JP4749696B2 - Novel glyceroglycolipid and its utilization - Google Patents
Novel glyceroglycolipid and its utilization Download PDFInfo
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- JP4749696B2 JP4749696B2 JP2004307072A JP2004307072A JP4749696B2 JP 4749696 B2 JP4749696 B2 JP 4749696B2 JP 2004307072 A JP2004307072 A JP 2004307072A JP 2004307072 A JP2004307072 A JP 2004307072A JP 4749696 B2 JP4749696 B2 JP 4749696B2
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- glyceroglycolipid
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Description
本発明は、新規なグリセロ糖脂質と、それを利用したインターロイキン４産生抑制剤、抗アレルギー組成物、抗炎症組成物、メラニン生成抑制剤、美白剤およびこれらの経口用又は皮膚外用組成物に関する。
The present invention relates to a novel glyceroglycolipid, an
近年、花粉症や食物アレルギー、気管支喘息、アトピー性皮膚炎といった種々のアレルギーが問題になっている。このような症状の治療には一般に薬理効果の高いホルモン剤が使用されているが、副腎皮質機能不全や消化管潰瘍といった副作用が大きいという問題がある。また、非ステロイド系のヒスタミン、ロイコトリエンの遊離抑制剤やＩｇＥ抗体産生抑制剤なども使用されているが、その効果は必ずしも十分ではない。 In recent years, various allergies such as hay fever, food allergies, bronchial asthma, and atopic dermatitis have become problems. Hormonal agents with high pharmacological effects are generally used for the treatment of such symptoms, but there is a problem that side effects such as adrenocortical dysfunction and gastrointestinal ulcers are large. Nonsteroidal histamine, leukotriene release inhibitors, IgE antibody production inhibitors, and the like are also used, but their effects are not always sufficient.
インターロイキン４（以下「ＩＬ−４」という。）は、抗原で刺激されたＴリンパ球によって産生される糖蛋白質である。Ｂリンパ球に作用してＩｇＥなどの抗体産生を増強し、炎症部位への炎症細胞の浸潤促進作用を有することが知られている。近年では、このアレルギー性疾患に関連のあるＩＬ−４の産生を抑制することができれば、従来の治療法及び予防法と異なった点で、アレルギー性疾患や炎症を治療できるのではないかと考えられている。 Interleukin 4 (hereinafter referred to as “IL-4”) is a glycoprotein produced by antigen-stimulated T lymphocytes. It is known to act on B lymphocytes to enhance the production of antibodies such as IgE and to promote the infiltration of inflammatory cells into the inflammatory site. In recent years, if it is possible to suppress the production of IL-4 related to this allergic disease, it may be possible to treat allergic disease and inflammation in a point different from conventional treatments and prevention methods. ing.
ＩＬ−４産生抑制剤としては、スルホニウム誘導体（例えば、非特許文献１参照）が知られており、ＩＬ−４産生抑制作用を有する植物としては、イラクサやタイム、セイヨウノコギリソウなどの抽出物（例えば、特許文献１参照）やインチンコウ抽出物（例えば、特許文献２参照）が報告されているが、これらの効果は十分ではない。そこで、安定性、安全性に優れ、価格においても問題のないＩＬ−４産生抑制剤が求められている。 As an IL-4 production inhibitor, a sulfonium derivative (see, for example, Non-Patent Document 1) is known, and as a plant having an IL-4 production inhibitory action, an extract (eg, nettle, thyme, or yarrow) , Patent Document 1) and Inchinkou extract (see, for example, Patent Document 2) have been reported, but these effects are not sufficient. Therefore, there is a demand for an IL-4 production inhibitor that is excellent in stability and safety and has no problem in price.
これまでに、ブロッコリー、カリフラワー、なずな、すずしろ、キャベツ、りんごなどにＩｇＥ増加抑制作用があることは報告されている（例えば、特許文献３参照）が、野菜類でのＩＬ−４産生抑制作用は知られていない。また、パイナップル等の植物の抽出物、或いは特定の微生物の生産物から得られるグリセロ糖脂質のうち、モノガラクトシルジアシルグリセロール及びジガラクトシルジアシルグリセロールが肥満細胞からのヒスタミン遊離抑制活性を有し、抗アレルギー剤として有用であることが開示されているが（例えば、特許文献４参照）、グリセロ糖脂質のＩＬ−４産生抑制作用は知られていない。
一方、本発明者らは野菜飲料などに使用されているアブラナ科の野菜であるケールまたはそのエタノール抽出物がＩＬ−４産生抑制活性を有することを見出し、既に特許出願を行なった（特許文献５，６参照）。
So far, broccoli, cauliflower, nazuna, suzushiro, cabbage, apples and the like have been reported to have an inhibitory effect on IgE increase (see, for example, Patent Document 3). unknown. Also, among glyceroglycolipids obtained from plant extracts such as pineapples or products of specific microorganisms, monogalactosyl diacylglycerol and digalactosyl diacylglycerol have an activity of inhibiting histamine release from mast cells, and are antiallergic. Although it is disclosed that it is useful as an agent (see, for example, Patent Document 4), the IL-4 production inhibitory action of glyceroglycolipids is not known.
On the other hand, the present inventors have found that kale which is a cruciferous vegetable used in vegetable beverages or the like, or its ethanol extract has IL-4 production inhibitory activity, and has already filed a patent application (Patent Document 5). , 6).
また、大気汚染やオゾン層の破壊などに起因して、人の表皮に届く紫外線量は年々増加する傾向にあり、それに伴い、紫外線による肌のシミ、ソバカス、色黒などの肌悩みが大きな問題となっている。紫外線が照射されることにより、皮膚内に存在するチロシンがチロシナーゼ酵素の働きにより酸化されてメラニン色素が産生され、これが過剰に産生されると、シミ、ソバカス、色黒などの肌悩みとなって表れる。このメラニン色素の産生を抑制し、シミ、ソバカス、色黒を予防する方法として、従来より、皮膚の美白を目的として、皮膚化粧料にL-アスコルビン酸及びその誘導体であるL-アスコルビン酸グルコース配糖体を配合することが行なわれており（例えば、特許文献７参照）、さらにL-アスコルビン酸グルコース配糖体とアミノ酸又はその誘導体を組み合わせて配合した皮膚外用剤（例えば、特許文献８参照）など多数提案されている。しかしながら、これらの美白剤は美白効果が必ずしも十分に認められないものであったり、美白効果を示す成分を、美白効果を認める濃度で配合すると安全性や安定性に問題を生じることがあった。
一方、本発明者は、このような皮膚の美白を目的としてメラニン生成抑制剤の探索を行っていたが、アブラナ科の野菜であるケールまたはその抽出物が紫外線によるメラニン生成抑制作用を有することを見出し、既に特許出願を行った（特許文献９参照）。
In addition, the amount of ultraviolet rays that reach the human epidermis tends to increase year by year due to air pollution and the destruction of the ozone layer, and as a result, skin problems such as skin spots, buckwheat, and dark black due to ultraviolet rays are a major problem. It has become. By irradiating with ultraviolet rays, tyrosine present in the skin is oxidized by the action of tyrosinase enzyme to produce melanin pigment, and if this is produced excessively, it causes skin problems such as spots, freckles, and darkness. appear. As a method for inhibiting the production of this melanin pigment and preventing spots, freckles, and darkness, L-ascorbic acid and its derivative L-ascorbic acid glucose distribution have been conventionally applied to skin cosmetics for the purpose of skin whitening. A saccharide is blended (for example, see Patent Document 7), and a skin external preparation formulated by combining L-ascorbic acid glucose glycoside with an amino acid or a derivative thereof (for example, see Patent Document 8). Many have been proposed. However, these whitening agents do not always have a sufficient whitening effect, and if a component showing the whitening effect is blended in a concentration that allows the whitening effect, there may be problems in safety and stability.
On the other hand, the present inventor has been searching for a melanin production inhibitor for the purpose of whitening the skin, but kale which is a cruciferous vegetable or an extract thereof has an action to inhibit melanin production by ultraviolet rays. The patent application has already been filed (see Patent Document 9).
本発明は、新規なグリセロ糖脂質、およびこの新規グリセロ糖脂質を含有するＩＬ−４産生抑制剤、抗アレルギー組成物又は抗炎症組成物、あるいは新規グリセロ糖脂質を含有するメラニン生成抑制剤又は美白剤、並びにこれらを利用した医薬、食品組成物、化粧料、皮膚外用剤を提供することを目的とするものである。 The present invention relates to a novel glyceroglycolipid, an IL-4 production inhibitor containing the novel glyceroglycolipid, an antiallergic composition or an anti-inflammatory composition, or a melanin production inhibitor or whitening containing the novel glyceroglycolipid. It is an object of the present invention to provide an agent, and a medicine, a food composition, a cosmetic, and an external preparation for skin using the same.
本発明者は、上記のような課題を解決すべく鋭意研究を重ね、種々の植物抽出物について探索を続けた結果、ケールのエタノール抽出物から分離した新規なグリセロ糖脂質に、特にアレルギー性疾患の原因の一つと考えられているＩＬ−４の産生抑制活性に優れ、更に皮膚のシミ、ソバカスの原因となるメラニンの生成抑制作用があることを見出し、本発明を完成した。 The present inventor has conducted extensive research to solve the above-mentioned problems, and has continued to search for various plant extracts. As a result, novel glyceroglycolipids separated from kale's ethanol extract are particularly useful for allergic diseases. The present invention was completed by finding that it has excellent IL-4 production inhibitory activity, which is considered to be one of the causes of the above, and that it has an inhibitory action on the production of melanin that causes skin spots and freckles.
即ち、本発明は、以下の内容をその要旨とするものである。
（１）次の化学式（Ｉ）で表わされる新規グリセロ糖脂質。
That is, the gist of the present invention is as follows.
(1) A novel glyceroglycolipid represented by the following chemical formula (I).
［ここで、式中Ｒは、次の式（II） [Wherein R represents the following formula (II)
で示される基、または次の式（III） Or a group represented by the following formula (III)
で示される基を表す。式（II）および式（III）において、＊印は式（Ｉ）との結合位置を示す。］
Represents a group represented by In the formula (II) and the formula (III), the asterisk (*) indicates the bonding position with the formula (I) . ]
（２）前記化学式（Ｉ）で表わされる化合物を含有することを特徴とするインターロイキン４産生抑制剤。
（３）前記化学式（Ｉ）で表わされる化合物を含有することを特徴とする抗アレルギー組成物。
（４）前記化学式（Ｉ）で表わされる化合物を含有することを特徴とする抗炎症組成物。
（５）前記化学式（Ｉ）で表わされる化合物を含有することを特徴とするメラニン生成抑制剤。
（６）前記化学式（Ｉ）で表わされる化合物を含有することを特徴とする美白剤。
（７）前記化学式（Ｉ）で表わされる化合物を含有することを特徴とする医薬。
（８）前記化学式（Ｉ）で表わされる化合物を含有することを特徴とする食品組成物。
（９）前記化学式（Ｉ）で表わされる化合物を含有することを特徴とする化粧料。
（１０）前記化学式（Ｉ）で表わされる化合物を含有することを特徴とする皮膚外用剤。
(2) An
(3) An antiallergic composition comprising a compound represented by the chemical formula (I).
(4) An anti-inflammatory composition comprising the compound represented by the chemical formula (I).
(5) A melanin production inhibitor comprising a compound represented by the chemical formula (I).
(6) A whitening agent comprising a compound represented by the chemical formula (I).
(7) A pharmaceutical comprising the compound represented by the chemical formula (I).
(8) A food composition comprising the compound represented by the chemical formula (I).
(9) A cosmetic comprising the compound represented by the chemical formula (I).
(10) A skin external preparation characterized by containing the compound represented by the chemical formula (I).
本発明により、ＩＬ−４産生抑制作用並びにメラニン生成抑制作用に優れる新規なグリセロ糖脂質を提供することができる。また、本発明の新規グリセロ糖脂質を含むＩＬ−４産生抑制剤を使用して、これを医薬、食品組成物、皮膚外用剤等に利用することにより、アレルギー性鼻炎や花粉症などのアレルギーや種々の炎症に対して優れた効果を有する、抗アレルギー組成物および抗炎症組成物を提供することができる。
更に、本発明の新規グリセロ糖脂質を含むメラニン抑制剤を使用して、これを医薬、食品組成物、化粧料、皮膚外用剤等に利用することにより、メラニンの生成抑制に優れた効果を有し、美白作用を有する有用な組成物を提供することができる。
ADVANTAGE OF THE INVENTION By this invention, the novel glyceroglycolipid excellent in the IL-4 production inhibitory effect and the melanin production inhibitory effect can be provided. In addition, by using the IL-4 production inhibitor containing the novel glyceroglycolipid of the present invention and using it as a pharmaceutical, a food composition, an external preparation for skin, etc., allergies such as allergic rhinitis and hay fever It is possible to provide an antiallergic composition and an antiinflammatory composition having an excellent effect on various inflammations.
Furthermore, by using the melanin inhibitor containing the novel glyceroglycolipid of the present invention and using it for pharmaceuticals, food compositions, cosmetics, external preparations for skin, etc., it has an excellent effect on inhibiting the production of melanin. In addition, a useful composition having a whitening effect can be provided.
以下、本発明の新規なグリセロ糖脂質、これを含有するＩＬ−４産生抑制剤、抗アレルギー組成物又は抗炎症組成物、或いはこれを含むメラニン生成抑制剤又は美白剤、並びにこれらを利用した医薬、食品組成物、化粧料、皮膚外用剤について説明する。
まず、本発明のグリセロ糖脂質は、前記化学式（Ｉ）で表わされる新規な化合物であり、糖類基としてガラクトース、アシル基として不飽和結合を含む炭素数１８のアシル基を有するグリセロ糖脂質である。
Hereinafter, the novel glyceroglycolipid of the present invention, an IL-4 production inhibitor containing the same, an antiallergic composition or an anti-inflammatory composition, a melanin production inhibitor or a whitening agent containing the same, and a medicine using these The food composition, cosmetics, and external preparation for skin will be described.
First, the glyceroglycolipid of the present invention is a novel compound represented by the above chemical formula (I), and is a glyceroglycolipid having a saccharide group containing galactose as a saccharide group and an acyl group having 18 carbon atoms containing an unsaturated bond as an acyl group. .
具体的には、本発明の新規なグリセロ糖脂質は、ＩＵＰＡＣ名によって以下のように表記できる前記化学式（Ｉ）で表わされる新規な化合物である。
置換基Ｒが式（II）の場合:
(9Z,12Z,15Z)-2-hydroxy-3-((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-2-yloxy)methyl)-tetrahydro-2H-pyran-2-yloxy)propyl octadeca-9,12,15-trienoate
置換基Ｒが式（III）の場合:
(12Z,15Z)-2-hydroxy-3-((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-2-yloxy)methyl)-tetrahydro-2H-pyran-2-yloxy)propyl octadeca-12,15-dienoate
Specifically, the novel glyceroglycolipid of the present invention is a novel compound represented by the above chemical formula (I) which can be expressed as follows by the IUPAC name.
When the substituent R is formula (II):
(9Z, 12Z, 15Z) -2-hydroxy-3-((2R, 3R, 4S, 5R, 6R) -3,4,5-trihydroxy-6-(((2R, 3R, 4S, 5R, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) methyl) -tetrahydro-2H-pyran-2-yloxy) propyl octadeca-9,12,15-trienoate
When substituent R is of formula (III):
(12Z, 15Z) -2-hydroxy-3-((2R, 3R, 4S, 5R, 6R) -3,4,5-trihydroxy-6-(((2R, 3R, 4S, 5R, 6R) -3 , 4,5-trihydroxy-6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yloxy) methyl) -tetrahydro-2H-pyran-2-yloxy) propyl octadeca-12,15-dienoate
本発明の前記化学式（Ｉ）で表わされるグリセロ糖脂質は、例えば、アブラナ科植物の野菜であるケールのエタノール抽出物から分離して入手することができる。このケールは、南ヨーロッパ原産のアブラナ科植物の野菜で、キャベツの原種と言われており、その学名は、Brassicca Oleracea L．var．acephala DC.である。このケールには、キッチンケール、マローケール、ブッシュケール、ツリーケール、コラード、緑藻カンランなどの種類があり、これらのいずれでも本発明の新規なグリセロ糖脂質を製造するために使用することができる。本発明の新規なグリセロ糖脂質を得るためのケールの使用部位としては、葉など通常食用に供されているもののほかケールの茎、花、根なども使用することができ、特に制限されるものではなく、その栽培方法や栽培地も特に限定されるものではない。 The glyceroglycolipid represented by the above chemical formula (I) of the present invention can be obtained, for example, by separating it from an ethanol extract of kale, which is a vegetable of the cruciferous plant. This kale is a cruciferous vegetable native to Southern Europe and is said to be the original species of cabbage. Its scientific name is Brassicca Oleracea L. var. acephala DC. There are various types of kale such as kitchen kale, mallow kale, bush kale, tree kale, collard, green alga kanran, and any of these can be used to produce the novel glyceroglycolipid of the present invention. The use part of kale for obtaining the novel glyceroglycolipid of the present invention is not limited to those usually used for food such as leaves, but can also use kale stems, flowers, roots, etc. However, the cultivation method and cultivation place are not particularly limited.
本発明の前記化学式（Ｉ）で表わされるグリセロ糖脂質は、上述のようなケールの葉、茎、花、根などを濃度５０〜９９．５質量％、好ましくは７０〜８０質量％のエタノールで抽出して得られた抽出物の脂溶性画分に多く含まれている。具体的には、例えば、ケールの葉、茎、花や根などの乾燥物に濃度５０〜９９．５質量％、好ましくは７０〜８０質量％エタノールを加え、室温で数時間ないし数十時間の間浸漬・攪拌することによりその抽出液を得て、この抽出液をおよそ１０〜２０倍程度まで加熱蒸発等によって濃縮し、分液ロートなどによって水溶性画分と脂溶性画分とに分離して得られた脂溶性画分である。ここで得られた脂溶性画分は、さらにその濃度が５０質量％のエタノールを用いて再度抽出を行い、分液ロートによって２層に分離することができる。これらのうちの水溶性画分は主に水溶性の高い糖類や食物繊維などから構成されており、一方、脂溶性画分のうちの５０質量％エタノールに溶解しない画分（脂溶性画分Ｉ）は主としてクロロフィルやフィトステロールなどであり、また、５０質量％エタノールに溶解する画分（脂溶性画分Ｓ）は主としてポリフェノール類などから構成されている。本発明の前記化学式（Ｉ）で表わされるグリセロ糖脂質はこの脂溶性画分Ｓに含まれているので、脂溶性画分Ｓから逆相ＨＰＬＣなどでグリセロ糖脂質を分離精製することによって入手することができる。 The glyceroglycolipid represented by the chemical formula (I) of the present invention contains kale leaves, stems, flowers, roots and the like as described above in ethanol having a concentration of 50 to 99.5% by mass, preferably 70 to 80% by mass. It is abundant in the fat-soluble fraction of the extract obtained by extraction. Specifically, for example, a concentration of 50 to 99.5% by mass, preferably 70 to 80% by mass of ethanol is added to dry matter such as kale leaves, stems, flowers and roots, and the mixture is used for several hours to several tens of hours at room temperature. The extract is obtained by immersing and agitating for a while, and the extract is concentrated to about 10 to 20 times by heat evaporation or the like, and separated into a water-soluble fraction and a fat-soluble fraction by a separating funnel. It is a fat-soluble fraction obtained in this way. The fat-soluble fraction obtained here can be extracted again with ethanol having a concentration of 50% by mass and separated into two layers by a separatory funnel. Of these, the water-soluble fraction is mainly composed of highly water-soluble saccharides, dietary fibers, and the like, while the fat-soluble fraction that does not dissolve in 50% by mass ethanol (lipid-soluble fraction I). ) Is mainly chlorophyll, phytosterol, and the like, and the fraction dissolved in 50% by mass ethanol (fat-soluble fraction S) is mainly composed of polyphenols and the like. Since the glyceroglycolipid represented by the chemical formula (I) of the present invention is contained in the fat-soluble fraction S, it is obtained by separating and purifying the glyceroglycolipid from the fat-soluble fraction S by reverse phase HPLC or the like. be able to.
次に、本発明のＩＬ−４産生抑制剤、抗アレルギー組成物、抗炎症組成物、メラニン生成抑制剤又は美白剤は、このようにして得られたグリセロ糖脂質をそのままその有効成分として使用してもよいし、或いは上記のようにして得たケールのエタノール抽出物の脂溶性画分をそのままの状態で含有する組成物として使用してもよい。このような組成物としては、本発明の効果を損なわず、悪影響を及ぼさない任意の種々の成分をその助剤、媒体または担体として使用し、これに本発明の新規なグリセロ糖脂質を含有させることによって組成物を構成することができる。 Next, the IL-4 production inhibitor, antiallergic composition, anti-inflammatory composition, melanin production inhibitor or whitening agent of the present invention uses the glyceroglycolipid thus obtained as it is as an active ingredient. Or you may use as a composition which contains the fat-soluble fraction of the ethanol extract of the kale obtained as mentioned above as it is. In such a composition, any of various components that do not impair the effects of the present invention and do not adversely affect them are used as an auxiliary, a medium or a carrier, and the composition contains the novel glyceroglycolipid of the present invention. Thus, the composition can be constituted.
本発明の新規なグリセロ糖脂質はＩＬ−４産生抑制作用を有している。ＩＬ−４は、ＩｇＥやＩｇＧ４という抗体の産生を増強する作用を有すると共に、炎症部位への炎症性細胞の浸潤を促進する作用を有している。さらに、ＩＬ−４は、未成熟なＴリンパ球を成熟Ｔリンパ球に分化させる機能をも有しており、成熟Ｔリンパ球は未成熟Ｔリンパ球よりＩＬ−４の産生量が多い。しかも、ＩＬ−４は皮膚のトラブルにも関与し、特に皮膚の炎症に関与している。即ち，ＩＬ−４の産生を抑制することは、一連のアレルギー反応の初期段階を抑制することであり、有効な薬剤開発につながる。本発明の新規なグリセロ糖脂質は、このようなＩＬ−４の産生抑制に優れた効果を発揮し、アトピー性皮膚炎のようなアレルギー性疾患の予防、治療に有効である。さらに、本発明の新規なグリセロ糖脂質は、ＩＬ−４の関与する皮膚トラブルである、シワ、たるみ、かゆみ等の抑制にも有効に使用することができる。 The novel glyceroglycolipid of the present invention has an IL-4 production inhibitory action. IL-4 has the effect of enhancing the production of antibodies such as IgE and IgG4, and also has the effect of promoting the infiltration of inflammatory cells into the inflammatory site. Furthermore, IL-4 also has a function of differentiating immature T lymphocytes into mature T lymphocytes, and mature T lymphocytes produce more IL-4 than immature T lymphocytes. Moreover, IL-4 is also involved in skin troubles, particularly in skin inflammation. That is, suppressing the production of IL-4 suppresses the initial stage of a series of allergic reactions, leading to the development of an effective drug. The novel glyceroglycolipid of the present invention exhibits an excellent effect in suppressing the production of IL-4 and is effective for the prevention and treatment of allergic diseases such as atopic dermatitis. Furthermore, the novel glyceroglycolipid of the present invention can also be used effectively to suppress wrinkles, sagging, itching, etc., which are skin problems involving IL-4.
また、本発明の新規なグリセロ糖脂質は皮膚のメラニン生成抑制作用を有している。紫外線により、皮膚内に存在するチロシンがチロシナーゼ酵素の働きにより酸化されてメラニン色素が産生されるが、これが過剰に産生されると、シミ、ソバカス、色黒などの肌悩みとなる。本発明の新規グリセロ糖脂質を用いることにより、紫外線が照射されたときの皮膚のメラニンの生成が抑制され、このような肌悩みを改善のために有効である。 In addition, the novel glyceroglycolipid of the present invention has a skin melanin production inhibitory action. Ultraviolet rays oxidize tyrosine present in the skin by the action of the tyrosinase enzyme to produce melanin pigment. If this is excessively produced, it causes skin problems such as spots, freckles, and darkness. By using the novel glyceroglycolipid of the present invention, the production of melanin in the skin when irradiated with ultraviolet rays is suppressed, and such skin troubles are effective for improvement.
本発明の新規なグリセロ糖脂質は、ＩＬ−４産生抑制剤、抗アレルギー組成物、抗炎症組成物、メラニン生成抑制剤又は美白剤成分として使用する場合には、その適用量は、摂取者の年齢、体重、症状、適用経路、適用スケジュール、製剤形態などにより、適宜決定することができるが、例えば、経口投与の場合、グリセロ糖脂質の重量基準として、通常成人換算で０．０００１〜０．５ｇ／ｋｇ程度、より好ましくは０．００１〜０．２ｇ／ｋｇ程度で、１日数回に分けて投与してもよい。
また、適当な基剤、担体、媒体や賦形剤とともに本発明の新規なグリセロ糖脂質を配合することによって、ＩＬ−４産生抑制剤、抗アレルギー組成物、抗炎症組成物、メラニン生成抑制剤若又は美白剤とすることができる。
When the novel glyceroglycolipid of the present invention is used as an IL-4 production inhibitor, an antiallergic composition, an anti-inflammatory composition, a melanin production inhibitor or a whitening agent component, its application amount is Although it can be appropriately determined depending on age, body weight, symptoms, application route, application schedule, formulation form, etc., for example, in the case of oral administration, the weight standard of glyceroglycolipid is usually 0.0001-0. The dose may be divided into several times a day at about 5 g / kg, more preferably about 0.001 to 0.2 g / kg.
In addition, by incorporating the novel glyceroglycolipid of the present invention together with an appropriate base, carrier, medium and excipient, an IL-4 production inhibitor, an antiallergic composition, an anti-inflammatory composition, and a melanin production inhibitor It can be a young or whitening agent.
本発明の新規グリセロ糖脂質、ＩＬ−４産生抑制剤、抗アレルギー組成物、抗炎症組成物、メラニン生成抑制剤又は美白剤は、医薬又は食品用の経口組成物として使用することができ、化粧料または医薬として皮膚外用組成物として使用することもできる。 The novel glyceroglycolipid, IL-4 production inhibitor, antiallergic composition, anti-inflammatory composition, melanin production inhibitor or whitening agent of the present invention can be used as an oral composition for pharmaceuticals or foods, It can also be used as a composition for external use as a preparation or medicine.
医薬用としての本発明の新規グリセロ糖脂質の適用方法は、経口投与又は非経口投与のいずれも採用することができる。投与に際しては、有効成分を経口投与、直腸内投与、注射などの投与方法に適した固体又は液体の医薬用無毒性担体と混合して、慣用の医薬製剤の形態として投与することができる。このような製剤としては、例えば、錠剤、顆粒剤、散剤、カプセル剤などの固形剤、溶液剤、懸濁剤、乳剤などの液剤、凍結乾燥製剤などが挙げられ、これらの製剤は製剤上の常套手段により調製することができる。上記の医薬用無毒性担体としては、例えば、グルコース、乳糖、ショ糖、澱粉、マンニトール、デキストリン、脂肪酸グリセリド、ポリエチレングリコール、ヒドロキシエチルデンプン、エチレングリコール、ポリオキシエチレンソルビタン脂肪酸エステル、アミノ酸、ゼラチン、アルブミン、水、生理食塩水などが挙げられる。また、必要に応じて、安定化剤、湿潤剤、乳化剤、結合剤、等張化剤などの慣用の添加剤を適宜添加することもできる。 As a method for applying the novel glyceroglycolipid of the present invention for pharmaceutical use, either oral administration or parenteral administration can be employed. In administration, the active ingredient can be mixed with a solid or liquid non-toxic pharmaceutical carrier suitable for administration methods such as oral administration, rectal administration and injection, and administered in the form of a conventional pharmaceutical preparation. Examples of such preparations include solid preparations such as tablets, granules, powders and capsules, solutions such as solutions, suspensions and emulsions, freeze-dried preparations, and the like. It can be prepared by conventional means. Examples of the non-toxic pharmaceutical carrier include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, amino acid, gelatin, albumin , Water, physiological saline and the like. In addition, conventional additives such as stabilizers, wetting agents, emulsifiers, binders, tonicity agents and the like can be appropriately added as necessary.
食品用組成物としては、本発明の新規グリセロ糖脂質をそのまま、又は種々の栄養成分を加えて、又は飲食品中に含有せしめて、アレルギー症状の治療及び予防に有用な保健用食品又は食品素材として使用することができる。例えば、澱粉、乳糖、麦芽糖、植物油脂粉末、カカオ脂末、ステアリン酸などの適当な助剤を添加した後、慣用の手段を用いて、経口用に適した形態、例えば顆粒状、粒状、錠剤、カプセル、ペーストなどに成形して食用に供してもよく、また種々の食品、例えば、ハム、ソーセージなどの食肉加工食品、かまぼこ、ちくわなどの水産加工食品、パン、菓子、バター、粉乳、発酵乳製品に添加して使用してもよい。本発明の新規グリセロ糖脂質の配合量は、当該食品または食品用素材の種類や状態等により適宜設定することができる。 As a composition for food, the novel glyceroglycolipid of the present invention is used as it is, added with various nutritional components, or contained in foods and drinks, and is useful for the treatment and prevention of allergic symptoms. Can be used as For example, after adding a suitable auxiliary agent such as starch, lactose, maltose, vegetable oil powder, cacao butter powder, stearic acid, etc., using conventional means, a form suitable for oral use, such as granule, granule, tablet It may be formed into capsules, pastes, etc. and used for food, and various foods such as processed foods such as ham and sausage, fishery processed foods such as kamaboko and chikuwa, bread, confectionery, butter, milk powder, fermented milk It may be used by adding to dairy products. The blending amount of the novel glyceroglycolipid of the present invention can be appropriately set depending on the type or state of the food or food material.
また、本発明の新規グリセロ糖脂質は、これを配合した化粧料素材、化粧料又は皮膚外用剤の形態で製造することができる。例えば、新規グリセロ糖脂質を小麦胚芽油あるいはオリーブ油に添加して、これを化粧料素材として使用することができる。 Moreover, the novel glyceroglycolipid of the present invention can be produced in the form of a cosmetic material, cosmetic or skin external preparation containing the same. For example, a novel glyceroglycolipid can be added to wheat germ oil or olive oil and used as a cosmetic material.
また、本発明の新規グリセロ糖脂質を、直接化粧料成分として使用し、化粧料を製造することもできる。このような化粧料には、植物油のような油脂類、高級脂肪酸、高級アルコール、シリコーン、アニオン界面活性剤、カチオン界面活性剤、両性界面活性剤、非イオン界面活性剤、防腐剤、糖類、金属イオン封鎖剤、水溶性高分子のような高分子、増粘剤、粉体成分、紫外線吸収剤、紫外線遮断剤、ヒアルロン酸のような保湿剤、香料、ｐＨ調整剤、乾燥剤などを含有させることができる。さらに、ビタミン類、皮膚賦活剤、血行促進剤、常在菌コントロール剤、活性酸素消去剤、抗炎症剤、抗癌剤、美白剤、殺菌剤等のほかの薬効成分、生理活性成分を含有させることもできる。 Further, the novel glyceroglycolipid of the present invention can be directly used as a cosmetic ingredient to produce a cosmetic. Such cosmetics include oils and fats such as vegetable oils, higher fatty acids, higher alcohols, silicones, anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants, preservatives, sugars, metals Contains sequestering agents, polymers such as water-soluble polymers, thickeners, powder components, UV absorbers, UV blockers, moisturizers such as hyaluronic acid, perfumes, pH adjusters, desiccants, etc. be able to. In addition, vitamins, skin activators, blood circulation promoters, resident bacteria control agents, active oxygen scavengers, anti-inflammatory agents, anticancer agents, whitening agents, bactericides, and other medicinal and physiologically active ingredients may be included. it can.
化粧料の種類としては、化粧水、乳液、クリーム、パック等の皮膚化粧料、メイクアップベースローション、メイクアップクリーム、乳液状又はクリーム状あるいは軟膏型のファンデーション、口紅、アイカラー、チークカラーといったメイクアップ化粧料、ハンドクリーム、レッグクリーム、ボディローション等の身体用化粧料、および入浴剤、口腔化粧料、毛髪化粧料等とすることができる。本発明の新規グリセロ糖脂質を含有せしめた化粧料としては、その機能面からは、例えば乳液、化粧液、フェイスクリーム、ハンドクリーム、ローション、エッセンスなどが好ましい。 The types of cosmetics include skin cosmetics such as lotions, emulsions, creams, packs, makeup base lotions, makeup creams, emulsions, creams or ointment foundations, lipsticks, eye colors, and cheek colors. Cosmetics for the body such as up cosmetics, hand creams, leg creams, body lotions, and the like, and bathing agents, oral cosmetics, hair cosmetics, and the like. As the cosmetics containing the novel glyceroglycolipid of the present invention, for example, emulsions, cosmetics, face creams, hand creams, lotions, essences and the like are preferable from the functional aspect.
このような本発明の新規グリセロ糖脂質を含有する化粧料は、常法に従って製造することができる。化粧料における本発明の新規グリセロ糖脂質の添加量は、特に限定されるものではないが、一例としてあげると、化粧料全重量の０．００１〜２０質量％、好ましくは０．０１〜１０質量％が適当である。 Such a cosmetic containing the novel glyceroglycolipid of the present invention can be produced according to a conventional method. The addition amount of the novel glyceroglycolipid of the present invention in cosmetics is not particularly limited, but as an example, 0.001 to 20 mass%, preferably 0.01 to 10 mass% of the total cosmetic weight. % Is appropriate.
次に、本発明を実施例によって更に詳しく説明する。以下の製造例、実施例、処方例は本発明の好ましい例を示すものであり、これに限定されるものではない。また、各例中の「％」は質量基準である。 Next, the present invention will be described in more detail with reference to examples. The following production examples, examples and formulation examples show preferred examples of the present invention and are not limited thereto. Further, “%” in each example is based on mass.
１）新規グリセロ糖脂質の製造
乾燥させたケールの葉を粉砕し、ケール粉砕物１ｋｇを７０％エタノールカラム（カラムサイズ４５ｍｍΦ×４１５ｍｍ）を用いて２０Ｌの７０％エタノールで抽出し、この抽出液をエバポレーターを用いて１Ｌまで濃縮した。得られた濃縮物１Ｌを分液ロートにより、水溶性画分と脂溶性画分に分け、更に、脂溶性画分を５０％エタノール２Ｌに溶解した。このエタノール溶液を、さらに分液ロートで分配して二層に分離し、５０％エタノールに溶解している画分を濃縮乾固させてケールエタノール抽出物の「脂溶性画分Ｓ」として２４ｇを得た。
1) Production of novel glyceroglycolipid The dried kale leaf was pulverized, and 1 kg of the pulverized kale was extracted with 20 L of 70% ethanol using a 70% ethanol column (column size 45 mmΦ × 415 mm). Concentrated to 1 L using an evaporator. 1 L of the resulting concentrate was separated into a water-soluble fraction and a fat-soluble fraction by a separating funnel, and the fat-soluble fraction was dissolved in 2 L of 50% ethanol. This ethanol solution was further divided into two layers by separating a separating funnel, and the fraction dissolved in 50% ethanol was concentrated to dryness to obtain 24 g as a “fat-soluble fraction S” of the kale ethanol extract. Obtained.
２）脂溶性画分Ｓ中の成分の中圧液体クロマトグラフィーによる分取
得られた脂溶性画分Ｓの２４ｇのうちの５ｇを用いて、以下の方法と条件によって分離精製した。
・機器構成：
中圧液体クロマトグラフィーシステム：Ｋｒｏｎｌａｂ ＧｍｂＨ
逆相カラム：Ｐｏｌｙｇｏｐｒｅｐ ６０−５０ ＲＰ−１８（Ｍａｃｈｅｒｅｙ＆Ｎａｇｅｌ）
・溶離液：
精製水１００％、続いて、精製水１００％→メタノール１００％のグラジエント、続いて、イソプロパノール１００％
・分取物
溶離液が精製水１００％で溶出した分画Ｐ（０．８９ｇ）を得た。分画ＰをＳＰＥカラム（Ｌｉｃｈｒｏｌｕｔ ＥＮ-Ｍｅｒｃｋ）で処理し、０．１５ｇの脱塩物を得た。
2) using 5g of 24g of fat-soluble fraction S of lipophilic fraction S obtained fractionated by medium pressure liquid chromatography component, it was separated and purified by the following method and conditions.
·Equipment configuration:
Medium pressure liquid chromatography system: Kronlab GmbH
Reversed phase column: Polyprep 60-60 RP-18 (Macheley & Nagel)
・ Eluent:
・ Preparation
Fraction P (0.89 g) was obtained in which the eluent eluted with 100% purified water. Fraction P was treated with an SPE column (Lichlort EN-Merck) to obtain 0.15 g of desalted product.
３）分画Ｐ脱塩物の高速液体クロマトグラフィーによる分離
分画Ｐ脱塩物０．１５ｇを用いて、以下の方法と条件によって分離精製した。
・機器構成：
全自動分画・精製・分取システム：ＳＥＰＢＯＸＬｉｇｈｔ
分取カラム： Ｍｅｒｃｋ Ｓｅｌｅｃｔ Ｂ ２５０×１６ｍｍ、１０μｍ
検出器：ＥＬＳＤ（Ｓｅｄｅｘ７５）
ＵＶ（Ｍｅｒｃｋ、２５４ｎｍ）
・溶離液：
流 速：１５ｍＬ／ｍｉｎ
溶離液：Ａ・・・０．５ｍＭギ酸アンモニウム、０．１％ギ酸水溶液
Ｂ・・・０．５ｍＭギ酸アンモニウム、０．１％ギ酸のアセトニトリル：メ
タノール＝１：１溶液
グラジエント：
時間（分） Ａ（％） Ｂ（％）
０．０ ６４ ３６
５７．７ １１ ８９
５７．８ ０ １００
６５．８ ０ １００
・分取物
分画Ｐ脱塩物からサンプル（ａ）２．３１ｍｇ、サンプル（ｂ）１．１５ｍｇを分取した。
3) Separation of fraction P desalted product by high-performance liquid chromatography Using 0.15 g of fraction P desalted product, separation and purification were performed according to the following method and conditions.
·Equipment configuration:
Fully automatic fractionation / purification / sorting system: SEPBOXLight
Preparative column: Merck Select B 250 × 16 mm, 10 μm
Detector: ELSD (Sedex75)
UV (Merck, 254nm)
・ Eluent:
Flow rate: 15 mL / min
Eluent: A ... 0.5 mM ammonium formate, 0.1% formic acid aqueous solution
B: 0.5 mM ammonium formate, 0.1% formic acid acetonitrile:
Tanol = 1: 1 solution Gradient:
Time (minutes) A (%) B (%)
0.0 64 36
57.7 11 89
57.8 0 100
65.8 0 100
-Fractionated matter From fraction P desalted product, 2.31 mg of sample (a) and 1.15 mg of sample (b) were collected.
４）サンプル（ａ）、サンプル（ｂ）の高速液体クロマトグラフィーによる純度確認、並びに保持時間の確認
・機器構成：
ＨＰＬＣシステム：Ｍｅｒｃｋ Ｈｉｔａｃｈｉ
分析カラム： Ｍｅｒｃｋ Ｓｅｌｅｃｔ Ｂ ２５０×４ｍｍ、５μｍ
検出器：ＥＬＳＤ（Ｓｅｄｅｘ７５）
・溶離液：
流 速：１ｍＬ／ｍｉｎ
溶離液：Ａ・・・０．５ｍＭギ酸アンモニウム、０．１％ギ酸水溶液
Ｂ・・・０．５ｍＭギ酸アンモニウム、０．１％ギ酸のアセトニトリル：メ
タノール＝１：１溶液
グラジエント：
時間（分） Ａ（％） Ｂ（％）
０．０ ８５ １５
３０．０ ０ １００
４０．０ ０ １００
本分析条件により、サンプル（ａ）、サンプル（ｂ）が単一ピークを示すことを確認した。保持時間はサンプル(ａ)２６．６分、サンプル(ｂ)２７．９分である。
4) Purity confirmation of sample (a) and sample (b) by high performance liquid chromatography, confirmation of retention time, and equipment configuration:
HPLC system: Merck Hitachi
Analysis column: Merck Select B 250 × 4 mm, 5 μm
Detector: ELSD (Sedex75)
・ Eluent:
Flow rate: 1 mL / min
Eluent: A ... 0.5 mM ammonium formate, 0.1% formic acid aqueous solution
B: 0.5 mM ammonium formate, 0.1% formic acid acetonitrile:
Tanol = 1: 1 solution Gradient:
Time (minutes) A (%) B (%)
0.0 85 15
30.0 0 100
40.0 0 100
It was confirmed that the sample (a) and the sample (b) show a single peak under the analysis conditions. Retention times are 26.6 minutes for sample (a) and 27.9 minutes for sample (b).
５）グリセロ糖脂質の構造決定
上記の３）で分取したサンプル(ａ)及びサンプル(ｂ)の２個のサンプルについて、ＬＣ／ＭＳ分析装置及びＮＭＲ分析装置を用いて化合物の構造決定を行なった。
ＬＣ／ＭＳ分析の溶離液は４）と同じものを用い、グラジエント条件は適宜調整した。ＭＳシステムはＰＥ-Ｓｃｉｅｘ ＡＰＩ１５０（+/(-)-ＥＳＩ、Ｆａｓｔ-Ｓｗｉｔｃｈｉｎｇ-Ｍｏｄｅ）を使用した。
１Ｈ−ＮＭＲ、ＨＳＱＣ、ＨＭＢＣ、ＨＨ−ＣＯＳＹは共鳴周波数４００ＭＨｚあるいは５００ＭＨｚで測定した。１３Ｃ−ＮＭＲのスペクトルはＨＭＢＣ、ＨＳＱＣの手法を用いて帰属した。溶媒は重メタノールを用い、化学シフト基準に使用した（１Ｈ−ＮＭＲ３．３０ｐｐｍ、１３Ｃ−ＮＭＲ４９．０ｐｐｍ）。
サンプル（ｂ）については上記４）のクロマト分析条件では単一ピークであるが、２種類の化合物の混合物（以降、「化合物（ｂ１）」、「化合物（ｂ２）」と呼ぶ）であることが判明した。ＭＳ分析、並びにＮＭＲ分析によって化合物（ｂ１）、化合物（ｂ２）個々の構造を決定することができた。化合物（ｂ１）と化合物（ｂ２）は適切なクロマト分離条件を選択するにより分離することができる。
抽出分離した各サンプルのＬＣ／ＭＳ分析、ＮＭＲ分析の結果を以下に示す。表１ないし表３おいて、「Gal」はガラクトース、「FA」は脂肪酸を表す。
5) Determination of structure of glyceroglycolipid The structure of the compound was determined using the LC / MS analyzer and the NMR analyzer for the two samples (a) and (b) separated in 3) above. It was.
The same eluent for LC / MS analysis was used as in 4), and the gradient conditions were appropriately adjusted. The MS system used PE-Sciex API150 (+ / (-)-ESI, Fast-Switching-Mode).
1 H-NMR, HSQC, HMBC, and HH-COSY were measured at a resonance frequency of 400 MHz or 500 MHz. The 13 C-NMR spectrum was assigned using the methods of HMBC and HSQC. The solvent was deuterated methanol and used for the chemical shift standard ( 1 H-NMR 3.30 ppm, 13 C-NMR 49.0 ppm).
Sample (b) has a single peak under the chromatographic analysis conditions of 4) above, but is a mixture of two types of compounds (hereinafter referred to as “compound (b 1 )” and “compound (b 2 )”). It has been found. The individual structures of the compound (b 1 ) and the compound (b 2 ) could be determined by MS analysis and NMR analysis. Compound (b 1 ) and compound (b 2 ) can be separated by selecting appropriate chromatographic separation conditions.
The results of LC / MS analysis and NMR analysis of each sample extracted and separated are shown below. In Tables 1 to 3, “Gal” represents galactose and “FA” represents fatty acid.
(i)サンプル(ａ)：
ＬＣ／ＭＳとＮＭＲのデータを以下に示す。
ＬＣ／ＭＳ
（+)−ＥＳＩ：６９９[Ｍ＋Ｎａ]＋、５１５[Ｍ−Ｇａｌ＋Ｈ]＋、３５３[Ｍ−２Ｇａｌ＋Ｈ]＋、２６１[Ｃ１８Ｈ２９Ｏ]＋
（-)−ＥＳＩ：７２１[Ｍ＋ＨＣＯＯ]−、６７５[Ｍ−Ｈ]−、２７７[Ｃ１８Ｈ29Ｏ２]−
１ Ｈ−ＮＭＲ、 １３ Ｃ−ＮＭＲ
スペクトルの帰属と化学シフトを表１に示す。
(i) Sample (a):
The LC / MS and NMR data are shown below.
LC / MS
(+)-ESI: 699 [M + Na] + , 515 [M-Gal + H] + , 353 [M-2Gal + H] + , 261 [C 18 H 29 O] +
(−)-ESI: 721 [M + HCOO] − , 675 [M−H] − , 277 [C 18 H 29 O 2 ] −
1 H-NMR, 13 C-NMR
The spectral assignments and chemical shifts are shown in Table 1.
サンプル(ａ)は前記化学式（Ｉ）において置換基Ｒが前記式（II）で示される基である新規なグリセロ糖脂質であり、上記のようなスペクトルデータを示す。 Sample (a) is a novel glyceroglycolipid in which the substituent R in the chemical formula (I) is a group represented by the above formula (II), and shows the above spectral data.
(ii)サンプル(ｂ)：
サンプル（ｂ）中の化合物（ｂ１）のＬＣ／ＭＳとＮＭＲのデータを以下に示す。
ＬＣ／ＭＳ
（+)−ＥＳＩ：６９６[Ｍ＋ＮＨ４]＋、３５５[Ｍ−２Ｇａｌ＋Ｈ]＋
（-)−ＥＳＩ：６７７[Ｍ−Ｈ]−
１ Ｈ−ＮＭＲ、 １３ Ｃ−ＮＭＲ
スペクトルの帰属と化学シフトを表２に示す。
(ii) Sample (b):
The LC / MS and NMR data of the compound (b 1 ) in the sample (b) are shown below.
LC / MS
(+)-ESI: 696 [M + NH4] + , 355 [M-2Gal + H] +
(−)-ESI: 677 [M−H] −
1 H-NMR, 13 C-NMR
The spectral assignments and chemical shifts are shown in Table 2.
サンプル(ｂ)中の化合物（ｂ１）は前記化学式（Ｉ）において置換基Ｒが前記式（III）で示される基である新規なグリセロ糖脂質であり、上記のようなスペクトルデータを示す。 The compound (b 1 ) in the sample (b) is a novel glyceroglycolipid in which the substituent R is a group represented by the formula (III) in the chemical formula (I), and exhibits the above spectrum data.
サンプル（ｂ）中の化合物（ｂ２）のＬＣ／ＭＳとＮＭＲのデータを以下に示す。
ＬＣ／ＭＳ
（+）−ＥＳＩ：５３７[Ｍ＋Ｎａ]＋、５３２[Ｍ＋ＮＨ４]＋、３５３[Ｍ−Ｇａｌ＋Ｈ]＋、２６１[Ｃ１８Ｈ２９Ｏ]＋
（-）−ＥＳＩ：５５９[Ｍ＋ＨＣＯＯ]−、５１３[Ｍ−Ｈ]−、２７７[Ｃ１８Ｈ２９Ｏ２]−
１ Ｈ−ＮＭＲ、 １３ Ｃ−ＮＭＲ
スペクトルの帰属と化学シフトを表３に示す。
The LC / MS and NMR data of the compound (b 2 ) in the sample (b) are shown below.
LC / MS
(+)-ESI: 537 [M + Na] + , 532 [M + NH 4 ] + , 353 [M-Gal + H] + , 261 [C 18 H 29 O] +
(−)-ESI: 559 [M + HCOO] − , 513 [M−H] − , 277 [C 18 H 29 O 2 ] −
1 H-NMR, 13 C-NMR
The spectral assignments and chemical shifts are shown in Table 3.
サンプル(ｂ)中の化合物（ｂ２）は前記化学式（Ｉ）からガラクトシル基が一つはずれた構造において置換基Ｒが前記式（II）で示される基である、下記の化学式（IV）で表わされるグリセロ糖脂質である。この化合物（ｂ２）は既知化合物であった。ＮＭＲ分析の結果、サンプル（ｂ）は主成分である新規化合物（ｂ１）と少量成分である既知化合物（ｂ２）から構成されることがわかった。 The compound (b 2 ) in the sample (b) has the following chemical formula (IV), in which the substituent R is a group represented by the formula (II) in a structure in which one galactosyl group is deviated from the chemical formula (I). The glyceroglycolipid represented. This compound (b 2 ) was a known compound. As a result of NMR analysis, it was found that sample (b) was composed of a novel compound (b 1 ) as a main component and a known compound (b 2 ) as a minor component.
次に、上記のようにして得たサンプル(ａ)及びサンプル(ｂ)の前記化学式（Ｉ）で表わされる新規なグリセロ糖脂質について、以下に記載する方法によって末梢血単核球（ＰＢＭＣ）によるＩＬ−４産生抑制評価試験を行なった。 Next, the novel glyceroglycolipid represented by the chemical formula (I) of the sample (a) and the sample (b) obtained as described above is obtained from peripheral blood mononuclear cells (PBMC) by the method described below. An IL-4 production inhibition evaluation test was conducted.
１）ＩＬ−４産生抑制評価用培養上清サンプルの作製
ＩＬ−４産生抑制評価試験は、Ｅｎｄｏらの方法を参考にした（Int. arch. Allergy Immunol. Vol.1, p425-430,1993）。ＰＢＭＣ（CAMBREX社製）を、１０％ウシ胎児血清、３００ｍｇ／Ｌグルタミン（ＳＩＧＭＡ社製）、１００Ｕ／ｍＬペニシリン、１００μｇ／ｍＬストレプトマイシン（大日本製薬製）を添加したＲＰＭＩ１６４０培地（大日本製薬製）に懸濁し、９６マイクロプレート（Ｎｕｎｃ社製）に２×１０５細胞／ウェルずつ播種した。播種後、各ウェルにコンカナバリンＡ（ＳＩＧＭＡ社製）を２０μｇ／ｍＬになるように添加し、さらに陽性対照区には強いＩＬ−４産生抑制作用が知られているデキサメタゾン（以下「ＤＸＭ」という）３．９μｇ／ｍＬ（０．０１μＭ）を添加し、陰性対照区には培地のみとし、試験区には５．０μｇ／ｍＬまたは５０μｇ／ｍＬの化学式（Ｉ）で表わされるグリセロ糖脂質のサンプル(ａ)又はサンプル(ｂ)をそれぞれ添加し、引き続き２日間培養した。培養終了後、各ウェルよりＰＢＭＣを含んだ培養液を各々回収し、遠心分離（４００×ｇ、８ｍｉｎ）によって得た培養上清を、ＥＬＩＳＡ法によるＩＬ−４産生抑制評価試験に供した。
1) Preparation of culture supernatant sample for evaluating inhibition of IL-4 production The IL-4 production inhibition evaluation test was based on the method of Endo et al. (Int. Arch. Allergy Immunol. Vol. 1, p425-430, 1993). . PBMC (manufactured by CAMBREX), RPMI1640 medium (manufactured by Dainippon Pharmaceutical) supplemented with 10% fetal calf serum, 300 mg / L glutamine (manufactured by SIGMA), 100 U / mL penicillin, 100 μg / mL streptomycin (manufactured by Dainippon Pharmaceutical) And 2 × 10 5 cells / well were seeded on a 96 microplate (Nunc). After seeding, Concanavalin A (manufactured by SIGMA) is added to each well so as to be 20 μg / mL, and dexamethasone (hereinafter referred to as “DXM”), which is known to have a strong IL-4 production inhibitory effect, in the positive control group. 3.9 μg / mL (0.01 μM) was added, only the medium was added to the negative control group, and the sample of the glyceroglycolipid represented by the chemical formula (I) of 5.0 μg / mL or 50 μg / mL ( Each of a) or sample (b) was added, followed by culturing for 2 days. After completion of the culture, each culture solution containing PBMC was recovered from each well, and the culture supernatant obtained by centrifugation (400 × g, 8 min) was subjected to an IL-4 production inhibition evaluation test by ELISA.
２）ＥＬＩＳＡ法によるＩＬ−４産生抑制評価試験
評価試験には、「IL-4 ELISA Kit」（BIO SOURCE社製）を用いた。標準曲線を作成するため、スタンダードサンプルとして、キットに付属したスタンダード希釈液を用いて、ＩＬ−４の濃度がそれぞれ、０、7.8、15.6、31.2、62.5、125、250、500pg/mLになるように希釈調製した。
次に、９８ウェルプレート（Ｎｕｎｃ社製）の各ウェルに、上記１）で得た培養上清サンプルとスタンダードサンプルをそれぞれ１００μＬずつ入れた後、ビオチン標識した抗ヒトＩＬ−４抗体を５０μＬずつ加え、プレートカバーをして室温（２０〜２５℃）にて２時間インキュベートした。各ウェルの底には、あらかじめＩＬ−４と結合する抗ＩＬ−４抗体がコーティングされており、細胞が産生したＩＬ-4と結合し、さらにキットに付属のＩＬ−４抗体が、これとしっかりと結合し、ウェル内に固定される（サンドイッチELISA）。インキュベート終了後、これらのウェル中の液体を吸引除去し、各ウェルを１５０μＬの洗浄用緩衝液にて４回ずつ洗浄した。洗浄後、Streptavidin−Peroxidase(HRP)溶液を１００μＬずつ各ウェルに適用し、プレートカバーをして室温（２０〜２５℃）にて３０分間インキュベートした。インキュベート終了後、ウェル中の液体を吸引除去し、各ウェルを１５０μＬの洗浄用緩衝液にて４回ずつ洗浄した。Tetramethylbenzidine(ＴＭＢ)基質溶液１００μＬを各ウェルに入れ、暗所下、室温（２０〜２５℃）にて３０分間インキュベートした。インキュベート終了後、直ちに反応停止液１００μＬを各ウェルに適用して、マイクロプレートリーダーを用いて、４５０ｎｍ波長における吸光度を測定して、各ウェル内に固定されたＩＬ−４産生量を求めた。即ち、スタンダードサンプルの吸光度とＩＬ−４濃度から得られた標準曲線を基準として、供試各サンプルの吸光度の測定値からＩＬ−４産生量を算出した。
各供試サンプルについて得られた結果を表４および図１に示す。
2) “IL-4 ELISA Kit” (manufactured by BIO SOURCE) was used for the evaluation test of the IL-4 production inhibition evaluation test by ELISA. To create a standard curve, use the standard diluent supplied with the kit as the standard sample so that the IL-4 concentrations are 0, 7.8, 15.6, 31.2, 62.5, 125, 250, and 500 pg / mL, respectively. Diluted and prepared.
Next, after adding 100 μL each of the culture supernatant sample and the standard sample obtained in 1) above to each well of a 98-well plate (manufactured by Nunc), add 50 μL of biotin-labeled anti-human IL-4 antibody. The plate was covered and incubated at room temperature (20-25 ° C.) for 2 hours. The bottom of each well is pre-coated with an anti-IL-4 antibody that binds to IL-4, binds to IL-4 produced by the cells, and the IL-4 antibody attached to the kit is firmly attached to this. And fixed in the well (sandwich ELISA). After the incubation, the liquid in these wells was removed by aspiration, and each well was washed 4 times with 150 μL of washing buffer. After washing, 100 μL of Streptavidin-Peroxidase (HRP) solution was applied to each well, covered with a plate, and incubated at room temperature (20-25 ° C.) for 30 minutes. After completion of the incubation, the liquid in the wells was removed by aspiration, and each well was washed 4 times with 150 μL of washing buffer. 100 μL of Tetramethylbenzidine (TMB) substrate solution was placed in each well and incubated at room temperature (20-25 ° C.) for 30 minutes in the dark. Immediately after the incubation, 100 μL of the reaction stop solution was applied to each well, and the absorbance at a wavelength of 450 nm was measured using a microplate reader to determine the amount of IL-4 produced immobilized in each well. That is, the production amount of IL-4 was calculated from the measured value of the absorbance of each test sample, based on the standard curve obtained from the absorbance of the standard sample and the IL-4 concentration.
The results obtained for each sample are shown in Table 4 and FIG.
これらの結果から、前記化学式（Ｉ）で表わされる新規グリセロ糖脂質は、その置換基Ｒが式(II)のもの（サンプル(ａ)）と式(III)の化合物（ｂ１）を含有するもの（サンプル(ｂ)）のいずれの場合にも、デキサメタゾンとほぼ同等の非常に優れたＩＬ−４産生抑制作用を示すことがわかった。また、サンプル(ａ)又はサンプル(ｂ)を５．０μｇ／ｍＬ添加すると、培地のみのときと比べてＩＬ−４の産生が３０％に抑制され、サンプル(ａ)又はサンプル(ｂ)を５０μｇ／ｍＬ添加すると、培地のみのときと比べてＩＬ−４の産生が約６０〜７０％に抑制される。 From these results, the novel glyceroglycolipid represented by the chemical formula (I) contains the substituent R having the formula (II) (sample (a)) and the compound (b 1 ) of the formula (III). In both cases (sample (b)), it was found that IL-4 production inhibitory action almost equivalent to that of dexamethasone was exhibited. Further, when 5.0 μg / mL of sample (a) or sample (b) is added, the production of IL-4 is suppressed to 30% compared to the case of using only the medium, and 50 μg of sample (a) or sample (b) is added. When / mL is added, the production of IL-4 is suppressed to about 60 to 70% as compared with the case of only the medium.
メラニン生成抑制評価試験
メラニンを生成する細胞としてマウス由来の培養Ｂ１６メラノーマ細胞を用いて、ウシ胎児血清を終濃度１０％になるように添加したイーグルＭＥＭ培地で培養し、該細胞を１×１０３細胞／wellで、９６ウェルプレートに播種し、５日間ＣＯ２インキュベーター内で培養した。その後、被検試料を添加した培地に交換し、さらに３日間同条件で培養した。培養終了後細胞を洗浄し、細胞をドデシル硫酸ナトリウム（SDS）により可溶化して４７５ｎｍ、２６０ｎｍの吸光度を測定し、これをＳ４７５、Ｓ２６０とする。メラニン抑制率は、被検試料を添加しない培地で培養した細胞の４７５ｎｍ、２６０ｎｍにおける吸光度をＣ４７５、Ｃ２６０として次式により計算した。
Melanin Production Inhibition Evaluation Test Using mouse-derived cultured B16 melanoma cells as cells producing melanin, the cells are cultured in Eagle's MEM medium supplemented with fetal bovine serum to a final concentration of 10%, and the cells are 1 × 10 3. Cells / well were seeded in 96-well plates and cultured in a CO 2 incubator for 5 days. Thereafter, the medium was replaced with the medium to which the test sample was added, and further cultured for 3 days under the same conditions. After completion of the culture, the cells are washed, the cells are solubilized with sodium dodecyl sulfate (SDS), and the absorbance at 475 nm and 260 nm is measured, and these are designated as S475 and S260. The melanin inhibition rate was calculated by the following equation using the absorbance at 475 nm and 260 nm of cells cultured in a medium not added with the test sample as C475 and C260.
尚、被検試料としては、前記実施例１で得た化学式（Ｉ）で表わされるグリセロ糖脂質であるサンプル(ａ)又は化学式（Ｉ）で表わされるグリセロ糖脂質である化合物（ｂ１）を含有するサンプル(ｂ)を用い、それぞれ培地に１２．５μｇ／ｍＬ、２５．０μｇ／ｍＬ、及び５０．０μｇ／ｍＬ添加した。陽性対照区としては美白成分として広く使用されているコウジ酸（Kojic acid）を用い、これを培地に１２．５μｇ／ｍＬ、２５．０μｇ／ｍＬ、及び５０．０μｇ／ｍＬ添加した。
これらのメラニン生成抑制評価試験の結果を図２に示す。図２に示したように、本発明の新規グリセロ糖脂質のサンプル（ａ）、サンプル（ｂ）ともに陽性対照区のコウジ酸（Kojic acid）とほぼ同等のメラニン生成抑制効果を示した。
As the test sample, the sample (a) which is the glyceroglycolipid represented by the chemical formula (I) obtained in Example 1 or the compound (b 1 ) which is the glyceroglycolipid represented by the chemical formula (I) is used. Using the contained sample (b), 12.5 μg / mL, 25.0 μg / mL, and 50.0 μg / mL were added to the medium, respectively. As a positive control, kojic acid, which is widely used as a whitening component, was used, and 12.5 μg / mL, 25.0 μg / mL, and 50.0 μg / mL were added to the medium.
The results of these melanin production inhibition evaluation tests are shown in FIG. As shown in FIG. 2, both the sample (a) and the sample (b) of the novel glyceroglycolipid of the present invention showed almost the same melanin production inhibitory effect as that of the positive control group Kojic acid.
次に、以下に、本発明の新規グリセロ糖脂質の具体的な使用形態である医薬、食品，化粧品としての処方例を示す。 Next, formulation examples as pharmaceuticals, foods, and cosmetics, which are specific usage forms of the novel glyceroglycolipid of the present invention, are shown below.
処方例１: ＩＬ−４産生抑制用組成物（錠剤）
上記の実施例１で得られた化学式（Ｉ）で表わされる新規グリセロ糖脂質（サンプル(a)）を用いて、常法により下記の配合組成のＩＬ−４産生抑制用組成物の錠剤を製造した。
（組 成） （質量％）
グリセロ糖脂質（サンプル(ａ)） ２．０
乳 糖 ７７．０
コーンスターチ ２０．０
グアーガム １．０
Formulation Example 1: Composition for inhibiting IL-4 production (tablet)
Using the novel glyceroglycolipid (sample (a)) represented by the chemical formula (I) obtained in Example 1 above, a tablet of a composition for inhibiting IL-4 production having the following formulation composition is produced by a conventional method. did.
(Composition) (mass%)
Glyceroglycolipid (sample (a)) 2.0
Lactose 77.0
Corn starch 20.0
Guar gum 1.0
処方例２:ジュース
上記の実施例１で得られた化学式（Ｉ）で表わされるグリセロ糖脂質を含有するサンプル(ｂ)を用いて、常法により下記の配合組成のジュースを製造した。
（組 成） （質量％）
冷凍濃縮温州みかん果汁 ５．０
果糖ブドウ糖液糖 １１．０
クエン酸 ０．２
Ｌ−アスコルビン酸 ０．０２
香 料 ０．２
色 素 ０．１
グリセロ糖脂質（サンプル(b）） ０．２
水 ８３．２８
Formulation Example 2: Juice Using the sample (b) containing the glyceroglycolipid represented by the chemical formula (I) obtained in Example 1 above, a juice having the following composition was produced by a conventional method.
(Composition) (mass%)
Frozen and concentrated Wenzhou orange juice 5.0
Fructose glucose liquid sugar 11.0
Citric acid 0.2
L-ascorbic acid 0.02
Perfume 0.2
Color element 0.1
Glyceroglycolipid (sample (b)) 0.2
Water 83.28
処方例３：化粧水
上記の実施例１で得られた化学式（Ｉ）で表わされるグリセロ糖脂質（サンプル(a)）を用いて、常法により下記の配合組成の化粧水を製造した。
（組 成） （質量％）
グリセリン ８．０
１，３-ブチレングリコール ２．０
クエン酸 ０．１
Ｌ−セリン ０．０５
パラオキシ安息香酸エステル ０．２
香料 ０．０５
グリセロ糖脂質（サンプル(a）） ０．５
精製水 ８９．１
Formulation Example 3: Lotion Toner lotion having the following composition was prepared by a conventional method using the glyceroglycolipid (sample (a)) represented by the chemical formula (I) obtained in Example 1 above.
(Composition) (mass%)
Glycerin 8.0
1,3-butylene glycol 2.0
Citric acid 0.1
L-serine 0.05
P-Hydroxybenzoate ester 0.2
Fragrance 0.05
Glyceroglycolipid (sample (a)) 0.5
Purified water 89.1
処方例４：クリーム
上記の実施例１で得られた新規グリセロ糖脂質を含有するサンプル(b)を用いて、常法により下記の配合組成のクリームを製造した。
（組 成） （質量％）
ステアリルアルコール ６．０
ステアリン酸 ２．０
スクワラン ９．０
オクチルドデカノール １０．０
１，３-ブチレングリコール ８．０
ポリエチレングリコール１５００ ４．０
POE（25)セチルアルコールエーテル ３．０
モノステアリン酸グリセリル ２．０
グリセロ糖脂質（サンプル(b）） １．０
精製水 残余
Formulation Example 4: Cream Using the sample (b) containing the novel glyceroglycolipid obtained in Example 1 above, a cream having the following composition was produced by a conventional method.
(Composition) (mass%)
Stearyl alcohol 6.0
Stearic acid 2.0
Squalane 9.0
Octyldodecanol 10.0
1,3-butylene glycol 8.0
Polyethylene glycol 1500 4.0
POE (25) Cetyl alcohol ether 3.0
Glyceryl monostearate 2.0
Glyceroglycolipid (sample (b)) 1.0
Purified water residue
処方例５：化粧パック
上記の実施例１で得られた新規グリセロ糖脂質（サンプル(a)）を用いて、常法により下記の配合組成の化粧パックを製造した。
（組 成） （質量％）
ポリビニルアルコール １５．０
カルボキシメチルセルロース ５．０
１，３-ブチレングリコール ５．０
エタノール １２．０
POE(25）オレイルアルコールエーテル ０．５
クエン酸 ０．０２
クエン酸ナトリウム ０．０４
グリセロ糖脂質（サンプル(a）） １．０
精製水 残余
Formulation Example 5: Cosmetic Pack Using the novel glyceroglycolipid (sample (a)) obtained in Example 1 above, a cosmetic pack having the following composition was produced by a conventional method.
(Composition) (mass%)
Polyvinyl alcohol 15.0
Carboxymethylcellulose 5.0
1,3-butylene glycol 5.0
Ethanol 12.0
POE (25) oleyl alcohol ether 0.5
Citric acid 0.02
Sodium citrate 0.04
Glyceroglycolipid (sample (a)) 1.0
Purified water residue
本発明によれば、新規なグリセロ糖脂質である化学式(Ｉ)で表わされるグリセロ糖脂質を提供する。この新規グリセロ糖脂質は、優れたＩＬ−４産生抑制作用を有し、優れた安全性と安定性を有するＩＬ−４産生抑制、抗アレルギー組成物、抗炎症組成物を提供することができ、また、優れたメラニン生成抑制作用を有し、メラニン生成抑制剤又は美白剤を提供することができる。さらに、これらを含んだ食品、医薬、化粧料等の組成物として利用することができる。従って、この新規グリセロ糖脂質を含有する、例えば食品、医薬、化粧料等の組成物とすることができ、抗アレルギー性や抗炎症性、メラニン生成抑制性を持った種々の製品を製造するのに有用である。 According to the present invention, there is provided a glyceroglycolipid represented by the chemical formula (I), which is a novel glyceroglycolipid. This novel glyceroglycolipid has an excellent IL-4 production inhibitory action and can provide an IL-4 production inhibitory, antiallergic composition, and anti-inflammatory composition having excellent safety and stability. Moreover, it has the outstanding melanin production inhibitory effect and can provide a melanin production inhibitor or a whitening agent. Furthermore, it can utilize as compositions, such as a foodstuff, a pharmaceutical, and cosmetics containing these. Therefore, it can be made into compositions such as foods, medicines, cosmetics, etc. containing this novel glyceroglycolipid, and various products having antiallergic properties, anti-inflammatory properties, and melanin production inhibitory properties are produced. Useful for.
Claims (9)
A skin external preparation comprising the compound represented by the chemical formula (I) according to claim 1 as an active ingredient .
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