JP2005179246A - Allergic hypersensitivity inhibitor - Google Patents

Allergic hypersensitivity inhibitor Download PDF

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JP2005179246A
JP2005179246A JP2003421507A JP2003421507A JP2005179246A JP 2005179246 A JP2005179246 A JP 2005179246A JP 2003421507 A JP2003421507 A JP 2003421507A JP 2003421507 A JP2003421507 A JP 2003421507A JP 2005179246 A JP2005179246 A JP 2005179246A
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allergic
allergic hypersensitivity
honey
hypersensitivity
inhibitor
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Haruki Shibata
治樹 柴田
Shuichi Hashizume
秀一 橋爪
Masatoshi Kato
正俊 加藤
Shigekatsu Kono
茂勝 河野
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Morinaga and Co Ltd
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<P>PROBLEM TO BE SOLVED: To obtain a novel drug or drink which ameliorates many symptoms observed in allergic hypersensitivity. <P>SOLUTION: The subject allergic hypersensitivity inhibitor contains molasses as an active ingredient. This inhibitor contains honey originated from Chinese milk vetches (Astragalus sinicus L.). <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

本発明は、アレルギー物質の暴露により過敏症となったアレルギー性過敏症の抑制剤に関する。   The present invention relates to an inhibitor of allergic hypersensitivity that has become hypersensitive by exposure to allergens.

花粉、窒素酸化物、ハウスダスト等の様々なアレルゲンによって引き起こされるアレルギー疾患は、現在日本の人口の約20%以上が罹患していると言われるほどに、国民的な健康問題の一つとなっている。特に、発症した場合の症状がいわゆる鼻詰まり、鼻汁や涙の亢進、眼ならびに鼻粘膜の炎症といった、日常生活に支障をきたす大変に煩わしいものであり、かかる症状の緩和剤の開発が盛んに行われている。   Allergic diseases caused by various allergens such as pollen, nitrogen oxides, and house dust have become one of the national health problems as it is said that more than 20% of the Japanese population is currently affected. Yes. In particular, the symptoms at the onset are so-called nasal congestion, increased nasal discharge and tears, inflammation of the eyes and nasal mucosa, and are very troublesome to interfere with daily life. It has been broken.

このアレルギー性疾患に罹患する患者の中には、繰り返しアレルゲンに暴露されることにより、アレルゲンに対する即時性及び遅発性の反応性が増強され、さらに非特異的な刺激に対する過剰反応をも示すことが知られている。この様な症状はアレルギー性過敏症と言われる。   Some patients suffering from this allergic disease have increased immediate and delayed responsiveness to allergens by repeated exposure to allergens, and also exhibit excessive responses to nonspecific stimuli. It has been known. Such symptoms are called allergic hypersensitivity.

このアレルギー性過敏症は、繰り返し暴露されるアレルゲンのみならず、他のアレルゲンによっても引き起こされる。これらのアレルゲンの全てを完全に回避することは、事実上不可能である。従って、アレルギー性過敏症に対する対処法としては、このアレルギー反応を抑制する物質の投与に頼らざるを得ないのが実情である。   This allergic hypersensitivity is caused not only by repeatedly exposed allergens but also by other allergens. It is virtually impossible to avoid all of these allergens completely. Therefore, as a countermeasure against allergic hypersensitivity, the fact is that the administration of a substance that suppresses this allergic reaction must be relied upon.

この様な物質として、マレイン酸クロルフェニラミン、マレイン酸カルビノキサミンなどの抗ヒスタミン剤が広く用いられている。しかしこれらは同時に生体の免疫反応を抑制する機能を持つ他、服用時に眠くなるなどの副作用もある。従って、天然成分に由来する、より安全な抗アレルギー性過敏症物質が待望されていた。   As such substances, antihistamines such as chlorpheniramine maleate and carbinoxamine maleate are widely used. However, they have the function of suppressing the immune response of the living body, and also have side effects such as sleepiness when taken. Therefore, a safer antiallergic hypersensitivity substance derived from natural ingredients has been awaited.

本発明者らは、アレルギー性過敏症の症状を呈するモデル動物を利用し、同症状に対して有効な物質の探索を試みた結果、蜂蜜に同症状を緩和する効果を見出し、本発明を完成した。   The inventors of the present invention have used a model animal exhibiting symptoms of allergic hypersensitivity, and as a result of trying to search for an effective substance for the same symptoms, found the effect of alleviating the same symptoms on honey and completed the present invention. did.

すなわち本発明は、蜂蜜を有効成分とするアレルギー性過敏症抑制剤に関する。特に、レンゲ草由来の蜂蜜または脱蛋白蜂蜜を有効成分とするアレルギー性過敏症抑制剤に関する。   That is, the present invention relates to an allergic hypersensitivity inhibitor containing honey as an active ingredient. In particular, the present invention relates to an allergic hypersensitivity inhibitor containing honey derived from astragalus grass or deproteinized honey as an active ingredient.

本発明は、蜂蜜という安全性の確立された食品を摂取することにより、副作用を伴うことなく、アレルギー性過敏症の症状を緩和することが出来る。   The present invention can relieve symptoms of allergic hypersensitivity without side effects by ingesting honey, a food with established safety.

本発明において使用しうる蜂蜜としては、各種蜜由来のものを用いることが出来るが、主にレンゲ植物、特にレンゲ草(Astragalus sinicus L.)の花を蜜源とした養蜂により得られる蜂蜜の利用が好ましい。また、脱蛋白質などの簡易な精製処理が施された蜂蜜の利用も好適である。   As the honey that can be used in the present invention, those derived from various honeys can be used. However, the use of honey obtained by beekeeping mainly using the flowers of astragalus plants, particularly the flowers of astragalus grass (Astragalus sinicus L.). preferable. In addition, use of honey that has been subjected to a simple purification treatment such as deproteinization is also suitable.

なお、事実上、養蜂に際して蜜源となる植物を厳格に制限することは不可能であるから、レンゲ草を主要蜜源として養蜂を行った場合でも、他の植物由来の花蜜の混入を完全に防止することは出来ない。しかしながら、そのような場合であっても、レンゲ植物を主要蜜源とした養蜂により採集され、現に当該レンゲ植物由来の花蜜が実質上主要な成分となる蜂蜜を含む組成物であれば、それらはアレルギー性過敏症を抑制することができ、当然に本発明にいうアレルギー性過敏症抑制剤として利用することができる。   In fact, it is impossible to strictly limit the plants that serve as nectar for beekeeping. Therefore, even if beekeeping is performed using astragalus grass as the main nectar source, the contamination of nectar from other plants is completely prevented. I can't do that. However, even in such a case, if the composition contains honey collected by beekeeping using astragalus plants as the main nectar and the nectar derived from the astragalus plants is substantially the main ingredient, they are allergic. It can be used as an allergic hypersensitivity inhibitor according to the present invention.

投与あるいは服用すべき蜂蜜の量は、適用対象となるアレルギー性過敏症患者の年齢、性別、症状の重篤度等、および投与形態や投与方法に基づいて、個別に決定されるべきものである。   The amount of honey to be administered or taken should be determined individually based on the age, sex, severity of symptoms, etc. of the allergic hypersensitivity patient to be applied, and the dosage form and method of administration. .

蜂蜜は、採取されたそのままの形態のほか、例えば当業者に公知の方法により殺菌、乾燥、或いは精製、例えば脱蛋白処理などを行ったものであっても差し支えない。   In addition to the collected honey, the honey may be sterilized, dried, or purified by, for example, a method known to those skilled in the art, such as deproteinization.

本発明の抑制剤は、例えば、医薬や食品の形態として用いることができる。医薬品の場合、そのような組成物は、特に、経口投与に適している。本発明の組成物を医薬組成物として臨床的に用いる場合は、その投与形態にあわせて薬学的に許容される添加剤を加え各種製剤とすることができる。該薬学的に許容される添加剤としては、製剤分野において通常用いられる各種の添加剤が使用可能であり、例えば、ゼラチン、乳糖、白糖、酸化チタン、澱粉、結晶セルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、コーンスターチ、マイクロクリスタリンワックス、白色ワセリン、メタケイ酸アルミン酸マグネシウム、無水リン酸カルシウム、クエン酸、クエン酸三ナトリウム、ヒドロキシプロピルセルロース、ソルビトール、ソルビタン脂肪酸エステル、ポリソルベート、ショ糖脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリビニルピロリドン、ステアリン酸マグネシウム、軽質無水ケイ酸、タルク、植物油、ベンジルアルコール、アラビアガム、プロピレングリコール、ポリアルキレングリコール、シクロデキストリンまたはヒドロキシプロピルシクロデキストリン等が挙げられる。これらの添加剤との混合物として製剤化される剤形としては、例えば、錠剤、カプセル剤、顆粒剤等の固形製剤;または例えばシロップ剤等の液体製剤が挙げられ、これらは、製剤分野における通常の方法によって調製することができる。また、本発明の抑制剤は、種々の食品、例えば、固体、液体、ゾル、ゲル状食品等に任意に配合することも可能である。該配合は、当該技術分野で公知の任意の製造方法によって行うことができ、例えば、キャラメル、ビスケット或いはチョコレート等の固体食品;飲料等の液体食品;あずき粥等のレトルト食品等に原料として、あるいは、別途、容易に配合することができる。特に日常生活における簡便な使用の観点からは、食品の形態であることが望ましい。   The inhibitor of the present invention can be used, for example, as a pharmaceutical or food form. In the case of pharmaceuticals, such compositions are particularly suitable for oral administration. When the composition of the present invention is clinically used as a pharmaceutical composition, various preparations can be prepared by adding pharmaceutically acceptable additives according to the administration form. As the pharmaceutically acceptable additive, various additives generally used in the pharmaceutical field can be used. For example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose , Corn starch, microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil , Polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol Lumpur, cyclodextrin or hydroxypropyl cyclodextrin and the like. Examples of the dosage form formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules and the like; or liquid preparations such as syrups, which are usually used in the pharmaceutical field. It can be prepared by the method. Moreover, the inhibitor of this invention can also be arbitrarily mix | blended with various foodstuffs, for example, solid, liquid, sol, a gel-like foodstuff, etc. The blending can be performed by any production method known in the art, for example, a solid food such as caramel, biscuit or chocolate; a liquid food such as beverage; a retort food such as azuki bean as a raw material, or It can be easily blended separately. In particular, from the viewpoint of simple use in daily life, it is desirable to be in the form of food.

又、上記の抑制剤は、アレルギー性過敏症を抑制する食品添加物としての使用にも供することができる。当該食品添加物として使用する場合は、当業者にとって周知の方法を用いて、例えば、デキストリン、コーンスターチ、乳糖等の各種の賦型剤類や乳化剤等の副原料と共に、本発明のレンゲ草由来の蜂蜜または脱蛋白蜂蜜を混合またはカプセル化等をすることにより製造することができる。また、所望により、保存料や香料等を添加してもよい。   Moreover, said inhibitor can also be used for the use as a food additive which suppresses allergic hypersensitivity. When used as the food additive, using methods well known to those skilled in the art, for example, various excipients such as dextrin, corn starch, and lactose, and auxiliary materials such as emulsifiers, and the like derived from the astragalus grass of the present invention. It can be produced by mixing or encapsulating honey or deproteinized honey. Moreover, you may add a preservative, a fragrance | flavor, etc. if desired.

以下、本発明を更に非限定的な実施例によって詳細に説明する   The invention will now be described in more detail by way of non-limiting examples.

中国レンゲから採集した蜂蜜(秋田屋本店)20mLを20mLの水を用いて2倍に希釈して、液状のアレルギー性過敏症抑制剤を調製した。   A liquid allergic hypersensitivity inhibitor was prepared by diluting 20 mL of honey (Akitaya Honten) collected from Chinese astragalus with 20 mL of water.

脱蛋白蜂蜜(秋田屋本店)20mLを20mLの水を用いて2倍に希釈して、脱蛋白蜂蜜を含む液状のアレルギー性過敏症抑制剤を調製した。
<試験例>
1)アレルギー性鼻過敏症モデル動物の構築
i)水酸化アルミニウム(Al(OH))を含むスギ花粉抽出液の調製
10gのスギ花粉を100mLのリン酸緩衝生理食塩水(PBS)に加え、48時間4℃にて懸濁したのち、3000rpm、15分間遠心分離を行い上澄を回収し、蛋白濃度が200μg/mLとなるようにPBSで希釈した。
20 mL of deproteinized honey (Akitaya Honten) was diluted twice with 20 mL of water to prepare a liquid allergic hypersensitivity inhibitor containing deproteinized honey.
<Test example>
1) Construction of allergic nasal hypersensitivity model animal i) Preparation of cedar pollen extract containing aluminum hydroxide (Al (OH) 3 ) 10 g of cedar pollen was added to 100 mL of phosphate buffered saline (PBS), After suspending at 4 ° C. for 48 hours, the supernatant was collected by centrifugation at 3000 rpm for 15 minutes, and diluted with PBS so that the protein concentration was 200 μg / mL.

200mg/mLのAl(OH)水溶液を調製し、この水溶液1mLに塩化ナトリウム9mgを加え、さらに上記の希釈したスギ花粉抽出液1mLを氷中で攪拌しながら滴下し、Al(OH)を含むスギ花粉抽出液を調製した。
ii)モルモットへのスギ花粉による感作
i)で調製したスギ花粉抽出液をモルモットの鼻腔内に、1日2回、3μLずつ滴下し、7日間連続して投与した。さらに最終感作より1週間に1回スギ花粉を片鼻に3mgずつ吸入させて反応惹起を行った。この吸入によりモルモットにアレルギー性鼻炎を発症させることができる。さらに、スギ花粉による反復反応惹起を繰り返すと、反応惹起4回目以降で惹起後30分〜2時間(即時性)ならびに惹起後4〜6時間(遅発性)にそれぞれ鼻腔抵抗の上昇のピークが再現性よく観察された。また、ヒスタミンを鼻腔に投与しても濃度依存的な鼻腔抵抗の上昇が見られ、非感作群に対して1000倍以上の低濃度から反応性を示すようになった。この様な二相性のアレルギー反応を示すモルモットを、アレルギー性鼻過敏症モデル動物として使用した。
iii)モデル動物に対する本発明のアレルギー性過敏症抑制剤の効果
スギ花粉による感作を行っていないモルモットに常用餌のみを与える群A、ii)で用意したモルモットに常用餌とアレルギー性過敏症抑制剤のかわりに水を4mL/kg体重/回/日与える群B、ii)で用意したモルモットに常用餌と実施例1で調製したアレルギー性過敏症抑制剤を4mL/kg体重/回/日与える群C、ii)で用意したモルモットに常用餌と実施例2で調製したアレルギー性過敏症抑制剤を4mL/kg体重/回/日与える群D、計4群を用意し、16日間連続してそれぞれの餌と水又はアレルギー性過敏症抑制剤を経口投与した。
A 200 mg / mL aqueous solution of Al (OH) 3 was prepared, 9 mg of sodium chloride was added to 1 mL of this aqueous solution, and 1 mL of the above diluted cedar pollen extract was added dropwise with stirring in ice, and Al (OH) 3 was added. A cedar pollen extract containing was prepared.
ii) Sensitization of guinea pigs with cedar pollen The cedar pollen extract prepared in i) was dropped into the nasal cavity of the guinea pig twice a day at a dose of 3 μL and administered continuously for 7 days. Furthermore, cedar pollen was inhaled into one nose at a rate of 3 mg once a week from the final sensitization to elicit a reaction. This inhalation can cause allergic rhinitis in guinea pigs. Furthermore, when repeated reaction induction by cedar pollen is repeated, the rise of nasal resistance increases after the 4th reaction induction from 30 minutes to 2 hours (immediate) and from 4 to 6 hours (late) after induction. Observed with good reproducibility. In addition, even when histamine was administered to the nasal cavity, the concentration-dependent increase in nasal resistance was observed, and the non-sensitized group showed reactivity from a low concentration of 1000 times or more. A guinea pig showing such a biphasic allergic reaction was used as a model animal for allergic nasal hypersensitivity.
iii) Effect of the allergic hypersensitivity inhibitor of the present invention on model animals Group A, which gives only regular diet to guinea pigs not sensitized with cedar pollen, and suppresses regular diet and allergic hypersensitivity to guinea pigs prepared in ii) Group B, ii) giving 4 mL / kg body weight / times / day of water in place of the agent, giving 4 mL / kg body weight / times / day of the allergic hypersensitivity inhibitor prepared in Example 1 to the guinea pigs prepared in ii) Prepare a total of 4 groups, 4 groups / group D, giving 4 mL / kg body weight / times / day of the allergic hypersensitivity inhibitor prepared in Example 2 to the guinea pigs prepared in Group C, ii) for 16 consecutive days Each bait and water or allergic hypersensitivity inhibitor was orally administered.

水またはアレルギー性過敏症抑制剤の最後の投与から1時間後にコイロトリエンD4(LTD4)を点鼻投与し、鼻腔抵抗の変化をモニターした。その結果を図1に示す。   One hour after the last administration of water or the allergic hypersensitivity inhibitor, Koirotriene D4 (LTD4) was administered nasally, and changes in nasal resistance were monitored. The result is shown in FIG.

アレルギー症状を呈さない群A(○印)では、LTD4の投与量を上げても鼻腔抵抗が変化しないのに対して、スギ花粉でアレルギー症状を示す群B(●印)ではLTD4の投与量に依存して鼻腔抵抗が増大した。一方、この様なモルモットに16日間実施例1で調製したアレルギー性過敏症抑制剤を投与した群C(□印)、実施例2で調製したアレルギー性過敏症抑制剤を投与した群D(■印)は、群Aとほぼ同様の結果を示し、投与した本発明のアレルギー性過敏症抑制剤により、LTD4の投与によるアレルギー性鼻過敏症発症の抑制が観察された。   In group A (marked with ○) that does not show allergic symptoms, nasal resistance does not change even if the dose of LTD4 is increased, whereas in group B (marked with ●) that shows allergic symptoms with cedar pollen, the dose of LTD4 is increased. In dependence, nasal resistance increased. On the other hand, group C (□ mark) in which the allergic hypersensitivity inhibitor prepared in Example 1 was administered to such guinea pigs for 16 days, and group D (■ in which allergic hypersensitivity inhibitor prepared in Example 2 was administered). (Symbols) showed almost the same results as those of Group A, and the administration of the allergic hypersensitivity inhibitor of the present invention was observed to suppress the development of allergic nasal hypersensitivity by the administration of LTD4.

一方、同条件下でスギ花粉を感作させることにより観察される即時性のくしゃみの回数は、実施例1、2で調製したアレルギー性過敏症抑制剤を事前に投与した場合でも有意な抑制は認められなかった(図2)。従って、本発明のアレルギー性過敏症抑制剤は、IgEに対する作用とは異なる機構により効果を発揮しているものと推定される。   On the other hand, the number of immediate sneezes observed by sensitizing cedar pollen under the same conditions is not significantly suppressed even when the allergic hypersensitivity inhibitor prepared in Examples 1 and 2 is administered in advance. It was not recognized (FIG. 2). Therefore, it is presumed that the allergic hypersensitivity inhibitor of the present invention exhibits an effect by a mechanism different from the action on IgE.

図1は、アレルギー性鼻過敏症に対する本発明の抑制効果を示すグラフである。FIG. 1 is a graph showing the inhibitory effect of the present invention on allergic nasal hypersensitivity. 図2は、スギ花粉によるアレルギー反応惹起後に確認されるくしゃみの回数に対する本発明の影響を示すグラフである。FIG. 2 is a graph showing the effect of the present invention on the number of sneezing confirmed after induction of an allergic reaction with cedar pollen.

Claims (5)

蜂蜜を有効成分とするアレルギー性過敏症抑制剤。   An allergic hypersensitivity inhibitor containing honey as an active ingredient. 蜂蜜がレンゲ草(Astragalus sinicus L.)由来である、請求項1に記載のアレルギー性過敏症抑制剤。   2. The allergic hypersensitivity inhibitor according to claim 1, wherein the honey is derived from astragalus sinicus L .. 蜂蜜が脱蛋白蜂蜜である、請求項1または2に記載のアレルギー性過敏症抑制剤。   The allergic hypersensitivity inhibitor according to claim 1 or 2, wherein the honey is deproteinized honey. アレルギー性過敏症がアレルギー性鼻過敏症である、請求項1から3のいずれかに記載のアレルギー性過敏症抑制剤。   The allergic hypersensitivity inhibitor according to any one of claims 1 to 3, wherein the allergic hypersensitivity is allergic nasal hypersensitivity. 食品の形態である、請求項1〜4のいずれかに記載のアレルギー性過敏症抑制剤。   The allergic hypersensitivity inhibitor according to any one of claims 1 to 4, which is in the form of food.
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