JP2021066673A - Allergic rhinitis symptom inhibitor - Google Patents
Allergic rhinitis symptom inhibitor Download PDFInfo
- Publication number
- JP2021066673A JP2021066673A JP2019190827A JP2019190827A JP2021066673A JP 2021066673 A JP2021066673 A JP 2021066673A JP 2019190827 A JP2019190827 A JP 2019190827A JP 2019190827 A JP2019190827 A JP 2019190827A JP 2021066673 A JP2021066673 A JP 2021066673A
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- JP
- Japan
- Prior art keywords
- allergic rhinitis
- proanthocyanidin
- epigallocatechin gallate
- derived
- lotus root
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Images
Abstract
Description
本発明は、アレルギー性の鼻炎症状抑制剤に関する。 The present invention relates to an allergic rhinitis symptom suppressant.
近年、自然環境や食生活の変化、ストレスの増加等により、アレルギー患者の数は、年々増加している。アレルギーの発症機構は通常Ｉ型からＩＶ型の４つに分類されており、これらの混合型も存在する。花粉症、アレルギー性鼻炎、アトピー性皮膚炎、気管支喘息、蕁麻疹などのＩ型アレルギーは抗原が作用してから短時間で症状が出てくるため即時型アレルギーと呼ばれている。 In recent years, the number of allergic patients has been increasing year by year due to changes in the natural environment, eating habits, and increased stress. The onset mechanism of allergy is usually classified into four types, type I to type IV, and a mixed type of these is also present. Type I allergies such as pollinosis, allergic rhinitis, atopic dermatitis, bronchial asthma, and urticaria are called immediate allergies because symptoms appear in a short time after the antigen acts.
Ｉ型アレルギーの作用機序は、ＩｇＥ抗体の誘導と肥満細胞や好塩基球からのヒスタミンやロイコトリエン等のケミカルメディエーターの放出（脱顆粒）を特徴とする。まず、外界から侵入したアレルゲン（花粉、室内塵、ダニ、カビ等）は、樹状細胞やマクロファージ等の抗原提示細胞によってその一部をＭＨＣ ｃｌａｓｓ ＩＩ分子に結合した状態でＴ細胞に対して提示され、Ｔｈ２細胞が活性化・分化する。Ｔｈ２細胞が放出したＴｈ２サイトカイン（ＩＬ−４、ＩＬ−５、ＩＬ−９、ＩＬ−１３等）はＢ細胞のクラススイッチを誘導し、ＩｇＥ抗体が産生され、ＩｇＥ抗体は組織内の肥満細胞や血中の好塩基球表面のＦｃεＲＩに結合する。アレルゲンは次回の侵入時に肥満細胞や好塩基球表面に結合しているＩｇＥ抗体に認識され、ＩｇＥ抗体間に架橋が形成され、この刺激を引き金として肥満細胞や好塩基球がケミカルメディエーターを放出（脱顆粒）することによって、アレルギーの諸症状が発現する。例えば、アレルギー性鼻炎（花粉症を含む）では、鼻粘膜の肥満細胞、好塩基球から放出されるヒスタミンにより、血管拡張、血管透過性亢進が起こった結果、くしゃみ、水性鼻漏、鼻閉（鼻づまり）等の不快な鼻炎症状が現れる。これまでこのようなＩｇＥ抗体やケミカルメディエーターを介するアレルギー症状を抑制及び改善する薬剤としては、例えば、肥満細胞の活性を弱めてケミカルメディエーターの遊離を抑制するケミカルメディエーター遊離抑制薬、ヒスタミンＨ１受容体にヒスタミンと拮抗的に結合することによってその機能を阻害するヒスタミンＨ１拮抗薬、ロイコトリエン受容体にロイコトリエンと拮抗的に結合することによってその機能を阻害するロイコトリエン拮抗薬、トロンボキサンの産生及び作用を抑制するトロンボキサン阻害・拮抗薬、ＩＬ−４及びＩＬ−５の産生を抑制するＴｈ２サイトカイン阻害薬といった抗アレルギー剤のほか、免疫応答性を弱めることによって炎症を軽減するステロイド剤などがある。また、抗ヒスタミン薬のなかでも、ヒスタミン拮抗作用と肥満細胞からのケミカルメディエーターの遊離の抑制作用を併せ持つ第２若しくは第３世代の抗ヒスタミン薬が日本では抗アレルギー薬として呼ばれることもある。しかしながら、これまで上記のような薬剤はアレルギー症状の治療に十分な効果が得られているとはいえず、また、眠気や倦怠感といった副作用を起こしたり、他の疾患を有する患者には使用禁忌であるなどの問題がある。さらに、上記のような薬剤の長期にわたる使用は、医療経済上大きな負担ともなる。よって、治療効果が高く、安全かつ安価な次世代の抗アレルギー剤の開発が要求されている。 The mechanism of action of type I allergy is characterized by induction of IgE antibody and release (degranulation) of chemical mediators such as histamine and leukotriene from mast cells and basophils. First, allergens (pollen, indoor dust, mites, molds, etc.) that have invaded from the outside world are presented to T cells in a state where a part of them is bound to MHC class II molecules by antigen-presenting cells such as dendritic cells and macrophages. Then, Th2 cells are activated and differentiated. Th2 cytokines (IL-4, IL-5, IL-9, IL-13, etc.) released by Th2 cells induce B cell class switches to produce IgE antibodies, which are used for mast cells in tissues and It binds to FcεRI on the surface of basophils in blood. The allergen is recognized by the IgE antibody bound to the surface of mast cells and basophils at the next invasion, a bridge is formed between the IgE antibodies, and this stimulus triggers the mast cells and basophils to release the chemical mediator ( By degranulation), various allergic symptoms develop. For example, in allergic rhinitis (including pollinosis), mast cells in the nasal mucosa and histamine released from basophils cause vasodilation and vascular hyperpermeability, resulting in squeezing, aqueous rhinorrhea, and nasal congestion ( Unpleasant rhinitis symptoms such as stuffy nose) appear. So far, as a drug that suppresses and improves allergic symptoms mediated by such IgE antibody and chemical mediator, for example, a chemical mediator release inhibitor that suppresses the release of chemical mediator by weakening the activity of obese cells, histamine H1 receptor Suppresses the production and action of histamine H1 antagonist, which inhibits its function by antagonistically binding to histamine, and thromboxane, a leukotriene antagonist which inhibits its function by antagonistically binding to leukotriene receptor. In addition to antiallergic agents such as thromboxane inhibitors / antagonists and Th2 cytokine inhibitors that suppress the production of IL-4 and IL-5, there are steroids that reduce inflammation by weakening the immune responsiveness. Among antihistamines, second- or third-generation antihistamines that have both histamine antagonism and inhibitory action on the release of chemical mediators from mast cells are sometimes called antihistamines in Japan. However, it cannot be said that the above-mentioned drugs have been sufficiently effective in treating allergic symptoms, and they are contraindicated for patients with side effects such as drowsiness and malaise, or for patients with other diseases. There are problems such as. Furthermore, the long-term use of the above-mentioned drugs poses a great burden on the medical economy. Therefore, there is a demand for the development of next-generation antiallergic agents that have high therapeutic effects, are safe and inexpensive.
一方、上記の副作用等の問題に対処するために、Ｉ型アレルギー反応による症状や疾患の抑制及び改善を目的とした抗アレルギー剤やステロイド剤などの医薬品に代えて、食品由来の抗アレルギー素材の探索と利用が研究されている。例えば、植物のハスはその地下茎の肥大した部分がレンコンとして食用とされ、古くから滋養強壮に優れていることが知られているほか、近年では抗アレルギー作用を有することも見出されており、ハスの粉砕物若しくは抽出物、またはこれらの組み合わせを含む抗アレルギー剤（特許文献１）、ハスの粉砕物及び／又は抽出物と乳酸菌を含む抗アレルギー剤（特許文献２）などが報告されている。また、抗ヒスタミン薬のエピナスチンにレンコンの節部抽出物を併用すると、抗ヒスタミン薬の単独使用に比べてアレルギー性鼻炎などのアレルギー症状が顕著に抑制されることも報告されている（特許文献３）。また、各種の植物由来ポリフェノールは、主にin vitro試験によりアレルギー症状を抑制する作用があることが確認されており、例えばリンゴポリフェノール、カカオポリフェノール、茶ポリフェノールなどがある。とりわけ緑茶に含まれるカテキン類は、血圧上昇抑制作用、血中コレステロール低下作用、抗酸化作用、抗菌・抗ウイルス作用、抗がん作用など様々な作用が知られており、抗アレルギー作用もその一つである。例えば、特許文献４には、非重合体の非エピ体カテキン類と非重合体のエピ体カテキン類を特定の比率で配合した組成物が、くしゃみ発作や鼻漏症状の改善に有効であることが開示されている。しかしながら、当該組成物には、非エピ体カテキン類４種とエピ体カテキン類４種の計８種類のカテキン類が含まれており、どの成分が有効であったか明確ではない。 On the other hand, in order to deal with the above-mentioned problems such as side effects, instead of pharmaceuticals such as antiallergic agents and steroids for the purpose of suppressing and improving symptoms and diseases caused by type I allergic reaction, food-derived antiallergic materials are used. Exploration and utilization are being studied. For example, the enlarged part of the rhizome of the plant sacred lotus is edible as lotus root, and it has been known for a long time that it has excellent nourishing tonicity, and in recent years, it has been found to have an anti-allergic effect. Anti-allergic agents containing crushed lotus or extracts or combinations thereof (Patent Document 1), crushed lotus and / or anti-allergic agents containing extracts and lactic acid bacteria (Patent Document 2) have been reported. .. It has also been reported that the combined use of epinastine, an antihistamine, with a nodal extract of rencon significantly suppresses allergic symptoms such as allergic rhinitis as compared with the use of an antihistamine alone (Patent Document 3). ). In addition, various plant-derived polyphenols have been confirmed to have an effect of suppressing allergic symptoms mainly by in vitro tests, and examples thereof include apple polyphenols, cacao polyphenols, and tea polyphenols. In particular, catechins contained in green tea are known to have various actions such as blood pressure increase inhibitory action, blood cholesterol lowering action, antioxidant action, antibacterial / antiviral action, and anticancer action, and antiallergic action is one of them. It is one. For example, Patent Document 4 states that a composition containing non-polymer non-epimeric catechins and non-polymeric epimeric catechins in a specific ratio is effective in improving sneezing attacks and rhinorrhea symptoms. Is disclosed. However, the composition contains four types of non-epimeric catechins and four types of epimeric catechins, for a total of eight types of catechins, and it is not clear which component was effective.
上記のように、抗ヒスタミン薬はアレルギー性の鼻炎症状や花粉症などのアレルギー症状に対する代表的な抗アレルギー剤であるが、単独では完全にアレルギー症状を抑制することができず、効果を上げるために投薬量を増やすと副作用が発生したり、費用がかかるなどの問題がある。 As mentioned above, antihistamines are typical antiallergic agents for allergic symptoms such as allergic rhinitis symptoms and hay fever, but they cannot completely suppress allergic symptoms by themselves and are effective. There are problems such as side effects and high cost when the dosage is increased.
従って、本発明の課題は、アレルギー性の鼻炎症状に対し、抗ヒスタミン薬と同様な優れた抑制効果を示し、副作用がなく、安全かつ安価な食品由来の成分を含む薬剤を提供することにある。 Therefore, an object of the present invention is to provide a drug containing a safe and inexpensive food-derived ingredient, which exhibits an excellent inhibitory effect on allergic rhinitis symptoms as well as an antihistamine drug, and has no side effects. ..
本発明者らは上記課題を解決するために鋭意研究を重ねた結果、レンコン節部の抗アレルギー作用物質が特定の構造を有するプロアントシアニジン重合体であることを確認するとともに、このレンコン節部由来のプロアントシアニジンと、緑茶成分であるエピガロカテキンガレートを併用すると、単独使用よりもアレルギー性の鼻炎症状が顕著に抑制されることを見出し、本発明を完成させるに至った。 As a result of intensive studies to solve the above problems, the present inventors have confirmed that the antiallergic agent of the lencon node is a proanthocyanidin polymer having a specific structure, and derived from this lencon node. We have found that the combined use of proanthocyanidins and epigallocatechin gallate, which is a green tea component, significantly suppresses allergic rhinitis symptoms as compared with the use alone, and has completed the present invention.
すなわち、本発明は、以下の発明を包含する。
（１）下記の一般式（Ｉ）で表される、レンコン節部由来のプロアントシアニジンと、エピガロカテキンガレート又はエピガロカテキンガレート含有物質を有効成分として含有する、アレルギー性の鼻炎症状抑制剤。
（２）前記鼻炎症状が、くしゃみ、水性鼻漏、又は鼻の腫れ若しくは発赤である、（１）に記載のアレルギー性の鼻炎症状の抑制剤。
（３）前記プロアントシアニジンの一日の投与量が、患者の体重１ｋｇあたり０．２〜１０ｍｇである、（１）又は（２）に記載のアレルギー性の鼻炎症状抑制剤。
（４）前記エピガロカテキンガレート含有物質が緑茶抽出物である、（１）〜（３）のいずれかに記載のアレルギー性の鼻炎症状抑制剤。
That is, the present invention includes the following inventions.
(1) An allergic rhinitis symptom inhibitor containing proanthocyanidin derived from lotus root node and epigallocatechin gallate or epigallocatechin gallate-containing substance as active ingredients, which is represented by the following general formula (I).
(2) The agent for suppressing allergic rhinitis symptoms according to (1), wherein the rhinitis symptoms are sneezing, rhinorrhea, or swelling or redness of the nose.
(3) The allergic rhinitis symptom inhibitor according to (1) or (2), wherein the daily dose of the proanthocyanidin is 0.2 to 10 mg per 1 kg of the body weight of the patient.
(4) The allergic rhinitis symptom inhibitor according to any one of (1) to (3), wherein the epigallocatechin gallate-containing substance is a green tea extract.
本発明によれば、レンコン節部由来のプロアントシアニジンと、緑茶成分であるエピガロカテキンガレートとを含むアレルギー性鼻炎抑制剤が提供される。本発明のアレルギー性鼻炎抑制剤は、天然物である食用のレンコンや緑茶に含まれる成分を有効成分とするため、日常的に使用しても副作用がなく、安全性が高い。よって、医薬品や健康食品などに安心して使用できる。また、レンコンは安価にかつ容易に入手可能である材料であるから、アレルギー治療の費用負担が軽減される。 According to the present invention, an allergic rhinitis inhibitor containing proanthocyanidins derived from lotus root nodes and epigallocatechin gallate, which is a green tea component, is provided. Since the allergic rhinitis inhibitor of the present invention contains an ingredient contained in edible lotus root or green tea, which is a natural product, as an active ingredient, it has no side effects even when used on a daily basis and is highly safe. Therefore, it can be safely used for pharmaceuticals and health foods. Moreover, since lotus root is an inexpensive and easily available material, the cost burden of allergy treatment is reduced.
以下、本発明を詳細に説明する。
本発明のアレルギー性鼻炎症状抑制剤は、レンコン節部由来のプロアントシアニジンと、エピガロカテキンガレート又はエピガロカテキンガレート含有物質を有効成分として含有する。
Hereinafter, the present invention will be described in detail.
The allergic rhinitis symptom inhibitor of the present invention contains proanthocyanidin derived from lotus root node and epigallocatechin gallate or epigallocatechin gallate-containing substance as active ingredients.
（レンコン節部由来のプロアントシアニジン）
本発明のアレルギー性鼻炎症状抑制剤の有効成分であるプロアントシアニジンは、下記の一般式（Ｉ）で示される、フラバン−３−オールを構成単位とする重合体である。
(Proanthocyanidin derived from lotus root node)
The proanthocyanidin, which is the active ingredient of the allergic rhinitis symptom inhibitor of the present invention, is a polymer having flavan-3-ol as a constituent unit, which is represented by the following general formula (I).
構造上の特徴としては、Ｒ２及びＲ４が水酸基であるガロカテキン型が、Ｒ２及びＲ４が水素原子であるカテキン型よりも多いことで、Ｒ２はＯＨ：Ｈ＝６５〜８５：１５〜３５、Ｒ４はＯＨ：Ｈ＝７５〜８５：１５〜２５である。また、プロアントシアニジンは立体異性体も含まれ、Ｒ１及びＲ３の水酸基はそれぞれ異なる比率でα型とβ型をとりうる。 As a structural feature, there are more galocatechin types in which R 2 and R 4 are hydroxyl groups than in catechin types in which R 2 and R 4 are hydrogen atoms, and R 2 has OH: H = 65 to 85:15. ~ 35, R 4 is OH: H = 75 ~ 85: 15-25. In addition, proanthocyanidins also contain stereoisomers, and the hydroxyl groups of R 1 and R 3 can take α-type and β-type in different ratios, respectively.
上記プロアントシアニジンは、レンコン節部からプロアントシアニジン画分を抽出し、更にガロカテキンとカテキンを除いた２量体以上のプロアントシアニジン（ガロカテキン）重合体を抽出・精製することにより得られる。また、化学的合成法などにより得ることもできる。上記プロアントシアニジンの重合度は、限定はされないが、推定重合度が３〜５であることが好ましい。 The above proanthocyanidin can be obtained by extracting a proanthocyanidin fraction from a lencon node and further extracting and purifying a dimer or more proanthocyanidin (galocatechin) polymer excluding galocatechin and catechin. It can also be obtained by a chemical synthesis method or the like. The degree of polymerization of the proanthocyanidins is not limited, but the estimated degree of polymerization is preferably 3 to 5.
レンコン節部を材料として上記プロアントシアニジンを調製する方法の具体例を以下に示す。 Specific examples of the method for preparing the above proanthocyanidins using the lotus root node as a material are shown below.
本発明においてレンコン（Lotus root)とは、ハス（Nelumbo nucifera）の地下茎が肥大したものをいい、本発明において「レンコン節部」とは、節又は節の端から1cm以内の節近傍部をいう。レンコンの品種（カッコ内は産地）としては、例えば、備中（徳島県鳴門産、石井産）、オオジロ（徳島県川内産）、ロータス（徳島県川内産）等が挙げられるが、品種や産地はこれらに特に限定されるものではない。 In the present invention, the lotus root refers to an enlarged rhizome of the lotus root (Nelumbo nucifera), and in the present invention, the "lotus root node" refers to a node or a node vicinity portion within 1 cm from the end of the node. .. Examples of lotus root varieties (produced in parentheses) include Bichu (produced in Naruto, Tokushima Prefecture, Ishii), Ojiro (produced in Kawauchi, Tokushima Prefecture), Lotus (produced in Kawauchi, Tokushima Prefecture), etc. It is not particularly limited to these.
レンコン節部からプロアントシアニジン画分を抽出する方法は、特に限定されないが、水若しくは熱水、又は水と有機溶媒の混合溶媒を用い、撹拌又はカラム抽出する方法により行うことができる。有機溶媒としては、水溶性有機溶媒、例えば、メタノール、エタノール、プロピルアルコール、イソプロピルアルコール、ブタノール、イソブタノール等の低級アルコール又は含水低級アルコール、プロピレングリコール、1,3-ブチレングリコール、グリセリン等の多価アルコール又は含水多価アルコール、アセトン、酢酸エチル、あるいはこれらの２種以上の混合溶媒が挙げられる。これらの溶媒のなかでも、本発明で使用する溶媒は、水、熱水、エタノールが好ましく、熱水がより好ましい。溶媒の使用量については、特に限定はなく、例えば上記レンコン節部（乾燥重量）に対し、３倍以上、好ましくは６倍以上であればよいが、抽出後に濃縮を行ったり、単離したりする場合の操作の便宜上１００倍以下であることが好ましい。また、抽出温度や時間は、用いる溶媒の種類によるが、例えば、水を溶媒として用いる場合、１０〜１２０℃、好ましくは２０〜１００℃で、１０分〜２４時間、好ましくは３０分〜５時間を例示することができる。 The method for extracting the proanthocyanidin fraction from the lencon node is not particularly limited, but it can be carried out by a method of stirring or column extraction using water or hot water or a mixed solvent of water and an organic solvent. Examples of the organic solvent include water-soluble organic solvents such as lower alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, butanol and isobutanol, hydrous lower alcohols, propylene glycol, 1,3-butylene glycol and glycerin. Alcohol or hydrous polyhydric alcohol, acetone, ethyl acetate, or a mixed solvent of two or more of these can be mentioned. Among these solvents, the solvent used in the present invention is preferably water, hot water, or ethanol, and more preferably hot water. The amount of the solvent used is not particularly limited, and may be, for example, 3 times or more, preferably 6 times or more the amount of the lotus root node (dry weight), but may be concentrated or isolated after extraction. It is preferably 100 times or less for convenience of operation in the case. The extraction temperature and time depend on the type of solvent used. For example, when water is used as the solvent, the temperature is 10 to 120 ° C., preferably 20 to 100 ° C., 10 minutes to 24 hours, preferably 30 minutes to 5 hours. Can be exemplified.
抽出物は、遠心分離により不溶物を除去した後、濃縮乾固、噴霧乾燥、凍結乾燥等の処理により粉末化してレンコンエキス粉末を得る。得られたレンコンエキス粉末をプロアントシアニジン画分(当該画分には重合度の異なるプロアントシアニジンが含まれ、それらの混合物の含有量は約６％（ｗ／ｗ）と推定される)とし、このプロアントシアニジン画分を、孔径０．１〜２．０μｍのフィルター濾過処理に供し、低分子画分が含まれる透過液を採取し、これをさらに、吸着剤処理法、膜分離法、溶剤分別法などの精製処理に供することにより、低重合度、例えば重合度が３〜５のプロアントシアニジンを主体とするプロアントシアニジンオリゴマーを得ることができる。また、レンコンエキス粉末にはプロアントシアニジン以外のポリフェノール配糖体やエステル体などの夾雑成分が含まれているため、プロアントシアニジンの純度向上のために、上記の精製処理に供する前に、加水分解酵素で処理して予めアグリコンにすることにより、該夾雑成分を除去することが好ましい。 After removing the insoluble matter by centrifugation, the extract is pulverized by treatments such as concentrated dryness, spray drying, and freeze-drying to obtain lotus root extract powder. The obtained lencon extract powder was used as a proanthocyanidin fraction (the fraction contains proanthocyanidins having different degrees of polymerization, and the content of the mixture thereof is estimated to be about 6% (w / w)). The proanthocyanidin fraction is subjected to a filter filtration treatment having a pore size of 0.1 to 2.0 μm, and a permeate containing a low molecular weight fraction is collected, which is further subjected to an adsorbent treatment method, a membrane separation method, and a solvent fractionation method. By subjecting to the purification treatment such as, a proanthocyanidin oligomer containing a low degree of polymerization, for example, a degree of polymerization of 3 to 5 proanthocyanidins as a main component can be obtained. In addition, since the lotus root extract powder contains contaminants such as polyphenol glycosides and esters other than proanthocyanidins, a hydrolyzing enzyme is used before being subjected to the above purification treatment in order to improve the purity of proanthocyanidins. It is preferable to remove the contaminating component by treating with the above to make an aglycone in advance.
精製処理を具体的に説明すると、吸着剤処理法としては、例えば、修飾デキストランゲル（セファデックスＬＨ−２０等）、ポリスチレン系樹脂、ポリアミド、逆相系シリカゲル、親水性ビニルポリマー等の吸着剤を用いてプロアントシアニジン画分を吸着させた後、水洗し、溶離液（極性溶媒）で溶出して分取する方法、膜分離法としては、例えば、逆浸透膜、限外濾過膜を用い分画分子量１，０００〜１００，０００の画分を分取する方法、溶剤分別法としては、例えば、酢酸エチルで分配抽出したのち、酢酸エチル層を脱水処理後、クロロホルムなどの非極性溶媒で分別沈殿させて分取する方法が挙げられる。上記の吸着剤を用いる方法において、吸着画分の溶出に使用する溶離液としては、エタノール、メタノール、プロパノール、アセトン等が挙げられる。吸着画分の主成分は、抽出工程でレンコン節部より抽出された重合度が３〜５のプロアントシアニジンを主体とするプロアントシアニジンオリゴマーである。プロアントシアニジンオリゴマーを含む吸着画分は、さらに濃縮、乾燥、粉末化等の処理を行ってもよい。 To explain the purification treatment in detail, examples of the adsorbent treatment method include adsorbents such as modified dextrangel (Cefadex LH-20, etc.), polystyrene-based resin, polyamide, reverse-phase silica gel, and hydrophilic vinyl polymer. The proanthocyanidin fraction is adsorbed using the method, washed with water, eluted with an eluent (polar solvent) and separated. As the membrane separation method, for example, a back-penetration membrane or an ultrafiltration membrane is used for fractionation. As a method for separating fractions having a molecular weight of 1,000 to 100,000 and a solvent separation method, for example, after partitioning and extracting with ethyl acetate, the ethyl acetate layer is dehydrated and then separated and precipitated with a non-polar solvent such as chloroform. There is a method of letting them sort. In the method using the above-mentioned adsorbent, examples of the eluent used for elution of the adsorbed fraction include ethanol, methanol, propanol, and acetone. The main component of the adsorption fraction is a proanthocyanidin oligomer mainly composed of proanthocyanidins having a degree of polymerization of 3 to 5 extracted from the lotus root node in the extraction step. The adsorbed fraction containing the proanthocyanidin oligomer may be further concentrated, dried, pulverized or the like.
本発明において、プロアントシアニジンの推定重合度は、プロアントシアニジンを含む画分を求核試薬（フロログルシノール等）と反応させて酸加水分解した後、HPLC分析により、各反応生成物の濃度を各反応生成物の標品の検量線から算出し、次に、反応生成物の総モル数をプロアントシアニジンの末端部を構成するフラバン−３−オール(ガロカテキン、エピガロカテキン、カテキン、エピカテキン)の総モル数で除することによって算出することができる。 In the present invention, the estimated degree of polymerization of proanthocyanidins is determined by reacting a fraction containing proanthocyanidins with a nucleating reagent (floroglucinol, etc.) and acid-hydrolyzing, and then analyzing the concentration of each reaction product by HPLC analysis. The total number of moles of the reaction product is calculated from the calibration line of the sample of the reaction product, and then the total number of moles of the reaction product is calculated from the flavan-3-ols (galocathetin, epigalocatecchin, catechin, epicatechin) constituting the terminal part of proanthocyanidins. It can be calculated by dividing by the total number of moles.
（エピガロカテキンガレート）
エピガロカテキンガレート（EGCG）は、緑茶ポリフェノールの主要成分である。本発明に用いるエピガロカテキンガレートは、化学的に合成されたもの、茶葉を含む各種の植物体から抽出・精製されたもの等、特に制限はなく、商業的に入手可能である。茶葉としては、ツバキ科の常緑樹であるチャ（学名:Camellia sinensis(L)O.Kuntze)から得られる茶葉から製茶された煎茶、番茶、ほうじ茶、玉露、てん茶、釜入り茶などの不発酵茶である緑茶、前記茶葉から半発酵又は発酵工程を経て製茶された半発酵茶である烏龍茶(鉄観音、黄金桂、武夷岩茶等)又は発酵茶である紅茶（ダージリン、アッサム、ジャワティー等）などが挙げられる。これらの茶葉を単独で又は２種以上を組み合わせて用いてもよい。なかでも、エピガロカテキンガレートを多く含有する緑茶が好ましい。
(Epigallocatechin gallate)
Epigallocatechin gallate (EGCG) is a major component of green tea polyphenols. The epigallocatechin gallate used in the present invention is not particularly limited and is commercially available, such as those chemically synthesized and those extracted and purified from various plants including tea leaves. As tea leaves, unfermented teas such as roasted tea, bancha, roasted tea, tamaro, tencha, and potted tea made from tea leaves obtained from tea (scientific name: Camellia sinensis (L) O. Kuntze), which is an evergreen tree of the Tsubaki family. Green tea, Karyu tea (Tetsukannon, Kogane Katsura, Budoiwa tea, etc.) or fermented tea (Darjirin, Assam, Java tea, etc.) And so on. These tea leaves may be used alone or in combination of two or more. Of these, green tea containing a large amount of epigallocatechin gallate is preferable.
茶葉からエピガロカテキンガレートを含むカテキン類の抽出は、水若しくは熱水、又は水と有機溶媒の混合溶媒を用いて撹拌抽出（バッチ抽出）、カラム抽出、向流抽出（ドリップ抽出）等の公知の方法により行うことができる。有機溶媒としては、アルコール類、エーテル類、エステル類などを用いることができるが、エタノール、メタノール、アセトン等の水溶性有機溶媒が好ましい。溶媒の使用量については、特に限定はなく、例えば茶葉（乾燥重量）に対し、１０倍以上、好ましくは２０倍以上であればよいが、抽出後に濃縮を行ったり、単離したりする場合の操作の便宜上１００倍以下であることが好ましい。また、抽出温度や時間は、用いる溶媒の種類によるが、例えば、１０〜１００℃、好ましくは３０〜９０℃で、３０分〜２４時間、好ましくは１〜１０時間を例示することができる。また、茶葉抽出物は、抽出した溶液のまま用いてもよいが、必要に応じて、その効果に影響のない範囲で更に、濃縮（有機溶媒、減圧濃縮、膜濃縮などによる濃縮）、希釈、濾過、活性炭等による脱色、脱臭、エタノール沈殿等の処理をして用いてもよい。さらには、抽出した溶液を濃縮乾固、噴霧乾燥、凍結乾燥等の処理を行い、乾燥物として用いてもよい。 Extraction of catechins containing epigallocatechin gallate from tea leaves is known such as stirring extraction (batch extraction), column extraction, countercurrent extraction (drip extraction) using water or hot water, or a mixed solvent of water and an organic solvent. It can be done by the method of. As the organic solvent, alcohols, ethers, esters and the like can be used, but water-soluble organic solvents such as ethanol, methanol and acetone are preferable. The amount of the solvent used is not particularly limited, and may be, for example, 10 times or more, preferably 20 times or more the amount of the tea leaves (dry weight), but the operation for concentration or isolation after extraction. For convenience of the above, it is preferably 100 times or less. The extraction temperature and time depend on the type of solvent used, and for example, 10 to 100 ° C., preferably 30 to 90 ° C., 30 minutes to 24 hours, preferably 1 to 10 hours can be exemplified. The tea leaf extract may be used as it is in the extracted solution, but if necessary, further concentration (concentration by organic solvent, vacuum concentration, membrane concentration, etc.), dilution, etc. is performed within a range that does not affect the effect. It may be used after treatment such as filtration, decolorization with activated carbon, deodorization, ethanol precipitation and the like. Further, the extracted solution may be subjected to treatments such as concentrated drying, spray drying, freeze drying and the like, and used as a dried product.
上記のようにして得られるレンコン節部由来のプロアントシアニジンは、後記実施例で示すように、エピガロカテキンガレートと併用投与することにより、TDI感作鼻過敏症モデルラットの鼻炎症状をそれぞれ単独よりも有意に抑制することができる。よって、レンコン節部由来のプロアントシアニジンは、エピガロカテキンガレートとともに、そのままで、あるいは適当な担体を加え、所望の形態に製剤化して「アレルギー性の鼻炎症状抑制剤」として使用できる。 The lotus root node-derived proanthocyanidins obtained as described above can be administered in combination with epigallocatechin gallate to cause rhinitis symptoms in TDI-sensitized nasal hypersensitivity model rats, respectively, as shown in Examples below. Can also be significantly suppressed. Therefore, the lotus root node-derived proanthocyanidin can be used as an "allergic rhinitis symptom suppressant" as it is or by adding an appropriate carrier together with epigallocatechin gallate.
本発明のアレルギー性の鼻炎症状抑制剤は、レンコン節部由来のプロアントシアニジンとエピガロカテキンガレートの別個の製剤から構成されていてもよく、レンコン節部由来のプロアントシアニジンとエピガロカテキンガレートを混合して含む単一の製剤から構成されていてもよい。 The allergic rhinitis suppressant of the present invention may be composed of separate preparations of lencon node-derived proanthocyanidins and epigallocatechin gallate, or a mixture of lencon node-derived proanthocyanidins and epigallocatechin gallate. It may be composed of a single preparation containing the above.
本発明のアレルギー性の鼻炎症状抑制剤の投与の方法は、レンコン節部由来のプロアントシアニジンとエピガロカテキンガレートを実質上同時に投与する方法であればよく、例えば、レンコン節部由来のプロアントシアニジンとエピガロカテキンガレートを、投与対象に対して完全に同時に投与してもよいし、短時間（好ましくは数分以内）に連続的に投与してもよい。さらに効果を最大限に高めるためには、レンコン節部由来のプロアントシアニジンとエピガロカテキンガレートをあらかじめよく混和した製剤を投与することが好ましい。従って、本発明のアレルギー性の鼻炎症状抑制剤の投与形態には、例えば、（a）レンコン節部由来のプロアントシアニジンとエピガロカテキンガレートとを同時に製剤化して得られる単一の製剤の投与、（b）レンコン節部由来のプロアントシアニジンとエピガロカテキンガレートとを別々に製剤化して得られる２種の製剤の同一投与経路での同時投与、（c）レンコン節部由来のプロアントシアニジンとエピガロカテキンガレートとを別々に製剤化して得られる２種の製剤の同一投与経路での時間差をおいての投与（例えば、レンコン節部由来のプロアントシアニジンとエピガロカテキンガレートの順序での投与、あるいは逆の順序での投与）、（d）レンコン節部由来のプロアントシアニジンとエピガロカテキンガレートとを別々に製剤化して得られる２種の製剤の異なる投与経路での同時投与、（e）レンコン節部由来のプロアントシアニジンとエピガロカテキンガレートとを別々に製剤化して得られる２種の製剤の異なる投与経路での時間差をおいての投与態様が含まれる。 The method for administering the allergic rhinitis suppressant of the present invention may be a method in which proanthocyanidin derived from lencon node and epigallocatechin gallate are administered substantially simultaneously, for example, with proanthocyanidin derived from lencon node. Epigallocatechin gallate may be administered to the subject completely simultaneously or continuously for a short period of time (preferably within a few minutes). In order to further maximize the effect, it is preferable to administer a preparation in which proanthocyanidins derived from the lotus root node and epigallocatechin gallate are well mixed in advance. Therefore, in the administration form of the allergic nasal inflammation inhibitor of the present invention, for example, (a) administration of a single preparation obtained by simultaneously formulating (a) proanthocyanidins derived from lencon nodes and epigalocatechingalate, (B) Simultaneous administration of two preparations obtained by separately formulating lencon node-derived proanthocyanidins and epigalocatecingalate by the same route of administration, (c) lencon node-derived proanthocyanidins and epigallo Administration of two preparations obtained by separately formulating catechin gallate on the same route of administration (for example, administration of proanthocyanidins derived from lencon node and epigalocatechingalate in order, or vice versa) ), (D) Simultaneous administration of two preparations obtained by separately formulating proanthocyanidins derived from lencon node and epigalocatecingalate by different routes of administration, (e) lencon node Includes a time-lagging mode of administration of the two formulations obtained by separately formulating the derived proanthocyanidins and epigalocatecingalates on different routes of administration.
上記製剤中のレンコン節部由来のプロアントシアニジンとエピガロカテキンガレートの含有量は、目的や剤型によって異なり、特に限定されないが、製剤全重量に対して、レンコン節部由来のプロアントシアニジンは固形分換算で、１．０〜３０重量％が好ましく、１．５〜２０重量％がより好ましく、エピガロカテキンガレートは、１．６〜５０重量％が好ましく、２．４〜３５重量％がより好ましい。製剤化における有効成分の添加法については、予め加えておいても、製造途中で添加してもよく、作業性を考えて適宜選択すればよい。 The content of proanthocyanidin derived from lencon node and epigallocatechin gallate in the above-mentioned preparation varies depending on the purpose and the dosage form and is not particularly limited, but the solid content of proanthocyanidin derived from lencon node is based on the total weight of the preparation. In terms of conversion, 1.0 to 30% by weight is preferable, 1.5 to 20% by weight is more preferable, and epigallocatechin gallate is preferably 1.6 to 50% by weight, more preferably 2.4 to 35% by weight. .. The method of adding the active ingredient in the formulation may be added in advance or may be added during the production, and may be appropriately selected in consideration of workability.
本発明のアレルギー性の鼻炎症状抑制剤は、本発明の効果を損なわない範囲で適当な添加物とともに医薬品や飲食品等の組成物に配合することができる。なお、本発明の医薬品には、動物に用いる薬剤、即ち獣医薬も包含されるものとする。 The allergic rhinitis symptom inhibitor of the present invention can be blended with a composition such as a pharmaceutical product or a food or drink together with an appropriate additive as long as the effect of the present invention is not impaired. The pharmaceutical product of the present invention also includes a drug used for animals, that is, a veterinary drug.
本発明の医薬品は、アレルギー性の鼻炎症状の発症を抑制する予防薬として、及び／又は、当該症状を改善又は緩和する治療薬として機能する。 The pharmaceutical product of the present invention functions as a preventive agent for suppressing the onset of allergic rhinitis symptoms and / or as a therapeutic agent for improving or alleviating the symptom.
アレルギー性の鼻炎症状としては、例えば、アレルギー性鼻炎、花粉症、鼻水、鼻づまり、くしゃみ、鼻腔又は咽頭のかゆみ等を挙げることができる。なかでも、鼻過敏症、特に、カルシニューリン／ＮＦＡＴシグナル伝達系を介したＩＬ−９の発現増加によって生じるアレルギー性鼻過敏症が好ましい。ここで、「アレルギー鼻過敏症」とは、反復性のくしゃみ、水性鼻漏、鼻閉（鼻づまり）のうちのいくつかの症状を呈することを特徴とするアレルギー性の疾患を意味する。 Examples of allergic rhinitis symptoms include allergic rhinitis, runny nose, nasal congestion, sneezing, and itching of the nasal cavity or pharynx. Of these, nasal hypersensitivity, particularly allergic nasal hypersensitivity caused by increased expression of IL-9 via the calcineurin / NFAT signaling system, is preferred. Here, "allergic nasal hypersensitivity" means an allergic disease characterized by exhibiting some symptoms of repetitive sneezing, rhinorrhea, and nasal congestion (stuffy nose).
本発明の医薬品の有効成分は、天然物由来であるため、安全性が高く副作用がないため、前述のアレルギー性の鼻炎症状の予防又は改善用医薬として用いる場合、ヒト、マウス、ラット、ウサギ、イヌ、ネコ等の哺乳動物に対して広い範囲の投与量で経口的に又は非経口的に投与することができる。 Since the active ingredient of the drug of the present invention is derived from a natural product, it is highly safe and has no side effects. Therefore, when it is used as a drug for preventing or ameliorating the above-mentioned allergic rhinitis symptoms, humans, mice, rats, rabbits, etc. It can be administered orally or parenterally in a wide range of doses to mammals such as dogs and cats.
本発明の医薬品は、上記アレルギー性の鼻炎症状抑制剤を、薬理学的及び製剤学的に許容しうる添加物と混合し、患部に適用するのに適した製剤形態の各種製剤に製剤化することができる。薬理学的及び製剤学的に許容しうる添加物としては、その剤形、用途に応じて、適宜選択した製剤用基材や担体、賦形剤、希釈剤、結合剤、滑沢剤、コーティング剤、崩壊剤又は崩壊補助剤、安定化剤、保存剤、防腐剤、増量剤、分散剤、湿潤化剤、緩衝剤、溶解剤又は溶解補助剤、等張化剤、ｐＨ調節剤、噴射剤、着色剤、甘味剤、矯味剤、香料等を適宜添加し、公知の種々の方法にて経口又は非経口的に全身又は局所投与することができる各種製剤形態に調製すればよい。本発明の医薬品を上記の各形態で提供する場合、通常当業者に用いられる製法、たとえば日本薬局方の製剤総則［２］製剤各条に示された製法等により製造することができる。 The pharmaceutical product of the present invention mixes the above-mentioned allergic rhinitis symptom inhibitor with pharmacologically and pharmaceutically acceptable additives to formulate various preparations in a preparation form suitable for application to the affected area. be able to. Examples of pharmacologically and pharmaceutically acceptable additives include pharmaceutical substrates and carriers, excipients, diluents, binders, preservatives, and coatings, which are appropriately selected according to the dosage form and application. Agents, disintegrants or disintegrants, stabilizers, preservatives, preservatives, bulking agents, dispersants, wetting agents, buffers, solubilizers or solubilizers, isotonic agents, pH adjusters, propellants , Coloring agents, sweeteners, flavoring agents, fragrances and the like may be appropriately added to prepare various pharmaceutical forms that can be orally or parenterally administered systemically or topically by various known methods. When the pharmaceutical product of the present invention is provided in each of the above forms, it can be produced by a manufacturing method usually used by those skilled in the art, for example, the manufacturing method shown in each article of the general formulation [2] formulation of the Japanese Pharmacopoeia.
経口投与用製剤には、例えば、デンプン、ブドウ糖、ショ糖、果糖、乳糖、ソルビトール、マンニトール、結晶セルロース、炭酸マグネシウム、酸化マグネシウム、リン酸カルシウム、又はデキストリン等の賦形剤；カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、デンプン、又はヒドロキシプロピルセルロース等の崩壊剤又は崩壊補助剤；ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、アラビアゴム、又はゼラチン等の結合剤；ステアリン酸マグネシウム、ステアリン酸カルシウム、又はタルク等の滑沢剤；ヒドロキシプロピルメチルセルロース、白糖、ポリエチレングリコール、又は酸化チタン等のコーティング剤；ワセリン、流動パラフィン、ポリエチレングリコール、ゼラチン、カオリン、グリセリン、精製水、又はハードファット等の基剤などを用いることができるが、これらに限定はされない。 Formulations for oral administration include, for example, excipients such as starch, glucose, sucrose, fructose, lactose, sorbitol, mannitol, crystalline cellulose, magnesium carbonate, magnesium oxide, calcium phosphate, or dextrin; carboxymethyl cellulose, carboxymethyl cellulose calcium, etc. Disintegrants or disintegrants such as starch or hydroxypropyl cellulose; binders such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, gum arabic, or gelatin; lubricants such as magnesium stearate, calcium stearate, or talc. Coating agents such as hydroxypropylmethyl cellulose, sucrose, polyethylene glycol, or titanium oxide; bases such as vaseline, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat can be used. Not limited to these.
本発明の医薬品の形態としては、特に制限されるものではないが、例えば錠剤、糖衣錠剤、カプセル剤、トローチ剤、顆粒剤、散剤、液剤、丸剤、乳剤、シロップ剤、懸濁剤、エリキシル剤などの経口剤、注射剤（例えば、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤）、点滴剤、点鼻剤、点眼剤、座剤、軟膏剤、ローション剤、噴霧剤、経皮吸収剤、経粘膜吸収剤、貼付剤などの非経口剤などが挙げられる。また、使用する際に再溶解させる乾燥生成物にしてもよく、注射用製剤の場合は単位投与量アンプル又は多投与量容器の状態で提供される。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。 The form of the pharmaceutical product of the present invention is not particularly limited, but for example, tablets, sugar-coated tablets, capsules, troches, granules, powders, liquids, pills, emulsions, syrups, suspensions, elixirs. Oral agents such as drugs, injections (for example, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections), drip, nasal drops, eye drops, suppositories, ointments, lotions, Examples thereof include parenteral agents such as sprays, transdermal absorbents, transmucosal absorbents, and patches. It may also be a dried product that is redissolved upon use, and in the case of an injectable product, it is provided in the form of a unit dose ampoule or a multidose container. These formulations can be prepared by conventional means of formulation.
本発明の医薬品の投与量は、疾患の種類、投与対象の年齢、性別、体重、症状、投与経路、投与スケジュール、製剤形態などに応じて適宜決定することができる。例えば、患者（成人）に経口投与する場合には、一日の投与量として、レンコン節部由来のプロアントシアニジンは固形分換算で、患者の体重１ｋｇあたり０．２〜１０ｍｇ、好ましくは０．３〜９ｍｇ、より好ましくは０．４〜８ｍｇ、エピガロカテキンガレートは０．３〜１６ｍｇ、好ましくは０．５〜１４．５ｍｇ、より好ましくは０．６〜１３ｍｇである。 The dose of the drug of the present invention can be appropriately determined according to the type of disease, the age, sex, body weight, symptoms, administration route, administration schedule, formulation form, etc. of the administration target. For example, when orally administered to a patient (adult), the daily dose of proanthocyanidin derived from the lotus root node is 0.2 to 10 mg, preferably 0.3, per kg of the patient's body weight in terms of solid content. ~ 9 mg, more preferably 0.4-8 mg, epigallocatechin gallate 0.3-16 mg, preferably 0.5-14.5 mg, more preferably 0.6-13 mg.
また、本発明のアレルギー性の鼻炎症状抑制剤は、飲食品にも配合できる。本発明の飲食品は、前記のアレルギー性の鼻炎症状を有する患者に、予防又は治療等の目的で使用される機能性食品として利用できる。本発明において、飲食品とは、一般的な飲食品のほか、医薬品以外で健康の維持や増進を目的として摂取できる食品、例えば、健康食品、機能性食品、保健機能食品、又は特別用途食品を含む意味で用いられる。健康食品には、栄養補助食品、健康補助食品、サプリメント等の名称で提供される食品を含む。保健機能食品は食品衛生法又は食品増進法により定義され、特定の保健の効果や栄養成分の機能、疾病リスクの低減などを表示できる、特定保健用食品及び栄養機能食品、ならびに科学的根拠に基づいた機能性について消費者庁長官に届け出た内容を表示できる機能性表示食品が含まれる。また特別用途食品には、特定の対象者や特定の疾患を有する患者に適する旨を表示する病者用食品、高齢者用食品、乳児用食品、妊産婦用食品等が含まれる。飲食品の形態は、食用に適した形態、例えば、固形状、液状、顆粒状、粒状、粉末状、カプセル状、クリーム状、ペースト状のいずれであってもよい。 In addition, the allergic rhinitis symptom inhibitor of the present invention can be blended in foods and drinks. The food and drink of the present invention can be used as a functional food used for the purpose of prevention or treatment for patients with the above-mentioned allergic rhinitis symptoms. In the present invention, foods and drinks include general foods and drinks, as well as foods other than pharmaceuticals that can be ingested for the purpose of maintaining or improving health, such as health foods, functional foods, health functional foods, or special purpose foods. It is used in the meaning of including. Health foods include foods provided under the names of dietary supplements, dietary supplements, supplements and the like. Health functional foods are defined by the Food Sanitation Law or the Food Promotion Law, and are based on specified health foods and nutritionally functional foods that can display specific health effects, functions of nutritional components, reduction of disease risk, etc., and scientific evidence. Includes foods with functional claims that can display the contents notified to the Commissioner of the Consumer Affairs Agency. In addition, special-purpose foods include foods for the sick, foods for the elderly, foods for babies, foods for pregnant women, etc. that indicate that they are suitable for a specific target person or a patient having a specific disease. The form of the food or drink may be any of edible forms such as solid, liquid, granular, granular, powdery, capsule-like, cream-like, and paste-like.
飲食品の種類としては、パン類、麺類、菓子類、乳製品、水産・畜産加工食品、油脂及び油脂加工食品、調味料、各種飲料（清涼飲料、炭酸飲料、栄養飲料、果実飲料、乳飲料など）及び該飲料の濃縮原液及び調整用粉末等が挙げられるが、これらに限定はされない。 The types of foods and drinks include breads, noodles, confectionery, dairy products, processed marine and livestock foods, fats and oils, processed fats and oils, seasonings, and various beverages (soft drinks, carbonated drinks, nutritional drinks, fruit drinks, and milk drinks). Etc.) and concentrated stock solutions of the beverages, preparation powders, etc., but are not limited thereto.
本発明の飲食品は、その種類に応じて通常使用される添加物を適宜配合してもよい。添加物としては、食品衛生上許容されうる添加物であればいずれも使用できるが、例えば、ブドウ糖、ショ糖、果糖、異性化液糖、アスパルテーム、ステビア等の甘味料；クエン酸、リンゴ酸、酒石酸等の酸味料；デキストリン、澱粉等の賦形剤；結合剤、希釈剤、香料、着色料、緩衝剤、増粘剤、ゲル化剤、安定剤、保存剤、乳化剤、分散剤、懸濁化剤、防腐剤などが挙げられる。食品には上記した必須成分の他に、本発明の効果を損なわない範囲で、通常食品に用いられる材料、添加物（例えば賦形剤、崩壊剤、乳化剤、安定剤、滑沢剤、緩衝剤、香料等）を必要に応じて適宜配合することができる。 The food and drink of the present invention may appropriately contain additives that are usually used depending on the type of food and drink. As the additive, any additive that is acceptable in terms of food hygiene can be used, and for example, sweeteners such as starch, sucrose, fructose, isomerized liquid sugar, aspartame, and stevia; citric acid, malic acid, etc. Acidulants such as tartaric acid; excipients such as dextrin and starch; binders, diluents, fragrances, colorants, buffers, thickeners, gelling agents, stabilizers, preservatives, emulsifiers, dispersants, suspensions Examples include agents and preservatives. In addition to the above-mentioned essential ingredients in foods, materials and additives (for example, excipients, disintegrants, emulsifiers, stabilizers, lubricants, buffers) usually used in foods are used as long as the effects of the present invention are not impaired. , Fragrance, etc.) can be appropriately blended as needed.
本発明の飲食品におけるアレルギー性の鼻炎症状抑制剤の含有量は、前記アレルギー性の鼻炎症状の抑制作用を発揮できる量であればよく、飲食品の一般的な摂取量、飲食品の形態、呈味性、嗜好性及びコストなどを考慮して適宜決定すればよいが、例えば飲食品全体に対して０．１〜９９．０重量％となるように配合できる。 The content of the allergic rhinitis symptom inhibitor in the food and drink of the present invention may be an amount capable of exerting the inhibitory effect on the allergic rhinitis symptom, and the general intake amount of the food and drink, the form of the food and drink, and the form of the food and drink. It may be appropriately determined in consideration of taste, taste, cost and the like, and for example, it can be blended so as to be 0.1 to 99.0% by weight based on the whole food and drink.
本発明の飲食品の摂取量は、前記アレルギー性の鼻炎症状の予防や改善を目的として摂取する場合、摂取させる対象の状態、摂取形態、摂食量等により異なるが、患者（成人）１日につき、レンコン節部由来のプロアントシアニジンは固形分換算で、患者の体重１ｋｇあたり０．２〜１０ｍｇ、好ましくは０．３〜９ｍｇ、より好ましくは０．４〜８ｍｇ、エピガロカテキンガレートは０．３〜１６ｍｇ、好ましくは０．５〜１４．５ｍｇ、より好ましくは０．６〜１３ｍｇである。前記の量は１回で摂取してもよいが、数回（２〜４回）に分けて摂取してもよい。本発明の飲食品は、摂取量の目安とするため１回に摂取するべき量の飲食品が、１個の袋やビン等の容器に包装又は充填されていることが好ましい。 When the food or drink of the present invention is ingested for the purpose of preventing or ameliorating the allergic rhinitis symptom, it varies depending on the condition of the subject to be ingested, the ingestion form, the amount of food intake, etc. , Proanthocyanidins derived from rencon nodules, in terms of solid content, 0.2-10 mg, preferably 0.3-9 mg, more preferably 0.4-8 mg, epigalocatecingalate 0.3 per kg body weight of the patient. It is ~ 16 mg, preferably 0.5 ~ 14.5 mg, more preferably 0.6 ~ 13 mg. The above amount may be taken once, or may be taken in several times (2 to 4 times). In the food and drink of the present invention, it is preferable that the amount of food and drink to be ingested at one time is packaged or filled in a container such as one bag or bottle in order to use it as a guideline for the amount of intake.
(実施例１）レンコン節部由来のプロアントシアニジンの製造
（１）レンコンエキス粉末の調製
徳島県産(主に備中種)のレンコン節部793kgをフードカッターで粉砕し、これに水2382kgを加え、95℃以上で1時間撹拌抽出した。抽出液に常温の水1588kgを加え温度を50℃まで低下させた後、0.476kgのプロテアーゼM「アマノ」を添加し、酵素処理を1時間行った。酵素活性失活のために95℃以上に加温し、１００メッシュのフィルターでろ過した後、遠心分離処理により固形分を分離除去し、抽出液を珪藻土濾過処理により清澄化した。得られた濾過液を、減圧濃縮器により710kgまで濃縮した。濃縮液に、濃縮液中の固形分が80％（W/W）、添加するデキストリン固形分が20％（W/W）になるように、デキストリンを添加溶解し、スプレードライ法によって粉末化し、レンコンエキスの粉末75.6kgを回収した。
(Example 1) Production of proanthocyanidin derived from lotus root node (1) Preparation of lotus root extract powder 793 kg of lotus root node produced in Tokushima prefecture (mainly Bichu species) was crushed with a food cutter, and 2382 kg of water was added thereto. Extraction was performed by stirring at 95 ° C. or higher for 1 hour. After adding 1588 kg of room temperature water to the extract to lower the temperature to 50 ° C., 0.476 kg of protease M "Amano" was added, and the enzyme treatment was performed for 1 hour. The mixture was heated to 95 ° C. or higher for inactivation of enzyme activity, filtered through a 100-mesh filter, and then the solid content was separated and removed by centrifugation, and the extract was clarified by diatomaceous earth filtration. The obtained filtrate was concentrated to 710 kg with a vacuum concentrator. Dextrin is added and dissolved in the concentrate so that the solid content in the concentrate is 80% (W / W) and the dextrin solid content to be added is 20% (W / W). 75.6 kg of lotus root extract powder was recovered.
（２）レンコンエキス粉末からのプロアントシアニジンの精製
（１）で調製したレンコンエキス粉末60.89gを0.5M塩化ナトリウム水溶液6000gに溶解した。この溶液を0.2μmフィルターにより濾過した。濾過液を2等分し、精製水で膨潤させたSephadex LH-20（GEヘルスケア・ジャパン株式会社）を充填した50ｘ200mmのカラムに2等分した濾過液を連続して負荷し、プロアントシアニジンを吸着させた。続いてカラムを0.5M塩化ナトリウム水溶液で洗浄し、さらに精製水6000ｇを通液し、塩化ナトリウムを除去した。その後、カラム吸着成分を50％（V/V）アセトン水溶液で溶出した。この溶出液を減圧濃縮器によりアセトンを除去することで濃縮し、凍結乾燥処理により粉末化した。2回のカラム処理により、凍結乾燥粉末2.0085gを回収した。
(2) Purification of proanthocyanidins from lotus root extract powder 60.89 g of lotus root extract powder prepared in (1) was dissolved in 6000 g of 0.5 M sodium chloride aqueous solution. The solution was filtered through a 0.2 μm filter. Divide the filtrate into two equal parts and load the 50x200 mm column filled with Sephadex LH-20 (GE Healthcare Japan Co., Ltd.) inflated with purified water into two equal parts, and load proanthocyanidins into two equal parts. It was adsorbed. Subsequently, the column was washed with a 0.5 M aqueous sodium chloride solution, and 6000 g of purified water was passed through the column to remove sodium chloride. Then, the column adsorption component was eluted with a 50% (V / V) acetone aqueous solution. This eluate was concentrated by removing acetone with a vacuum concentrator, and pulverized by freeze-drying treatment. 2.085 g of lyophilized powder was recovered by two column treatments.
上記の凍結乾燥粉末から1.809gを秤取り、精製水に溶解し、さらにエタノールを添加して粉末濃度が0.25％（W/V）で90％（V/V）エタノール水溶液になるように調製した。このエタノール水溶液を0.45μmのフィルターにて濾過した。濾過液を2等分し、エタノールで膨潤させたSephadex LH-20樹脂を充填した50mm×150 mmのカラムに2等分した濾過液を連続して負荷した。続いてカラムをエタノールで十分に洗浄し、未吸着画分を得た。その後、50％（V/V）アセトン水溶液でカラム吸着成分を溶出し、吸着画分を得た。回収した未吸着画分と吸着画分は、減圧濃縮処理により有機溶媒を除去し、凍結乾燥処理により粉末化し、未吸着画分82.07mg、吸着画分1.7996gを回収した。 1.809 g of the above lyophilized powder was weighed, dissolved in purified water, and ethanol was further added to prepare a 90% (V / V) ethanol aqueous solution at a powder concentration of 0.25% (W / V). .. This aqueous ethanol solution was filtered through a 0.45 μm filter. The filtrate was bisected and the bisected filtrate was continuously loaded onto a 50 mm × 150 mm column filled with ethanol-swelled Sephadex LH-20 resin. Subsequently, the column was thoroughly washed with ethanol to obtain an unadsorbed fraction. Then, the column adsorption component was eluted with a 50% (V / V) acetone aqueous solution to obtain an adsorption fraction. The recovered unadsorbed fraction and the adsorbed fraction were concentrated under reduced pressure to remove the organic solvent, and then lyophilized to be pulverized, and 82.07 mg of the unadsorbed fraction and 1.7996 g of the adsorbed fraction were recovered.
（３）レンコンエキス節部由来のプロアントシアニジンの構造解析
（２）で得られた吸着画分を、メタノールに溶解し、酸性条件下でベンジルメルカプタン（シグマ・アルドリッチ）を作用させチオール分解処理を行った。この分解液をC18カラム（ODS-3 ジーエルサイエンス社製）により分析した結果、9種類の成分（P1〜P9）から構成される成分であることが判明した（図１）。この9種類の成分は、NMR等による分析により、P1はガロカテキン、P2はエピガロカテキン、P3はカテキン、P4はエピカテキン、P5は（+）-ガロカテキンチオール誘導体（ガロカテキンチオール1）、P6は（-）-ガロカテキンチオール誘導体（ガロカテキンチオール2）、P7はエピガロカテキンチオール誘導体、P8はカテキンチオール誘導体、P9はエピカテキン誘導体であることを確認した。各構成成分の濃度を測定し、組成比率及び推定重合度（構成成分の総モル数）/（末端部の総モル数）を分析した。結果を表１に示す。
(3) Structural analysis of proanthocyanidins derived from lotus root extract nodes The adsorbed fraction obtained in (2) is dissolved in methanol and benzyl mercaptan (Sigma-Aldrich) is allowed to act under acidic conditions to perform thiol decomposition treatment. It was. As a result of analyzing this decomposition solution by a C18 column (manufactured by ODS-3 GL Sciences Co., Ltd.), it was found that it is a component composed of 9 kinds of components (P1 to P9) (Fig. 1). By analysis by NMR etc., these 9 kinds of components are P1 for galocatechin, P2 for epigalocatechin, P3 for catechin, P4 for epicatechin, P5 for (+)-galocatechinthiol derivative (galocatecinthiol 1), P6. (-)-Galocatechinthiol derivative (galocatecchinthiol 2), P7 is an epigalocatecchinthiol derivative, P8 is a catechinthiol derivative, and P9 is an epicatechin derivative. The concentration of each component was measured, and the composition ratio and the estimated degree of polymerization (total number of moles of components) / (total number of moles at the end) were analyzed. The results are shown in Table 1.
吸着画分に含まれるプロアントシアニジンは２量体以上の重合体であり、推定重合度は3.8であった。また、吸着画分に含まれるプロアントシアニジン重合体の構造の模式図を図２に示す。 The proanthocyanidin contained in the adsorption fraction was a dimer or higher polymer, and the estimated degree of polymerization was 3.8. Further, FIG. 2 shows a schematic diagram of the structure of the proanthocyanidin polymer contained in the adsorption fraction.
（実施例２）レンコン節部由来のプロアントシアニジンとエピガロカテキンガレートの組み合わせによるアレルギー性の鼻炎症状抑制試験
レンコン節部由来のプロアントシアニジンと精製エピガロカテキンガレート（長良サイエンス株式会社）の組み合わせによるアレルギー性の鼻炎症状抑制効果について鼻過敏症モデルラットを用いて評価した。本試験には、レンコン節部由来のプロアントシアニジンとして、実施例１でレンコンエキス粉末より精製したプロアントシアニジン重合体を含むセファデックス吸着画分を使用した。
(Example 2) Allergic rhinitis symptom suppression test by combination of lencon node-derived proanthocyanidin and epigalocatecingalate Allergy by combination of lencon node-derived proanthocyanidin and purified epigalocatecingalate (Nagara Science Co., Ltd.) The effect of suppressing sexual nasal inflammation was evaluated using a model rat with nasal hypersensitivity. In this test, a sephadex adsorption fraction containing the proanthocyanidin polymer purified from the lotus root extract powder in Example 1 was used as the proanthocyanidin derived from the lotus root node.
１．試験方法
（１）鼻過敏症モデルラットの作成
6週齢Brown-Norway系雄性ラット（200 g、SLC, Hamamatsu, Japan）を使用した。動物は22±1℃の室温で12時間毎の昼夜サイクルで飼育した。TDI(トルエン2,4-ジイソシアン酸)によるラットの感作は、Kitamuraらの方法(Acta Otolaryngol. 2004, 124, 1053-1058)の変法を用いた。すなわち、Brown- Norway系雄性ラットの両側鼻前庭に、極細耳鼻用綿棒を用いて10μLの10% TDI-酢酸エチル溶液を連日5日間×2回塗布した(TDI感作)。その後1週間無処置期間をおいた上で10% TDI-酢酸エチル溶液の鼻前庭塗布にて発作を誘発した。図３にTDI感作鼻過敏症モデルラットの作成スケジュールを示す。また、上記のTDIによる感作と発作誘発と同スケジュールで、TDIに代えて酢酸エチル溶液を塗布した対照モデルラット（陽性対照）を作成した。
1. 1. Test method (1) Creation of nasal hypersensitivity model rat
Six-week-old Brown-Norway male rats (200 g, SLC, Hamamatsu, Japan) were used. Animals were bred at room temperature of 22 ± 1 ° C. in a day / night cycle every 12 hours. For rat sensitization by TDI (
TDI感作鼻過敏症モデルラットに対し、その作成過程の間に一日一回、薬剤として、レンコンエキス粉末由来プロアントシアニジン（LR）（14 mg/kg/dayと28 mg/kg/day）、エピガロカテキンガレート(EGCG)（長良サイエンス株式会社）（45 mg/kg/day）、及びこれらの組み合わせMix14（LR 14mg/kg/day+EGCG 45mg/kg/day、1：3.2）とMix28（LR 28mg/kg/day+EGCG 45mg/kg/day、1：1.6）を、3週間連続で経口投与した。
For TDI sensitized nasal hypersensitivity model rats, once daily during the preparation process, as a drug, proanthocyanidin (LR) derived from lencon extract powder (14 mg / kg / day and 28 mg / kg / day), Epigallocatechin gallate (EGCG) (Nagara Science Co., Ltd.) (45 mg / kg / day), and combinations of these Mix14 (
（２）アレルギー性のくしゃみの回数の評価
経口投与の終了日に、「くしゃみ」の回数を10分間測定し、その回数を記録した。
(2) Evaluation of the number of allergic sneezes The number of "sneezes" was measured for 10 minutes on the end day of oral administration, and the number of times was recorded.
（３）鼻過敏症症状（水溶性鼻漏、鼻の腫れ及び発赤）の評価
経口投与の終了日に、鼻過敏症症状として、「水溶性鼻漏」、「鼻の腫れ及び発赤」を下記表２に示す指標により評価しスコア化した。
(3) Evaluation of nasal hypersensitivity symptoms (water-soluble rhinorrhea, nasal swelling and redness) On the end date of oral administration, "water-soluble rhinorrhea" and "nasal swelling and redness" were listed below as nasal hypersensitivity symptoms. It was evaluated and scored according to the indicators shown in Table 2.
２．試験結果
くしゃみの回数の結果を図４に、鼻過敏症症状（鼻症状スコア）の結果を図５に示す。
アレルギー性のくしゃみ回数は、レンコンエキス粉末由来のプロアントシアニジンとエピガロカテキンガレートとを組み合わせて投与したTDI感作鼻過敏症モデルラット(陽性対照）に対し、28mg/kg投与群(Mix28)においてそれぞれの単独投与群(LR14、LR28、EGCG)に比べて有意に低下した。また低用量投与群の14mg/kg投与群(Mix14)では有意なくしゃみ回数の低下は確認されなかった。また、鼻症状スコアは、TDI（陽性対照）に対して、28mg/kg投与群(Mix28)において有意な低下が認められた。
2. Test Results The results of the number of sneezes are shown in FIG. 4, and the results of nasal hypersensitivity symptoms (nasal symptom score) are shown in FIG.
The number of allergic sneezes was determined in the 28 mg / kg administration group (Mix28) for TDI sensitized nasal hypersensitivity model rats (positive control) administered in combination with proanthocyanidins derived from lotus root extract powder and epigallocatechin gallate. It was significantly lower than that of the single administration group (LR14, LR28, EGCG). In addition, no significant decrease in the number of sneezes was confirmed in the 14 mg / kg administration group (Mix 14) of the low dose administration group. In addition, the nasal symptom score was significantly decreased in the 28 mg / kg administration group (Mix 28) with respect to TDI (positive control).
これらの結果から、レンコンエキス粉末由来プロアントシアニジン（LR）とエピガロカテキンガレート（EGCG）を特定の割合で組み合わせることにより、アレルギー性のくしゃみ症状を抑制することが判明した。 From these results, it was found that the combination of lotus root extract powder-derived proanthocyanidin (LR) and epigallocatechin gallate (EGCG) in a specific ratio suppresses allergic sneezing symptoms.
本発明は、アレルギー性の鼻炎症状、特にくしゃみ症状を予防又は改善するための医薬品、健康食品や機能性食品などの飲食品の製造分野において利用できる。 The present invention can be used in the field of manufacturing foods and drinks such as pharmaceuticals, health foods and functional foods for preventing or ameliorating allergic rhinitis symptoms, particularly sneezing symptoms.
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