JP2005350375A - Reducing agent for blood uric acid value - Google Patents
Reducing agent for blood uric acid value Download PDFInfo
- Publication number
- JP2005350375A JP2005350375A JP2004170633A JP2004170633A JP2005350375A JP 2005350375 A JP2005350375 A JP 2005350375A JP 2004170633 A JP2004170633 A JP 2004170633A JP 2004170633 A JP2004170633 A JP 2004170633A JP 2005350375 A JP2005350375 A JP 2005350375A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- antioxidant
- agent
- ellagic acid
- uric 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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Abstract
Description
本発明は、キサンチンオキシダーゼ阻害剤、血中尿酸値低下剤、高尿酸血症の予防または改善剤、及び痛風の予防剤、並びにそれらを含有する、飲食品、医薬品または化粧品などに関する。 The present invention relates to a xanthine oxidase inhibitor, a blood uric acid level-lowering agent, a prophylactic or ameliorating agent for hyperuricemia, a prophylactic agent for gout, and a food, beverage, pharmaceutical or cosmetic containing them.
痛風は、プリン体の代謝異常による高尿酸血症を基礎とし、関節内または関節周囲に尿酸塩の結晶が沈着して痛風結節、関節機能障害、関節の変形などが生じる疾患であり、腎障害、血管障害など、多くの合併症を引き起こす病気である。食事によるプリン体過剰摂取、体内で尿酸合成促進、あるいは、尿中への尿酸排泄が阻害されると血中尿酸値は上昇する。そこで、消化管におけるプリン体吸収阻害、尿酸合成抑制、尿酸排泄促進することにより血中尿酸レベルを改善することができると考えられる。キサンチンオキシダーゼは体内での尿酸合成に関わる酵素のひとつであり、この酵素を阻害することにより血中尿酸値を低下させることが期待できる。 Gout is a disease based on hyperuricemia caused by abnormal metabolism of purines, causing the formation of gout nodules, joint dysfunction, joint deformation, etc. by depositing uric acid crystals in or around the joint. It is a disease that causes many complications, such as vascular disorders. The blood uric acid level increases when purine overdose by meals, promotion of uric acid synthesis in the body, or uric acid excretion in the urine is inhibited. Therefore, it is considered that the blood uric acid level can be improved by inhibiting purine body absorption in the digestive tract, suppressing uric acid synthesis, and promoting uric acid excretion. Xanthine oxidase is one of the enzymes involved in uric acid synthesis in the body, and it can be expected to reduce blood uric acid levels by inhibiting this enzyme.
近年の生活様式の急速な変化にともない、痛風の発症事例は増えている。このため、痛風あるいはそのリスクファクターである高尿酸血症の予防と治療に対する関心が高まっている。 With the rapid changes in lifestyle in recent years, the incidence of gout has increased. For this reason, there is a growing interest in the prevention and treatment of gout or its risk factor hyperuricemia.
キサンチンオキシダーゼ阻害剤は、血中尿酸値低下剤、高尿酸血症の予防または改善剤、痛風の予防剤として有用であると考えられる。キサンチンオキシダーゼ阻害活性を有する組成物・化合物としては、プロシアニジン（非特許文献１参照。）、ブドウ抽出物（特許文献１参照。）、エラグ酸（特許文献２参照。）が公知である。また、エピガロカテキンガレートは血中尿酸値低下活性を有することが公知である（特許文献３参照。）。
本発明の課題は、新規なキサンチンオキシダーゼ阻害剤、血中尿酸値低下剤、高尿酸血症の予防または改善剤、及び痛風の予防剤、並びに、それらを含有する、飲食品、医薬品または化粧品などを提供することにある。 An object of the present invention is to provide a novel xanthine oxidase inhibitor, a blood uric acid level-lowering agent, a hyperuricemia preventing or ameliorating agent, a gout preventing agent, and a food, beverage, medicine or cosmetic containing them Is to provide.
本発明者らは、エラグ酸および抗酸化剤を併用すると、相乗的なキサンチンオキシダーゼ阻害活性、血中尿酸値低下作用が得られることを見出し、本発明を完成した。すなわち本発明は、以下に係るものである。
（１）エラグ酸および抗酸化剤を有効成分とする、キサンチンオキシダーゼ阻害剤 。
（２）エラグ酸および抗酸化剤を有効成分とする、血中尿酸値低下剤。
（３）エラグ酸および抗酸化剤を有効成分とする、高尿酸血症の予防または改善剤。
（４）エラグ酸および抗酸化剤を有効成分とする、痛風の予防剤。
（５）抗酸化剤がブドウ抽出物、エピガロカテキンガレート、没食子酸、及びアスコルビン酸から成る群から選択される、上記（１）〜（４）のいずれか一項に記載の剤。
（６）エラグ酸および抗酸化剤の含有比が10:1〜1:2（重量比）の範囲である、上記（１）〜（５）のいずれか一項に記載の剤。
（７）上記（１）〜（６）のいずれか一項に記載の剤を含有する、飲食品、医薬品または化粧品。
（８）エラグ酸および抗酸化剤を含有し、血中尿酸値低下、高尿酸血症の予防あるいは改善、または痛風の予防のために用いられるものである旨の表示を付した飲食品。
The present inventors have found that when ellagic acid and an antioxidant are used in combination, synergistic xanthine oxidase inhibitory activity and blood uric acid level lowering action can be obtained, and the present invention has been completed. That is, the present invention relates to the following.
(1) A xanthine oxidase inhibitor comprising ellagic acid and an antioxidant as active ingredients.
(2) A blood uric acid level lowering agent comprising ellagic acid and an antioxidant as active ingredients.
(3) A prophylactic or ameliorating agent for hyperuricemia, comprising ellagic acid and an antioxidant as active ingredients.
(4) A gout preventive agent comprising ellagic acid and an antioxidant as active ingredients.
(5) The agent according to any one of (1) to (4), wherein the antioxidant is selected from the group consisting of grape extract, epigallocatechin gallate, gallic acid, and ascorbic acid.
(6) The agent according to any one of (1) to (5) above, wherein the content ratio of ellagic acid and antioxidant is in the range of 10: 1 to 1: 2 (weight ratio).
(7) Food / beverage products, pharmaceuticals, or cosmetics containing the agent according to any one of (1) to (6) above.
(8) A food / beverage product which contains ellagic acid and an antioxidant and is labeled as being used for lowering blood uric acid level, preventing or improving hyperuricemia, or preventing gout.
本発明は、安全性の高い天然物由来の成分であるエラグ酸及び抗酸化剤を有効成分として併用したことにより、キサンチンオキシダーゼ阻害効果に関して、それらの間に相乗的な効果が確認された。更に、動物試験において、エラグ酸及びブドウ抽出物それぞれ単独では血中尿酸値低下効果が認められない低い投与量においても、これらを併用することにより、有意な血中尿酸値低下効果が認められた。 In the present invention, synergistic effects were confirmed between xanthine oxidase inhibitory effects by using ellagic acid and an antioxidant, which are highly safe components derived from natural products, as active ingredients. Furthermore, in animal studies, a significant blood uric acid level lowering effect was observed when these were used in combination even at low doses where ellagic acid and grape extract alone did not show blood uric acid level lowering effects. .
本発明において、「エラグ酸」とは、エラグ酸（ellagic acid）またはその誘導体を意味する。エラグ酸誘導体とは、例えば、エラグ酸の基本骨格に糖・脂質・アミノ酸・タンニン等が結合した化合物、エラグ酸の金属塩、エラグ酸のメチル化物あるいはアセチル化物、エラグ酸の配糖体・エステルである。 In the present invention, “ellagic acid” means ellagic acid or a derivative thereof. Examples of ellagic acid derivatives include compounds in which sugar, lipid, amino acid, tannin, etc. are bound to the basic skeleton of ellagic acid, metal salts of ellagic acid, methylated or acetylated ellagic acid, and glycosides / esters of ellagic acid It is.
エラグ酸誘導体の一例は、植物に多く含まれるエラジタンニンである。エラジタンニンを摂取すると生体内の加水分解反応によってエラグ酸を生成する。使用者の生体内における化学反応により、エラグ酸あるいはエラグ酸誘導体を生成可能な化合物（エラグ酸前駆体）も、本発明でいうエラグ酸に含まれる。 An example of an ellagic acid derivative is ellagitannin, which is abundant in plants. Ingestion of ellagitannin produces ellagic acid by in vivo hydrolysis reaction. A compound (ellagic acid precursor) capable of producing ellagic acid or an ellagic acid derivative by a chemical reaction in a user's living body is also included in the ellagic acid referred to in the present invention.
エラグ酸は、植物体や微生物体から、当業者に公知の任意の抽出法、発酵法、化学的もしくは酵素的合成法等により得ることができる。又、市販品を使用しても良い。植物体及び微生物体としては、エラグ酸を含有するものである限り特に制限はない。植物体としては、例えば、ザクロ、レッドラズベリー、ストロベリー、ウォールナッツ、ピーカン、クランベリー等を例示することが出来る。植物体としては、本発明の目的を達成できる部分であれば、どの部分、例えば、花、実、種子、果実若しくはそれらの果肉または皮類、及び根、樹木、樹皮、葉などを使用してもよい。それらは乾燥したもの、生のものどちらでもよい。
更に、果実のジュース類若しくはリンゴ酒、ブドウ酒などの果実酒、ビール類、またはそれらの製造の際、副産物として生成する粕類、または植物体の加工物なども挙げることができる。植物体や微生物体由来のエラグ酸は、当該原料からの粗精製物であってもよいし、カラムクロマトグラフ等を用いて精製した高純度標品であってもよい。
Ellagic acid can be obtained from a plant or microorganism by any extraction method, fermentation method, chemical or enzymatic synthesis method, etc. known to those skilled in the art. Moreover, you may use a commercial item. The plant body and the microorganism body are not particularly limited as long as they contain ellagic acid. Examples of plant bodies include pomegranate, red raspberry, strawberry, walnut, pecan, and cranberry. As a plant body, any part that can achieve the object of the present invention, for example, a flower, a fruit, a seed, a fruit or a flesh or a skin thereof, and a root, a tree, a bark, a leaf or the like is used. Also good. They can be either dry or raw.
Furthermore, fruit juices such as fruit juices, apple wine, fruit wines such as grape wine, beers, potatoes produced as a by-product in the production thereof, or processed products of plants can also be mentioned. The ellagic acid derived from a plant or microorganism may be a crude product from the raw material or a high-purity sample purified using a column chromatograph or the like.
本発明でいう「抗酸化剤」とは、抗酸化作用を有し、且つエラグ酸と併用された場合にキサンチンオキシダーゼ阻害活性、血中尿酸値低下活性、高尿酸血症の予防あるいは改善効果、または痛風の予防効果を増強し、特にそれらを相乗的に発揮することができる物質であれば特に制限はない。これら抗酸化剤は植物体や微生物体から当業者に公知の任意の方法で容易に調製することが出来、或いは、各種の市販品を使用することも出来る The “antioxidant” as used in the present invention has an antioxidant action, and when used in combination with ellagic acid, xanthine oxidase inhibitory activity, blood uric acid level lowering activity, prevention or improvement of hyperuricemia, Alternatively, there is no particular limitation as long as it is a substance that can enhance the gout prevention effect and can exhibit them synergistically. These antioxidants can be easily prepared from plants and microorganisms by any method known to those skilled in the art, or various commercial products can be used.
本発明の抗酸化剤の好適例としては、例えば、ブドウ、茶、ザクロ、マンゴー等の植物を由来とする植物抽出物、プロアントシアニジン、エピガロカテキンガレート、没食子酸、アスコルビン酸等の天然物由来又は天然物に含まれている物質を挙げることが出来る。特に、本明細書の実施例に示されるように、ブドウ抽出物、エピガロカテキンガレート、没食子酸、及びアスコルビン酸から成る群から選択される抗酸化剤が好ましい。 Preferable examples of the antioxidant of the present invention include, for example, plant extracts derived from plants such as grape, tea, pomegranate and mango, derived from natural products such as proanthocyanidins, epigallocatechin gallate, gallic acid and ascorbic acid Or the substance contained in the natural product can be mentioned. In particular, as shown in the Examples herein, an antioxidant selected from the group consisting of grape extract, epigallocatechin gallate, gallic acid, and ascorbic acid is preferred.
尚、ブドウ抽出物、プロアントシアニジンあるいはエピガロカテキンガレートは、単独でもキサンチンオキシダーゼ阻害活性あるいは血中尿酸値低下活性を有することが知られている。しかしながら、以下の実施例に示す通り、上記の抽出物や化合物はエラグ酸と併用することにより、それら単独では実質的な活性を示さないような低濃度用量においても、エラグ酸の活性を増強し、キサンチンオキシダーゼ阻害活性に関する相乗効果が得られる。 In addition, it is known that grape extract, proanthocyanidins or epigallocatechin gallate alone has xanthine oxidase inhibitory activity or blood uric acid level lowering activity. However, as shown in the following examples, the above extracts and compounds can be used in combination with ellagic acid to enhance the activity of ellagic acid even at low concentration doses that do not exhibit substantial activity by themselves. , A synergistic effect on xanthine oxidase inhibitory activity is obtained.
抗酸化剤である植物抽出物は当業者に公知の任意の方法で調製することが出来る。植物抽出物として好適に使用できるブドウ抽出物は、例えば以下の方法により調製可能である。 Plant extracts that are antioxidants can be prepared by any method known to those skilled in the art. A grape extract that can be suitably used as a plant extract can be prepared, for example, by the following method.
抽出原料となるブドウの種類は、白ブドウ、赤ブドウ、黒ブドウ等のいずれでもよく、例えばシャルドネ種、リースリング種、ミラトルガウ種、ナイアガラ種、ネオ・マスカット種、甲州種、白羽種（リカチテリ種）等が挙げられる。 The grapes used as the extraction raw material may be white grapes, red grapes, black grapes, etc., for example, Chardonnay, Riesling, Miratorgau, Niagara, Neo Muscat, Koshu, and Shirahane (Rikachiteri) Etc.
上記ブドウの種子、果実、果肉、皮類が抽出に供される。飲料やワイン製造において利用されたブドウ果実を圧搾して果汁を採取した残渣、すなわち搾汁粕や赤ワイン製造の際の前発酵後に圧搾して得られる搾汁粕を抽出に供してもよい。種子は通常搾汁粕中に約５〜２０％（ｗ／ｗ）含まれるが、プロアントシアニジン含量が高く、糖類などの夾雑物の含量も少ないため、好適な原料である。 The grape seeds, fruits, pulp and skins are used for extraction. You may use for the extraction the residue which pressed the grape fruit utilized in drink and wine manufacture, and extract | collected the fruit juice, ie, the squeeze cake obtained by pressing after the pre-fermentation in the case of red wine manufacture. Seeds are usually contained in about 5 to 20% (w / w) in the squeezed lees, but are high in proanthocyanidin content and low in impurities such as sugars, and thus are suitable raw materials.
上記のブドウ原料を、水又は有機溶媒等を用いて適当な条件下で抽出することにより有効成分が得られる。抽出に際しては、還流させながら抽出を行うことが好ましい。有機溶媒とは例えば、メタノール、エタノール、イソプロパノール、ｎ−ブタノール等の水溶性アルコール類、アセトン、酢酸等である。水溶性有機溶媒は単独で用いてもよいが、任意の比で水と混合して用いてもよい。 An active ingredient is obtained by extracting said grape raw material on suitable conditions using water or an organic solvent. In the extraction, it is preferable to perform the extraction while refluxing. Examples of the organic solvent include water-soluble alcohols such as methanol, ethanol, isopropanol, and n-butanol, acetone, acetic acid, and the like. The water-soluble organic solvent may be used alone, but may be used by mixing with water at an arbitrary ratio.
毒性が低い、沸点が比較的低いため抽出後の除去が容易、入手容易等の理由から、水溶性有機溶媒としてはエタノールが好ましい。抽出効率を高く、不純物の割合を少なくするためには、エタノール：水の混合比は１：１〜４：１（ｖ／ｖ）が好ましい。 Ethanol is preferred as the water-soluble organic solvent because it has low toxicity and has a relatively low boiling point so that it can be easily removed after extraction and is easily available. In order to increase extraction efficiency and reduce the proportion of impurities, the ethanol: water mixing ratio is preferably 1: 1 to 4: 1 (v / v).
抽出する際のブドウ原料（無水物換算）に対する溶媒の量は特に限定しないが、通常１〜２０倍量（ｖ／ｗ）、好ましくは２〜６倍量である。また必要により少量の界面活性剤（例えばショ糖脂肪酸エステル等）や酸化防止剤（例えばアスコルビン酸等）などを加えてもよい。また必要により、不活ガス雰囲気下で抽出を行ってもよい。 Although the quantity of the solvent with respect to the grape raw material (anhydride conversion) at the time of extracting is not specifically limited, Usually, 1-20 times amount (v / w), Preferably it is 2-6 times amount. If necessary, a small amount of a surfactant (such as sucrose fatty acid ester) or an antioxidant (such as ascorbic acid) may be added. If necessary, the extraction may be performed in an inert gas atmosphere.
ブドウ原料の抽出に際しては、還流させながら抽出を行うことが好ましい。抽出時間は、溶媒量、溶媒の種類、温度等の抽出条件に左右されるが、通常１０分〜２４時間であり、好ましくは３０分〜２時間程度である。 When extracting the grape raw material, it is preferable to perform the extraction while refluxing. The extraction time depends on extraction conditions such as the amount of solvent, the type of solvent, and temperature, but is usually 10 minutes to 24 hours, preferably about 30 minutes to 2 hours.
上記で得られたブドウ抽出物を本発明の抗酸化剤として使用することもできるが、更に、セファデックス、ポリアミド、シリカゲル、ＯＤＳ等を用いたカラムクロマトグラフ、セルロース膜等を用いた膜分離、酢酸エチル−水等を用いた液液分離、酵母等の微生物の添加による不純物の分解など精製・分離・脱色操作を行うことにより、より高純度に有効成分を含有する抽出物を得ることができる。 The grape extract obtained above can also be used as an antioxidant of the present invention, but further, column separation using Sephadex, polyamide, silica gel, ODS, etc., membrane separation using a cellulose membrane, Extracts containing active ingredients with higher purity can be obtained by liquid-liquid separation using ethyl acetate-water, etc., and purification, separation, and decolorization operations such as decomposition of impurities by adding microorganisms such as yeast. .
本発明の抗酸化剤として使用できる「プロアントシアニジン」とは、各種植物体中に存在する縮合型タンニン、すなわちフラバン−３−オールまたはフラバン−３，４−ジオールを構成単位として重合により結合した化合物群であって、酸処理によりシアニジン、デルフィニジン、ペラルゴニジン等のアントシアニジンを生成するものである。本発明のプロアントシアニジンには、上記構成単位の重合体（2量体以上）であるプロシアニジン、プロデルフィニジン、プロペラルゴニジン等が含まれる。また、本発明のプロアントシアニジンは上記化合物の立体異性体、配糖体、没食子酸エステルまたはカフェ酸エステル等の各種誘導体が含まれる。本発明においてプロアントシアニジンは、種々の分子量（重合度）のプロアントシアニジンとして使用できる。また、分子量（重合度）に応じて分画したプロアントシアニジン組成物を単独または混合して使用することもできる。 “Proanthocyanidins” that can be used as an antioxidant of the present invention are condensed tannins present in various plant bodies, that is, compounds in which flavan-3-ols or flavan-3,4-diols are combined as a constituent unit by polymerization. A group that produces anthocyanidins such as cyanidin, delphinidin, and pelargonidin by acid treatment. The proanthocyanidins of the present invention include procyanidins, prodelphinidins, propelargonidins and the like, which are polymers of the above structural units (dimers or more). The proanthocyanidins of the present invention include various derivatives such as stereoisomers, glycosides, gallic acid esters and caffeic acid esters of the above compounds. In the present invention, proanthocyanidins can be used as proanthocyanidins having various molecular weights (degrees of polymerization). Moreover, the proanthocyanidin composition fractionated according to molecular weight (polymerization degree) can also be used individually or in mixture.
プロアントシアニジンは、植物体や微生物体から、当業者に公知の任意の抽出法、発酵法、化学的もしくは酵素的合成法等により得ることができる。また、プロアントシアニジンとしては市販品、例えばブドウ種子由来の商品名「グラヴィノール」（キッコーマン(株)）、りんご未熟果由来の商品名「アップルフェノン」（ニッカウヰスキー(株)）、海岸松の樹皮由来の商品名「ピクノジェノール」（ホーファーリサーチ社（スイス））等が使用できる。 Proanthocyanidins can be obtained from plants and microorganisms by any extraction method, fermentation method, chemical or enzymatic synthesis method, etc. known to those skilled in the art. Proanthocyanidins are commercially available products, for example, “Gravinol” (Kikkoman Co., Ltd.) derived from grape seeds, “Applephenon” (Nikka Whiskey Co., Ltd.), derived from unripe apples, and bark of shore pine "Pycnogenol" (Hofer Research (Switzerland)) and the like can be used.
プロアントシアニジンを抽出するための植物体として特に制限はないが、ブドウ、クランベリー、カカオ、リンゴ、小豆、柿、及び松等が好適に利用できる。プロアントシアニジンが得られる限り植物体のどの部分を抽出してもよく、例えば、花、実、種子、果実、果肉、皮類、根、樹木、樹皮、葉などの組織が使用できる。植物体は、乾燥物、生のもの、発酵させたものの何れでもよい。更に、果実のジュース、酒類またはそれらの製造の際副産物として生成する粕類、または植物体の加工品なども利用できる。プロアントシアニジン含有量が高いという点で、抽出原料としてはブドウ種子または果皮が好適である。ブドウ原料から高純度のプロアントシアニジンを得るためには、特開平11-080148号公報記載の方法を使用すればよい。 Although there is no restriction | limiting in particular as a plant body for extracting a proanthocyanidin, Grape, cranberry, cacao, an apple, a red bean, a persimmon, a pine etc. can utilize suitably. Any part of the plant body may be extracted as long as proanthocyanidins can be obtained. For example, tissues such as flowers, fruits, seeds, fruits, flesh, skins, roots, trees, bark, leaves can be used. The plant body may be any of a dried product, a raw product, and a fermented product. Furthermore, fruit juice, alcoholic beverages, moss produced as a by-product during the production thereof, or processed products of plants can be used. Grape seeds or fruit peels are suitable as the extraction raw material in that the content of proanthocyanidins is high. In order to obtain high-purity proanthocyanidins from grape raw materials, the method described in JP-A-11-080148 may be used.
各種の植物体原料を、溶媒を用いて適当な条件下で抽出し、抽出液から溶媒を減圧留去などによって除去すれば、濃縮物や乾燥物の状態で粗プロアントシアニジン画分が得られる。抽出に際しては、還流させながら抽出を行うことが好ましい。溶媒とは例えば、冷水、熱水、低級アルコール、アセトン、アルキルケトン、酢酸、酢酸エチル、ｎ−ヘキサン、液体二酸化炭素等であり、特に含水低級アルコールおよび含水アセトンが好適である。溶媒は２種類以上混合してもよい。 If various plant raw materials are extracted using a solvent under suitable conditions, and the solvent is removed from the extract by distillation under reduced pressure or the like, a crude proanthocyanidin fraction can be obtained in the form of a concentrate or a dried product. In the extraction, it is preferable to perform the extraction while refluxing. Examples of the solvent include cold water, hot water, lower alcohol, acetone, alkyl ketone, acetic acid, ethyl acetate, n-hexane, liquid carbon dioxide, and the like. In particular, water-containing lower alcohol and water-containing acetone are preferable. Two or more kinds of solvents may be mixed.
上記で得られた粗プロアントシアニジンを本発明の抗酸化剤としてもよいが、上記で得られた粗プロアントシアニジン画分を更に、セファデックス、ポリアミド、シリカゲル、ＯＤＳ等を用いたカラムクロマトグラフ、セルロース膜等を用いた膜分離、酢酸エチル−水等を用いた液液分離など精製・分離・脱色操作を行うことにより、より高純度の、あるいは望む重合度のプロアントシアニジンを得ることができる。 The crude proanthocyanidins obtained above may be used as the antioxidant of the present invention, but the crude proanthocyanidins obtained above are further subjected to column chromatography using Sephadex, polyamide, silica gel, ODS, etc., cellulose Proanthocyanidins with higher purity or desired degree of polymerization can be obtained by performing purification, separation, and decolorization operations such as membrane separation using a membrane or the like, and liquid-liquid separation using ethyl acetate-water or the like.
本発明の抗酸化剤として使用できる「没食子酸」は、没食子酸またはその誘導体を意味する。没食子酸誘導体とは、例えば、没食子酸の基本骨格に糖・脂質・アミノ酸等が結合した化合物、金属塩、メチル化物あるいはアセチル化物、配糖体・エステルである。
没食子酸は、植物体や微生物体から、当業者に公知の任意の抽出法、発酵法、化学的もしくは酵素的合成法等により得ることができる。没食子酸は植物の各部に遊離した状態、あるいはタンニンの構成成分として存在するので、抽出原料としては植物体が好適である。
“Gallic acid” that can be used as an antioxidant of the present invention means gallic acid or its derivatives. The gallic acid derivative is, for example, a compound, a metal salt, a methylated product, an acetylated product, or a glycoside / ester in which a sugar, lipid, amino acid or the like is bonded to the basic skeleton of gallic acid.
Gallic acid can be obtained from a plant or microorganism by any extraction method, fermentation method, chemical or enzymatic synthesis method, etc. known to those skilled in the art. Since gallic acid is present in a free state in each part of the plant or as a constituent component of tannin, a plant body is suitable as an extraction raw material.
没食子酸を主な構成成分とするタンニンなどの没食子酸誘導体は、加水分解すると没食子酸を生成するので、摂取することで没食子酸と同等の効果を示すことができる。使用者の生体内における化学反応により、没食子酸あるいは没食子酸誘導体を生成可能な化合物（タンニン等）も、本発明でいう没食子酸に含まれる。
Since gallic acid derivatives such as tannin containing gallic acid as a main constituent generate gallic acid when hydrolyzed, the same effects as gallic acid can be exhibited by ingestion. A compound capable of producing gallic acid or a gallic acid derivative (tannin or the like) by a chemical reaction in the living body of the user is also included in the gallic acid referred to in the present invention.
本発明の抗酸化剤として使用できる「エピガロカテキンガレート」は、エピガロカテキンガレートまたはその誘導体を意味する。エピガロカテキンガレートは、緑茶、柿、樹木等に含まれるポリフェノールの１種である。エピガロカテキンガレート誘導体とは、例えば、エピガロカテキンガレートの基本骨格に糖・脂質・アミノ酸等が結合した化合物、金属塩、メチル化物あるいはアセチル化物、配糖体・エステルである。なお、使用者の生体内における化学反応により、エピガロカテキンガレートあるいはエピガロカテキンガレート誘導体を生成可能な化合物も、本発明でいうエピガロカテキンガレートに含まれる。 “Epigallocatechin gallate” that can be used as an antioxidant of the present invention means epigallocatechin gallate or a derivative thereof. Epigallocatechin gallate is a kind of polyphenol contained in green tea, persimmon, trees and the like. The epigallocatechin gallate derivative is, for example, a compound in which sugar, lipid, amino acid or the like is bonded to the basic skeleton of epigallocatechin gallate, metal salt, methylated product or acetylated product, glycoside / ester. In addition, the compound which can produce | generate epigallocatechin gallate or an epigallocatechin gallate derivative by the chemical reaction in a user's biological body is also contained in the epigallocatechin gallate as used in the field of this invention.
エピガロカテキンガレートはカテキン類の一種であり、植物体や微生物体から、当業者に公知の任意の抽出法、発酵法、化学的もしくは酵素的合成法等により得ることができる。 Epigallocatechin gallate is a kind of catechins, and can be obtained from plants and microorganisms by any extraction method, fermentation method, chemical or enzymatic synthesis method known to those skilled in the art.
本発明の抗酸化剤として使用できる「アスコルビン酸」は、アスコルビン酸またはその誘導体を意味する。アスコルビン酸誘導体とは、例えば、アスコルビン酸の基本骨格に糖・脂質・アミノ酸等が結合した化合物、金属塩、メチル化物あるいはアセチル化物、配糖体・エステルである。なお、使用者の生体内における化学反応により、アスコルビン酸あるいはアスコルビン酸誘導体を生成可能な化合物も、本発明でいうアスコルビン酸に含まれる。 “Ascorbic acid” that can be used as an antioxidant of the present invention means ascorbic acid or a derivative thereof. The ascorbic acid derivative is, for example, a compound, a metal salt, a methylated product or an acetylated product, a glycoside or an ester, in which sugar, lipid, amino acid or the like is bonded to the basic skeleton of ascorbic acid. A compound capable of producing ascorbic acid or an ascorbic acid derivative by a chemical reaction in the user's living body is also included in the ascorbic acid referred to in the present invention.
アスコルビン酸は、植物体や微生物体から、当業者に公知の任意の抽出法、発酵法、化学的もしくは酵素的合成法等により得ることができる。 Ascorbic acid can be obtained from a plant or microorganism by any extraction method, fermentation method, chemical or enzymatic synthesis method, etc. known to those skilled in the art.
本発明の各種剤に有効成分として含まれるエラグ酸および抗酸化剤の含有量及びその割合は、本発明の相乗効果が達成される限り特に制限はない。例えば、エラグ酸および抗酸化剤の含有比は各抗酸化成分の量及び種類などにも依るが、通常、20:1〜1:10（重量比）、好ましくは10:1〜1:2（重量比）の範囲である。尚、本発明の各種剤には、有効成分の効果に実質的な影響を及ぼさない限り、当業者に公知のその他の各種成分が含まれていても良い。 The content and ratio of ellagic acid and antioxidant contained as active ingredients in the various agents of the present invention are not particularly limited as long as the synergistic effect of the present invention is achieved. For example, the content ratio of ellagic acid and antioxidant depends on the amount and type of each antioxidant component, but is usually 20: 1 to 1:10 (weight ratio), preferably 10: 1 to 1: 2 ( Weight ratio). The various agents of the present invention may contain various other components known to those skilled in the art as long as the effects of the active ingredients are not substantially affected.
上記の諸効果を有する各種剤を含有する本発明の飲食品、医薬品または化粧品の種類、形態、及びその他の含有成分等に特に制約にはなく、当業者に公知の任意の各種方法で容易に調製することが出来る。 There are no particular restrictions on the type, form, and other ingredients of the food / beverage products, pharmaceuticals or cosmetics of the present invention containing various agents having the above-mentioned effects, and they can be easily obtained by any of various methods known to those skilled in the art. Can be prepared.
例えば、本発明の医薬品は、例えば錠剤、顆粒剤、散剤、カプセル剤などの固形剤、又は、注射剤などの液剤などいずれの形態にも公知の方法により適宜調製することができる。これらの医薬品には通常用いられる結合剤、崩壊剤、増粘剤、分散剤、再吸収促進剤、矯味剤、緩衝剤、界面活性剤、溶解補助剤、保存剤、乳化剤、等張化剤、安定化剤やｐＨ調製剤などの賦形剤を適宜使用してもよい。 For example, the pharmaceutical of the present invention can be appropriately prepared by a known method in any form such as a solid preparation such as a tablet, granule, powder, capsule, or a liquid preparation such as an injection. For these pharmaceuticals, binders, disintegrating agents, thickeners, dispersants, reabsorption accelerators, taste-masking agents, buffers, surfactants, solubilizers, preservatives, emulsifiers, tonicity agents, Excipients such as stabilizers and pH adjusters may be used as appropriate.
本発明の医薬品は、経口的にあるいは非経口的に適宜に使用される。すなわち、経口、静脈、腹腔内の投与などによって所望の効果を表すものである。 The pharmaceutical of the present invention is appropriately used orally or parenterally. That is, a desired effect is expressed by oral, intravenous, intraperitoneal administration or the like.
本発明の医薬品における有効成分の投与量は、その種類、その剤型、また患者の年令、体重、適応症状などによって異なるが、例えば経口投与の場合は、成人一日１回又は数回投与され、一日当たり１回約50 mg 〜 5 g、好ましくは0.1 〜 5 ｇ／ｋｇ体重程度投与するのがよい。 The dose of the active ingredient in the pharmaceutical product of the present invention varies depending on the type, dosage form, age, weight, indication, etc. of the patient. For example, in the case of oral administration, it is administered once or several times a day for an adult. And about 50 mg to 5 g, preferably about 0.1 to 5 g / kg body weight once a day.
また、本発明の飲食品の形態としては、例えば、顆粒状、粒状、ペースト状、ゲル状、固形状、又は、液体状に任意に成形することが出来る。これらには、食品中に含有することが認められている当業者に公知の各種物質、例えば、結合剤、崩壊剤、増粘剤、分散剤、再吸収促進剤、矯味剤、緩衝剤、界面活性剤、溶解補助剤、保存剤、乳化剤、等張化剤、安定化剤やｐＨ調製剤などの賦形剤を適宜含有させることが出来る。 Moreover, as a form of the food / beverage products of this invention, it can shape | mold arbitrarily, for example in granular form, a granular form, a paste form, a gel form, solid form, or a liquid form. These include various substances known to those skilled in the art that are known to be contained in foods, such as binders, disintegrants, thickeners, dispersants, reabsorption accelerators, corrigents, buffers, interfaces. Excipients such as activators, solubilizers, preservatives, emulsifiers, tonicity agents, stabilizers and pH adjusters can be included as appropriate.
本発明の化粧品も、例えば、液体状、ペースト状、又は、ゲル状の任意の形態とすることができる。これらの中にも、化粧品中に含有することが認められている、当業者に公知の各種物質を適宜含有させることが出来る。 The cosmetic of the present invention can also be in any form, for example, liquid, paste, or gel. Among these, various substances known to those skilled in the art that are recognized to be contained in cosmetics can be appropriately contained.
本発明の飲食品又は化粧品中に含まれる有効成分の量は、それらの種類、目的、形態、利用方法などに応じて、適宜決めることが出来、例えば、数重量％〜数十重量％程度とすることができる。特に、保健用飲食品等として利用する場合には、本発明の有効成分を所定の効果が十分発揮されるような量で含有させることが好ましい。従ってこのような場合には、本発明の飲食品は、エラグ酸および抗酸化剤を含有し、血中尿酸値低下、高尿酸血症の予防あるいは改善、または痛風の予防のために用いられるものである旨の表示を付した飲食品とすることができる。 The amount of the active ingredient contained in the food or drink or cosmetic of the present invention can be appropriately determined according to the type, purpose, form, method of use, etc., for example, about several weight% to several tens weight%. can do. In particular, when used as a health food or drink, it is preferable to contain the active ingredient of the present invention in such an amount that a predetermined effect is sufficiently exhibited. Therefore, in such a case, the food / beverage product of the present invention contains ellagic acid and an antioxidant and is used for lowering blood uric acid level, preventing or improving hyperuricemia, or preventing gout. It can be set as the food-drinks which attached | subjected the indication that it is.
以下、実施例に則して本発明を具体的に説明するが、本発明の技術的範囲はこれらの記載によって何等制限されるものではない。 EXAMPLES Hereinafter, although this invention is concretely demonstrated according to an Example, the technical scope of this invention is not restrict | limited at all by these description.
本発明の効果を確認するため以下の実験を行った。なお、エラグ酸は市販の試薬（和光純薬社製）を使用した。抗酸化剤としては、以下の４種類を使用した。 In order to confirm the effect of the present invention, the following experiment was conducted. As ellagic acid, a commercially available reagent (manufactured by Wako Pure Chemical Industries, Ltd.) was used. The following four types were used as antioxidants.
１）ブドウ抽出物「グラヴィノール スーパー」（キッコーマン社製：プロアントシアニジンを８６％以上含む）、
２）エピガロカテキンガレート（和光純薬社製：純度90％以上）、
３）アスコルビン酸（和光純薬社製：純度99.5％）、
４）没食子酸（東京化成工業社製：純度98％以上）
1) Grape extract “Gravinol Super” (Kikkoman Corporation: contains 86% or more proanthocyanidins),
2) Epigallocatechin gallate (Wako Pure Chemical Industries, Ltd .: purity 90% or more),
3) Ascorbic acid (Wako Pure Chemical Industries, Ltd .: purity 99.5%),
4) Gallic acid (Tokyo Kasei Kogyo Co., Ltd .: Purity 98% or more)
〔キサンチンオキシダーゼ(XOD)阻害活性試験〕
XOD阻害活性試験は、Chem.Pharm.Bull. 38, 1224-1229 (1990)に従って測定した。すなわち、試験管に720μl の0.1 M りん酸緩衝液 (pH 7.5)、352μlの蒸留水及び48μl
のジメチルスルホキシドに溶解した試料溶液を加え混合後、80μl の0.1Mリン酸緩衝液に溶解したXOD (Roche社製、0.04 unit /ml)を加えて、37℃で10分間プレインキュベーションした。次に、1200μlの 0.1 mM キサンチン(和光純薬社製) 水溶液を基質として加えて37℃で30分間反応させた。200μl の1N HClを加えることで反応を停止させ、生成した尿酸をHPLCにて測定した。
(Xanthine oxidase (XOD) inhibitory activity test)
The XOD inhibitory activity test was measured according to Chem. Pharm. Bull. 38, 1224-1229 (1990). In a test tube, 720 μl 0.1 M phosphate buffer (pH 7.5), 352 μl distilled water and 48 μl
A sample solution dissolved in dimethyl sulfoxide was added and mixed, and then 80 μl of XOD (Roche, 0.04 unit / ml) dissolved in 0.1 M phosphate buffer was added and preincubated at 37 ° C. for 10 minutes. Next, 1200 μl of 0.1 mM xanthine (manufactured by Wako Pure Chemical Industries, Ltd.) aqueous solution was added as a substrate and reacted at 37 ° C. for 30 minutes. The reaction was stopped by adding 200 μl of 1N HCl, and the produced uric acid was measured by HPLC.
HPLCによる尿酸測定は、以下のように行った。カラムはCAPCELL PAK C18 UG120 5 mm 4.6 mm×150 mm (資生堂)を用い、溶離液50mM NH4H2PO4を流速1.0 ml/minで通液し、尿酸を280nmで検出した。 The uric acid measurement by HPLC was performed as follows. The column was CAPCELL PAK C18 UG120 5 mm 4.6 mm × 150 mm (Shiseido), and 50 mM NH 4 H 2 PO 4 as an eluent was passed at a flow rate of 1.0 ml / min, and uric acid was detected at 280 nm.
XODの阻害活性は、コントロールとして試料溶液の代わりにDMSOを添加した場合の尿酸量を100%として、サンプル添加による尿酸量の減少量により計算した。 The inhibitory activity of XOD was calculated from the amount of decrease in the amount of uric acid due to the addition of the sample, with the amount of uric acid when DMSO was added instead of the sample solution as a control as 100%.
XOD阻害活性試験の結果を図１−４に示した。図１で明らかなように、エラグ酸、あるいは没食子酸単独使用に比べて、両者を併用した場合のキサンチンオキシダーゼ阻害効果は相乗的に増強した。つまり、0.25μg/mlのエラグ酸に0.05μg/mlの没食子酸を添加することで、0.5μg/mlエラグ酸と同等の阻害活性を示した。 The results of the XOD inhibitory activity test are shown in FIGS. As is clear from FIG. 1, the xanthine oxidase inhibitory effect when both were used in combination was synergistically enhanced as compared to the use of ellagic acid or gallic acid alone. That is, when 0.05 μg / ml gallic acid was added to 0.25 μg / ml ellagic acid, the same inhibitory activity as 0.5 μg / ml ellagic acid was exhibited.
図２で明らかなように、エラグ酸、あるいはブドウ抽出物単独使用に比べて、両者を併用した場合のキサンチンオキシダーゼ阻害効果は相乗的に増強した。
図３で明らかなように、エラグ酸、あるいはエピガロカテキンガレート単独使用に比べて、両者を併用した場合のキサンチンオキシダーゼ阻害効果は相乗的に増強した。
図４で明らかなように、エラグ酸、あるいはアスコルビン酸単独使用に比べて、両者を併用した場合のキサンチンオキシダーゼ阻害効果は相乗的に増強した。
尚、図１−４中の横軸は、最終的な反応系における各試料添加量（濃度）を示す。
As is clear from FIG. 2, the xanthine oxidase inhibitory effect when both were used in combination was synergistically enhanced as compared to the use of ellagic acid or grape extract alone.
As is clear from FIG. 3, the xanthine oxidase inhibitory effect when both are used in combination is synergistically enhanced as compared with the use of ellagic acid or epigallocatechin gallate alone.
As is clear from FIG. 4, the xanthine oxidase inhibitory effect when both are used in combination is synergistically enhanced as compared with the use of ellagic acid or ascorbic acid alone.
In addition, the horizontal axis in FIGS. 1-4 shows each sample addition amount (concentration) in the final reaction system.
〔血中尿酸値低下活性試験〕
動物試験法は次の通り行った。つまり、正常マウス（ICR、オリエンタル酵母工業社製） オス 6-7週令（1群8匹）をMF粉末飼料（オリエンタル酵母工業社製）にて1週間予備飼育したものを実験に用いた。サンプルであるエラグ酸やブドウ抽出物はMF粉末飼料に混餌し、自由摂取にて飼育した。混餌飼育後5日目に眼窩静脈より採血を行った。血液は30-60分放置後、10,000
rpmで10分間遠心し血清を得た。血清中尿酸値は、以下の条件でHPLCにて分析した。
[Blood uric acid level lowering activity test]
The animal test method was performed as follows. That is, normal mice (ICR, manufactured by Oriental Yeast Co., Ltd.) Male 6-7 weeks old (8 mice per group) preliminarily raised for 1 week with MF powdered feed (produced by Oriental Yeast Co., Ltd.) were used for the experiment. Samples of ellagic acid and grape extract were mixed with MF powder feed and reared freely. Blood was collected from the orbital vein on the fifth day after feeding the mixed diet. After leaving blood for 30-60 minutes, 10,000
Serum was obtained by centrifugation at rpm for 10 minutes. Serum uric acid levels were analyzed by HPLC under the following conditions.
HPLCカラムはWakosil GP-N6（15ｃｍｘ4.6ｍｍ I.D.）を用い、溶離液として0.2 M リン酸Ｎａ（ｐＨ6）-アセトニトリル（98:2）を流速0.4 ml/minで通液し、化学検出 (800 mV)で尿酸を検出した。 The HPLC column was Wakosil GP-N6 (15 cm x 4.6 mm ID), and 0.2 M Na phosphate (pH 6) -acetonitrile (98: 2) was passed as the eluent at a flow rate of 0.4 ml / min for chemical detection (800 mV ) Detected uric acid.
血中尿酸値低下活性試験の結果を図５に示した。図５で明らかなように、エラグ酸、あるいはブドウ抽出物単独使用では有意な効果を示さない投与量で両者を併用した場合、血清中の尿酸値は有意に低下した。 The results of the blood uric acid level lowering activity test are shown in FIG. As is clear from FIG. 5, when ellagic acid or grape extract alone was used at a dose that showed no significant effect, the serum uric acid level was significantly reduced.
本発明の各種剤に有効成分として含まれるエラグ酸及び抗酸化剤は、少量の有効成分で、キサンチンオキシダーゼ阻害及び血中尿酸値低下に優れた相乗効果が得られる。従って、それらを併用することによって、高尿酸血症の予防または改善、痛風の予防に優れた相乗効果が期待される。又、これらの相乗効果が少量の有効成分で得られるので、これら含む各種剤、及び飲食品、医薬品又は化粧品を経済的に提供することが可能となる。 The ellagic acid and antioxidant contained in the various agents of the present invention as active ingredients are small amounts of active ingredients, and a synergistic effect excellent in inhibiting xanthine oxidase and lowering blood uric acid level is obtained. Therefore, by using them together, an excellent synergistic effect for preventing or improving hyperuricemia and preventing gout is expected. Moreover, since these synergistic effects can be obtained with a small amount of active ingredients, it is possible to economically provide various agents, foods and drinks, pharmaceuticals or cosmetics containing them.
Claims (8)
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