JP2012025706A - Antioxidant and use thereof - Google Patents
Antioxidant and use thereof Download PDFInfo
- Publication number
- JP2012025706A JP2012025706A JP2010167235A JP2010167235A JP2012025706A JP 2012025706 A JP2012025706 A JP 2012025706A JP 2010167235 A JP2010167235 A JP 2010167235A JP 2010167235 A JP2010167235 A JP 2010167235A JP 2012025706 A JP2012025706 A JP 2012025706A
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- JP
- Japan
- Prior art keywords
- mel
- antioxidant
- skin
- oil
- acid
- 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.)
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- 239000003963 antioxidant agent Substances 0.000 title claims abstract description 75
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- 125000001424 substituent group Chemical group 0.000 claims description 27
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- 238000002156 mixing Methods 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 13
- 150000004670 unsaturated fatty acids Chemical class 0.000 claims description 13
- 125000001931 aliphatic group Chemical group 0.000 claims description 12
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
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- 230000003712 anti-aging effect Effects 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
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Landscapes
- Cosmetics (AREA)
Abstract
Description
本発明は、糖脂質の一種であるマンノシルエリスリトールリピッド(以下、単にMELと称する場合もある。)を含有する抗酸化剤及びその利用に関し、例えば、微生物が生産するMELであって、分子構造中のマンノシルエリスリトール骨格が、4−O−β−D−マンノピラノシル−meso−エリスリトールあるいは1−O−β−D−マンノピラノシル−meso−エリスリトールであるMELを含有する抗酸化剤及びその利用に関するものである。 The present invention relates to an antioxidant containing mannosylerythritol lipid (hereinafter sometimes simply referred to as MEL), which is a type of glycolipid, and its use. The present invention relates to an antioxidant containing MEL in which the mannosylerythritol skeleton is 4-O-β-D-mannopyranosyl-meso-erythritol or 1-O-β-D-mannopyranosyl-meso-erythritol, and use thereof.
紫外線により活性酸素が発生することはよく知られている。活性酸素のうち、フリーラジカル型のものは脂質などの酸化性基質と反応すると、連鎖的な酸化反応を誘発する。このため、フリーラジカルとなる活性酸素は、皮膚等の身体組織に対して直接ダメージを与えるのみならず、連鎖的に過酸化脂質を増加させることによりダメージを増幅させる。 It is well known that active oxygen is generated by ultraviolet rays. Among active oxygens, free radicals react with an oxidizable substrate such as lipid to induce a chain oxidation reaction. For this reason, active oxygen which becomes free radicals not only directly damages body tissues such as skin, but also amplifies damage by increasing lipid peroxide in a chain.
皮膚は、常時、酸素や紫外線にさらされるため、活性酸素による酸化ストレスのダメージが最も大きな組織である。近年では、紫外線により発生した種々の活性酸素が、皮脂や脂質の過酸化、タンパク質変性、酵素阻害等を引き起こし、それが、短期的には皮膚の炎症などを誘発することが知られている。また、長期的には、老化やガンなどの原因となると考えられている。また、活性酸素や過酸化脂質は、アトピー性皮膚炎や接触皮膚炎、乾癬などの皮膚疾患にも関与すると報告されている。このように、皮膚老化や皮膚疾患には、活性酸素(特に、フリーラジカル型のもの)が深く関与している。 Since the skin is always exposed to oxygen and ultraviolet rays, it is a tissue that is most damaged by oxidative stress due to active oxygen. In recent years, various active oxygens generated by ultraviolet rays are known to cause peroxidation of sebum and lipids, protein denaturation, enzyme inhibition, and the like, which induce skin inflammation in the short term. In the long term, it is thought to cause aging and cancer. Active oxygen and lipid peroxide are also reported to be involved in skin diseases such as atopic dermatitis, contact dermatitis, and psoriasis. Thus, active oxygen (especially free radical type) is deeply involved in skin aging and skin diseases.
フリーラジカルを捕捉する能力を備える物質は、ラジカル連鎖反応を抑制したり、停止させたりすることができ、例えば抗酸化剤と呼ばれているものが相当する。それゆえ、抗酸化剤を配合した皮膚外用剤は、光酸化ストレスによる皮膚老化(例えば、シミ、しわ、たるみなど)に予防・改善効果が期待できる。また、フリーラジカルが関連する各種皮膚疾患用の皮膚外用剤としても、予防・改善効果が期待できる。 A substance having the ability to trap free radicals can suppress or stop the radical chain reaction, and for example, what is called an antioxidant is equivalent. Therefore, a skin external preparation containing an antioxidant can be expected to have a preventive / improving effect on skin aging (for example, spots, wrinkles, sagging) due to photooxidative stress. In addition, a preventive / improving effect can be expected as a skin external preparation for various skin diseases related to free radicals.
一方、酸化防止剤として知られているビタミンEやビタミンCは、生体内におけるフリーラジカル捕捉型の抗酸化物質である。また、BHTやBHAといった合成抗酸化物質も知られている。また、植物由来の酸化防止剤としては、シイタケ、エノキタケ、シメジ、カワラタケ、マツタケ、マンネンタケ、ホウウロクタケ、ナメコ、その他の担子菌類の抽出物が報告されている(特許文献1〜3)。さらに、ゴマノハグサ科モウズイカ属植物の抽出物からなる抗酸化剤や(特許文献4)、ムラサキ科カキバチシャノキ属植物の抽出物からなる抗酸化剤(特許文献5)が報告されている。 On the other hand, vitamin E and vitamin C known as antioxidants are free radical scavenging antioxidants in vivo. Synthetic antioxidants such as BHT and BHA are also known. In addition, as plant-derived antioxidants, extracts of shiitake, enokitake, shimeji, kawatake, matsutake, garlic mushroom, spinach, nameko, and other basidiomycetes have been reported (Patent Documents 1 to 3). Furthermore, an antioxidant composed of an extract of the genus Solanum spp. (Patent Document 4) and an antioxidant composed of an extract of the plant of the genus Pleurotus (Patent Document 5) have been reported.
ところで、糖脂質は、糖の性質に由来する親水性と脂質の性質に由来する親油性の二つの性質を合わせ持つ両親媒性物質であり、このような性質を有する物質は界面活性物質と呼ばれている。石油化学工業が隆盛となるまでは、レシチン、サポニン等の生体成分由来の界面活性剤(バイオサーファクタント)が利用されてきたが、石油化学工業の発展により合成界面活性剤が開発され、界面活性剤の生産量は飛躍的に増加し、日常生活には無くてはならない物質となった。しかしながら、合成界面活性剤の使用量の拡大につれて環境汚染が広がってきた。そこで、安全性が高く、環境に対する負荷を低減するために、再度生分解性の高い界面活性物質であるバイオサーファクタントが見直されており、それに伴い様々な種類のバイオサーファクタントの開発が望まれている。 By the way, glycolipids are amphiphilic substances that have both hydrophilic properties derived from the properties of sugars and lipophilic properties derived from the properties of lipids. Substances having such properties are called surfactant substances. It is. Until the petrochemical industry flourished, surfactants derived from biological components such as lecithin and saponin (biosurfactants) have been used, but synthetic surfactants have been developed by the development of the petrochemical industry. The production volume of cereals has increased dramatically, making it an indispensable substance in daily life. However, environmental pollution has spread as the amount of synthetic surfactant used has increased. Therefore, biosurfactants, which are highly biodegradable surfactants, have been reviewed again in order to reduce the burden on the environment with high safety, and development of various types of biosurfactants is desired accordingly. .
バイオサーファクタントとしては、微生物が生産する界面活性物質が代表的なものとして挙げられる。現在、上述した微生物が生産する界面活性物質としては、糖型、アシルペプタイド型、リン脂質型、脂肪酸型及び高分子化合物型の5つに大別されている。これらのうち、リン脂質型バイオサーファクタントは、古くから乳化剤として用いられているばかりでなく、水に懸濁させると、このリン脂質が会合して二分子膜を形成し、水相を閉じこめたベシクルを形成することが知られている。このベシクルは、リポソームとも呼ばれ、生体膜のモデルや、化粧品や薬物の担体としても極めて利用価値が高い。 A typical example of a biosurfactant is a surfactant produced by a microorganism. At present, the above-mentioned surfactants produced by microorganisms are roughly classified into five types: sugar type, acyl peptide type, phospholipid type, fatty acid type, and polymer compound type. Among these, phospholipid-type biosurfactant has long been used as an emulsifier, but when suspended in water, this phospholipid associates to form a bilayer and confine the aqueous phase. Is known to form. This vesicle is also called a liposome, and is very useful as a model for biological membranes, as a carrier for cosmetics and drugs.
代表的な糖型バイオサーファクタントの一つにマンノシルエリスリトールリピッド(MEL)がある。MELは、ウスチラゴ ヌーダ(Ustilago nuda)とシゾネラ メラノグラマ(Shizonella melanogramma)から発見された物質である(非特許文献1,2参照)。その後、イタコン酸生産の変異株であるキャンデダ(Candida)属酵母(特許文献1及び非特許文献3参照)、キャンデダ アンタークチカ(Candida antarctica)(現在はシュードザイマ アンタークチカ(Pseudozyma antarctica))(非特許文献4,5参照)、クルツマノマイセス(Kurtzmanomyces)属(非特許文献6参照)等の酵母らによっても生産されることが報告されている。現在では、長時間の連続培養・生産を行うことで300g/L以上の生産が可能となっている。 One typical sugar type biosurfactant is mannosyl erythritol lipid (MEL). MEL is a substance discovered from Ustyago nuda and Shizonella melanogramma (see Non-Patent Documents 1 and 2). Thereafter, yeasts of the genus Candida (see Patent Document 1 and Non-Patent Document 3) that are mutant strains of itaconic acid production, Candida antarctica (currently Pseudozyma antarctica) (Non-patent Document 4, 5) and yeasts of the genus Kurtzmanomyces (see Non-Patent Document 6) have been reported. At present, production of 300 g / L or more is possible by continuous culture and production for a long time.
上記MELが有する糖骨格には複数の不斉炭素原子が存在し、その数をnとすると2n個の光学異性体が存在する。しかし、これまで報告されてきたMELは全て、その糖骨格が以下の式(3)に示されるような4−O−β−D−マンノピラノシル−meso−エリスリトール構造であった。 The sugar skeleton possessed by the MEL has a plurality of asymmetric carbon atoms. When the number is n, 2n optical isomers exist. However, all the MELs reported so far have a 4-O-β-D-mannopyranosyl-meso-erythritol structure whose sugar skeleton is represented by the following formula (3).
β−D−マンノピラノシル−meso−エリスリトール構造には、もう一つ1−O−β−D−マンノピラノシル−meso−エリスリトール構造(下記式(4))の異性体が想定される。 As the β-D-mannopyranosyl-meso-erythritol structure, another isomer of 1-O-β-D-mannopyranosyl-meso-erythritol structure (the following formula (4)) is assumed.
この1−O−β−D−マンノピラノシル−meso−エリスリトール構造を有するMELの1種を合成し、これとの比較によって従来のMELの糖骨格が上記式(3)の構造であることが証明されている(非特許文献7)。ごく最近、従来の4−O−β−D−マンノピラノシル−meso−エリスリトール構造を有するMELに対して、その光学異性体である上記式(4)の1−O−β−D−マンノピラノシル−meso−エリスリトール構造を有するMELをシュードザイマ・ツクバエンシス(Pseudozyma tsukubaensis)又はシュードザイマ・クラッサ(Pseudozyma crassa)等の微生物を用いて生産することによって、量産できることが判明した(非特許文献8)。 By synthesizing one kind of MEL having this 1-O-β-D-mannopyranosyl-meso-erythritol structure, it was proved that the sugar skeleton of the conventional MEL has the structure of the above formula (3). (Non-patent Document 7). Most recently, the MEL having a conventional 4-O-β-D-mannopyranosyl-meso-erythritol structure is an optical isomer of 1-O-β-D-mannopyranosyl-meso- of the above formula (4). It has been found that MEL having an erythritol structure can be mass-produced by producing it using a microorganism such as Pseudozyma tsukubaensis or Pseudozyma crassa (Non-patent Document 8).
従来の4−O−β−D−マンノピラノシル−meso−エリスリトール構造を有するMELについては、抗菌性、抗腫瘍性、糖タンパク結合能をはじめ、様々な生理活性を有することが報告されている(非特許文献9)。また、この従来のMELは極めて特異な自己集合特性を示し、分子構造の僅かな違いが自己集合体の形成に多大な影響を与えるばかりでなく、それを活用したベシクル形成について、希薄溶液(6.3×10−2wt%以下)においてのみ報告されている(非特許文献10)。 MEL having a conventional 4-O-β-D-mannopyranosyl-meso-erythritol structure has been reported to have various physiological activities including antibacterial properties, antitumor properties, glycoprotein binding ability (non- Patent Document 9). In addition, this conventional MEL exhibits extremely unique self-assembly characteristics, and not only a slight difference in molecular structure greatly affects the formation of self-assemblies, but also dilute solutions (6 3 × 10 −2 wt% or less) (non-patent document 10).
また、MELの外用剤や化粧品としての用途として、抗炎症剤及び抗アレルギー剤(特許文献6)、養毛・育毛剤(特許文献7)としての有用性や、抗菌作用(特許文献8)や界面張力低下作用(特許文献9)が知られている。さらに、細胞賦活化剤やこれを利用した皮膚外用剤等への用途も報告されている(特許文献10)。 In addition, as a use of MEL as an external preparation or cosmetic, useful as an anti-inflammatory agent and an antiallergic agent (Patent Document 6), a hair nourishing / hair-growth agent (Patent Document 7), an antibacterial action (Patent Document 8), An interfacial tension reducing action (Patent Document 9) is known. Furthermore, the use to a cell activation agent, the skin external preparation using the same, etc. is also reported (patent document 10).
皮膚への高い保湿効果及び細胞の賦活化効果を有するスキンケア剤、毛髪に滑らかさ、しっとり感、つや等を付与するヘアケア剤として、化粧品への実用化が進んでいる機能性化粧品素材であるMELについて、新たな機能を開発し、付加価値を高めていくことは、実用上、極めて重要な課題である。 MEL is a functional cosmetic material that has been put to practical use in cosmetics as a skin care agent that has a high moisturizing effect on the skin and a cell activation effect, and a hair care agent that imparts smoothness, moisturization, gloss, etc. to hair. Developing new functions and increasing added value is an extremely important issue for practical use.
本発明は、上記の課題に鑑みてなされたものであり、D−マンノピラノシル−meso−エリスリトール構造を有するMELの新たな機能を開発し、その用途を提供することにある。 The present invention has been made in view of the above-mentioned problems, and is to develop a new function of MEL having a D-mannopyranosyl-meso-erythritol structure and provide its use.
上記の課題を解決するために、本発明者等が鋭意検討を行った結果、MELにフリーラジカル捕捉能があり、抗酸化剤として有用であることを見出し、本発明を完成するに至った。すなわち、本発明は以下の発明を包含する。
1.下記一般式(1)あるいは(2)で表される構造を有するマンノシルエリスリトールリピッドを含有する抗酸化剤。
As a result of intensive studies by the present inventors in order to solve the above problems, the present inventors have found that MEL has a free radical scavenging ability and is useful as an antioxidant, thereby completing the present invention. That is, the present invention includes the following inventions.
1. An antioxidant containing mannosyl erythritol lipid having a structure represented by the following general formula (1) or (2).
(式(1),(2)中、置換基R1は同一でも異なっていてもよく炭素数4〜24の脂肪族アシル基であり、置換基R2は同一でも異なっていてもよく水素又はアセチル基を表す。また、置換基R3は水素又は炭素数2〜24の脂肪族アシル基を表す。)
2.上記一般式(1)あるいは(2)で表される構造を有するマンノシルエリスリトールリピッドにおける不飽和脂肪酸の含量が10%以上である1に記載の抗酸化剤。
3.上記1又は2に記載の抗酸化剤を有効成分として含有する活性酸素消去剤。
4.上記1に記載の抗酸化剤を含有する抗酸化用の皮膚外用剤。
5.上記1に記載の抗酸化剤を配合する工程を有する抗酸化用の皮膚外用剤の製造方法。
6.皮膚の抗酸化及び/又は抗老化のための化粧処置方法であって、上記1に記載の抗酸化剤を含有する組成物を皮膚に適用する化粧処置方法。
(In the formulas (1) and (2), the substituent R 1 may be the same or different and may be an aliphatic acyl group having 4 to 24 carbon atoms, and the substituent R 2 may be the same or different from hydrogen or Represents an acetyl group, and the substituent R 3 represents hydrogen or an aliphatic acyl group having 2 to 24 carbon atoms.
2. 2. The antioxidant according to 1, wherein the content of unsaturated fatty acid in the mannosyl erythritol lipid having the structure represented by the general formula (1) or (2) is 10% or more.
3. The active oxygen scavenger which contains the antioxidant of said 1 or 2 as an active ingredient.
4). Antioxidant skin external preparation containing the antioxidant of 1 above.
5. A method for producing an anti-oxidant skin external preparation comprising a step of blending the antioxidant described in 1 above.
6). A cosmetic treatment method for antioxidation and / or anti-aging of the skin, wherein the composition comprising the antioxidant according to the above 1 is applied to the skin.
本発明に係る抗酸化剤は、MELを有効成分として含有するため、優れた抗酸化効果を奏する。特に、フリーラジカル捕捉能、活性酸素消去能、酸化ストレス防御能を有する。このため、皮膚の酸化を抑制し、シミ、シワ、たるみなどの皮膚の弾力性低下等の老化、皮膚の炎症、肌の色素沈着等の予防用あるいは治療用の用途に利用可能である。 Since the antioxidant according to the present invention contains MEL as an active ingredient, it has an excellent antioxidant effect. In particular, it has free radical scavenging ability, active oxygen scavenging ability, and oxidative stress protection ability. For this reason, it suppresses the oxidation of the skin and can be used for preventive or therapeutic uses such as aging such as skin elasticity reduction such as spots, wrinkles and sagging, skin inflammation, and skin pigmentation.
また、有効成分であるMELは、生体への安全性が高く、細胞に対する賦活化効果や皮膚への保湿効果をも有するため、化粧品等の皮膚外用剤へと適用できる、優れた機能性材料である。 In addition, MEL, which is an active ingredient, is an excellent functional material that can be applied to skin external preparations such as cosmetics because it has high safety to the living body and also has an activating effect on cells and a moisturizing effect on the skin. is there.
<1.抗酸化剤>
本発明に係る抗酸化剤は、上記一般式(1)あるいは(2)で表される構造を有するMELを含有するものであればよく、その他の構成は特に限定されるものではない。以下、本発明の特徴部分であるMELについて説明する。
<1. Antioxidant>
The antioxidant which concerns on this invention should just contain MEL which has a structure represented by the said General formula (1) or (2), and another structure is not specifically limited. Hereinafter, the MEL which is a characteristic part of the present invention will be described.
<1−1.マンノシルエリスリトールリピッド(MEL)>
MELにはマンノースとエリスリトールの結合様式から、1−O−β−D−マンノピラノシル−meso−エリスリトール構造を有するMEL(上記一般式(1)で表される構造を有するMEL)と、その光学異性体である4−O−β−D−マンノピラノシル−meso−エリスリトール構造を有するMEL(上記一般式(2)で表される構造を有するMEL)の大きく二種類に分けられる。本発明では、上記いずれのMELも使用することができる。
<1-1. Mannosyl erythritol lipid (MEL)>
MEL includes MEL having a 1-O-β-D-mannopyranosyl-meso-erythritol structure (MEL having a structure represented by the above general formula (1)) and optical isomers thereof, based on the binding mode of mannose and erythritol. MEL having a 4-O-β-D-mannopyranosyl-meso-erythritol structure (MEL having a structure represented by the above general formula (2)) is roughly divided into two types. In the present invention, any of the above MELs can be used.
上記一般式(1),(2)中、置換基R1は同一でも異なっていてもよく炭素数4〜24の脂肪族アシル基である。置換基R1は飽和脂肪族アシル基であっても不飽和脂肪族アシル基であってもよく、限定されるものではない。不飽和結合を有している場合、複数の二重結合を有していてもよい。炭素鎖は直鎖状であってもよく分岐鎖状であってもよい。また、酸素原子含有炭化水素基の場合、含まれる酸素原子の数及び位置は限定されない。置換基R2は同一でも異なっていてもよく水素又はアセチル基を表す。 In the above general formulas (1) and (2), the substituents R 1 may be the same or different and are aliphatic acyl groups having 4 to 24 carbon atoms. The substituent R 1 may be a saturated aliphatic acyl group or an unsaturated aliphatic acyl group, and is not limited. When it has an unsaturated bond, it may have a plurality of double bonds. The carbon chain may be linear or branched. In the case of an oxygen atom-containing hydrocarbon group, the number and position of oxygen atoms contained are not limited. The substituent R 2 may be the same or different and represents hydrogen or an acetyl group.
MELの中で、特に抗酸化剤への使用が好ましいMELとして、上記一般式(1),(2)中、置換基R1または置換基R3おける不飽和脂肪酸の含量が10%以上のMELが好ましく、また20%以上、30%以上、40%以上、50%以上のMELが好ましく、60%以上がより好ましく、また70%以上がより好ましく、さらには不飽和脂肪酸の含量が80%以上、90%以上のMELが好ましい。後述の実施例に示すように、不飽和脂肪酸の含量が増加するにつれ、抗酸化能が高まる傾向があるためである。 Among the MELs, MELs that are particularly preferred for use as antioxidants are those in which the content of unsaturated fatty acids in the substituents R 1 or R 3 in the general formulas (1) and (2) is 10% or more. MEL of 20% or more, 30% or more, 40% or more, 50% or more is preferable, 60% or more is more preferable, 70% or more is more preferable, and the content of unsaturated fatty acid is 80% or more 90% or more of MEL is preferred. This is because the antioxidant ability tends to increase as the content of unsaturated fatty acid increases, as shown in the Examples described later.
本明細書でいう「不飽和脂肪酸の含量」とは、MEL分子中の脂肪酸の不飽和度のことをいい、具体的には上記一般式(1),(2)中、置換基R1または置換基R3における脂肪族アシル基における脂肪酸の不飽和度をいい、GC/MS分析での重量(%)により測定することができる。例えば、後述する実施例に示すように、アジレント・テクノロジー社製のGC−MS装置6890および5973Nを用い、添付のマニュアルにしたがって測定することができる。より具体的には、「脂肪酸の不飽和度(重量%)」は、MELを塩酸メタノール存在下で分解し、脂肪酸部位をヘキサンで抽出し、GC/MS分析によって、ヘキサン抽出液中の全脂肪酸の重量を分母とし、不飽和脂肪酸(1つ以上の炭素−炭素二重結合を有する脂肪酸)の重量を分子として、100をかけて算出する。 As used herein, “content of unsaturated fatty acid” refers to the degree of unsaturation of fatty acids in the MEL molecule. Specifically, in the general formulas (1) and (2), the substituent R 1 or It refers to the degree of unsaturation of the fatty acid in the aliphatic acyl group in the substituent R 3 and can be measured by weight (%) in GC / MS analysis. For example, as shown in the Example mentioned later, it can measure according to an attached manual using GC-MS apparatus 6890 and 5973N made from Agilent Technologies. More specifically, the “unsaturation degree of fatty acid (% by weight)” is determined by decomposing MEL in the presence of methanol and extracting the fatty acid site with hexane, and analyzing all the fatty acids in the hexane extract by GC / MS analysis. And the weight of the unsaturated fatty acid (fatty acid having one or more carbon-carbon double bonds) as a numerator.
また、「不飽和脂肪酸」とは、1つ以上の不飽和の炭素結合をもつ脂肪酸であり、上記一般式(1),(2)中、置換基R1における炭素数4〜24の脂肪族アシル基に含まれ得るもの、または置換基R3における炭素数2〜24の脂肪族アシル基に含まれ得るものであればよく、その具体的な組成については特に限定されない。不飽和炭素結合とは炭素分子鎖における炭素同士の不飽和結合、すなわち炭素二重結合または三重結合のことである。不飽和脂肪酸としては、例えば、9−ヘキサデセン酸(パルミトレイン酸)、cis−9−オクタデセン酸(オレイン酸)、11−オクタデセン酸(バクセン酸)、cis,cis−9,12−オクタデカジエン酸(リノール酸)、9,12,15−オクタデカトリエン酸(α−リノレン酸)、6,9,12−オクタデカトリエン酸(γ−リノレン酸)、9,11,13−オクタデカトリエン酸(エレオステアリン酸)等を挙げることができる。 The “unsaturated fatty acid” is a fatty acid having one or more unsaturated carbon bonds, and the aliphatic group having 4 to 24 carbon atoms in the substituent R 1 in the general formulas (1) and (2). those may be included in the acyl group, or may be those which may be contained in the aliphatic acyl group having from 2 to 24 carbon atoms in the substituent R 3, there is no particular limitation on its specific composition. An unsaturated carbon bond is an unsaturated bond between carbons in a carbon molecular chain, that is, a carbon double bond or a triple bond. Examples of unsaturated fatty acids include 9-hexadecenoic acid (palmitoleic acid), cis-9-octadecenoic acid (oleic acid), 11-octadecenoic acid (vaccenic acid), cis, cis-9,12-octadecadienoic acid ( Linoleic acid), 9,12,15-octadecatrienoic acid (α-linolenic acid), 6,9,12-octadecatrienoic acid (γ-linolenic acid), 9,11,13-octadecatrienoic acid (d) Leostearic acid) and the like.
また、後述の実施例に示すように、上記一般式(1)で表される構造を有するMELと、その光学異性体である上記一般式(2)で表される構造を有するMELとで抗酸化能を比べると、一般式(2)で表される構造を有するMELの方が優れているため、より好ましい。 Further, as shown in the examples described later, the MEL having the structure represented by the general formula (1) and the MEL having the structure represented by the general formula (2), which is an optical isomer thereof, are resistant. When comparing the oxidation ability, the MEL having the structure represented by the general formula (2) is more preferable because it is superior.
4−O−β−D−マンノピラノシル−meso−エリスリトール構造を有するMELを例として、MEL−A〜Dについて説明する。 MEL-A to D will be described by taking MEL having a 4-O-β-D-mannopyranosyl-meso-erythritol structure as an example.
上記一般式(5)中、置換基Rは炭化水素基(アルキル基又はアルケニル基)である。MELは、マンノースの4位及び6位のアセチル基の有無からMEL−A、MEL−B、MEL−C及びMEL−Dの4種類が知られている。MEL−Aは、上記一般式(5)中、置換基R1及びR2がともにアセチル基である。MEL−Bは、上記一般式(5)中、置換基R1がアセチル基で置換基R2は水素である。MEL−Cは、上記一般式(5)中、置換基R1が水素で置換基R2はアセチル基である。MEL−Dは、上記一般式(5)中、置換基R1及びR2がともに水素である。 In the general formula (5), the substituent R is a hydrocarbon group (an alkyl group or an alkenyl group). Four types of MEL are known, MEL-A, MEL-B, MEL-C, and MEL-D, depending on the presence or absence of acetyl groups at the 4-position and 6-position of mannose. In MEL-A, in the general formula (5), the substituents R 1 and R 2 are both acetyl groups. In MEL-B, in the general formula (5), the substituent R 1 is an acetyl group, and the substituent R 2 is hydrogen. In MEL-C, in general formula (5), substituent R 1 is hydrogen and substituent R 2 is an acetyl group. In MEL-D, in the general formula (5), the substituents R 1 and R 2 are both hydrogen.
上記MEL−A〜MEL−Dにおける置換基Rの炭素数は、MEL生産培地に含有させる油脂類中のトリグリセリドを構成する脂肪酸の炭素数及び使用するMEL生産菌の脂肪酸の資化の程度により変化する。また、上記トリグリセリドが不飽和脂肪酸残基を有する場合、MEL生産菌が上記不飽和脂肪酸の二重結合部分まで資化しなければ、置換基Rとして不飽和脂肪酸残基を含ませることも可能である。以上の説明から明らかなように、得られる各MELは、通常、置換基Rの脂肪酸残基部分が異なる化合物の混合物の形態である。 The carbon number of the substituent R in the above MEL-A to MEL-D varies depending on the carbon number of the fatty acid constituting the triglyceride in the fats and oils contained in the MEL production medium and the degree of utilization of the fatty acid of the MEL-producing bacterium used. To do. In addition, when the triglyceride has an unsaturated fatty acid residue, an unsaturated fatty acid residue can be included as the substituent R if the MEL-producing bacterium does not assimilate up to the double bond portion of the unsaturated fatty acid. . As is clear from the above description, each obtained MEL is usually in the form of a mixture of compounds in which the fatty acid residue portion of the substituent R is different.
例えば、MEL−A(アセチル基が2個)に比べて、MEL−B又はMEL−C(アセチル基が1個)は極性が高く、水中での自己組織化挙動が異なる。このため、形成される液晶の形態が異なり、MEL−Aでは幅広い濃度領域でスポンジ相(L3相)等を作るのに対して、MEL−B又はMEL−Cではラメラ相(Lα)を作りやすい。ラメラ相は肌の角質層と非常に近い形態ですので、肌浸透性が良くなり、スキンケア素材として有用である。さらに、MEL−Bは2分子膜がカプセル化したベシクル(リポソーム)を形成しやすく、カプセル内に薬剤を内包できることから、リポソーム化粧品、医薬品への応用が容易になると期待される(上記非特許文献8,9参照)。 For example, compared with MEL-A (two acetyl groups), MEL-B or MEL-C (one acetyl group) has higher polarity and different self-organization behavior in water. Therefore, unlike the liquid crystal of the form to be formed, with respect to making the sponge phase in MEL-A in wide concentration region (L 3 phase), etc., MEL-B or MEL-C in lamellar phase (L alpha) Easy to make. The lamellar phase is very close to the stratum corneum of the skin, so it has good skin penetration and is useful as a skin care material. Furthermore, since MEL-B can easily form vesicles (liposomes) encapsulated in bilayer membranes and encapsulate drugs in capsules, it is expected to be easily applied to liposome cosmetics and pharmaceuticals (the above non-patent document). (See 8, 9).
また、本発明に利用可能なMELには、トリアシル体MELも含まれる。一般式(1),(2)中、置換基R1及びR3がいずれも脂肪族アシル基であれば、トリアシルMELとなり、ジアシルMELとは異なった性質のMELを得ることができる。 The MEL that can be used in the present invention includes a triacyl MEL. In the general formulas (1) and (2), if both of the substituents R 1 and R 3 are aliphatic acyl groups, they are triacyl MELs, and MELs having properties different from those of diacyl MELs can be obtained.
トリアシル体のMELは、従来のジアシル体と比べてHLB(親水−疎水バランス)が低く、より親油性の高い界面活性剤である。このため、応用用途が異なってくる。例えば、W/Oエマルジョンや分散剤等への利用が考えられる。 Triacyl MEL has a lower HLB (hydrophilic-hydrophobic balance) than conventional diacyl and is a more lipophilic surfactant. For this reason, application uses differ. For example, utilization to a W / O emulsion, a dispersing agent, etc. can be considered.
MELの分子構造は、基本的には上記一般式(1),(2)における置換基R1の脂肪族アシル基の炭素数あるいは二重結合の有無等において異なる各化合物の混合物の形態で得られるが、これらはさらに分取HPLC等により精製すれば、単一のMEL化合物とすることもできる。もちろん、本発明の抗酸化剤に使用するMELは、単一のMEL化合物であってもよいし、また置換基Rの脂肪酸残基部分が異なるMEL化合物の混合物の形態であってもよい。 The molecular structure of MEL is basically obtained in the form of a mixture of compounds that differ in the number of carbons of the aliphatic acyl group of the substituent R 1 in the above general formulas (1) and (2) or the presence or absence of a double bond. However, these can be converted into a single MEL compound by further purification by preparative HPLC or the like. Of course, the MEL used for the antioxidant of the present invention may be a single MEL compound or may be in the form of a mixture of MEL compounds in which the fatty acid residue portion of the substituent R is different.
MELは、幅広い濃度・温度範囲においてベシクルを形成可能であることや、各種エマルション・マイクロエマルションなどの乳化組成物を容易に得ることができる。さらにMELは生分解性があり、高い安全性を有する点でも非常に意義ある物質である。つまり、生分解性が高く、低毒性で環境に優しいバイオサーファクタントである。 MEL can form vesicles in a wide range of concentrations and temperatures, and can easily obtain emulsified compositions such as various emulsions and microemulsions. Furthermore, MEL is a very significant substance in that it is biodegradable and has high safety. In other words, it is a biosurfactant with high biodegradability, low toxicity and environmental friendliness.
さらに、MELは様々な生理活性作用を有することが報告されている。例えば、ヒト急性前骨髄性白血病細胞性HL60株にMELを作用させると、顆粒系を分化させる白血病細胞分化誘導作用があること。またラット副腎髄質褐色細胞腫由来のPC12細胞にMELを作用させると神経突起の伸長が生ずる神経系細胞分化誘導作用等の生理活性作用を有すること、さらに微生物産生の糖脂質として初めて、メラノーマ細胞のアポトーシスを誘導することが可能となり(X. Zhao et. al., Cancer Research,59, 482-486 (1999))、癌細胞増殖抑制作用があること、等が報告されている。 Furthermore, MEL has been reported to have various physiologically active actions. For example, when MEL is allowed to act on human acute promyelocytic leukemia cell line HL60, it has the effect of inducing differentiation of leukemia cells that differentiates the granule system. In addition, when MEL is allowed to act on PC12 cells derived from rat adrenal medullary pheochromocytoma, it has physiological activity such as neural cell differentiation inducing action that causes neurite outgrowth, and for the first time as a microbially produced glycolipid, It has been reported that apoptosis can be induced (X. Zhao et. Al., Cancer Research, 59, 482-486 (1999)) and that it has a cancer cell growth inhibitory effect.
さらに、MELは、抗炎症剤及び抗アレルギー剤(特許文献6)、養毛・育毛剤(特許文献7)としての有用性や、抗菌作用(特許文献8)や界面張力低下作用(特許文献9)、細胞賦活化剤やこれを利用した皮膚外用剤等への用途も報告されている(特許文献10)。このような優れた機能を有するMELであるが、これまでフリーラジカル捕捉能や抗酸化能を有するという報告はなされておらず、本発明者らがはじめて明らかとし、本発明を完成させた。 Furthermore, MEL is useful as an anti-inflammatory agent and antiallergic agent (Patent Document 6), a hair nourishing / hair-growing agent (Patent Document 7), an antibacterial action (Patent Document 8), and an interfacial tension reducing action (Patent Document 9). ), Application to cell activators and skin external preparations using the same has also been reported (Patent Document 10). Although it is MEL which has such an excellent function, there has been no report that it has free radical scavenging ability or antioxidant ability so far, and the present inventors have made it clear for the first time and completed the present invention.
つまり、MELは、抗酸化剤として利用できることはもちろんであるが、従来用いられているエモリエント剤であるセラミド等と同等の保湿効果や細胞賦活化効果を有する。このため、例えば皮膚外用剤に配合した場合、種々の機能の相乗効果が得られることになるため、非常に優れた抗老化効果(アンチエイジング)を有する皮膚外用剤となる。 In other words, MEL can be used as an antioxidant, but has a moisturizing effect and cell activation effect equivalent to ceramide, which is a conventionally used emollient. For this reason, when it mix | blends with a skin external preparation, for example, since the synergistic effect of various functions will be acquired, it will become a skin external preparation which has the very outstanding anti-aging effect (anti-aging).
<1−2.MELの製造方法>
MELの製造方法は、MELの生産能を有する微生物を用いることが好ましい。例えば、上記特許文献6〜10や非特許文献1〜6,8〜10の記載に従って製造することができる。具体的には、例えば、シュードザイマ(Pseudozyma)属やウシチラゴ属(Ustilago)に属し、かつMELを生産する能力を有する微生物を培養し、上記一般式(1)又は(2)で表される構造を有するMELを製造する工程を有するMELの製造方法によればよい。
<1-2. Manufacturing method of MEL>
In the MEL production method, it is preferable to use a microorganism having the ability to produce MEL. For example, it can manufacture according to description of the said patent documents 6-10 and nonpatent literature 1-6, 8-10. Specifically, for example, a microorganism belonging to the genus Pseudozyma or Ustilago and capable of producing MEL is cultured, and the structure represented by the above general formula (1) or (2) is obtained. What is necessary is just to be based on the manufacturing method of MEL which has the process of manufacturing MEL which has.
一般式(1)で表される構造を有するMELを製造する場合には、例えば、シュードザイマ・ツクバエンシス(Pseudozyma tsukubaensis)又はシュードザイマ・クラッサ(Pseudozyma crassa)等に属する微生物が好ましく、特に、シュードザイマ・ツクバエンシスに属する微生物が好ましい。シュードザイマ・ツクバエンシスに属する微生物は、例えば25〜35℃で培養した場合、MELの生産性向上効果が高く、特にシュードザイマ・ツクバエンシスJCM 10324株の場合、培養温度30℃の場合に最も良好な生産性が得られる。 In the case of producing MEL having the structure represented by the general formula (1), for example, a microorganism belonging to Pseudozyma tsukubaensis or Pseudozyma crassa is preferable, and in particular, Pseudozyma crassa. Microorganisms belonging to Ensis are preferred. For example, microorganisms belonging to Pseudozyma tsukubaensis are highly effective in improving MEL productivity when cultured at 25 to 35 ° C., for example, in the case of Pseudozyma tsukubaensis JCM 10324, the best production is obtained at a culture temperature of 30 ° C. Sex is obtained.
また一般式(2)で表される構造を有するMELを製造する場合には、ウスチラゴ ヌーダ(Ustilago nuda)、ウスチラゴ スキタミネア(Ustilago scitaminea)、シゾネラ メラノグラマ(Shizonella melanogramma)、キャンデダ(Candida)属酵母、シュードザイマ アンタークチカ(Pseudozyma antarctica)、シュードザイマ グラミニコーラ(Pseudozyma graminicola)、シュードザイマ シアメンシス(Pseudozyma siamensis)、シュードザイマ フベイエンシス(Pseudozyma hubeiensis)、クルツマノマイセス(Kurtzmanomyces)属等の酵母らを利用することができる。 Moreover, when manufacturing MEL which has a structure represented by General formula (2), Ustyago nuda (Ustilago nuda), Ustylago sitaminea (Ustilago sitaminea), Shizonella melanogura (Candella melanogramma) Antarctica (Pseudozyma antarctica), Pseudozyma graminicola et al. Pseudozyma siemens (Pseudozyma siemens, etc.) Kill.
使用培地及び培養方法については、以下の通りである。まず、培地は、例えば、一般的な微生物又は酵母に対して一般に用いられる培地を使用でき、特に限定されるものではなく、特に酵母に用いられる培地が好ましい。このような培地としては、例えば、YPD培地(イーストイクストラクト10g、ポリペプトン20g、及びグルコース100g)を挙げることができる。 The medium used and the culture method are as follows. First, for example, a medium generally used for general microorganisms or yeast can be used as the medium, and is not particularly limited, and a medium used for yeast is particularly preferable. Examples of such a medium include YPD medium (yeast extract 10 g, polypeptone 20 g, and glucose 100 g).
例えば、MELの製造において、シュードザイマ・ツクバエンシスJCM 10324株を用いてMELを生産する場合の好適な培地組成は、以下のとおりである。
・酵母エキス;0.1〜2g/Lが好ましく、1g/Lが特に好ましい。
・硝酸ナトリウム;0.1〜1g/Lが好ましく、0.3g/Lが特に好ましい。
・リン酸2水素カリウム;0.1〜1g/Lが好ましく、0.3g/Lが特に好ましい。
・硫酸マグネシウム;0.1〜1g/Lが好ましく、0.3g/Lが特に好ましい。
・油脂類;40g/L以上が好ましく、80g/Lが特に好ましい。
For example, in the production of MEL, the preferred medium composition when producing MEL using Pseudozyma tsukubaensis JCM 10324 strain is as follows.
-Yeast extract; 0.1 to 2 g / L is preferable, and 1 g / L is particularly preferable.
-Sodium nitrate; 0.1-1 g / L is preferable, and 0.3 g / L is particularly preferable.
-Potassium dihydrogen phosphate; 0.1-1 g / L is preferable and 0.3 g / L is particularly preferable.
Magnesium sulfate: 0.1 to 1 g / L is preferable, and 0.3 g / L is particularly preferable.
-Fats and oils; 40 g / L or more is preferable, and 80 g / L is particularly preferable.
また、上記微生物の培養においては、培地に炭素源を添加することが好ましい。炭素源としては油脂類、脂肪酸、脂肪酸誘導体(脂肪酸トリグリセリド等の脂肪酸エステル類)、あるいは合成エステルを少なくとも1種、さらには複数種混合して含有させればよく、その他の諸条件については、特に制限はなく、本発明の利用当時の技術水準に基づいて適宜選定することができる。 In the culture of the microorganism, it is preferable to add a carbon source to the medium. As the carbon source, fats and oils, fatty acids, fatty acid derivatives (fatty acid esters such as fatty acid triglycerides), or synthetic esters may be contained, and a mixture of plural kinds may be contained. There is no restriction and can be selected as appropriate based on the technical level at the time of use of the present invention.
「油脂類」としては、植物油、動物油、鉱物油及びその硬化油であればよい。具体的には、アボカド油、オリーブ油、ゴマ油、ツバキ油、月見草油、タートル油、マカデミアンナッツ油、トウモロコシ油(コーン油)、ミンク油、ナタネ油、卵黄油、パーシック油、ピーナッツ油、ベニバナ油、小麦胚芽油、サザンカ油、ヒマシ油、アマニ油、サフラワー油、綿実油、エノ油、大豆油、落花生油、茶実油、カヤ油、コメヌカ油、キリ油、ホホバ油、カカオ脂、ヤシ油、馬油、パーム油、パーム核油、牛脂、羊脂、豚脂、ラノリン、鯨ロウ、ミツロウ、カルナウバロウ、モクロウ、キャンデリラロウ、スクワラン等の動植物油及びその硬化油、流動パラフィン、ワセリン等の鉱物油、トリパルミチン酸グリセリン等の合成トリグリセリンが挙げられる。好ましくはアボカド油、オリーブ油、ゴマ油、ツバキ油、月見草油、タートル油、マカデミアンナッツ油、トウモロコシ油、ミンク油、ナタネ油、卵黄油、パーシック油、小麦胚芽油、サザンカ油、ヒマシ油、アマニ油、サフラワー油、綿実油、エノ油、大豆油、落花生油、茶実油、カヤ油、コメヌカ油、より好ましくはオリーブ油、大豆油である。 “Oils and fats” may be vegetable oils, animal oils, mineral oils and hardened oils thereof. Specifically, avocado oil, olive oil, sesame oil, camellia oil, evening primrose oil, turtle oil, macadamia nut oil, corn oil (corn oil), mink oil, rapeseed oil, egg yolk oil, persic oil, peanut oil, safflower oil , Wheat germ oil, sasanqua oil, castor oil, flaxseed oil, safflower oil, cottonseed oil, eno oil, soybean oil, peanut oil, teaseed oil, kaya oil, rice bran oil, kiri oil, jojoba oil, cacao butter, palm oil Such as horse oil, palm oil, palm kernel oil, beef tallow, sheep fat, lard, lanolin, whale wax, beeswax, carnauba wax, molasses, candelilla wax, squalane, etc. and its hardened oil, liquid paraffin, petrolatum, etc. Synthetic triglycerin such as mineral oil and glycerin tripalmitate. Preferably avocado oil, olive oil, sesame oil, camellia oil, evening primrose oil, turtle oil, macadamia nut oil, corn oil, mink oil, rapeseed oil, egg yolk oil, persic oil, wheat germ oil, southern oil, castor oil, flaxseed oil , Safflower oil, cottonseed oil, eno oil, soybean oil, peanut oil, tea seed oil, kaya oil, rice bran oil, and more preferably olive oil and soybean oil.
「脂肪酸」又は「脂肪酸誘導体」としては、高級脂肪酸由来が好ましく、例えばカプロン酸、カプリル酸、カプリン酸、ラウリン酸、ミリスチン酸、パルミチン酸、オレイン酸、リノール酸、リノレン酸、ステアリン酸、ベヘン酸、12−ヒドロキシステアリン酸、イソステアリン酸、ウンデシン酸、トール酸、エイコサペンタエン酸、ドコサヘキサエン酸などが挙げられる。好ましくはラウリン酸、ミリスチン酸、パルミチン酸、オレイン酸、リノール酸、リノレン酸、ステアリン酸、ウンデシレン酸、より好ましくはオレイン酸、リノール酸、ウンデシレン酸である。 The “fatty acid” or “fatty acid derivative” is preferably derived from higher fatty acids, such as caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, oleic acid, linoleic acid, linolenic acid, stearic acid, behenic acid. , 12-hydroxystearic acid, isostearic acid, undecic acid, toluic acid, eicosapentaenoic acid, docosahexaenoic acid and the like. Preferred are lauric acid, myristic acid, palmitic acid, oleic acid, linoleic acid, linolenic acid, stearic acid and undecylenic acid, and more preferred are oleic acid, linoleic acid and undecylenic acid.
「合成エステル」としては、例えば、カプロン酸メチル、カプリル酸メチル、カプリン酸メチル、ラウリン酸メチル、ミリスチン酸メチル、パルミチン酸メチル、オレイン酸メチル、リノール酸メチル、リノレン酸メチル、ステアリン酸メチル、ウンデシン酸メチル、カプロン酸エチル、カプリル酸エチル、カプリン酸エチル、ラウリン酸エチル、ミリスチン酸エチル、パルミチン酸エチル、オレイン酸エチル、リノール酸エチル、リノレン酸エチル、ステアリン酸エチル、ウンデシン酸エチル、カプロン酸ビニル、カプリル酸ビニル、カプリン酸ビニル、ラウリン酸ビニル、ミリスチン酸ビニル、パルミチン酸ビニル、オレイン酸ビニル、リノール酸ビニル、リノレン酸ビニル、ステアリン酸ビニル、ウンデシン酸ビニル、オクタン酸セチル、ミリスチン酸オクチルドデシル、ミリスチン酸イソプロピル、ミリスチン酸ミリスチル、パルミチン酸イソプロピル、ステアリン酸ブチル、ラウリン酸ヘキシル、オレンイ酸デシル、ジメチルオクタン酸、乳酸セチル、乳酸ミリスチル等が挙げられる。好ましくはラウリン酸メチル、ミリスチン酸メチル、パルミチン酸メチル、オレイン酸メチル、リノール酸メチル、リノレン酸メチル、ステアリン酸メチル、ウンデシレン酸メチル、より好ましくはオレイン酸メチル、リノール酸メチル、ウンデシレン酸メチルである。 Examples of the “synthetic ester” include methyl caproate, methyl caprylate, methyl caprate, methyl laurate, methyl myristate, methyl palmitate, methyl oleate, methyl linoleate, methyl linolenate, methyl stearate, undecine. Methyl acid, ethyl caproate, ethyl caprylate, ethyl caprate, ethyl laurate, ethyl myristate, ethyl palmitate, ethyl oleate, ethyl linoleate, ethyl linolenate, ethyl stearate, ethyl undecinate, vinyl caproate , Vinyl caprylate, vinyl caprate, vinyl laurate, vinyl myristate, vinyl palmitate, vinyl oleate, vinyl linoleate, vinyl linolenate, vinyl stearate, vinyl undecinate, cetyl octanoate , Octyldodecyl myristate, isopropyl myristate, myristyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, Oren'i acid decyl dimethyl octanoate, cetyl lactate, myristyl lactate, and the like. Preferred are methyl laurate, methyl myristate, methyl palmitate, methyl oleate, methyl linoleate, methyl linolenate, methyl stearate, methyl undecylate, more preferably methyl oleate, methyl linoleate, and methyl undecylate. .
これらは、1種を単独で又は2種以上を適宜混合して用いてもよい。 You may use these individually by 1 type or in mixture of 2 or more types as appropriate.
MELの製造方法の具体的な工程については、特に限定されるものではなく、目的に応じて適宜選定することができるが、例えば、種培養、本培養及びMEL生産培養の順にスケールアップしていくことが好ましい。これらの培養における、培地並びに培養条件を例示すると以下のとおりである。
a)種培養;グルコース40g/L、酵母エキス1g/L、硝酸ナトリウム0.3g/L、リン酸2水素カリウム 0.3g/L、及び硫酸マグネシウム0.3g/Lの組成の液体培地5mLが入った試験管に1白金耳接種し、30℃で1日間振とう培養を行う。
b)本培養;所定量の植物性油脂等の油脂類と、酵母エキス1g/L、硝酸ナトリウム0.3g/L、リン酸2水素カリウム0.3g/L、及び硫酸マグネシウム0.3g/Lの組成の液体培地100mLの入った坂口フラスコにa)の培養液を接種して、30℃で2日間培養を行う。
c)マンノシルエリスリトールリピッド生産培養;所定量の植物性油脂等の油脂類と酵母エキス1g/L、硝酸ナトリウム0.3g/L、リン酸2水素カリウム0.3g/L、及び硫酸マグネシウム0.3g/Lの組成の液体培地1.4Lが入ったジャーファメンターに接種して、30℃で800rpmの撹拌速度で培養を行う。この培養においては、培養途中から植物性油脂を培養容器中に流下させて、培地中の油脂類濃度を20〜200g/Lに保持することが好ましい。
The specific steps of the MEL production method are not particularly limited, and can be appropriately selected according to the purpose. For example, scale-up is performed in the order of seed culture, main culture, and MEL production culture. It is preferable. Examples of culture media and culture conditions in these cultures are as follows.
a) Seed culture: 5 mL of liquid medium having a composition of glucose 40 g / L, yeast extract 1 g / L, sodium nitrate 0.3 g / L, potassium dihydrogen phosphate 0.3 g / L, and magnesium sulfate 0.3 g / L Inoculate one platinum loop into the test tube and shake culture at 30 ° C for 1 day.
b) Main culture; predetermined amount of fats and oils such as vegetable oil and fat, yeast extract 1 g / L, sodium nitrate 0.3 g / L, potassium dihydrogen phosphate 0.3 g / L, and magnesium sulfate 0.3 g / L A culture medium of a) is inoculated into a Sakaguchi flask containing 100 mL of the liquid medium having the composition of 2 and cultured at 30 ° C. for 2 days.
c) Mannosyl erythritol lipid production culture; predetermined amount of fats and oils such as vegetable oil and fat, yeast extract 1 g / L, sodium nitrate 0.3 g / L, potassium dihydrogen phosphate 0.3 g / L, and magnesium sulfate 0.3 g A jar fermenter containing 1.4 L of a liquid medium having a composition of / L is inoculated and cultured at 30 ° C. with a stirring speed of 800 rpm. In this culture, it is preferable that the vegetable fats and oils flow down into the culture vessel from the middle of the culture to maintain the fats and oils concentration in the medium at 20 to 200 g / L.
MELの回収方法についても従来公知の脂質の精製方法を用いることができ、特に限定されるものではない。例えば、培養終了後、当容積〜4容積倍の酢酸エチルで脂質成分を抽出し、酢酸エチルを、エバポレーターを用いて留去して脂質及び糖脂質成分を回収する工程を挙げることができる。その後、この脂質成分を等量のクロロホルムに溶解し、これをシリカゲルクロマトグラフィーにかけ、クロロホルム、クロロホルム:アセトン(80:20)、同(70:30)、同(60:40)、同(50:50)、同(30:70)、アセトンの順で溶出させる。各溶液を薄層クロマトグラフィー(TLC)プレートにチャージし、クロロホルム:メタノール:アンモニア水=65:15:2(容積比)で展開する。展開終了後、アンスロン硫酸試薬で糖脂質の存在を確認する。糖脂質の含まれる溶出液を集め、溶媒を留去して糖脂質成分を得ることができる。 The MEL recovery method can also be a conventionally known lipid purification method, and is not particularly limited. For example, after completion of the culture, a step of extracting the lipid component with this volume to 4 times volume of ethyl acetate and distilling off the ethyl acetate using an evaporator to recover the lipid and glycolipid component can be mentioned. Thereafter, this lipid component was dissolved in an equal amount of chloroform, and this was subjected to silica gel chromatography, and chloroform, chloroform: acetone (80:20), (70:30), (60:40), and (50: 50), the same (30:70), and acetone. Each solution is charged on a thin layer chromatography (TLC) plate and developed with chloroform: methanol: aqueous ammonia = 65: 15: 2 (volume ratio). After completion of the development, the presence of glycolipid is confirmed with an anthrone sulfate reagent. The eluate containing the glycolipid can be collected and the solvent can be distilled off to obtain a glycolipid component.
<2.抗酸化剤の用途>
本発明に係る抗酸化剤は、活性酸素消去剤として利用できる。活性酸素消去剤とは、活性酸素の発生を抑制及び/又は発生した活性酸素を消去することを意図する。また、本発明に係る抗酸化剤は、活性酸素の存在下で生体(細胞を含む)が受ける酸化ストレスを軽減する作用も有するため、酸化ストレス軽減剤(あるいは酸化ストレス保護剤)としても利用できる。対象となる活性酸素としては、スーパーオキシドアニオン、ヒドロキシラジカル等のフリーラジカルだけでなく、過酸化水素、一重項酸素、一酸化窒素、二酸化窒素、オゾン及び過酸化脂質等を挙げることができる。
<2. Applications of antioxidants>
The antioxidant according to the present invention can be used as an active oxygen scavenger. The active oxygen scavenger is intended to suppress the generation of active oxygen and / or to erase the generated active oxygen. Moreover, since the antioxidant according to the present invention has an action of reducing oxidative stress that a living body (including cells) receives in the presence of active oxygen, it can also be used as an oxidative stress reducing agent (or oxidative stress protecting agent). . Examples of the target active oxygen include not only free radicals such as superoxide anion and hydroxy radical, but also hydrogen peroxide, singlet oxygen, nitric oxide, nitrogen dioxide, ozone, lipid peroxide, and the like.
また、本発明の抗酸化剤は、活性酸素(例えば、フリーラジカル)を捕捉することによって、皮膚の酸化を抑制し、シミ、シワ、たるみなどの皮膚老化の予防・改善に優れた効果を有するものであるため、抗老化剤として使用することも可能である。以下の説明では、抗酸化剤、活性酸素消去剤、酸化ストレス軽減剤(あるいは酸化ストレス保護剤)及び抗老化剤をまとめて「抗酸化剤等」と称する。 In addition, the antioxidant of the present invention captures active oxygen (for example, free radicals) to suppress skin oxidation and has an excellent effect in preventing and improving skin aging such as spots, wrinkles and sagging. Therefore, it can be used as an anti-aging agent. In the following description, the antioxidant, the active oxygen scavenger, the oxidative stress reducing agent (or oxidative stress protecting agent) and the anti-aging agent are collectively referred to as “antioxidant etc.”.
本発明に係る抗酸化剤等は、各種の組成物に配合して用いることができる。ここでいう組成物とは、具体的には、対象物(生体を含む)に適用することにより、対象物に対する活性酸素の悪影響を除去するための組成物、また活性酸素を生成するおそれのある成分を含んでなる組成物を意図しており、例えば、皮膚外用剤(化粧品、医薬部外品、医薬品等)、飲食品、化学品等を挙げることができる。皮膚外用剤に配合する場合、本発明に係る抗酸化剤等は、外用剤中の成分に対する酸化防止剤というよりは、活性酸素(例えば、フリーラジカル)による皮膚のダメージを予防あるいは改善するために配合される添加成分(有効成分)であるといえる。 The antioxidant etc. which concern on this invention can be mix | blended and used for various compositions. Specifically, the composition here refers to a composition for removing the adverse effects of active oxygen on the object (including living organisms), and may generate active oxygen. A composition comprising an ingredient is intended, and examples thereof include external preparations for skin (cosmetics, quasi drugs, pharmaceuticals, etc.), foods and drinks, and chemicals. When blended in an external preparation for skin, the antioxidant or the like according to the present invention is used to prevent or improve skin damage caused by active oxygen (for example, free radicals) rather than an antioxidant for components in the external preparation. It can be said that it is an additive component (active ingredient) to be blended.
本発明に係る抗酸化剤等を組成物に配合する場合、その配合方法は特に限定されず、その利用目的に応じて、原料の段階から製品の段階に至るまでの適宜の工程、或いは、既存の製品に対して、例えば、混和、混捏、溶解、融解、分散、懸濁、乳化、浸漬、浸透、散布、塗布、被覆、噴霧、注入などの1種又は2種以上の方法を適宜組み合わせて用いることができる。必要に応じて、これらの方法を、高圧条件下、減圧条件下で実施することも随意である。 When blending the antioxidant or the like according to the present invention into the composition, the blending method is not particularly limited, and depending on the purpose of use, an appropriate process from the raw material stage to the product stage, or existing For example, one or two or more methods such as mixing, kneading, dissolving, melting, dispersing, suspending, emulsifying, dipping, penetrating, spreading, coating, coating, spraying, and pouring are appropriately combined. Can be used. Optionally, these methods are optionally carried out under high pressure and reduced pressure.
本発明に係る抗酸化剤等は、化粧料などの皮膚外用剤に配合して、抗酸化作用に優れた抗酸化用の皮膚外用剤(抗酸化用化粧料)として使用することができる。抗酸化用の皮膚外用剤を頭皮や肌に適用することにより、生体における活性酸素の生成を抑制及び/又は生成した活性酸素を消去して、皮膚の老化防止や、皺・小皺、シミ・ソバカスなどの発生防止などに効果を発揮する。本発明の抗酸化剤等を化粧料に配合して抗酸化用の皮膚外用剤とする場合、有効成分であるMEL(乾燥重量)が外用剤の総質量の0.01質量%以上20質量%以下、より好ましくは0.1質量%以上15質量%以下、さらに好ましくは0.5質量%以上10質量%以下、さらには1.0質量%以上5質量%以下を配合することが好ましい。この範囲内であれば抗酸化剤等の機能が十分に発揮できるし、この範囲を超えて配合しても効果のさらなる増加は実質上望めないし、組成物への配合も難しくなる傾向にある。 Antioxidants and the like according to the present invention can be blended in a skin external preparation such as cosmetics and used as an anti-oxidative skin external preparation (antioxidant cosmetic) having an excellent antioxidant action. By applying an anti-oxidative skin external preparation to the scalp and skin, the generation of active oxygen in the living body is suppressed and / or the generated active oxygen is eliminated, and skin aging is prevented, wrinkles / small wrinkles, and stains and freckles It is effective in preventing the occurrence of When the antioxidant of the present invention or the like is blended in cosmetics to prepare an anti-oxidation skin external preparation, the active ingredient MEL (dry weight) is 0.01 mass% or more and 20 mass% of the total mass of the external preparation. In the following, it is preferable to blend 0.1 to 15% by mass, more preferably 0.5 to 10% by mass, and further preferably 1.0 to 5% by mass. If it is within this range, the function of an antioxidant or the like can be sufficiently exerted, and even if it exceeds this range, a further increase in the effect cannot be substantially expected, and blending into the composition tends to be difficult.
抗酸化用の皮膚外用剤の形態は、医薬品、医薬部外品、化粧品等の分野にて使用される形態であれば特に限定されず、例えば、乳液、軟膏、クリーム、化粧水、美容液、洗浄料、パック等の基礎化粧品、ファンデーション、口紅、アイシャドー、アイライナー、マスカラ等のメークアップ化粧品、日焼け・日焼け止め化粧品、パーマネント液、毛髪のセット剤等の毛髪化粧品、浴用剤等といった本発明の所望の効果が達成できればいかなる形態であってもよい。 The form of the anti-oxidative skin external preparation is not particularly limited as long as it is a form used in the fields of pharmaceuticals, quasi drugs, cosmetics, and the like, for example, emulsions, ointments, creams, lotions, cosmetic liquids, Basic inventions such as cleaning agents, packs, makeup cosmetics such as foundations, lipsticks, eye shadows, eyeliners, mascaras, sunscreen / sunscreen cosmetics, permanent cosmetics, hair cosmetics such as hair setting agents, bath preparations, etc. Any form may be used as long as the desired effect can be achieved.
また、抗酸化用の皮膚外用剤には、上記抗酸化剤等以外に、医薬品、医薬部外品、化粧品等に通常使用される各種の成分、すなわち、水、アルコール、油剤、界面活性剤、増粘剤、粉体、キレート剤、pH調節剤、紫外線吸収剤、動植物・微生物由来の抽出物、保湿剤、美白剤、抗炎症剤、細胞賦活剤、各種皮膚栄養剤、各種薬剤、酸化防止剤、色材、香料などを本発明の効果を損なわない範囲で適宜配合することができる。 In addition, the anti-oxidant skin external preparation, in addition to the above-mentioned antioxidant, etc., various components usually used in pharmaceuticals, quasi drugs, cosmetics, etc., that is, water, alcohol, oil agent, surfactant, Thickeners, powders, chelating agents, pH regulators, UV absorbers, extracts from animals, plants and microorganisms, moisturizers, whitening agents, anti-inflammatory agents, cell activators, various skin nutrients, various drugs, antioxidants Agents, coloring materials, fragrances, and the like can be appropriately blended within a range that does not impair the effects of the present invention.
また、本発明に係る抗酸化剤等は、特に、組織や細胞レベルのラジカル生成をも抑制することから、生体内で発生するラジカル生成を伴う炎症反応の抑制剤や炎症性分子の発現抑制剤として、医薬品に配合することもできる。 In addition, since the antioxidants and the like according to the present invention also suppress radical generation at the tissue or cell level, in particular, inhibitors of inflammatory reactions accompanied by radical generation generated in vivo and inhibitors of expression of inflammatory molecules As such, it can also be incorporated into pharmaceutical products.
また、本発明には、上記抗酸化剤等を配合する工程を有する抗酸化用の皮膚外用剤の製造方法も含まれる。かかる製造方法は、皮膚外用剤の基材に、本発明に係る抗酸化剤等を配合する工程を有するものであればよく、その他の具体的な条件等は特に限定されない。配合する方法も、上述した配合方法を適宜利用できる。 Moreover, the manufacturing method of the skin external preparation for antioxidant which has the process of mix | blending the said antioxidant etc. is also contained in this invention. This manufacturing method should just have a process of mix | blending the antioxidant etc. which concern on this invention with the base material of a skin external preparation, Other specific conditions etc. are not specifically limited. As a method of blending, the blending method described above can be used as appropriate.
また、皮膚の抗酸化及び/又は抗老化のための化粧処置方法であって、本発明に係る抗酸化剤等を含有する組成物を皮膚に適用する化粧処置方法も含まれる。かかる化粧処置方法は、非治療的な態様で行われるものであり、医療行為を意図していない。皮膚に本発明に係る抗酸化剤等を含有する組成物を適用(塗布、噴霧等)することにより、皮膚の活性酸素の生成を抑制及び/又は生成した活性酸素を消去して(例えば、皮膚上あるいは皮膚生体内の活性酸素やラジカルの発生を阻害・消去したり、過酸化脂質の生成を抑制したりすることにより)、皮膚の老化防止や、皺・小皺、シミ・ソバカスなどの発生防止などを行う方法である。 Also included is a cosmetic treatment method for antioxidation and / or anti-aging of the skin, in which a composition containing the antioxidant or the like according to the present invention is applied to the skin. Such cosmetic treatment methods are performed in a non-therapeutic manner and are not intended for medical practice. By applying (applying, spraying, etc.) the composition containing the antioxidant according to the present invention to the skin, the production of active oxygen in the skin is suppressed and / or the generated active oxygen is eliminated (for example, the skin By inhibiting or eliminating the generation of active oxygen and radicals in the skin or the living body, and suppressing the formation of lipid peroxide), preventing skin aging, and preventing the generation of wrinkles / small wrinkles, spots, freckles, etc. It is a method to do.
以上のように、本発明の抗酸化剤は、フリーラジカル捕捉能を有し、優れた抗酸化作用を有するとともに、細胞に対する賦活化効果も有し、酸化ストレスにさらされた細胞の生育に対して、抗酸化効果と賦活化効果の相乗効果を示す。すなわち、本発明によって、MELの化粧品素材としての価値は高まり、MELの用途開発に向けて大きく貢献できる。 As described above, the antioxidant of the present invention has a free radical scavenging ability, has an excellent antioxidant action, and also has an activation effect on cells, which is effective against the growth of cells exposed to oxidative stress. The synergistic effect of the antioxidant effect and the activation effect is shown. That is, the present invention increases the value of MEL as a cosmetic material, and can greatly contribute to the development of MEL applications.
また、本発明の皮膚外用剤は、上記抗酸化剤等を配合したことによって、皮膚の酸化を抑制し、シミ、シワ、たるみなどの皮膚老化の予防・改善に有効である共に、フリーラジカルに関連する皮膚疾患の予防・改善効果も有するものである。特に、本発明に係るMELは、皮膚の保湿や細胞の賦活化効果も兼ね備えており、化粧品素材として優れた性能を有する。 In addition, the external preparation for skin of the present invention is effective in preventing skin skin aging such as spots, wrinkles, sagging, and the like by freezing radicals by suppressing the oxidation of the skin by blending the above antioxidant and the like. It also has the effect of preventing and improving related skin diseases. In particular, the MEL according to the present invention also has skin moisturizing and cell activation effects, and has excellent performance as a cosmetic material.
また、本発明に係る抗酸化剤等は、組成物に配合することにより当該組成物中で活性酸素の生成を抑制及び/又は生成した活性酸素を消去することから、活性酸素の存在により引き起こされる、過酸化脂質、ジオンやアルデヒドの生成、含硫アミノ酸の分解に起因する硫化物の生成、メーラード反応による褐変などをも抑制し、これらの反応に由来する、不快味、不快臭、着色・褐変、香料や色素の劣化などを抑制するので、組成物の品質を長期間安定に保持することができる。 In addition, the antioxidants and the like according to the present invention are caused by the presence of active oxygen because they are incorporated into the composition to suppress the generation of active oxygen and / or eliminate the generated active oxygen in the composition. It also suppresses the formation of lipid peroxides, diones and aldehydes, the formation of sulfides due to the decomposition of sulfur-containing amino acids, and browning due to the Maillard reaction, resulting in unpleasant taste, unpleasant odor, coloring and browning Moreover, since deterioration of a fragrance | flavor or a pigment | dye etc. is suppressed, the quality of a composition can be hold | maintained stably for a long period of time.
このため、本発明に係る抗酸化剤等は、飲食品に配合しても活性酸素の生成を抑制及び/又は生成した活性酸素を消去し、その結果、活性酸素に起因する過酸化物が飲食品に含まれるタンパク質、着色料、香料などを修飾、変性させる過程を抑制することができるので、タンパク変性抑制剤、着色料や香料の安定化剤などとして飲食品の風味(品質)保持に極めて有利に利用できる。 Therefore, the antioxidant or the like according to the present invention suppresses the generation of active oxygen and / or eliminates the generated active oxygen even when blended in food and drink, and as a result, the peroxide resulting from the active oxygen is consumed by the food and drink. The process of modifying and denaturing proteins, colorants, flavors, etc. contained in products can be suppressed, so it is extremely useful for maintaining the flavor (quality) of foods and beverages as protein denaturation inhibitors, colorants, and flavorants. It can be used advantageously.
また、本発明に係る抗酸化剤等は、合成高分子樹脂に配合することにより、紫外線をはじめとする光、熱、放射線、圧力などにより誘発されるラジカルによる樹脂の劣化を防止することに利用できるだけでなく、塗料、インク、接着剤、コーティング剤などのように、その成分として上記合成高分子樹脂を含む組成物の劣化(色、可塑性、剛性、接着性などの劣化を含む)を抑制することもできる。 In addition, the antioxidant and the like according to the present invention are used to prevent deterioration of the resin due to radicals induced by light such as ultraviolet rays, heat, radiation, pressure, etc. by blending with the synthetic polymer resin. Not only can it suppress the deterioration (including deterioration of color, plasticity, rigidity, adhesiveness, etc.) of the composition containing the synthetic polymer resin as its component, such as paint, ink, adhesive, coating agent, etc. You can also.
本発明に係る抗酸化剤等を飲食品や合成高分子樹脂等の組成物に配合する量は、その組成物からの活性酸素の生成を抑制及び/又は生成した活性酸素を消去できる量であればよく、特に制限はない。しかしながら、配合量が0.01質量%未満では活性酸素の生成等を効果的に抑制するには不充分な場合があり、通常、組成物に対して、本発明のラジカル生成抑制剤を無水物としての換算で、0.01質量%以上20質量%以下、さらに好ましくは、1.0質量%以上10質量%以下、均一に含有せしめるのが好適である。 The amount of the antioxidant or the like according to the present invention to be added to a composition such as a food or drink or a synthetic polymer resin is an amount capable of suppressing the generation of active oxygen from the composition and / or eliminating the generated active oxygen. There is no particular limitation. However, if the blending amount is less than 0.01% by mass, it may be insufficient to effectively suppress the production of active oxygen and the like. Usually, the radical production inhibitor of the present invention is an anhydride for the composition. It is preferable that it is contained in an amount of 0.01% by mass or more and 20% by mass or less, more preferably 1.0% by mass or more and 10% by mass or less.
すなわち、本発明には、上記抗酸化剤等を組成物に配合する工程を有し、当該組成物中の成分からの活性酸素の生成抑制及び/又は生成した活性酸素の消去を行う方法も含まれる。かかる方法は、主として皮膚外用剤(化粧品、医薬部外品、医薬品等)、飲食品、化学品等の品質劣化を防止することを意図したものである。 That is, the present invention includes a method of blending the above-mentioned antioxidant or the like into the composition, and suppressing the generation of active oxygen from the components in the composition and / or eliminating the generated active oxygen. It is. This method is mainly intended to prevent deterioration in quality of external preparations for skin (cosmetics, quasi-drugs, pharmaceuticals, etc.), foods and drinks, chemicals and the like.
本発明は上述した各実施形態に限定されるものではなく、請求項に示した範囲で種々の変更が可能であり、異なる実施形態にそれぞれ開示された技術的手段を適宜組み合わせて得られる実施形態についても本発明の技術的範囲に含まれる。 The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope shown in the claims, and embodiments obtained by appropriately combining technical means disclosed in different embodiments. Is also included in the technical scope of the present invention.
以下に実施例を示して本発明をより具体的に説明するが、これらは単なる例示であって、本発明の範囲を何ら限定するものではない。 EXAMPLES The present invention will be described more specifically with reference to the following examples. However, these are merely examples and do not limit the scope of the present invention.
<実施例1:MELの調製>
各種MEL(MEL−A,MEL−B,MEL−C)は、下記表1に記載のMEL生産菌を用いて、大豆油、アマニ油、オリーブ油、紅花油、スクロースなどの炭素源を原料として生産した。各種MELを塩酸メタノール存在下で分解し、脂肪酸部位をヘキサンで抽出し、GC/MS分析によって、各種MELの脂肪酸組成を分析した。具体的には、アジレント・テクノロジー社製のGC−MS装置6890および5973Nを用い、GLサイエンス社のTC−WAXカラムで、ヘキサン抽出液中の各種脂肪酸を分離した後、マススペクトルから脂肪酸組成を分析した。各種MELの脂肪酸組成は表1に記載の通りである。脂肪酸の不飽和度(重量%)は、ヘキサン抽出液中の全脂肪酸の重量を分母とし、不飽和脂肪酸(1つ以上の炭素−炭素二重結合を有する脂肪酸)の重量を分子として、100をかけて算出した。
<Example 1: Preparation of MEL>
Various MELs (MEL-A, MEL-B, MEL-C) are produced using carbon sources such as soybean oil, linseed oil, olive oil, safflower oil, and sucrose using MEL producing bacteria described in Table 1 below. did. Various MELs were decomposed in the presence of methanolic hydrochloric acid, fatty acid sites were extracted with hexane, and fatty acid compositions of various MELs were analyzed by GC / MS analysis. Specifically, using a GC-MS device 6890 and 5973N manufactured by Agilent Technologies, the TC-WAX column of GL Sciences was used to separate various fatty acids in the hexane extract, and then the fatty acid composition was analyzed from the mass spectrum. did. The fatty acid composition of various MELs is as shown in Table 1. The degree of unsaturation of fatty acids (% by weight) is 100 using the weight of all fatty acids in the hexane extract as the denominator and the weight of unsaturated fatty acids (fatty acids having one or more carbon-carbon double bonds) as the numerator. It was calculated over time.
<実施例2 抗酸化活性(フリーラジカル捕捉活性)の測定>
実施例1で調製したMELを試料として用い、フリーラジカルの一種であるDPPH(1,1−Diphenyl−2−picrylhydrazyl)ラジカルの消去活性を測定した。また、アルブチン(Arbutin)は、天然のポリフェノールであり、強力な抗酸化作用を示すことが知られているため、実施例2においてポジティブコントロールとして用いた。
<Example 2 Measurement of antioxidant activity (free radical scavenging activity)>
Using the MEL prepared in Example 1 as a sample, the scavenging activity of DPPH (1,1-Diphenyl-2-picrylhydrazyl) radical, which is a kind of free radical, was measured. Arbutin is a natural polyphenol and is known to exhibit a strong antioxidant action, so it was used as a positive control in Example 2.
各濃度の試料溶液0.05mLに0.05mLのトリス緩衝液(pH7.2)及び0.3mMのDPPHエタノール溶液を0.05mL加え、25℃で40分間反応させた後、波長517nmにおける吸光度を測定した。なお、各試料溶液はエタノールを用いて、それぞれのMEL濃度が最終濃度で、1.25、2.5、5及び10%になるように、アルブチンは最終濃度で、0.063、0.13、0.25及び0.5%になるようにそれぞれ調製し、試験に用いた。また、コントロールはMELを含まない溶媒(エタノール)のみの測定値とした。吸光度の減少がラジカル捕捉による抗酸化作用を示すものである。各試料のDPPHラジカル消去率は、次の式で算出した。 After adding 0.05 mL of Tris buffer (pH 7.2) and 0.3 mM DPPH ethanol solution to 0.05 mL of each concentration of sample solution and reacting at 25 ° C. for 40 minutes, absorbance at a wavelength of 517 nm was measured. It was measured. In addition, each sample solution uses ethanol, and arbutin is 0.063, 0.13 in final concentration so that each MEL concentration may be 1.25, 2.5, 5 and 10% in final concentration. , 0.25 and 0.5%, respectively, and used for the test. Moreover, the control was made into the measured value only of the solvent (ethanol) which does not contain MEL. A decrease in absorbance indicates an antioxidant effect due to radical scavenging. The DPPH radical scavenging rate of each sample was calculated by the following formula.
DPPHラジカル消去率(%)=(1−試料溶液の吸光度/コントロールの吸光度)×100
試験結果を以下に示す。大豆油を原料としてPseudozyma antarcticaを培養して生産したMEL−A、アマニ油を原料としてPseudozyma antarcticaを培養して生産したMEL−A、オリーブ油を原料としてPseudozyma tsukubaensisを培養して生産したMEL−B、ショ糖を原料としてUstilago scitamineaを培養して生産したMEL−B、大豆油を原料としてPseudozyma graminicolaを培養して生産したMEL−C、ベニバナ油を原料としてPseudozyma siamensisを培養して生産したMEL−C、大豆油を原料としてPseudozyma hubeiensisを培養して生産したMEL−Cを用いて、DPPHラジカル消去活性を測定した結果を、図1に示す。図1からわかるように、MELは、DPPHラジカル消去活性を有することが明らかとなった。したがって、MELは、フリーラジカル捕捉型の抗酸化剤として有効である。
DPPH radical scavenging rate (%) = (1−absorbance of sample solution / absorbance of control) × 100
The test results are shown below. MEL-A produced by cultivating Pseudozyma antarctica using soybean oil as a raw material, MEL-A produced by cultivating Pseudozyma antarctica using linseed oil as a raw material, MEL-A produced by culturing Pseudozyma tsukubaensis using olive oil as a raw material, and B produced EL MEL-B produced by cultivating Ustilago scitamine using sucrose as a raw material, MEL-C produced by cultivating Pseudozyma gramicola using soybean oil as a raw material, MEL-C produced by culturing Pseudozyma siemensis using safflower oil as a raw material Measure DPPH radical scavenging activity using MEL-C produced by culturing Pseudozyma hubiensis using soybean oil as a raw material. The determined results are shown in FIG. As can be seen from FIG. 1, MEL was found to have DPPH radical scavenging activity. Therefore, MEL is effective as a free radical scavenging antioxidant.
また、脂肪酸の不飽和度が高いほど、DPPHラジカル消去活性が高かった。具体的には、MEL−Aの場合、脂肪酸の不飽和度が61.0%のMEL−Aの方が、26.1%のMEL−AよりDPPHラジカル消去活性が高かった。また、MEL−Cの場合、脂肪酸の不飽和度が33.3%のMEL−C、62.9%のMEL−C、94.0%のMEL−Cの順に、DPPHラジカル消去活性が高かった。 Moreover, the higher the degree of unsaturation of the fatty acid, the higher the DPPH radical scavenging activity. Specifically, in the case of MEL-A, MEL-A having 61.0% fatty acid unsaturation had higher DPPH radical scavenging activity than 26.1% MEL-A. In addition, in the case of MEL-C, the DPPH radical scavenging activity was higher in the order of fatty acid unsaturation of 33.3% MEL-C, 62.9% MEL-C, and 94.0% MEL-C. .
なお、Pseudozyma tsukubaensisが生産するMEL−Bの糖骨格は、1−O−β−D−マンノピラノシル−meso−エリスリトールであり、一方、Ustilago scitamineaが生産するMEL−Bは、4−O−β−D−マンノピラノシル−meso−エリスリトールであり、糖骨格の構造が異なる。これらの糖骨格の構造が異なるMEL−Bの抗酸化能を比較したところ、脂肪酸の不飽和度が16.7%のMEL−B(1−O−β−D−マンノピラノシル−meso−エリスリトール)の方が、39.2%のMEL−B(4−O−β−D−マンノピラノシル−meso−エリスリトール)よりDPPHラジカル消去活性が高かった。この結果より、糖骨格の構造が、DPPHラジカル消去活性に影響を与えていることを示された。具体的には、1−O−β−D−マンノピラノシル−meso−エリスリトール構造のMELの方が、4−O−β−D−マンノピラノシル−meso−エリスリトール構造のMELに比べて抗酸化能に優れることが示唆された。 The sugar skeleton of MEL-B produced by Pseudozyma tsukubaensis is 1-O-β-D-mannopyranosyl-meso-erythritol, whereas MEL-B produced by Ustilago scitaminea is 4-O-β-D. -Mannopyranosyl-meso-erythritol, which has a different sugar skeleton structure. When the antioxidant ability of MEL-B having different structures of these sugar skeletons was compared, MEL-B (1-O-β-D-mannopyranosyl-meso-erythritol) having a fatty acid unsaturation degree of 16.7% was compared. The DPPH radical scavenging activity was higher than that of 39.2% MEL-B (4-O-β-D-mannopyranosyl-meso-erythritol). From this result, it was shown that the structure of the sugar skeleton affects DPPH radical scavenging activity. Specifically, MEL having a 1-O-β-D-mannopyranosyl-meso-erythritol structure is superior in antioxidant capacity compared to MEL having a 4-O-β-D-mannopyranosyl-meso-erythritol structure. Was suggested.
これらのMELは、フリーラジカル捕捉型の抗酸化作用を有することから、シミ、しわ、たるみなどの皮膚老化を予防・改善する抗老化剤としても有効である。 These MELs are effective as anti-aging agents for preventing and improving skin aging such as spots, wrinkles and sagging because they have a free radical scavenging antioxidant effect.
<実施例3 培養細胞の酸化ストレスに対する防御効果の評価1>
ヒト新生児由来の線維芽細胞(NB1RGB)を、10%子牛血清(FBS)含有MEMα培地(ギブコ社製)を用いて、96穴プレートに1×105個/ウェルずつ播種し、5vol%CO2環境下、37℃で24時間培養した。培養後、実施例1で調製したMEL−C及びアルブチンを、それぞれ最終濃度で培地1mLあたり1、5及び10μgとなるよう添加して30分間培養した。培養後、酸化ストレス剤として過酸化水素水を最終濃度で0.2mMとなるように添加して更に3時間培養した。次いで3−(4,5−ジメチルチアゾール−2−イル)−5−(3−カルボキシメトキシフェニル)−2−(4−スルホニル)−2H−テトラゾリウム(MTS)を最終濃度で培地1mLあたりに1.9mgとなるように添加して2時間培養し、生じた水溶性フォルマザンの最大吸収波長である490nmの吸光度をマイクロプレートリーダーにて測定した。試料無添加条件において酸化ストレス剤を与えた細胞をコントロール、酸化ストレス剤を与えない細胞をコントロールブランクとして、それぞれの吸光度の差を標準生育値とした。また、各試料添加条件において酸化ストレス剤を与えた細胞及び酸化ストレス剤を与えない細胞のそれぞれの吸光度の差を試料生育値として、次の式により細胞保護活性(%)を算定した。
<Example 3 Evaluation 1 of protective effect against oxidative stress of cultured cells>
Human neonatal-derived fibroblasts (NB1RGB) were seeded at 1 × 10 5 cells / well in 96-well plates using 10% calf serum (FBS) -containing MEMα medium (Gibco), and 5 vol% CO The cells were cultured at 37 ° C. for 24 hours in two environments. After the culture, MEL-C and arbutin prepared in Example 1 were added at final concentrations of 1, 5 and 10 μg per 1 mL of the medium, respectively, and cultured for 30 minutes. After the culture, hydrogen peroxide water was added as an oxidative stress agent to a final concentration of 0.2 mM and further cultured for 3 hours. Then 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfonyl) -2H-tetrazolium (MTS) at a final concentration of 1. The resultant was added to 9 mg and cultured for 2 hours, and the absorbance at 490 nm, which is the maximum absorption wavelength of the resulting water-soluble formazan, was measured with a microplate reader. The cells to which the oxidative stress agent was added under the sample-free condition were used as the control, the cells to which the oxidative stress agent was not applied were used as the control blank, and the difference in absorbance between them was used as the standard growth value. Further, the cytoprotective activity (%) was calculated by the following formula using the difference in absorbance between the cells to which the oxidative stress agent was added and the cells to which the oxidative stress agent was not applied as the sample growth value under each sample addition condition.
細胞保護活性(%)=(1−試料生育値/標準生育値)×100
なお、本実施例で用いたMEL−Cは、大豆油を原料として、Pseudozyma hubeiensis KM−59株で生産したMELであって不飽和度が94.0%のものを、カラムクロマトグラフィーで精製した後、ジメチルスルホキシド(DMSO)に溶解し調整して使用した。また、アルブチンは、本実施例においてポジティブコントロールとして用いた。
Cytoprotective activity (%) = (1-sample growth value / standard growth value) × 100
The MEL-C used in this example was a MEL produced with Pseudozyma hubiensis KM-59 using soybean oil as a raw material and purified by column chromatography with an unsaturation degree of 94.0%. Thereafter, it was dissolved in dimethyl sulfoxide (DMSO) and used after adjustment. Arbutin was used as a positive control in this example.
MEL−Cの細胞に対する保護効果を調べた結果を図2に示す。図2に示すように、MEL−Cが細胞の生育を高めていることは明らかとなった。この結果は、MELが抗酸化能を発揮し、細胞を酸化ストレスから保護したためと考えられる。 The results of examining the protective effect of MEL-C on cells are shown in FIG. As shown in FIG. 2, it was revealed that MEL-C enhanced cell growth. This result is thought to be because MEL exerted antioxidant ability and protected cells from oxidative stress.
<実施例4 培養細胞の酸化ストレスに対する防御効果の評価2>
さらに、MEL−Cが、細胞の酸化ストレスを軽減していることを示すために、細胞内の炎症マーカーとして知られるタンパク質であるシクロオキシゲナーゼ(COX−2)を指標にして、酸化ストレス処理後のCOX−2の発現を次のように調べた。
<Example 4 Evaluation 2 of protective effect of cultured cells against oxidative stress>
Furthermore, in order to show that MEL-C reduces oxidative stress in cells, COX after oxidative stress treatment is performed using cyclooxygenase (COX-2), which is a protein known as an intracellular inflammatory marker, as an index. -2 expression was examined as follows.
実施例3と同様に、MEL及びアルブチンをそれぞれ最終濃度で培地1mLあたり10μgとなるよう添加して30分間培養した後、酸化ストレス剤として過酸化水素水を最終濃度で0.2mMとなるように添加して、さらに3時間培養した細胞、及び試料無添加条件で酸化ストレス剤を与えたコントロール群の細胞をセルスクレーパーで回収し、遠心して上清を除いた後、1%ドデシル硫酸ナトリウム(SDS)水溶液を加え氷中にて1分間超音波破砕し、タンパク質抽出液とした。それぞれのタンパク質抽出液の濃度を測定し、SDS−ポリアクリルアミド電気泳動ゲルにそれぞれ50μg/レーンのタンパク質を供し、電気泳動した。ゲル中のタンパク質は、ポリビニリデンジフルオライド膜にセミドライブロッティング装置(バイオラド社製)を用いて転写した。膜は5%スキムミルクでブロッキングした後、5μg/mlの抗COX−2モノクローナル抗体を室温で2時間処理した。0.01%Tween−20を含むPBS(PBS−T)で洗浄後、二次抗体として5000倍希釈したペルオキシダーゼ標識抗マウスIgG抗体を室温で1時間処理し、再びPBS−Tで洗浄しECLウエスタンブロッティングキットを用いて発色させた。発色は電荷結合素子(CCD)カメラを用いて確認した。なお、細胞中の内在性コントロールタンパク質としては、一般的に利用されているβ−アクチンを使用した。 As in Example 3, after adding MEL and arbutin to a final concentration of 10 μg per mL of medium and culturing for 30 minutes, hydrogen peroxide as an oxidative stress agent was 0.2 mM in the final concentration. The cells were added and cultured for 3 hours, and the cells of the control group to which the oxidative stress agent was added under the sample-free conditions were collected with a cell scraper, centrifuged to remove the supernatant, and then 1% sodium dodecyl sulfate (SDS ) Aqueous solution was added and sonicated for 1 minute in ice to obtain a protein extract. The concentration of each protein extract was measured, and 50 μg / lane of each protein was applied to an SDS-polyacrylamide electrophoresis gel for electrophoresis. The protein in the gel was transferred to a polyvinylidene difluoride film using a semi-driving device (Biorad). The membrane was blocked with 5% skim milk and then treated with 5 μg / ml anti-COX-2 monoclonal antibody for 2 hours at room temperature. After washing with PBS containing 0.01% Tween-20 (PBS-T), a peroxidase-labeled anti-mouse IgG antibody diluted 5000 times as a secondary antibody was treated at room temperature for 1 hour, washed again with PBS-T, and ECL Western Color was developed using a blotting kit. Color development was confirmed using a charge coupled device (CCD) camera. In addition, generally used β-actin was used as the endogenous control protein in the cells.
COX−2の発現試験の結果を図3に示す。図3によると、過酸化水素で酸化ストレスを受けた細胞に対して、MEL−Cを添加した細胞内のCOX−2の発現量は、アルブチンを添加した細胞内のCOX−2の発現量と同様に、低下していることがわかった。この結果は、MEL−Cが、細胞を酸化ストレスから保護していることを示している。 The results of the COX-2 expression test are shown in FIG. According to FIG. 3, the expression level of COX-2 in the cells to which MEL-C was added to the cells subjected to oxidative stress with hydrogen peroxide is the expression level of COX-2 in the cells to which arbutin was added. Similarly, it turned out that it has fallen. This result indicates that MEL-C protects cells from oxidative stress.
以下、MELを配合した皮膚外用剤の配合例を示す。 Hereinafter, the example of a skin external preparation which mix | blended MEL is shown.
〔配合例1〕
下記組成の乳液を常法により製造した。
MEL 5.0g
ホホバオイル 4.0g
カミツレエキス 0.1g
オリーブオイル 2.0g
スクワラン 2.0g
セタノール 2.0g
モノステアリン酸グリセリル 2.0g
ポリオキシエチレンセチルエーテル(20E.O.) 2.5g
オレイン酸ポリオキシエチレンソルビタン(20E.O.)2.0g
1,3−ブチレングリコール 3.0g
香料 0.05g
精製水 残部(全量を100gとする)
〔配合例2〕
下記組成のクリームを常法により製造した。
MEL 10.0g
カミツレエキス 0.1g
流動パラフィン 5.0g
サラシミツロウ 4.0g
セタノール 3.0g
スクワラン 10.0g
ラノリン 2.0g
ステアリン酸 1.0g
オレイン酸ポリオキシエチレンソルビタン(20E.O.)1.5g
モノステアリン酸グリセリル 3.0g
1,3−ブチレングリコール 6.0g
パラオキシ安息香酸メチル 1.5g
香料 0.1g
精製水 残部(全量を100gとする)
〔配合例3〕
下記組成の化粧水を常法により製造した。
MEL 5.0g
グリチルリチン酸ジカリウム 0.1g
カミツレエキス 0.1g
グリセリン 5.0g
1,3−ブチレングリコール 5.0g
ポリエチレングリコール 2.0g
ポリオキシエチレングリコール 2.0g
エタノール 7.0g
水酸化カリウム 0.01g
香料 0.01g
パラオキシ安息香酸ブチル 0.05g
精製水 残部(全量を100gとする)
[Formulation Example 1]
An emulsion having the following composition was produced by a conventional method.
MEL 5.0g
Jojoba oil 4.0g
Chamomile extract 0.1g
Olive oil 2.0g
Squalane 2.0g
Cetanol 2.0g
Glyceryl monostearate 2.0g
Polyoxyethylene cetyl ether (20E.O.) 2.5 g
Oleic acid polyoxyethylene sorbitan (20EO) 2.0 g
1,3-butylene glycol 3.0 g
Fragrance 0.05g
Purified water remainder (total amount is 100 g)
[Formulation Example 2]
A cream having the following composition was produced by a conventional method.
MEL 10.0g
Chamomile extract 0.1g
Liquid paraffin 5.0g
Salami beeswax 4.0g
Cetanol 3.0g
Squalane 10.0g
Lanolin 2.0g
Stearic acid 1.0g
Oleic acid polyoxyethylene sorbitan (20EO) 1.5g
3.0 g glyceryl monostearate
1,3-butylene glycol 6.0 g
1.5 g of methyl paraoxybenzoate
Fragrance 0.1g
Purified water remainder (total amount is 100 g)
[Composition Example 3]
A lotion having the following composition was produced by a conventional method.
MEL 5.0g
0.1g dipotassium glycyrrhizinate
Chamomile extract 0.1g
Glycerin 5.0g
1,3-butylene glycol 5.0 g
Polyethylene glycol 2.0g
Polyoxyethylene glycol 2.0g
7.0g ethanol
Potassium hydroxide 0.01g
Fragrance 0.01g
Butyl paraoxybenzoate 0.05g
Purified water remainder (total amount is 100 g)
MELは、保湿効果や細胞賦活化効果、毛髪修復効果等に加え、フリーラジカル捕捉能及び/又は酸化ストレス保護能を有し、安全性の高い抗酸化効果を有している。それゆえ、抗酸化剤及びこれを配合した皮膚外用剤、ならびに各種使用において非常に有用である。
MEL has a free radical scavenging ability and / or oxidative stress protection ability in addition to a moisturizing effect, cell activation effect, hair repair effect, and the like, and has a highly safe antioxidant effect. Therefore, it is very useful in an antioxidant and an external preparation for skin containing the same and various uses.
Claims (6)
請求項1に記載の抗酸化剤を含有する組成物を皮膚に適用することを特徴とする化粧処置方法。
A cosmetic treatment method for antioxidant and / or anti-aging of the skin, comprising:
A cosmetic treatment method comprising applying the composition comprising the antioxidant according to claim 1 to the skin.
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JP2018158899A (en) * | 2017-03-22 | 2018-10-11 | 大阪瓦斯株式会社 | Antioxidative enzyme group production promoter |
JP2020533326A (en) * | 2017-09-11 | 2020-11-19 | オレオン ナームロゼ フェンノートシャップ | Emulsification combination to obtain low viscosity water-in-oil emulsion |
JP7326253B2 (en) | 2017-09-11 | 2023-08-15 | オレオン ナームロゼ フェンノートシャップ | Emulsifying combinations for obtaining low-viscosity water-in-oil emulsions |
JP2019122308A (en) * | 2018-01-17 | 2019-07-25 | 国立研究開発法人産業技術総合研究所 | Method for producing antioxidant |
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