particularly preferably 50 (v / v)% butanediol.
抽出は、オオヤマザクラ（Cerasus sargentii (Rehder) H.Ohba）の果実１００ｇに対し、通常１００ｍＬ〜５００ｍＬの抽出溶媒を用いて行い、２００ｍＬ〜３００ｍＬの抽出溶媒を用いることが好ましい。
抽出条件は、抽出溶媒によっても異なるが、通常、１０℃〜３０℃で２日間〜９０日間程度である。特に、エタノールを含む抽出溶媒の場合、通常２０℃〜３０℃で２日間〜６０日間行い、２５℃〜３０℃で２日間〜７日間行うことが好ましい。また、ブタンジオールを含む抽出溶媒の場合は、通常２０℃〜３０℃で２日間〜６０日間行い、２５℃〜３０℃で７日間〜６０日間行うことが好ましい。
抽出後、定法に従い、たとえばろ過、遠心分離等により、抽出液を回収し、オオヤマザクラ（Cerasus sargentii (Rehder) H.Ohba）の果実の抽出物を得る。
Extraction, compared fruit 100g of Prunus Sargentii (Cerasus sargentii (Rehder) H.Ohba) , carried out with an extraction solvent typically 100ML～500mL, it is preferable to use an extraction solvent 200ML～300mL.
The extraction conditions vary depending on the extraction solvent, but are usually about 10 ° C. to 30 ° C. for about 2 days to 90 days. In particular, in the case of an extraction solvent containing ethanol, it is usually preferable to carry out at 20 ° C. to 30 ° C. for 2 days to 60 days, and at 25 ° C. to 30 ° C. for 2 days to 7 days. In the case of an extraction solvent containing butanediol, it is preferably carried out usually at 20 ° C. to 30 ° C. for 2 days to 60 days and at 25 ° C. to 30 ° C. for 7 days to 60 days.
After the extraction, the extract is collected by, for example, filtration, centrifugation, etc. according to a conventional method to obtain an extract of the fruit of Ceratos sargentii (Rehder) H. Ohba.
本発明においては、オオヤマザクラ（Cerasus sargentii (Rehder) H.Ohba）の果実の抽出物は、上記溶媒による抽出物をそのまま用いてもよく、該抽出物を希釈もしくは濃縮し、または乾燥して用いてもよく、粗精製または精製して用いてもよい。前記抽出物の粗精製および精製は常法に従って行えばよく、たとえば「ダイヤイオンＨＰ」（三菱化学株式会社製）等のイオン交換樹脂、「Ｓｅｐ−Ｐａｋ Ｃ−１８」（ウォーターズ社製）等の吸着剤による吸着および溶出、クロマトグラフィー等を適宜組み合わせて実施することができる。 In the present invention, the fruit extract of the cherry tree ( Cerasus sargentii (Rehder) H. Ohba) may be used as it is with the above solvent, and the extract may be diluted or concentrated, or used after drying. It may be used after crude purification or purification. Rough purification and purification of the extract may be performed according to a conventional method. For example, ion exchange resins such as “Diaion HP” (manufactured by Mitsubishi Chemical Corporation), “Sep-Pak C-18” (manufactured by Waters), etc. Adsorption and elution with an adsorbent, chromatography, and the like can be combined as appropriate.
上記したオオヤマザクラ（Cerasus sargentii (Rehder) H.Ohba）の果実の抽出物は、後述するように、強いＭＭＰ−１産生抑制活性を有し、特に、ヒト真皮線維芽細胞において、加齢や紫外線（ＵＶＢ）曝露等の外的刺激によって誘導されるＭＭＰ−１の過剰産生を抑制する作用を有する。それゆえ、これを有効成分として含有するＭＭＰ−１産生抑制剤は、加齢や紫外線等の外的刺激による過剰なＭＭＰ−１産生の誘導による真皮マトリックス成分の分解を抑制し、しわ、たるみ等の皮膚の老化症状の発現または進行を良好に抑制し、かかる症状を防止または改善することができる。また、前記抽出物は植物由来であり、ＭＭＰ−１産生抑制活性が強いことから、低濃度で十分なＭＭＰ−１産生抑制効果を奏し、皮膚に対する刺激性等、安全性および使用性における問題も生じにくい。 As described later, the fruit extract of Ceratos sargentii (Rehder) H.Ohba has a strong MMP-1 production inhibitory activity, particularly in human dermal fibroblasts. (UVB) has the effect of suppressing excessive production of MMP-1 induced by external stimuli such as exposure. Therefore, an MMP-1 production inhibitor containing this as an active ingredient suppresses the degradation of the dermal matrix component due to the induction of excessive MMP-1 production by external stimulation such as aging or ultraviolet rays, and wrinkles, sagging, etc. It is possible to satisfactorily suppress the onset or progression of skin aging symptoms and to prevent or ameliorate such symptoms. In addition, since the extract is derived from a plant and has a strong MMP-1 production inhibitory activity, it has a sufficient MMP-1 production inhibitory effect at a low concentration, and there are problems in safety and usability such as irritation to the skin. Hard to occur.
なお、本発明のＭＭＰ−１産生抑制剤において、十分な効果を得るために必要なオオヤマザクラ（Cerasus sargentii (Rehder) H.Ohba）の果実の抽出物の量は、抽出溶媒および抽出条件により異なるが、エタノールを含む抽出溶媒による抽出物の場合、乾燥重量として、０．００５重量％〜０．１重量％含有させることが好ましく、０．０５重量％〜０．１重量％含有させることがより好ましい。また、ブタンジオールを含む抽出溶媒による抽出物の場合、ポリフェノール（没食子酸）に換算した量として、０．０００５（ｗ／ｖ）％〜０．０１（ｗ／ｖ）％含有させることが好ましく、０．００５（ｗ／ｖ）％〜０．０１（ｗ／ｖ）％含有させることがより好ましい。 In the MMP-1 production inhibitor of the present invention, the amount of fruit extract of Ceratos sargentii (Rehder) H. Ohba necessary for obtaining a sufficient effect varies depending on the extraction solvent and the extraction conditions. However, in the case of an extract with an extraction solvent containing ethanol, the dry weight is preferably 0.005% to 0.1% by weight, more preferably 0.05% to 0.1% by weight. preferable. Further, in the case of an extract with an extraction solvent containing butanediol, it is preferable to contain 0.0005 (w / v)% to 0.01 (w / v)% as an amount converted to polyphenol (gallic acid), More preferably, 0.005 (w / v)% to 0.01 (w / v)% is contained.
本発明のＭＭＰ−１産生抑制剤は、オオヤマザクラ（Cerasus sargentii (Rehder) H.Ohba）の果実の上記抽出物をそのまま、または、水、エタノール、プロパノール等の低級アルコール、プロパンジオール、ブタンジオール、グリセリン等の多価アルコールといった液状担体、乳糖、デンプン、デキストリン等の粉末担体に含有させ、必要に応じて分散剤、懸濁剤、抗酸化剤、増粘剤、ゲル化剤、保存剤等、製剤化に際して一般的に使用される添加剤を加えて、液状、懸濁液状、乳液状、クリーム状、ゲル状、粉末状等の形態で提供することができる。 The MMP-1 production inhibitor of the present invention is obtained by using the above extract of the fruit of Ceratos sargentii (Rehder) H. Ohba as it is, or a lower alcohol such as water, ethanol, propanol, propanediol, butanediol, Included in liquid carriers such as polyhydric alcohols such as glycerin, powder carriers such as lactose, starch, dextrin, and dispersing agents, suspending agents, antioxidants, thickeners, gelling agents, preservatives, etc. Additives generally used for formulation can be added and provided in the form of liquid, suspension, emulsion, cream, gel, powder or the like.
さらに本発明は、上記本発明のＭＭＰ−１産生抑制剤を有効成分として含有する医薬品を提供する。
本発明の医薬品には、必要に応じて、動植物性油脂、ロウ、脂肪酸、脂肪族アルコール、エステル油、炭化水素油、シリコーン油等の油性基剤；エタノール、プロピレングリコール等の溶解剤；グリセリン、１，３−ブタンジオール、マクロゴール等の湿潤剤；アルギン酸ナトリウム、キサンタンガム、ソルビタン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリソルベート等の懸濁化剤；グリセリン脂肪酸エステル、ショ糖脂肪酸エステル、ポリソルベート等の乳化剤；アルギン酸プロピレングリコールエステル、ベントナイト、ポリソルベート、マクロゴール等の分散剤；カルボキシビニルポリマー、カルメロースナトリウム、ヒドロキシプロピルセルロース等の粘稠剤；クレー、結晶セルロース、デキストリン、トウモロコシデンプン等の賦形剤；アルファー化デンプン、カルメロース、乳糖、微結晶セルロース等の結合剤；ケイ酸マグネシウム、ステアリン酸アルミニウム、タルク等の滑沢剤；クロスポビドン、沈降炭酸カルシウム、ポビドン等の崩壊剤；アジピン酸ジオクチル、フタル酸ジオクチル、ミリスチン酸イソプロピル等の可塑剤；塩酸、クエン酸、クエン酸ナトリウム、水酸化カリウム、水酸化ナトリウム、乳酸、乳酸ナトリウム等のｐＨ調整剤；アスコルビン酸、エリソルビン酸、酢酸トコフェロール、ジブチルヒドロキシトルエン等の抗酸化剤；安息香酸ナトリウム、エデト酸ナトリウム、デヒドロ酢酸、パラオキシ安息香酸メチル等の防腐剤；ｄｌ−カンフル、スペアミント油、ハッカ油、ｄｌ−メントール等の芳香剤；アスパルテーム、サッカリンナトリウム、酢酸、ブドウ糖等の矯味剤；黄酸化鉄、黒酸化鉄、酸化亜鉛、食用青色１号、食用赤色２号等の着色剤など、製剤化に際し一般的に配合される添加剤を含有させることができる。
Furthermore, this invention provides the pharmaceutical which contains the MMP-1 production inhibitor of the said this invention as an active ingredient.
In the pharmaceutical of the present invention, if necessary, oily bases such as animal and vegetable oils, waxes, fatty acids, aliphatic alcohols, ester oils, hydrocarbon oils, silicone oils; solubilizers such as ethanol and propylene glycol; glycerin, Wetting agents such as 1,3-butanediol and macrogol; suspending agents such as sodium alginate, xanthan gum, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate; glycerin fatty acid ester, sucrose fatty acid ester, polysorbate, etc. Emulsifier: Dispersant such as propylene glycol alginate, bentonite, polysorbate, macrogol; Viscosity agent such as carboxyvinyl polymer, carmellose sodium, hydroxypropyl cellulose; clay, crystalline cellulose, dextrin, corn Excipients such as starch; binders such as pregelatinized starch, carmellose, lactose and microcrystalline cellulose; lubricants such as magnesium silicate, aluminum stearate and talc; disintegrants such as crospovidone, precipitated calcium carbonate and povidone Plasticizers such as dioctyl adipate, dioctyl phthalate and isopropyl myristate; pH adjusters such as hydrochloric acid, citric acid, sodium citrate, potassium hydroxide, sodium hydroxide, lactic acid and sodium lactate; ascorbic acid, erythorbic acid, Antioxidants such as tocopherol acetate and dibutylhydroxytoluene; antiseptics such as sodium benzoate, sodium edetate, dehydroacetic acid and methyl paraoxybenzoate; fragrances such as dl-camphor, spearmint oil, peppermint oil, and dl-menthol; Aspartame, quick Contains additives commonly used in formulation, such as phosphates such as sodium phosphate, acetic acid, and glucose; colorants such as yellow iron oxide, black iron oxide, zinc oxide, edible blue No. 1 and edible red No. 2 Can be made.
本発明の医薬品は、液剤、乳剤、ゲル剤、クリーム剤、散剤、顆粒剤、丸剤、錠剤、カプセル剤等の剤形で提供することができ、製剤学的に一般的な製造方法、たとえば第１６改正日本薬局方製剤総則に記載された方法により、調製することができる。
本発明の医薬品は、好ましくは、皮膚外用医薬品として提供される。かかる皮膚外用医薬品は、ローション剤、ゲル剤、乳剤、クリーム剤、軟膏剤、硬膏剤、リニメント剤等、種々の形態で提供することができる。
The pharmaceutical of the present invention can be provided in dosage forms such as liquids, emulsions, gels, creams, powders, granules, pills, tablets, capsules, etc. It can be prepared by the method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.
The medicament of the present invention is preferably provided as a skin external medicine. Such external preparations for skin can be provided in various forms such as lotions, gels, emulsions, creams, ointments, plasters, liniments and the like.
また、本発明は、上記本発明のＭＭＰ−１産生抑制剤を含有する医薬部外品を提供する。本発明の医薬部外品も、上記医薬品と同様に、必要に応じて油性基剤、分散剤、懸濁化剤、乳化剤、抗酸化剤、ｐＨ調整剤、矯味剤、着色剤等の添加剤を加えて、液剤、乳剤、ゲル剤、クリーム剤、粉末剤等の種々の剤形で提供され得る。
本発明の医薬部外品は、好ましくは皮膚外用医薬部外品として提供される。かかる皮膚外用医薬部外品は、ローション剤、ゲル剤、乳剤、クリーム剤、軟膏剤、硬膏剤、リニメント剤等の種々の形態とすることができる。
The present invention also provides a quasi-drug containing the MMP-1 production inhibitor of the present invention. The quasi-drug of the present invention is also an additive such as an oily base, a dispersant, a suspending agent, an emulsifier, an antioxidant, a pH adjuster, a corrigent, a colorant, etc. Can be provided in various dosage forms such as solutions, emulsions, gels, creams, powders and the like.
The quasi-drug of the present invention is preferably provided as a quasi-drug for external use on the skin. Such quasi-drugs for external use on skin can be in various forms such as lotions, gels, emulsions, creams, ointments, plasters, liniments and the like.
さらに本発明は、上記本発明のＭＭＰ−１産生抑制剤を含有する化粧品を提供する。
本発明の化粧品は、アーモンド油、アボカド油、オリーブ油、カカオ脂、ゴマ油、サフラワー油、大豆油、パーシック油、ヒマシ油、綿実油、モクロウ、ヤシ油等の植物性油脂；タートル油、ミンク油、卵黄油等の動物性油脂；カルナウバロウ、キャンデリラロウ、鯨ロウ、ミツロウ、ラノリン等のロウ；スクワラン、セレシン、マイクロクリスタリンワックス、流動パラフィン、ワセリン等の炭化水素油；ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、オレイン酸、イソステアリン酸等の脂肪酸；ラウリルアルコール、セタノール、ステアリルアルコール、オレイルアルコール、オクチルドデカノール、ラノリンアルコール等の脂肪アルコール；ミリスチン酸イソプロピル、パルミチン酸イソプロピル、ミリスチン酸オクチルデシル等のエステル；ステアリン酸ナトリウム、ラウリル硫酸ナトリウム等の陰イオン性界面活性剤；ポリオキシエチレンアルキルエーテル、ポリオキシエチレンアルキルフェニルエーテル、ポリオキシエチレンソルビタン脂肪酸エステル等の非イオン性界面活性剤；テトラアルキルアンモニウム塩、２−アルキル−１−アルキル−１−ヒドロキシエチルイミダゾリニウム塩等の陽イオン性界面活性剤；Ｎ，Ｎ−ジメチル−Ｎ−アルキル−Ｎ−カルボキシメチルアンモニウムベタイン、Ｎ，Ｎ−ジアルキルアミノアルキレンカルボン酸等の両性界面活性剤；赤色２号、黄色４号、青色１号、β−カロテン等の色素；タルク、カオリン、酸化チタン、ベンガラ、黄酸化鉄、黒酸化鉄等の顔料；ペパーミント油、スペアミント油、ローズ油等の香料；パラアミノ安息香酸エチル、パラメトキシ桂皮酸エチルヘキシル、オキシベンゾン等の紫外線吸収剤；酢酸トコフェロール、ビタミンＥ等の抗酸化剤；エデト酸ナトリウム、フェノキシエタノール、パラオキシ安息香酸メチル等の防腐剤など、一般的な化粧品原料を用いて、化粧水、乳液、クリーム、美容液、パック等の皮膚用化粧品、ファンデーション、アイカラー、チークカラー等のメイクアップ化粧品などとして提供される。
Furthermore, this invention provides the cosmetics containing the MMP-1 production inhibitor of the said invention.
The cosmetics of the present invention include vegetable oils such as almond oil, avocado oil, olive oil, cocoa butter, sesame oil, safflower oil, soybean oil, persic oil, castor oil, cottonseed oil, molasses, coconut oil; turtle oil, mink oil, Animal fats such as egg yolk oil; wax such as carnauba wax, candelilla wax, whale wax, beeswax, lanolin; hydrocarbon oils such as squalane, ceresin, microcrystalline wax, liquid paraffin, petrolatum; lauric acid, myristic acid, palmitic acid Fatty alcohols such as lauryl alcohol, cetanol, stearyl alcohol, oleyl alcohol, octyldodecanol, lanolin alcohol; isopropyl myristate, isopropyl palmitate, octyl myristate Esters such as syl; Anionic surfactants such as sodium stearate and sodium lauryl sulfate; Nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene alkylphenyl ether and polyoxyethylene sorbitan fatty acid ester; Tetra Cationic surfactants such as alkylammonium salts and 2-alkyl-1-alkyl-1-hydroxyethylimidazolinium salts; N, N-dimethyl-N-alkyl-N-carboxymethylammonium betaine, N, N- Amphoteric surfactants such as dialkylaminoalkylene carboxylic acids; pigments such as red No. 2, yellow No. 4, blue No. 1, β-carotene; pigments such as talc, kaolin, titanium oxide, bengara, yellow iron oxide, black iron oxide Perfumes such as peppermint oil, spearmint oil, rose oil Ultraviolet absorbers such as ethyl paraaminobenzoate, ethylhexyl paramethoxycinnamate and oxybenzone; antioxidants such as tocopherol acetate and vitamin E; preservatives such as sodium edetate, phenoxyethanol and methyl paraoxybenzoate Is used as cosmetics for skin such as lotion, milky lotion, cream, beauty essence, and pack, and makeup cosmetics such as foundation, eye color, and cheek color.
本発明の化粧品は、好ましくは、化粧水、乳液、クリーム、美容液、パック等の皮膚用化粧品として提供される。 The cosmetic of the present invention is preferably provided as a skin cosmetic such as a lotion, milky lotion, cream, cosmetic liquid, or pack.
なお、上記した本発明の医薬品、医薬部外品または化粧品は、加齢、紫外線等の外的刺激による皮膚の老化を防止または改善するための皮膚外用医薬品、皮膚外用医薬部外品または皮膚用化粧品として、特に好ましく提供される。 The pharmaceutical, quasi-drug or cosmetic of the present invention described above is a skin external medicine, skin external quasi-drug or skin for preventing or improving skin aging due to external stimulation such as aging or ultraviolet rays. It is particularly preferably provided as a cosmetic.
上記皮膚の老化を防止または改善するための皮膚外用医薬品、皮膚外用医薬部外品または皮膚用化粧品には、本発明の特徴を損なわない範囲で、グルコシルルチン、コメヌカ油、シソ抽出物、タンニン酸、ルイボス抽出物等の抗酸化剤；コエンザイムＱ１０、デオキシリボ核酸ナトリウム、アシタバ抽出物、クロレラ抽出物、酵母抽出物、オタネニンジン抽出物、ヒバマタ抽出物、ロイヤルゼリー抽出物等の細胞賦活剤；アスコルビルリン酸ナトリウム、アスコルビルリン酸マグネシウム、アルブチン、コウジ酸、ソウハクヒ抽出物、プラセンタ抽出物等の美白剤；加水分解シルク、カッコン抽出物、シャクヤク抽出物、卵殻膜タンパク質、レチノール等の抗シワ・抗老化剤；アズレン、アラントイン、カミツレ抽出物、カンゾウ抽出物、キダチアロエ抽出物、グリチルリチン酸等の抗炎症・肌荒れ防止剤；シコン抽出物、ビサボロール、ヒノキチオール等の抗菌剤；塩化セチルピリジニウム、グルコン酸亜鉛、オウバク抽出物等の抗ざ瘡剤；ＤＬ−アラニン、ピロリドンカルボン酸ナトリウム、コンドロイチン、スフィンゴ脂質、セラミド、ヒアルロン酸等の保湿剤；塩化カプロニウム、センブリ抽出物、ハトムギ抽出物等の血行促進剤などを含有させることができる。 In the above-mentioned topical medicine for skin, quasi-drug or dermatological cosmetic for preventing or improving the aging of the skin, glucosylrutin, rice bran oil, perilla extract, tannic acid, as long as the characteristics of the present invention are not impaired. Antioxidants such as rooibos extract; cell activators such as coenzyme Q 10 , deoxyribonucleic acid sodium, acitaba extract, chlorella extract, yeast extract, ginseng extract, hibamata extract, royal jelly extract; ascorbylline Whitening agent such as sodium acid, magnesium ascorbyl phosphate, arbutin, kojic acid, Soraku extract, placenta extract, etc .; Anti-wrinkle / anti-aging agent such as hydrolyzed silk, cuckoo extract, peony extract, eggshell membrane protein, retinol Azulene, allantoin, chamomile extract, licorice extract, Anti-inflammatory and rough skin prevention agents such as extract of dachialoe and glycyrrhizic acid; antibacterial agents such as sicon extract, bisabolol and hinokitiol; anti-acne agents such as cetylpyridinium chloride, zinc gluconate and agaric extract; DL-alanine and pyrrolidone Moisturizing agents such as sodium carboxylate, chondroitin, sphingolipid, ceramide, and hyaluronic acid; blood circulation promoters such as capronium chloride, extract of symbion, and pearl extract can be included.
以下、実施例により本発明をさらに具体的に説明するが、本発明の範囲はこれらの実施例に限定されるものではない。 EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to these examples.
［実施例１〜６］液状ＭＭＰ−１産生抑制剤
オオヤマザクラ（Cerasus sargentii (Rehder) H.Ohba）の果実１００ｇを水洗し、５０（ｖ／ｖ）％エタノール、７５（ｖ／ｖ）％エタノール、１００（ｖ／ｖ）％エタノール、５０（ｖ／ｖ）％１，３−ブタンジオール、７５（ｖ／ｖ）％１，３−ブタンジオール、１００（ｖ／ｖ）％１，３−ブタンジオール各３００ｍＬに浸漬し、ときどき撹拌しながら、２５℃にて静置して抽出した。５０（ｖ／ｖ）％エタノール、７５（ｖ／ｖ）％エタノール、１００（ｖ／ｖ）％エタノールのそれぞれにより抽出する場合は７日間、５０（ｖ／ｖ）％１，３−ブタンジオール、７５（ｖ／ｖ）％１，３−ブタンジオール、１００（ｖ／ｖ）％１，３−ブタンジオールのそれぞれにより抽出する場合は、２か月間静置した後、ろ過してろ液を回収し、実施例１〜６の液状ＭＭＰ−１産生抑制剤とした。
[Examples 1 to 6] Liquid MMP-1 production inhibitor 100 g of fruit of Ceratos sargentii (Rehder) H. Ohba was washed with water, 50 (v / v)% ethanol, 75 (v / v)% ethanol , 100 (v / v)% ethanol, 50 (v / v)% 1,3-butanediol, 75 (v / v)% 1,3-butanediol, 100 (v / v)% 1,3-butane It was immersed in 300 mL of each diol and extracted by standing at 25 ° C. with occasional stirring. When extracting with 50 (v / v)% ethanol, 75 (v / v)% ethanol, and 100 (v / v)% ethanol, respectively, 7 days, 50 (v / v)% 1,3-butanediol, When extracting with 75 (v / v)% 1,3-butanediol and 100 (v / v)% 1,3-butanediol, respectively, after leaving for 2 months, the filtrate is collected by filtration. The liquid MMP-1 production inhibitor of Examples 1 to 6 was used.
上記実施例１〜６の液状ＭＭＰ−１産生抑制剤について、下記の通り、ポリフェノール含量、タンパク質含量、糖含量および乾燥重量を定量した。
（１）ポリフェノール含量
没食子酸を標品として、Folin-Denins法により定量し、没食子酸量に換算した量により表した。
（２）タンパク質含量
Quick Star Protein Assay(Bio Rad)により、ウシ血清アルブミンを用いて検量線を作成して定量した。
（３）糖含量
グルコースを標品として、フェノール硫酸法により定量し、グルコース量に換算した量により表した
（４）乾燥重量
上記実施例のＭＭＰ−１産生抑制剤各１００ｍＬをエバポレーターで減圧濃縮し、次いで蒸留水に溶解し、−８０℃で凍結乾燥して、凍結乾燥後の重量を測定した。
About the liquid MMP-1 production inhibitor of the said Examples 1-6, the polyphenol content, protein content, sugar content, and dry weight were quantified as follows.
(1) Polyphenol content Using gallic acid as a standard, it was quantified by the Folin-Denins method and expressed as an amount converted to the amount of gallic acid.
(2) Protein content
A calibration curve was prepared using bovine serum albumin and quantified by Quick Star Protein Assay (Bio Rad).
(3) Sugar content Using glucose as a standard, quantified by the phenol-sulfuric acid method, and expressed by the amount converted to the amount of glucose. (4) Dry weight 100 mL of each MMP-1 production inhibitor of the above examples was concentrated under reduced pressure using an evaporator. Then, it was dissolved in distilled water, freeze-dried at −80 ° C., and the weight after freeze-drying was measured.
定量結果は、上記各実施例のＭＭＰ−１産生抑制剤における含量または乾燥重量（すなわちオオヤマザクラの果実１００ｇの抽出物中における量）として、表１に示した。なお、５０（ｖ／ｖ）％、７５（ｖ／ｖ）％、１００（ｖ／ｖ）％の１，３−ブタンジオールにより抽出して得た実施例４〜６のＭＭＰ−１産生抑制剤については、凍結乾燥することができなかった。 The quantitative results are shown in Table 1 as the content or dry weight in the MMP-1 production inhibitor of each of the above Examples (that is, the amount in the extract of 100 g fruit of the cherry tree). In addition, the MMP-1 production inhibitor of Examples 4-6 obtained by extracting with 50 (v / v)%, 75 (v / v)%, 100 (v / v)% 1,3-butanediol The lyophilization was not possible.
［実施例７］粉末状ＭＭＰ−１産生抑制剤
上記実施例１のＭＭＰ−１産生抑制剤（オオヤマザクラ（Cerasus sargentii (Rehder) H.Ohba）の果実の５０（ｖ／ｖ）％エタノールによる抽出物）を減圧下に濃縮し、次いで凍結乾燥して、実施例７の粉末状ＭＭＰ−１産生抑制剤を得た。
[Example 7] Powdered MMP-1 production inhibitor The extraction of the MMP-1 production inhibitor ( Cerasus sargentii (Rehder) H. Ohba) fruit of Example 1 with 50 (v / v)% ethanol Product) was concentrated under reduced pressure and then freeze-dried to obtain a powdery MMP-1 production inhibitor of Example 7.
［試験例１］ＭＭＰ−１産生抑制効果の評価
実施例７のＭＭＰ−１産生抑制剤を試料として、紫外線（ＵＶＢ）により誘導されるＭＭＰ−１産生に対する抑制効果を評価した。評価方法を以下に示す。
（１）５×１０４ｃｅｌｌｓ／ｍＬのヒト表皮角化細胞（HaCaT Keratinocyte）を各シャーレ（直径１０ｍｍ）に播種し、ＣＯ２インキュベーター（５％ＣＯ２濃度）にて、３７℃でコンフルエント状態になるまで培養した。
なお、培地は、５％牛胎児血清（FBS）含有ダルベッコ変法イーグル培地（Doulbecco’s modified Eagle’s Medium）（DMEM）（ニッスイ）＜１＞（日水製薬株式会社製、code:5915）と、CERTIFIED FOETAL BOVINE SERUM（BIOLOGICAL INDUTRIES社製、cat.04-001-1E）を用いて調製した。
（２）新鮮な培地に交換し、さらに２４時間培養後、Hanks緩衝液（HBSS+）１０ｍＬに交換し、ＵＶＢランプ（ＰＨＩＬＩＰＳ ＢＲＯＡＤＢＡＮＤ ＴＬ２０Ｗ１２ ＲＳ ＵＬＴＲＡＶＩＯＲＥＴ−Ｂ、フィリップス社製）でＵＶＢを照射（８００ｍＪ／ｃｍ２（照射強度０．４８５ｍＷ／ｃｍ２で２７分照射））した。
（３）各濃度の試料を含有する培地５ｍＬに交換し、２４時間培養後、培養上清を回収した。
ここで、試料を添加しないで同様に処理した群、および上記ＵＶＢ照射を行わない群を対照（コントロール）群とした（各群についてｎ＝２）。
（４）細胞密度１×１０５ｃｅｌｌｓ／ｍＬのFibroblast細胞分散液を調製し、各シャーレ（直径３．５ｃｍ）に２ｍＬずつ播種して、ＣＯ２インキュベーター（５％ＣＯ２濃度）にて、３７℃でほぼコンフルエント状態になるまで培養した。
（５）各シャーレの細胞をPBS（−）２ｍＬで１回洗浄した後、上記（３）で回収した各HaCaT Keratinocyte培養上清２ｍＬに交換し、４８時間培養した。
（６）各群の培養上清を回収し、ＥＬＩＳＡ (Enzyme-Linked ImmunoSorbent Assay)法によりＭＭＰ−１を定量した。また、培養上清回収後の各Fibroblast細胞をPBS（−）で１回洗浄した後、０．５％ Triton X-100溶液１ｍＬを添加して細胞を溶解し、BCA protein assay kitを用い、ＢＣＡ法により細胞溶解液のタンパク質を定量した。
なお、ＥＬＩＳＡ法によるＭＭＰ−１の定量は、Quantikine Human Pro-MMP-1 Immunoassay Kit（R&D Systems、Cat.#DMP100）を用い、Ｐｒｏ−ＭＭＰ−１産生量を定量することにより行った。
[Test Example 1] Evaluation of MMP-1 production inhibitory effect Using the MMP-1 production inhibitor of Example 7 as a sample, the inhibitory effect on MMP-1 production induced by ultraviolet light (UVB) was evaluated. The evaluation method is shown below.
(1) 5 × 10 4 cells / mL human epidermal keratinocytes (HaCaT Keratinocyte) are seeded in each petri dish (diameter: 10 mm) and brought to a confluent state at 37 ° C. in a CO 2 incubator (5% CO 2 concentration). Cultured until complete.
The medium is 5% fetal bovine serum (FBS) -containing Dulbecco's modified Eagle's Medium (DMEM) (Nissui) <1> (manufactured by Nissui Pharmaceutical Co., Ltd., code: 5915), CERTIFIED FOETAL It was prepared using BOVINE SERUM (manufactured by BIOLOGICAL INDUTRIES, cat.04-001-1E).
(2) Replaced with fresh medium, further cultured for 24 hours, then replaced with 10 mL of Hanks buffer (HBSS +), and irradiated with UVB with a UVB lamp (PHILIPS BROADBAND TL20W12 RS ULTRAVIORET-B, manufactured by Philips) (800 mJ / cm 2 (irradiation with an irradiation intensity of 0.485 mW / cm 2 for 27 minutes).
(3) The medium was replaced with 5 mL containing each concentration of sample, and after 24 hours of culture, the culture supernatant was collected.
Here, a group treated similarly without adding a sample and a group not subjected to the UVB irradiation were set as a control group (n = 2 for each group).
(4) A Fibroblast cell dispersion liquid having a cell density of 1 × 10 5 cells / mL is prepared, seeded at 2 mL each in a petri dish (diameter 3.5 cm), and 37 in a CO 2 incubator (5% CO 2 concentration). The cells were cultured until almost confluent at 0 ° C.
(5) The cells of each petri dish were washed once with 2 mL of PBS (−), then replaced with 2 mL of each HaCaT Keratinocyte culture supernatant collected in (3) above, and cultured for 48 hours.
(6) The culture supernatant of each group was collected, and MMP-1 was quantified by ELISA (Enzyme-Linked ImmunoSorbent Assay) method. In addition, each Fibroblast cell after collection of the culture supernatant was washed once with PBS (−), 1 mL of 0.5% Triton X-100 solution was added to lyse the cell, and BCA protein assay kit was used for BCA. The protein in the cell lysate was quantified by the method.
The quantification of MMP-1 by ELISA was performed by quantifying the amount of Pro-MMP-1 produced using Quantikine Human Pro-MMP-1 Immunoassay Kit (R & D Systems, Cat. # DMP100).
各群について、タンパク質１ｍｇあたりのＭＭＰ−１量を算出し、図１に示した。図１に示されるように、実施例７のＭＭＰ−１産生抑制剤を添加しないコントロール群では、ＵＶＢ照射によりＭＭＰ−１量が２倍近く増加したが、実施例７のＭＭＰ−１産生抑制剤を添加した群（０．５ｍｇ（乾燥重量）／ｍＬ添加群および１．０ｍｇ（乾燥重量）／ｍＬ添加群）では、有意なＭＭＰ−１量の減少が認められた。オオヤマザクラ果実の抽出物の乾燥重量にして、１．０ｍｇ／ｍＬのＭＭＰ−１産生抑制剤の添加により、紫外線により誘導されるＭＭＰ−１産生は、ＭＭＰ−１産生抑制剤無添加コントロール群の場合の約１／２まで減少した。 For each group, the amount of MMP-1 per 1 mg of protein was calculated and shown in FIG. As shown in FIG. 1, in the control group to which the MMP-1 production inhibitor of Example 7 was not added, the amount of MMP-1 increased nearly twice by UVB irradiation, but the MMP-1 production inhibitor of Example 7 A significant decrease in the amount of MMP-1 was observed in the groups to which (a 0.5 mg (dry weight) / mL addition group and a 1.0 mg (dry weight) / mL addition group) were added. MMP-1 production induced by ultraviolet rays by adding 1.0 mg / mL of MMP-1 production inhibitor in the dry weight of the extract of the fruit of the cherry tree is the MMP-1 production inhibitor-free control group. It was reduced to about 1/2 of the case.
上記結果より、本発明のＭＭＰ−１産生抑制剤は、ＵＶＢにより誘導されるＭＭＰ−１の産生を有意に抑制することが示された。 From the above results, it was shown that the MMP-1 production inhibitor of the present invention significantly suppresses the production of MMP-1 induced by UVB.
次に、本発明の皮膚外用医薬品および皮膚化粧品の処方例を示す。 Next, prescription examples of the external preparation for skin and skin cosmetics of the present invention will be shown.
［実施例８］ローション剤
（１）実施例１のＭＭＰ−１産生抑制剤 ０．５（重量％）
（２）グリセリン ５
（３）ポリエチレングリコール１５００ ２
（４）ポリオキシエチレンオレイルエーテル（１５Ｅ．Ｏ．） ２
（５）エタノール １５
（６）水酸化カリウム ０．０３
（７）パラオキシ安息香酸メチル ０．１
（８）精製水 全量を１００とする量
製法：（１）〜（３）および（６）を（８）に添加して溶解する。（５）に（４）および（７）を溶解して、前記溶液に加えて均一とし、ろ過する。
[Example 8] Lotion agent (1) MMP-1 production inhibitor of Example 1 0.5 (% by weight)
(2) Glycerin 5
(3) Polyethylene glycol 1500 2
(4) Polyoxyethylene oleyl ether (15E.O.) 2
(5) Ethanol 15
(6) Potassium hydroxide 0.03
(7) Methyl paraoxybenzoate 0.1
(8) Purified water Amount with a total amount of 100 Manufacturing method: Add (1) to (3) and (6) to (8) and dissolve. Dissolve (4) and (7) in (5), add to the solution and homogenize and filter.
［実施例９］水中油型乳剤性軟膏
（１）白色ワセリン ２５．０（重量％）
（２）ステアリルアルコール ２５．０
（３）グリセリン １２．０
（４）ラウリル硫酸ナトリウム １．０
（５）パラオキシ安息香酸メチル ０．１
（６）精製水 全量を１００とする量
（７）実施例７のＭＭＰ−１産生抑制剤 ０．０５
製法：（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、（５）を（６）に溶解して７５℃に加熱し、これに前記油相成分を添加して乳化し、冷却後４０℃にて（７）を添加、混合する。
[Example 9] Oil-in-water emulsion ointment (1) White petrolatum 25.0 (% by weight)
(2) Stearyl alcohol 25.0
(3) Glycerin 12.0
(4) Sodium lauryl sulfate 1.0
(5) Methyl paraoxybenzoate 0.1
(6) Purified water Amount that makes the total amount 100 (7) MMP-1 production inhibitor of Example 0.05 0.05
Production method: The oil phase components (1) to (4) are mixed, dissolved and made uniform, and heated to 75 ° C. On the other hand, (5) is dissolved in (6) and heated to 75 ° C., the oil phase component is added thereto to emulsify, and after cooling, (7) is added and mixed at 40 ° C.
［実施例１０］水中油型クリーム
（１）１，３−ブタンジオール ５（重量％）
（２）グリセリン １０
（３）キサンタンガム ０．１５
（４）クエン酸ナトリウム ０．１
（５）エデト酸二ナトリウム ０．０１
（６）パラオキシ安息香酸メチル ０．１２
（７）エタノール ２
（８）実施例１のＭＭＰ−１産生抑制剤 ０．５
（９）ジオクチルカルボン酸 ３
（１０）バチルアルコール １．８
（１１）ベヘニルアルコール １．２
（１２）マイクロクリスタリンワックス １
（１３）ミツロウ ２．５
（１４）キャンデリラロウ ０．８
（１５）水素添加パーム油 ２．５
（１６）ヘキサメチルシクロトリシロキサン ２５
（１７）スクワラン ３
（１８）精製ホホバ油 ２
（１９）マカデミアナッツ油 １
（２０）ポリヒドロキシステアリン酸 ０．２
（２１）トリポリヒドロキシステアリン酸ジペンタエリスリチル ０．３
（２２）香料 ０．０２
（２３）精製水 全量を１００とする量
製法：（２３）に（１）〜（６）を添加、溶解して７０℃〜７５℃に加熱する（水相成分）。（９）〜（２１）を混合し、７０℃〜７５℃に加熱して均一とする（油相成分）。前記水相成分を撹拌しながら、前記油相成分を徐々に添加して乳化する。４０℃まで冷却した後、（７）に溶解した（８）、および（２２）を順次添加して混合し、均一とする。
[Example 10] Oil-in-water cream (1) 1,3-butanediol 5 (% by weight)
(2) Glycerin 10
(3) Xanthan gum 0.15
(4) Sodium citrate 0.1
(5) Edetate disodium 0.01
(6) Methyl paraoxybenzoate 0.12
(7) Ethanol 2
(8) MMP-1 production inhibitor of Example 1 0.5
(9) Dioctylcarboxylic acid 3
(10) Batyl alcohol 1.8
(11) Behenyl alcohol 1.2
(12) Microcrystalline wax 1
(13) Beeswax 2.5
(14) Candelilla wax 0.8
(15) Hydrogenated palm oil 2.5
(16) Hexamethylcyclotrisiloxane 25
(17) Squalane 3
(18) Refined jojoba oil 2
(19) Macadamia nut oil 1
(20) Polyhydroxystearic acid 0.2
(21) Dipentaerythrityl tripolyhydroxystearate 0.3
(22) Perfume 0.02
(23) Purified water A mass production method in which the total amount is 100: (1) to (6) are added to (23), dissolved and heated to 70 ° C. to 75 ° C. (water phase component). (9) to (21) are mixed and heated to 70 ° C to 75 ° C to make uniform (oil phase component). While stirring the aqueous phase component, the oil phase component is gradually added to emulsify. After cooling to 40 ° C., (8) and (22) dissolved in (7) are sequentially added and mixed to make uniform.
以上詳述したように、本発明により、ＭＭＰ−１産生に対し、優れた抑制効果を有するＭＭＰ−１産生抑制剤を提供することができる。
本発明のＭＭＰ−１産生抑制剤は、加齢、紫外線等の外的刺激により誘導されるＭＭＰ−１の産生を良好に抑制することができるため、特に皮膚において、ＭＭＰ−１による細胞外マトリックス成分の分解を抑制し、加齢、紫外線等による皮膚の老化を良好に防止または改善することができる。
また、本発明のＭＭＰ−１産生抑制剤は、皮膚に対する刺激性等、安全性および使用性においても問題はなく、有利である。
As described above in detail, according to the present invention, an MMP-1 production inhibitor having an excellent inhibitory effect on MMP-1 production can be provided.
Since the MMP-1 production inhibitor of the present invention can satisfactorily suppress the production of MMP-1 induced by external stimuli such as aging and ultraviolet rays, the extracellular matrix by MMP-1 particularly in the skin. The decomposition of the components can be suppressed, and aging of the skin due to aging, ultraviolet rays, etc. can be prevented or improved satisfactorily.
Moreover, the MMP-1 production inhibitor of the present invention is advantageous because it has no problems in terms of safety and usability such as irritation to the skin.
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