JP6882730B2 - Immunoregulatory composition containing Cirsium maritimum extract - Google Patents
Immunoregulatory composition containing Cirsium maritimum extract Download PDFInfo
- Publication number
- JP6882730B2 JP6882730B2 JP2016226161A JP2016226161A JP6882730B2 JP 6882730 B2 JP6882730 B2 JP 6882730B2 JP 2016226161 A JP2016226161 A JP 2016226161A JP 2016226161 A JP2016226161 A JP 2016226161A JP 6882730 B2 JP6882730 B2 JP 6882730B2
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- Prior art keywords
- cirsium
- maritimum
- cirsium maritimum
- extract
- composition
- 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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Description
本発明は、アレルギー予防及び/又は改善効果などの免疫調節機能を有し、飲食料品、医薬品、又は医薬部外品として有用な天然由来物に関する。 The present invention relates to a naturally derived product which has an immunomodulatory function such as an allergy prevention and / or ameliorating effect and is useful as a food or drink, a drug, or a quasi drug.
現在、日本国民の約3分の1が何らかのアレルギー症状を発症しているといわれている。アレルギーは発症機構により、即時型アレルギー(I型)から遅延型アレルギー(IV型)まで分類されるが、近年特に、花粉症、気管支喘息及びアトピー性皮膚炎などに代表される即時型アレルギーの症例数が急増している。I型アレルギー反応には肥満細胞や好塩基球が関わっており、細胞表面に結合しているIgEが抗原によって活性化されることで下流へとシグナルが伝達され、ヒスタミンやタンパク質分解酵素などの細胞内顆粒内容物が放出される。この現象を脱顆粒と呼ぶ。このようなI型アレルギーの発症を抑えるためには、肥満細胞や好塩基球からの脱顆粒の抑制が重要である。 Currently, it is said that about one-third of the Japanese people develop some allergic symptoms. Allergies are classified from immediate type allergy (type I) to delayed type allergy (type IV) according to the onset mechanism, but in recent years, cases of immediate type allergy represented by pollinosis, bronchial asthma, atopic dermatitis, etc. The number is skyrocketing. Mast cells and basophils are involved in the type I allergic reaction, and IgE bound to the cell surface is activated by an antigen to transmit a signal downstream, and cells such as histamine and proteolytic enzymes The contents of the inner granules are released. This phenomenon is called degranulation. In order to suppress the onset of such type I allergy, it is important to suppress degranulation from mast cells and basophils.
また、腸管免疫とアレルギーに強い関係性があることが近年の研究から明らかとなっている。特に腸管の代表的なリンパ組織であるパイエル板から分泌されるIgAは、粘膜面への細菌やウイルスの付着防止、外来抗原を捕捉して体外に排出する異物排除、異種タンパク質によるアレルギー発症の予防などの作用を有しており、粘膜免疫機能において重要な働きを担っている。よって、IgAの分泌を促進することは、粘膜免疫機能を増強させ、感染症やアレルギー疾患を予防するなどの効果が期待できるため、IgA分泌促進作用を有する食品素材の開発が望まれている。 In addition, recent studies have revealed that there is a strong relationship between intestinal immunity and allergies. In particular, IgA secreted from Peyer's patches, which is a typical lymphoid tissue of the intestinal tract, prevents the adhesion of bacteria and viruses to the mucosal surface, eliminates foreign substances that capture foreign antigens and excrete them from the body, and prevents the onset of allergies due to foreign proteins. It has such actions and plays an important role in mucosal immune function. Therefore, promoting IgA secretion can be expected to have effects such as enhancing mucosal immune function and preventing infectious diseases and allergic diseases. Therefore, development of a food material having an IgA secretion promoting action is desired.
これまでに、茶カテキン、シソエキス、及び甜茶などからアレルギー抑制成分が見いだされ、これらの機能を付与した食品を毎日摂取することによって、アレルギー症状の軽減だけでなく、アレルギー体質の改善につなげることが期待されている(非特許文献1〜3)。
So far, allergy-suppressing ingredients have been found in tea catechin, perilla extract, and sweet tea, and daily intake of foods with these functions can not only reduce allergic symptoms but also improve allergic constitution. It is expected (
安全性が高く、有効な免疫調節用組成物の開発が望まれている。 It is desired to develop a highly safe and effective immunomodulatory composition.
そこで本発明の目的は、天然物に由来し、安全性が高く、飲食料品への適用が可能である、優れた免疫調節用組成物を提供することにある。 Therefore, an object of the present invention is to provide an excellent immunomodulatory composition derived from a natural product, which is highly safe and can be applied to foods and drinks.
本発明者らは、前記課題を解決すべく鋭意検討を重ねた結果、キク科アザミ属ハマアザミ、ハマアザミ抽出物、又はハマアザミ抽出物の精製物が、アレルギー予防及び/又は改善効果や粘膜免疫賦活作用などの免疫調節機能を有することを見出し、本発明を完成するに至った。 As a result of diligent studies to solve the above problems, the present inventors have found that Cirsium maritimum, Cirsium maritimum extract, or purified product of Cirsium maritimum extract has an allergy prevention and / or ameliorating effect and a mucosal immunostimulatory effect. We have found that it has an immunomodulatory function such as, and have completed the present invention.
すなわち、本発明は、
[1]ハマアザミ又はハマアザミ抽出物を含有する免疫調節用組成物;
[2]アレルギー予防及び/又は改善用組成物である、項1記載の免疫調節用組成物;
[3]粘膜免疫賦活用組成物である、項1記載の免疫調節用組成物;
[4]上記ハマアザミ又はハマアザミ抽出物が、シルシマリンおよび/またはシルシマリチンを含む、項1〜3のいずれか1項に記載の免疫調節用組成物;
[5]上記ハマアザミが、ハマアザミの全草又は葉部、茎部、根部、種子、及び花部からなる群より選択される1又は2以上に由来する、項1〜4のいずれか1項に記載の免疫調節用組成物;
[6]上記ハマアザミ抽出物が、ハマアザミの酢酸エチル抽出物である、項1〜5のいずれか1項に記載の免疫調節用組成物。
[7]シルシマリンおよび/またはシルシマリチンを含有する、免疫調節用組成物。
[8]経口、静脈内注射、吸入又は経皮により投与される、項1〜7のいずれか1項に記載の免疫調節用組成物;
[9]飲食料品、医薬部外品、又は医薬品である、請求項1〜8のいずれか1項に記載の免疫調節用組成物;
[10]前記飲食料品が、茶飲料である、項1〜9のいずれか1項に記載の免疫調節用組成物;
に関する。
That is, the present invention
[1] An immunomodulatory composition containing Cirsium maritimum or Cirsium maritimum extract;
[2] The immunomodulatory composition according to
[3] The immunomodulatory composition according to
[4] The immunomodulatory composition according to any one of
[5]
[6] The composition for immunoregulation according to any one of
[7] An immunomodulatory composition containing silcymarin and / or silcimarintin.
[8] The immunomodulatory composition according to any one of
[9] The immunomodulatory composition according to any one of
[10] The immunomodulatory composition according to any one of
Regarding.
本発明の免疫調節用組成物は、天然由来のハマアザミから得られる有効成分を含有しており、安全性が高い。このような安全な免疫調節用組成物は、例えば抗アレルギー効果などを有しながら副作用の少ない飲食料品、医薬品又は医薬部外品に利用することができる。 The immunomodulatory composition of the present invention contains an active ingredient obtained from naturally occurring Cirsium maritimum and is highly safe. Such a safe immunomodulatory composition can be used for foods and drinks, pharmaceuticals or quasi-drugs having, for example, an antiallergic effect and few side effects.
本発明の免疫調節用組成物は、キク科アザミ属ハマアザミ(Cirsium maritimum Makino)又はその抽出物を含有する。ここで、抽出物には、単一成分または単一成分に近い画分にまで精製された精製物も含まれる。 The immunomodulatory composition of the present invention contains Cirsium maritimum Makino of the Asteraceae family or an extract thereof. Here, the extract also includes a purified product that has been purified to a single component or a fraction close to a single component.
ハマアザミは、温帯の海岸に生育する多年草であり、日本では、千葉県以南以西で九州まで分布している。砂地、砂礫地、草原に多く見られる。根は、食用として用いられている。 Cirsium maritimum is a perennial plant that grows on temperate coasts. In Japan, it is distributed west of Chiba prefecture to Kyushu. It is often found in sandy areas, gravel areas, and grasslands. The roots are used for food.
本発明において、ハマアザミをそのまま用いることができるが、その場合は、その調製方法が特に制限されるものではない。ハマアザミは、ハマアザミの全草又は一部、特に葉部、茎部、根部、種子、花部を別々に1種類ずつ又はそれらの2以上の組合せを乾燥物として、あるいはその乾燥物を適宜裁断し、破砕又は粉砕した粉末として調製することができる。ハマアザミの乾燥物又はその粉砕物は、例えば、熱湯で煮出して用いることができる。ハマアザミの破砕物又は粉砕物は、必要により焙煎して調製することもできる。 In the present invention, Cirsium maritimum can be used as it is, but in that case, the preparation method thereof is not particularly limited. Cirsium maritimum is a whole plant or part of Cirsium maritimum, especially leaves, stems, roots, seeds, and flowers, one type at a time or a combination of two or more of them as a dried product, or the dried product is cut as appropriate. , Can be prepared as a crushed or crushed powder. The dried product of Cirsium maritimum or the crushed product thereof can be used, for example, by boiling in boiling water. The crushed or crushed Cirsium maritimum can also be prepared by roasting if necessary.
ハマアザミの焙煎は、回転式焙煎機等を用いた公知の方法により行われ、特に限定はされない。焙煎温度は、例えば、150〜400℃とすることができ、180〜350℃が好ましく、200〜330℃がより好ましい。焙煎時間は、焙煎温度等の条件により適宜決定されるが、例えば、5〜120分とすることができ、10〜90分が好ましく、15〜60分がより好ましい。 The roasting of Cirsium maritimum is carried out by a known method using a rotary roasting machine or the like, and is not particularly limited. The roasting temperature can be, for example, 150 to 400 ° C, preferably 180 to 350 ° C, more preferably 200 to 330 ° C. The roasting time is appropriately determined depending on the conditions such as the roasting temperature, but can be, for example, 5 to 120 minutes, preferably 10 to 90 minutes, more preferably 15 to 60 minutes.
本発明において、ハマアザミ抽出物を用いる場合は、その抽出方法は特に制限されるものではない。ハマアザミ抽出物は、ハマアザミの全草又は一部、特に葉部、茎部、根部、種子、花部を別々に1種類ずつ又はそれらの2以上の組合せの乾燥物から、あるいはその乾燥物を適宜裁断し、破砕又は粉砕した粉末から、溶媒により抽出される。ハマアザミは、自生しているものから容易に入手可能であり、市販品を用いることもできる。 When Cirsium maritimum extract is used in the present invention, the extraction method is not particularly limited. Cirsium maritimum extract is a whole plant or part of Cirsium maritimum, especially leaves, stems, roots, seeds, flowers separately from a dried product of one type or a combination of two or more thereof, or a dried product thereof as appropriate. It is extracted with a solvent from the powder that has been cut, crushed or crushed. Cirsium maritimum is easily available from native ones, and commercial products can also be used.
ハマアザミの全草又は一部を乾燥させる場合は、限定はされないが、天日干し、風乾又は乾燥機を使用して行うことができる。天日干しを行う場合は、乾燥にかかる時間は天候等により左右されるが、例えば6時間以上、好ましくは1日以上、より好ましくは2日以上とすることができる。乾燥機を使用する場合は、一般的に100℃以下、好ましくは40℃以下の乾燥条件下で、例えば、回転乾燥機、熱風乾燥機、伝熱乾燥機、真空乾燥機、真空凍結乾燥機、冷風乾燥機、振動乾燥機、ろ過乾燥機、真空撹拌乾燥機等を用いることが可能である。 When the whole plant or a part of Cirsium maritimum is dried, it can be carried out by using a sun-drying, air-drying or a dryer, but not limited to. When sun-drying is performed, the time required for drying depends on the weather and the like, but can be, for example, 6 hours or more, preferably 1 day or more, and more preferably 2 days or more. When a dryer is used, it is generally under drying conditions of 100 ° C. or lower, preferably 40 ° C. or lower, for example, a rotary dryer, a hot air dryer, a heat transfer dryer, a vacuum dryer, a vacuum freeze dryer, etc. It is possible to use a cold air dryer, a vibration dryer, a filtration dryer, a vacuum stirring dryer, or the like.
ハマアザミ抽出物を免疫調節用組成物として用いる場合は、溶媒からハマアザミを抽出操作して得た抽出液をそのまま用いてもよく、適宜に希釈又は濃縮した液を抽出物として用いてもよい。ハマアザミ抽出物を得る場合には、新鮮な植物体を用いることが可能であり、冷蔵、凍結、又は乾燥保存されたハマアザミを用いることや、ハマアザミ抽出物の濃縮物を水等の適宜な溶媒に溶解又は希釈して用いることもできる。ハマアザミ抽出物の濃縮物は、限定はされないが、液状、ペースト状、泥状のものを用いることができる。 When Cirsium maritimum extract is used as an immunomodulatory composition, the extract obtained by extracting Cirsium maritimum from a solvent may be used as it is, or an appropriately diluted or concentrated solution may be used as the extract. When obtaining Cirsium maritimum extract, fresh plants can be used, and Cirsium maritimum that has been refrigerated, frozen, or dried and stored can be used, or the concentrate of Cirsium maritimum extract can be used in an appropriate solvent such as water. It can also be used after being dissolved or diluted. The concentrate of Cirsium maritimum extract is not limited, but liquid, paste-like, or muddy-like ones can be used.
ハマアザミの抽出に用いる溶媒としては、水、有機溶媒又は含水有機溶媒が挙げられる。適宜の抽出溶媒を用いることにより、ハマアザミの水抽出物、有機溶媒抽出物又は含水有機溶媒抽出物を得ることができる。これらの抽出溶媒は、限定はされないが、水、メタノール、エタノール、エチレングリコール、1,3−ブチレングリコール、イソプロピレングリコール、プロピレングリコール、グリセリン、酢酸エチル、イソプロピルアルコール、テトラヒドロフラン、n-プロパノール、メチルエチルケトン、ジオキサン、アセトン、アセトニトリル、酢酸、ジメチルホルムアミド、n-ヘキサン又はこれらの混合物が好ましい。より高い本発明の効果を得ることの観点から、これらの抽出溶媒のうち、酢酸エチルが特に好ましい。酢酸エチルを用いる場合の濃度は、限定はされないが、より高い抽出効率を得ることの観点から、例えば、100%〜40%、好ましくは100%〜60%、より好ましくは100%〜80%の濃度で用いることができる。 Examples of the solvent used for extracting Cirsium maritimum include water, an organic solvent, and a hydrous organic solvent. By using an appropriate extraction solvent, a water extract, an organic solvent extract or a water-containing organic solvent extract of Cirsium maritimum can be obtained. These extraction solvents are, but are not limited to, water, methanol, ethanol, ethylene glycol, 1,3-butylene glycol, isopropylene glycol, propylene glycol, glycerin, ethyl acetate, isopropyl alcohol, tetrahydrofuran, n-propanol, methyl ethyl ketone, Dioxane, acetone, acetonitrile, acetic acid, dimethylformamide, n-hexane or mixtures thereof are preferred. Of these extraction solvents, ethyl acetate is particularly preferable from the viewpoint of obtaining a higher effect of the present invention. When ethyl acetate is used, the concentration is not limited, but from the viewpoint of obtaining higher extraction efficiency, for example, 100% to 40%, preferably 100% to 60%, more preferably 100% to 80%. Can be used in concentration.
抽出に用いるハマアザミの部位は、限定はされないが、例えば、葉部、茎部、根部、種子、花部等が挙げられ、より高い本発明の効果を得ることの観点から葉部、花部又はこれらの組合せが好ましく、さらには、葉部が好ましい。 The site of Cirsium maritimum used for extraction is not limited, but includes, for example, leaves, stems, roots, seeds, flowers, etc., and from the viewpoint of obtaining a higher effect of the present invention, the leaves, flowers, or the like. A combination of these is preferable, and a leaf portion is more preferable.
抽出方法は特に限定はされないが、例えば、ハマアザミの全草または一部を裁断し、ミキサー等の公知の方法により破砕し、抽出溶媒を加えて撹拌し、室温ないし加熱を一定の抽出時間で処置後、抽出上清からハマアザミのエキスを分離抽出する方法が挙げられる。また、抽出方法は、ハマアザミを抽出溶媒に浸漬した後、室温ないし加熱する条件において、静置する方法でもよい。 The extraction method is not particularly limited, but for example, whole or a part of Cirsium maritimum is cut, crushed by a known method such as a mixer, added with an extraction solvent and stirred, and treated at room temperature or heating at a constant extraction time. After that, a method of separating and extracting Cirsium maritimum extract from the extraction supernatant can be mentioned. Further, the extraction method may be a method in which Cirsium maritimum is immersed in an extraction solvent and then allowed to stand at room temperature or under heating conditions.
破砕条件としては、限定はされないが、ハマアザミの全草または一部の裁断物が1kg〜10kg等の大スケールである場合は、大型バーチカルカッターミキサー等を用いることができ、数十g〜数百gの小スケールの場合は、家庭用ミキサー等を用いることができる。例えば、大スケールでの破砕条件を適用する場合は、原料の硬さ、含水率等によって適宜変更されるが、例えば、破砕時間は数十秒〜数分間、ミキサーの回転数は10〜3000rpmで行うことが可能である。 The crushing conditions are not limited, but if the whole plant of Cirsium maritimum or a part of the cut material is a large scale such as 1 kg to 10 kg, a large vertical cutter mixer or the like can be used, and tens of g to several hundreds can be used. In the case of a small scale of g, a household mixer or the like can be used. For example, when applying crushing conditions on a large scale, the crushing time is tens of seconds to several minutes, and the rotation speed of the mixer is 10 to 3000 rpm, although it is appropriately changed depending on the hardness of the raw material, the water content, etc. It is possible to do.
また、抽出条件は通常の条件を適用することができ、限定はされないが、ハマアザミの乾燥物を、例えば3〜100℃で溶媒に浸漬、加熱還流又はマイクロウェーブ加熱をする方法を採用することができる。抽出温度は、適切な抽出量が得られる限り限定はされないが、例えば、酢酸エチルを用いた場合は、20〜100℃とすることができ、22〜80℃が好ましく、25〜60℃がより好ましい。また、抽出温度は、例えば、水を用いた場合は20〜100℃とすることができ、50〜100℃が好ましく、70〜100℃がより好ましい。抽出時間は、適切な抽出量が得られる限り限定はされないが、例えば、5分以上14日以内、好ましくは10分以上7日以内、より好ましくは15分以上5日以内とすることができる。前記抽出は通常常圧下で行われるが、加圧下で行うことも可能である。溶媒の添加量は、ハマアザミの乾燥重量1kgに対して1L〜100L程度使用することができる。 Further, the extraction conditions can be applied to ordinary conditions, and the extraction conditions are not limited, but a method of immersing the dried product of Cirsium maritimum in a solvent at, for example, 3 to 100 ° C., heating at reflux or microwave heating can be adopted. it can. The extraction temperature is not limited as long as an appropriate extraction amount can be obtained, but for example, when ethyl acetate is used, it can be 20 to 100 ° C., preferably 22 to 80 ° C., more preferably 25 to 60 ° C. preferable. The extraction temperature can be, for example, 20 to 100 ° C., preferably 50 to 100 ° C., more preferably 70 to 100 ° C. when water is used. The extraction time is not limited as long as an appropriate extraction amount can be obtained, but can be, for example, 5 minutes or more and 14 days or less, preferably 10 minutes or more and 7 days or less, and more preferably 15 minutes or more and 5 days or less. The extraction is usually carried out under normal pressure, but it can also be carried out under pressure. The amount of the solvent added can be about 1 L to 100 L with respect to 1 kg of the dry weight of Cirsium maritimum.
抽出溶媒を加える前に、ハマアザミに、酸、アルカリ、または酵素を加えることで、抽出効率を高めることも可能である。 It is also possible to increase the extraction efficiency by adding an acid, alkali, or enzyme to Cirsium maritimum before adding the extraction solvent.
抽出溶媒を加えて撹拌する操作は、公知の方法を用いることができるが、例えば、ハマアザミの裁断物又は粉砕物と抽出溶媒とを含む抽出用容器を回転させる方法、前記抽出用容器を磁気式又は機械式の撹拌装置に設置して混合する方法、前記抽出用容器を振とうさせる方法等が挙げられる。 A known method can be used for the operation of adding the extraction solvent and stirring. For example, a method of rotating an extraction container containing a cut or crushed product of Cirsium maritimum and an extraction solvent, the method of rotating the extraction container is a magnetic method. Alternatively, a method of installing the mixture in a mechanical stirring device for mixing, a method of shaking the extraction container, and the like can be mentioned.
撹拌操作では、超音波処理により振動を起こし、抽出効率を高めることも可能である。超音波処理を行う場合は、限定はされないが、例えばハマアザミの全草または一部の裁断物が1kg〜10kg等の大スケールである場合は、市販の超音波発生器にハマアザミの裁断物又は粉砕物と抽出溶媒とを含む抽出用容器を設置し、26kHz超音波で60分間処理することにより、超音波処理物を得ることができ、数十g〜数百gの小スケールの場合は、40kHzの超音波で60分間処理することにより、超音波処理物を得ることができる。超音波処理の温度条件は、適切な抽出量が得られる限り限定はされないが、2℃〜100℃、好ましくは10℃〜70℃とすることができる。大スケール用の超音波発生器としては、例えば神明台工業(株)製UT−12を使用することができ、小スケール用の超音波発生器としては、例えばAS ONE(株)製US−3Rを使用することができる。 In the stirring operation, it is possible to increase the extraction efficiency by causing vibration by ultrasonic treatment. When performing ultrasonic treatment, there is no limitation, but for example, when the whole plant or a part of the Hama-Zami is cut on a large scale such as 1 kg to 10 kg, a commercially available ultrasonic generator is used to cut or crush the Hama-Zami. An ultrasonically treated product can be obtained by installing an extraction container containing the product and an extraction solvent and treating with 26 kHz ultrasonic waves for 60 minutes. In the case of a small scale of several tens of g to several hundred g, 40 kHz. An ultrasonically treated product can be obtained by treating with the ultrasonic waves of the above for 60 minutes. The temperature condition of the ultrasonic treatment is not limited as long as an appropriate extraction amount can be obtained, but can be 2 ° C to 100 ° C, preferably 10 ° C to 70 ° C. As the ultrasonic generator for large scale, for example, UT-12 manufactured by Shinmeidai Kogyo Co., Ltd. can be used, and as the ultrasonic generator for small scale, for example, US-3R manufactured by AS ONE Co., Ltd. can be used. Can be used.
抽出効率を高めるためには、同種又は複数種の抽出溶媒を用いた多段階抽出を行うことも可能である。多段階抽出を行う場合は、第1段階の抽出において得られた残渣に、さらに同種又は複数種の抽出溶媒を加え、室温ないし加熱を行った後、抽出上清からハマアザミのエキスを分離抽出することができる。 In order to increase the extraction efficiency, it is also possible to perform multi-step extraction using the same type or a plurality of types of extraction solvents. In the case of multi-step extraction, the same or more kinds of extraction solvents are further added to the residue obtained in the first step extraction, and after heating at room temperature or heating, the extract of Cirsium maritimum is separated and extracted from the extraction supernatant. be able to.
マイクロウェーブ加熱は、本発明の有効成分の活性が失われない範囲で、マイクロウェーブ照射装置の出力、マイクロウェーブの波長、照射時間等の条件を適宜設定することが可能である。例えば、ハマアザミの乾燥物100gに対して、2450MHz、500Wのマイクロウェーブを当てる場合は、10秒〜10分、好ましくは30秒〜5分で処理することが可能である。 In the microwave heating, conditions such as the output of the microwave irradiation device, the wavelength of the microwave, and the irradiation time can be appropriately set within a range in which the activity of the active ingredient of the present invention is not lost. For example, when a microwave of 2450 MHz and 500 W is applied to 100 g of a dried product of Cirsium maritimum, it can be processed in 10 seconds to 10 minutes, preferably 30 seconds to 5 minutes.
抽出上清をそのままハマアザミ抽出物として用いることができる。さらには、抽出上清からハマアザミ抽出物を分離抽出することもできる。この分離抽出段階においては、公知の方法を採用することができ、例えば、ろ過、遠心分離、吸引、圧搾等を行うことが可能である。 The extract supernatant can be used as it is as a Cirsium maritimum extract. Furthermore, Cirsium maritimum extract can be separated and extracted from the extract supernatant. In this separation / extraction step, a known method can be adopted, and for example, filtration, centrifugation, suction, squeezing, etc. can be performed.
ろ過により分離抽出する場合は、限定はされないが、例えば、膜ろ過を行うことができる。膜ろ過を行う場合は、例えば、温度条件を2℃〜70℃、好ましくは10℃〜40℃とすることができ、膜孔径を0.1μm〜10μm、好ましくは0.1μm〜5μmとすることが可能である。 In the case of separation and extraction by filtration, for example, membrane filtration can be performed, but not limited to. When performing membrane filtration, for example, the temperature condition can be 2 ° C. to 70 ° C., preferably 10 ° C. to 40 ° C., and the membrane pore diameter can be 0.1 μm to 10 μm, preferably 0.1 μm to 5 μm. Is possible.
遠心分離により分離抽出する場合は、公知の機器を用いることができ、遠心分離器としては、例えば、分離板型、円筒型、デカンター型等を挙げることができる。遠心分離を行う場合は、例えば、温度条件を2℃〜70℃、好ましくは10℃〜40℃とすることができ、回転数を1000rpm〜10000rpm、好ましくは1500rpm〜8000rpm、さらに好ましくは2000rpm〜6000rpmとすることができ、遠心時間を10秒〜30分、好ましくは20秒〜20分、さらに好ましくは30秒〜15分とすることができる。 In the case of separation and extraction by centrifugation, a known device can be used, and examples of the centrifuge include a separation plate type, a cylindrical type, and a decanter type. When centrifuging, for example, the temperature condition can be 2 ° C. to 70 ° C., preferably 10 ° C. to 40 ° C., and the rotation speed is 1000 rpm to 10000 rpm, preferably 1500 rpm to 8000 rpm, and more preferably 2000 rpm to 6000 rpm. The centrifugation time can be 10 seconds to 30 minutes, preferably 20 seconds to 20 minutes, and more preferably 30 seconds to 15 minutes.
圧搾による分離抽出は、圧搾機を用いることも可能であり、圧搾機としては公知の機器を用いることができ、例えば、空気圧式圧搾機、スクリュー式圧搾機等を挙げることができる。 For the separation and extraction by squeezing, a squeezing machine can also be used, and a known device can be used as the squeezing machine, and examples thereof include a pneumatic squeezing machine and a screw type squeezing machine.
ハマアザミ抽出物は、希釈や濃縮の前後等に、さらに精製処理に付することにより、精製物とすることができる。精製処理には、上記の溶媒による抽出以外に、当業者に公知な方法であるクロマトグラフ法、イオン交換クロマトグラフ法等を単独で、または組み合わせて用いることができる。 Cirsium maritimum extract can be refined by further purifying it before and after dilution or concentration. In addition to the above-mentioned extraction with a solvent, a chromatographic method, an ion exchange chromatograph method, or the like known to those skilled in the art can be used alone or in combination for the purification treatment.
クロマトグラフ法を用いる場合であっては、例えば、順相若しくは逆相の担体又はイオン交換樹脂を用いるカラムクロマトグラフィー、高速液体クロマトグラフィー、薄層クロマトグラフィー又は遠心液体クロマトグラフィー等のいずれか、又はそれらを組み合わせて用いる方法が挙げられる。クロマトグラフ法を用いる場合の担体、溶出溶媒等の精製条件は、各種のクロマトグラフ法に対応して適宜選択することができる。 When the chromatograph method is used, for example, either column chromatography using a normal phase or reverse phase carrier or an ion exchange resin, high performance liquid chromatography, thin layer chromatography, centrifugal liquid chromatography, or the like, or A method of using them in combination can be mentioned. When the chromatographic method is used, the purification conditions such as the carrier and the elution solvent can be appropriately selected according to various chromatographic methods.
ハマアザミの裁断物又は粉砕物と抽出溶媒とを混合する比率としては、より高い抽出効率を得ることの観点から、例えば、含水有機溶媒抽出物または含水抽出物を得る場合は、溶媒1Lに対して、ハマアザミの裁断物又は粉砕物を5g〜1kg、好ましくは10g〜500g、より好ましくは20g〜200gとすることができる。酢酸エチル抽出物を得る場合は、例えば、酢酸エチル1Lに対して、ハマアザミ乾燥体の裁断物又は粉砕物を5g〜300g、好ましくは10g〜200g、より好ましくは20g〜100gとすることができる。 The ratio of the cut or ground product of Cirsium maritimum to the extraction solvent is such that, from the viewpoint of obtaining higher extraction efficiency, for example, when a hydrous organic solvent extract or a hydrous extract is obtained, the ratio is relative to 1 L of the solvent. The cut or ground product of Cirsium maritimum can be 5 g to 1 kg, preferably 10 g to 500 g, and more preferably 20 g to 200 g. When the ethyl acetate extract is obtained, for example, the amount of the cut or ground product of dried Cirsium maritimum can be 5 g to 300 g, preferably 10 g to 200 g, and more preferably 20 g to 100 g with respect to 1 L of ethyl acetate.
本発明において、ハマアザミ、ハマアザミ抽出物の含有量は、より高い本発明の効果を得る観点から、免疫調節用組成物の総量を基準として、固形分換算で0.000001〜100w/w%、好ましくは0.00001〜90w/w%、さらに好ましくは0.0001〜80w/w%、最も好ましくは、0.0001〜50w/w%とすることができる。(w/w%は、重量%を表わす。以下同じ。) In the present invention, the content of Cirsium maritimum and Cirsium maritimum extract is preferably 0.000001 to 100 w / w% in terms of solid content, based on the total amount of the immunomodulatory composition, from the viewpoint of obtaining a higher effect of the present invention. Can be 0.00001 to 90 w / w%, more preferably 0.0001 to 80 w / w%, and most preferably 0.0001 to 50 w / w%. (W / w% represents weight%. The same shall apply hereinafter.)
また、本発明において、ハマアザミ、ハマアザミ抽出物の含有量は、より高い本発明の効果を得る観点から、免疫調節用組成物の総量を基準として、固形分換算で0.000001〜100w/v%、好ましくは0.00001〜90w/v%、さらに好ましくは0.0001〜80w/v%、最も好ましくは、0.0001〜50w/v%とすることができる。なお、ここで、w/vは、g/mlを示す。 Further, in the present invention, the content of Cirsium maritimum and Cirsium maritimum extract is 0.000001 to 100 w / v% in terms of solid content based on the total amount of the immunomodulatory composition from the viewpoint of obtaining a higher effect of the present invention. It can be preferably 0.00001 to 90 w / v%, more preferably 0.0001 to 80 w / v%, and most preferably 0.0001 to 50 w / v%. Here, w / v indicates g / ml.
本発明において、ハマアザミの精製物の含有量は、より高い本発明の効果を得る観点から、免疫調節用組成物の総量を基準として、固形分換算で0.000000001〜5w/w%、好ましくは0.00000001〜3w/w%、さらに好ましくは0.0000001〜2w/w%とすることができる。 In the present invention, the content of the purified product of Cirsium maritimum is 0.000000001 to 5 w / w% in terms of solid content, preferably 0.000000001 to 5 w / w%, based on the total amount of the immunomodulatory composition, from the viewpoint of obtaining a higher effect of the present invention. It can be 0.00000001-3w / w%, more preferably 0.000000001-2w / w%.
ここで、本発明においては、ハマアザミ抽出物又はさらなる精製物は、下記化学式を有するシルシマリチン(CAS Number:6601-62-3)またはシルシマリン(CAS Number:13020-19-4)を含有し得る。より好ましくは、ハマアザミ抽出物から精製して得られる物は、シルシマリチンおよび/またはシルシマリンである。 Here, in the present invention, Cirsium maritimum extract or a further purified product may contain silcimarintin (CAS Number: 6601-62-3) or silcimarin (CAS Number: 13020-19-4) having the following chemical formula. More preferably, the product obtained by purification from Cirsium maritimum extract is silcimarintin and / or silcimarin.
[用途]
本発明者らは、ハマアザミ又はその抽出物若しくは精製物であるシルシマリチンおよび/またはシルシマリンが、優れた免疫調節作用を有することを新たに見出した。ハマアザミは、天然に由来するものであり、古来より食用されていることから、安全で有効な免疫調節用途に好適である。
[Use]
The present inventors have newly found that Cirsium maritimum or its extract or purified product, silcimaritin and / or silcimarin, has an excellent immunomodulatory effect. Cirsium maritimum is naturally derived and has been edible since ancient times, making it suitable for safe and effective immunomodulatory applications.
ここで、本明細書において、「免疫調節」とは、抗アレルギーや免疫賦活を含む慨念である。免疫賦活には、限定はされないが、主に粘膜免疫賦活が含まれる。 Here, in the present specification, "immunomodulation" is a remorse including anti-allergy and immunostimulation. Immunostimulation includes, but is not limited to, mucosal immunostimulation.
ここで、本明細書において、「アレルギー予防及び/又は改善」と、抗アレルギーとは互換可能に用いられる用語である。本発明のハマアザミ又はその抽出物、精製物を含む抗アレルギー作用は、特に限定はされないが、特には即時型アレルギーの抑制であり得る。食物アレルギーおよび花粉アレルギーに代表されるI型アレルギーは過敏反応として定義される。I型アレルギーは、肥満細胞および好塩基球に発現するIgEのレセプター(FcεRI)が、抗原により活性化されることで起るとされている。このことは、ヒスタミン、プロスタグランジンおよびロイコトリエンを含む多くの化学伝達物質の細胞外リリースを誘発する最初のステップであり、これらのメディエーターは、即時アレルギー反応を引き起こす。 Here, in the present specification, "allergy prevention and / or improvement" and antiallergic are terms used interchangeably. The antiallergic action including Cirsium maritimum or its extract or purified product of the present invention is not particularly limited, but may be particularly immediate suppression of allergy. Type I allergies, represented by food allergies and pollen allergies, are defined as hypersensitivity reactions. Type I allergy is said to occur when the IgE receptor (FcεRI) expressed on mast cells and basophils is activated by an antigen. This is the first step in inducing extracellular release of many chemical messengers, including histamine, prostaglandins and leukotrienes, and these mediators cause an immediate allergic reaction.
本発明でいう抗アレルギー予防及び/又は改善用組成物は、特には、くしゃみ、かゆみ、鼻水、涙、皮膚炎、蕁麻疹、喘息等のアレルギー症状、および炎症性関節炎のような疾患の予防及び/改善に効果を有する。本発明の抗アレルギー予防及び/又は改善は、特にはI型アレルギーに効果を有する。あるいは本発明の予防及び/又は改善は、IgE依存性の疾患に有効であるとも言える。 The antiallergic preventive and / or ameliorating composition referred to in the present invention particularly prevents and prevents allergic symptoms such as sneezing, itchiness, runny nose, tears, dermatitis, urticaria, asthma, and diseases such as inflammatory arthritis. / Has an effect on improvement. The antiallergic prevention and / or amelioration of the present invention is particularly effective for type I allergies. Alternatively, it can be said that the prevention and / or improvement of the present invention is effective for IgE-dependent diseases.
このような抗アレルギー効果は、例えば、細胞からのβ‐ヘキソサミニザーゼ放出抑制効果、すなわち好塩基球の脱顆粒抑制効果として検証することができる。 Such an antiallergic effect can be verified, for example, as an effect of suppressing β-hexosaminize release from cells, that is, an effect of suppressing basophil degranulation.
また、本明細書において、「免疫賦活」とは、抗アレルギー作用の他に、一般的な免疫賦活、粘膜免疫の賦活を含む意味である。 Further, in the present specification, "immune activation" means to include general immunostimulation and mucosal immunity activation in addition to antiallergic action.
本発明でいう粘膜免疫賦活用組成物は、病原性細菌、寄生虫、病原性抗原、ウイルスによる感染や悪影響の予防またはそのような感染症や悪影響の改善に効果を有する。特には、腸管等の消化管免疫機能の低下や細菌性消化管感染による直接的な影響の他、間接的な影響の緩和にも有用である。 The mucosal immunostimulatory composition referred to in the present invention is effective in preventing infection or adverse effects caused by pathogenic bacteria, parasites, pathogenic antigens, viruses, or ameliorating such infectious diseases or adverse effects. In particular, it is useful for alleviating indirect effects as well as direct effects due to deterioration of gastrointestinal immune function such as intestinal tract and bacterial gastrointestinal infection.
粘膜免疫賦活によって、例えば消化管粘膜における防御系の免疫機能の低下を防ぐことができる。これには、消化管への微生物の定着や増殖による消化管感染等により、発熱、嘔吐、下痢、腹痛等の症状が発症することがあるが、これらの症状の予防や緩和が含まれる。さらに、粘膜免疫賦活は、細菌性の下痢症等の予防や緩和にも有用である。幼児、老人、体力が低下した人における抵抗力の強化にも役立つ。このように、粘膜免疫賦活により、細菌やウイルスの中和、組織への細菌の付着の抑制、食物抗原によるアレルギーの抑制が可能となる。 Mucosal immune activation can prevent, for example, a decrease in the immune function of the defense system in the gastrointestinal mucosa. This includes prevention and alleviation of symptoms such as fever, vomiting, diarrhea, and abdominal pain due to gastrointestinal infection due to colonization of microorganisms in the gastrointestinal tract and proliferation. Furthermore, mucosal immunostimulation is also useful for prevention and alleviation of bacterial diarrhea and the like. It also helps to strengthen resistance in infants, the elderly, and those who are weak. As described above, mucosal immunostimulation makes it possible to neutralize bacteria and viruses, suppress bacterial adhesion to tissues, and suppress allergies caused by food antigens.
このような免疫賦活作用に基づく抗アレルギー作用、免疫賦活作用は、血清中のIgE量の低下傾向や糞中のIgA量の増加として検証することができる。 Such anti-allergic action and immunostimulatory action based on the immunostimulatory action can be verified as a tendency of a decrease in the amount of IgE in serum and an increase in the amount of IgA in feces.
[飲食料品]
本発明の免疫調節用組成物は、飲食料品の一つの成分として配合することが可能である。これらの飲食料品は、限定はされないが、抗アレルギー作用や免疫賦活作用、特には粘膜免疫賦活作用を有する飲食料品として用いることも可能であり、例えば、病院等の医療機関で患者のために提供され得る。またはこれらの飲食料品は、限定はされないが、機能性飲料又は機能性食品、栄養機能飲料又は栄養機能食品として提供することも可能であり、これらの機能性飲食料品は、医療機関の他、ドラッグストア、コンビニエンスストア、スーパーマーケット、百貨店等で提供され得る。機能性飲食料品とは、国や公共団体が許可・指定している医薬品的な効能を有する飲食品又は企業が国等に所定の効果を届け出た内容に基づき機能性を表示した飲食料品を意味する。機能性食品には、特定保健用食品、栄養機能食品、機能性表示食品、老人用食品、健康補助食品(バランス栄養食、サプリメント)等が例として挙げられる。医薬品的な効能又は機能性を表示したパッケージや容器、添付文書、取扱い説明書等を含む飲食品も含まれる。国等への申請書に医薬品と同様の効能又は機能性を表示した飲食品も含まれる。
[Food and drink]
The immunomodulatory composition of the present invention can be blended as one component of foods and drinks. These foods and drinks are not limited, but can also be used as foods and drinks having an antiallergic action and an immunostimulatory action, particularly a mucosal immunostimulatory action. Can be provided to. Alternatively, these foods and drinks can be provided as functional beverages or functional foods, nutritional functional beverages or nutritional functional foods, and these functional foods and drinks can be provided by other medical institutions. , Drug stores, convenience stores, supermarkets, department stores, etc. Functional foods and drinks are foods and drinks that have medicinal properties permitted and designated by the national government and public organizations, or foods and drinks that display functionality based on the content that the company has notified the national government of the prescribed effects. Means. Examples of functional foods include foods for specified health use, foods with nutritional function, foods with functional claims, foods for the elderly, health supplements (balanced nutritional foods, supplements) and the like. It also includes foods and drinks including packages and containers, package inserts, instruction manuals, etc. that indicate pharmaceutical efficacy or functionality. Foods and drinks that have the same efficacy or functionality as pharmaceuticals are also included in the application form to the national government.
アレルギー予防や改善を目的とした表示の場合、限定はされないが、例えば、アレルギー体質の方用、花粉が気になる方用などの表示の他、鼻の調子を整える、目の調子を整える、目や鼻の不快感を緩和する、目の健康、鼻の健康、目の疲労感を緩和するなどの表示等が挙げられる。 In the case of labeling for the purpose of preventing or improving allergies, there is no limitation, but for example, in addition to labeling for those with allergies and those who are concerned about pollen, the nose is toned, the eyes are toned, etc. Labels such as alleviating discomfort in the eyes and nose, health of the eyes, health of the nose, and alleviation of tiredness of the eyes can be mentioned.
免疫賦活を目的とした表示の場合、限定はされないが、例えば、体力のない方用、虚弱体質の方用、お腹の調子を整える、などの表示等が挙げられる。 In the case of a display for the purpose of immunostimulation, the display is not limited, and examples thereof include a display for a person with weak physical strength, a display for a weak constitution, and a display for adjusting the condition of the abdomen.
食品としては、あらゆる食品が挙げられ、例えば、穀類、いも類、魚介類、肉類、卵類、油脂類、乳類、野菜類、豆類、果実類、砂糖類、海藻類、菓子類、調味料類、調理加工食品類等が挙げられる。 Foods include all kinds of foods, such as grains, potatoes, seafood, meats, eggs, fats and oils, milks, vegetables, legumes, fruits, sugars, seaweeds, confectionery, seasonings. Kind, cooked processed foods and the like.
調味加工食品としては、限定はされないが、例えば、ちくわ、かまぼこ等の水産加工品;ハムやソーセージ等の畜産加工品;クッキー、ビスケット、スナック、チョコレート、ケーキ等の菓子;そば、うどん、生麺、中華麺、パスタ等の麺類;食パン、菓子パン等のパン;納豆、味噌等の発酵加工食品;豆腐、おから等の大豆食品;浅漬け、糠漬け等の漬け物、水産品、加工肉、野菜、果物等の缶詰;バター、マーガリン、ヨーグルト、チーズ、牛乳等の乳製品;アイスクリーム、シャーベット等の冷菓食品等が挙げられる。 The seasoned processed foods are not limited, but for example, processed marine products such as chikuwa and kamaboko; processed livestock products such as ham and sausage; sweets such as cookies, biscuits, snacks, chocolates and cakes; buckwheat noodles, udon noodles and raw noodles. , Chinese noodles, noodles such as pasta; bread such as bread and sweet bread; fermented processed foods such as natto and miso; soybean foods such as tofu and okara; pickles such as lightly pickled and rice bran pickles, marine products, processed meats, vegetables, Canned fruits and the like; dairy products such as butter, margarine, yogurt, cheese and milk; frozen dessert foods such as ice cream and sherbet.
飲料としては、あらゆる飲料が挙げられ、限定はされないが、例えば、ハマアザミそのものをお茶とする飲料、お茶の葉の代用としての焙煎乾燥物、果汁飲料、果汁100%飲料、低果汁飲料、果肉飲料、野菜ジュース、フレーバー入り飲料、希釈用果実飲料等の果実飲料;炭酸飲料;コーヒー、コーヒー飲料、コーヒー入り清涼飲料、ココア飲料、紅茶、緑茶、抹茶、烏龍茶、麦茶、ほうじ茶等の嗜好飲料;食酢飲料;スポーツドリンク等の清涼飲料水;牛乳;乳飲料;乳性飲料;乳酸飲料;乳酸菌飲料;豆乳、調製豆乳等の大豆飲料;ビール、日本酒、焼酎、リキュール、ワイン等のアルコール飲料;タウリン、ローヤルゼリー、アミノ酸、ビタミン、ミネラル、鉄分等を含む栄養飲料等が挙げられる。 Beverages include, but are not limited to, all beverages, such as beverages made from Hama-Zami itself, roasted dried products as a substitute for tea leaves, fruit juice beverages, 100% fruit juice beverages, low fruit juice beverages, and fruit meat. Beverages, vegetable juices, flavored beverages, fruit beverages for dilution, and other fruit beverages; carbonated beverages; coffee, coffee beverages, soft beverages with coffee, cocoa beverages, tea, green tea, matcha, Karyu tea, barley tea, roasted tea, and other favorite beverages; Vinegar drinks; soft drinks such as sports drinks; milk; milk drinks; milk drinks; lactic acid drinks; lactic acid bacteria drinks; soybean drinks such as soymilk and prepared soymilk; alcoholic drinks such as beer, sake, shochu, liqueurs, and wine; taurine , Royal jelly, nutritional beverages containing amino acids, vitamins, minerals, iron and the like.
本発明を飲食料品に適用する時期に制限はないが、例えば、飲食料品の製造工程において、加工工程、調理工程、加熱工程、保存工程等の前後において適用され得る。例えば、加工工程や調理工程においては、原料に本発明の免疫調節用組成物を含ませることができる。適用方法は、飲食料品の種類、原料の形態等に応じて適宜変更することができ、混入、添加、塗布、噴霧、浸漬等の様々な方法を採用し得る。 There is no limitation on the time when the present invention is applied to foods and drinks, but for example, it can be applied before and after a processing step, a cooking step, a heating step, a storage step and the like in a food and drink manufacturing process. For example, in a processing step or a cooking step, the raw material may contain the immunomodulatory composition of the present invention. The application method can be appropriately changed depending on the type of food and drink, the form of the raw material, and the like, and various methods such as mixing, addition, coating, spraying, and dipping can be adopted.
本発明の免疫調節用組成物を飲料品に適用する場合、一つの実施形態において、茶飲料とすることが特に好ましい。限定はされないが、乾燥したハマアザミの葉部及び/又は茎部は、公知の方法により裁断された後、破砕又は粉砕され粉状物とされる。ハマアザミの粉状物の状態で、茶飲料として販売することが可能である。また、必要により、ハマアザミの粉状物は焙煎される。ハマアザミの粉状物は焙煎された状態で茶飲料として販売することも可能である。焙煎されたハマアザミは、熱湯で煮出すことで飲用される。 When the immunomodulatory composition of the present invention is applied to a beverage product, it is particularly preferable to use a tea beverage in one embodiment. Although not limited, the dried leaf and / or stem of Cirsium maritimum is cut by a known method and then crushed or crushed into a powder. It is possible to sell it as a tea beverage in the form of powdered Cirsium maritimum. If necessary, Cirsium maritimum powder is roasted. Cirsium maritimum powder can also be sold as a tea beverage in a roasted state. Roasted Cirsium maritimum is drunk by boiling it in boiling water.
また、前記飲料と他の茶飲料およびハマアザミ抽出液を混合物として、または水などで薄めてジュースやドリンク剤等として用いることができる。更に、前記混合物の濃縮品、噴霧乾燥等によって粉末状にした粉末茶、凍結乾燥したインスタント茶等として利用することができる。その場合、たとえば粉末茶やインスタント茶にお湯を注いで飲むことができる。また、例えば緑茶や紅茶などの茶調製物とハマアザミ調製物の混合物を飲料用茶葉としてそのまま用いることもできる。その場合、一般的な日本茶や紅茶の飲用物と同様にして、茶調製物とハマアザミ調製物との混合茶葉に湯を注いで飲むことができる。 In addition, the beverage can be used as a mixture of other tea beverages and Cirsium maritimum extract, or diluted with water or the like and used as a juice, a drink, or the like. Further, it can be used as a concentrated product of the mixture, powdered tea powdered by spray drying or the like, freeze-dried instant tea or the like. In that case, for example, hot water can be poured into powdered tea or instant tea to drink. Further, for example, a mixture of a tea preparation such as green tea or black tea and a cirsium maritimum preparation can be used as it is as tea leaves for beverages. In that case, hot water can be poured into the mixed tea leaves of the tea preparation and the cirsium maritimum preparation in the same manner as general Japanese tea and black tea drinks.
本発明の免疫調節用組成物を食品に適用する場合、一つの実施形態において、青汁食品とすることが望ましい。限定はされないが、ここでの青汁食品とは、生のハマアザミの葉部及び/又は茎部もしくは乾燥したハマアザミの葉部及び/又は茎部を細断、粉砕、磨砕等の微細化処理したもの、あるいは原料や前記微細化処理物を圧搾して得られる搾汁であって、その形状としては、微細固形状、半固形状、ペースト状、液状である。さらにこれら形状のものを乾燥させた後、粉砕して得られる粉末状のものであっても良い。粉末状のものとしては、原料を細断せずそのまま乾燥させたものを粉砕しても良い。乾燥の方法としては、自然乾燥、加熱乾燥、噴霧乾燥等の方法が挙げられるが、凍結乾燥法を用いると、熱により変質がなく、粉砕も容易であり、嗜好性に優れたものが得られるため好ましい。また保存性の面からも好ましい。 When the immunomodulatory composition of the present invention is applied to a food, it is desirable to use a green juice food in one embodiment. Although not limited, the green juice food here is a fine treatment such as shredding, crushing, and grinding the leaves and / or stems of raw Cirsium maritimum or dried Cirsium maritimum. The juice is obtained by pressing the raw material or the micronized product, and its shape is fine solid, semi-solid, paste, or liquid. Further, it may be in the form of a powder obtained by drying these shapes and then pulverizing them. As the powdery material, the raw material may be crushed as it is dried without being shredded. Examples of the drying method include natural drying, heat drying, spray drying, etc. However, when the freeze-drying method is used, it is not deteriorated by heat, is easily crushed, and has excellent palatability. Therefore, it is preferable. It is also preferable from the viewpoint of storage stability.
また、ハマアザミの葉や茎部を、他の青汁原料と組み合わせて使用することができる。これら青汁原料は、上記の場合と同様に処理され青汁食品とする。処理はハマアザミの葉や茎部と原料の段階から混合して処理しても、途中の段階で混合しても、別々に調製した青汁食品を混合しても良い。本発明におけるハマアザミの葉や茎部以外の他の青汁の素材としては、特に限定はないが、例えば、ケール、ブロッコリー、キャベツ、小松菜、ダイコン葉、クレソン、ナズナ、大麦若葉、明日葉、セリ、パセリ、ニンジン、セロリ、アスパラガス、ホウレン草、ニガウリ、緑茶、シソ、春菊、ニワトコ、ハコベ、ヨモギ、桑、シモン葉、クマザサ、モロヘイヤ等が挙げられ、これらの1種、又は2種以上をハマアザミの葉及び/又は茎部と組み合わせることができる。本発明において、ハマアザミの葉や茎部と上記他の青汁原料を組合せて青汁食品とする場合、青汁食品におけるハマアザミの葉及び/又は茎部由来の成分が、乾燥残分として、全乾燥残分量の10w/w%以上であることが望ましい。この範囲であると、ハマアザミ由来の栄養成分が有効に摂取され、青汁食品の嗜好性の改善効果に優れる。 In addition, the leaves and stems of Cirsium maritimum can be used in combination with other green juice raw materials. These green juice raw materials are processed in the same manner as in the above case to obtain green juice foods. The treatment may be carried out by mixing the leaves and stems of Cirsium maritimum from the raw material stage, in the middle stage, or by mixing separately prepared green juice foods. The material of green juice other than the leaves and stems of Hama-Azami in the present invention is not particularly limited, but for example, kale, broccoli, cabbage, Japanese mustard spinach, radish leaf, cresson, nazuna, young barley leaf, tomorrow's leaf, and auction. , Parsley, carrot, celery, asparagus, spinach, Japanese mustard spinach, green tea, perilla, spring chrysanthemum, Japanese mustard spinach, Japanese mustard spinach, Japanese mustard spinach, mulberry, Japanese mustard spinach, Japanese mustard spinach, Japanese mustard spinach, etc. Can be combined with leaves and / or stems. In the present invention, when the leaves and stems of Cirsium maritimum are combined with the other green juice raw materials to prepare a green juice food, the components derived from the leaves and / or stems of Cirsium maritimum in the green juice food are all as a dry residue. It is desirable that the amount of dry residue is 10 w / w% or more. Within this range, nutritional components derived from Cirsium maritimum are effectively ingested, and the effect of improving the palatability of green juice foods is excellent.
本発明の免疫調節用組成物を飲食料品に適用する場合は、本発明の効果を損なわない範囲で通常の食品及び飲料に使用されている助剤を適宜配合することが可能である。そのような助剤としては、例えば、ブドウ糖、ショ糖、果糖、オリゴ糖、水飴、マルトース、マルチトース、キシリトール、ソルビトール、アスパルテーム、スクラロース、ステビオサイド、ルブソサイド、コーンシロップ、乳糖、クエン酸、酒石酸、リンゴ酸、コハク酸、乳酸、L−アスコルビン酸、dL−α−トコフェノール、エリソルビン酸ナトリウム、グリセリン、グリセリン脂肪酸エステル、プロピレングリコール、ポリグリセリン脂肪酸エステル、ショ糖脂肪酸エステル、プロピレングリコール脂肪酸、ソルビタン脂肪酸エステル、エステルアラビアガム、カゼイン、ペクチン、ゼラチン、寒天、カラギーナン、ビタミンB類、ビタミンC類、ニコチン酸アミド、パントテン酸カルシウム、カルシウム塩類、アミノ酸類、色素、香料、保存剤等が挙げられる。 When the immunomodulatory composition of the present invention is applied to foods and drinks, an auxiliary agent used in ordinary foods and beverages can be appropriately blended as long as the effects of the present invention are not impaired. Such auxiliaries include, for example, glucose, sucrose, fructose, oligosaccharide, candy, maltose, multitose, xylitol, sorbitol, aspartame, sclarose, stebioside, rubusoside, corn syrup, lactose, citric acid, tartrate, malic acid. , Citric acid, lactic acid, L-ascorbic acid, dL-α-tocophenol, sodium erythorbicate, glycerin, glycerin fatty acid ester, propylene glycol, polyglycerin fatty acid ester, sucrose fatty acid ester, propylene glycol fatty acid, sorbitan fatty acid ester, ester Examples include arabic gum, casein, pectin, gelatin, agar, carrageenan, vitamin Bs, vitamin Cs, nicotinic acid amide, calcium pantothenate, calcium salts, amino acids, pigments, fragrances, preservatives and the like.
本発明の免疫調節用組成物を飲食料品に適用する場合のハマアザミ又はその抽出物の含有量は、限定はされないが、固形分換算で、ヒト及び動物であれば、一般に1日あたり0.00001〜5000mg/kg体重であり、好ましくは0.01〜200mg/kg体重であり、より好ましくは0.1〜100mg/kg体重である。 The content of Cirsium maritimum or its extract when the immunomodulatory composition of the present invention is applied to foods and drinks is not limited, but in terms of solid content, it is generally 0. per day for humans and animals. It is 0000001 to 5000 mg / kg body weight, preferably 0.01 to 200 mg / kg body weight, and more preferably 0.1 to 100 mg / kg body weight.
本発明の免疫調節用組成物を飲料品に適用する場合のpHは、飲料品の種類によって適宜調整されるが、例えば、茶飲料の場合は、pH3.5〜7.5とすることができ、3.8〜7.2が好ましく、4.0〜7.0がより好ましく、4.5〜〜6.5がさらに好ましい。飲料品のpHは、例えば、炭酸水素ナトリウム、クエン酸等を適宜配合することにより調整することができる。 The pH when the immunomodulatory composition of the present invention is applied to a beverage product is appropriately adjusted depending on the type of the beverage product. For example, in the case of a tea beverage, the pH can be 3.5 to 7.5. 3.8 to 7.2 is preferable, 4.0 to 7.0 is more preferable, and 4.5 to 6.5 is even more preferable. The pH of the beverage product can be adjusted by appropriately blending, for example, sodium hydrogen carbonate, citric acid, or the like.
[医薬品、医薬部外品]
本発明の免疫調節用組成物は、医薬品や医薬部外品とされる場合は、適宜の形態に製剤化し、任意の投与形態でヒト又は動物に投与することができる。投与形態としては、限定はされないが、例えば、経口、経皮、経腸、経粘膜、注射などが挙げられる。本発明の効果を顕著に奏する観点から、投与形態は経口投与が好ましい。
[Pharmaceuticals, quasi-drugs]
When the composition for immunomodulation of the present invention is a drug or a quasi-drug, it can be formulated into an appropriate form and administered to humans or animals in any administration form. The administration form is not limited, and examples thereof include oral, transdermal, enteral, transmucosal, and injection. From the viewpoint of remarkably exerting the effect of the present invention, the administration form is preferably oral administration.
本発明の免疫調節用組成物が経口投与される場合は、本発明の免疫調節用組成物は、例えば、錠剤、カプセル剤、顆粒剤、シロップ剤、散剤、フィルム状、ドロップ状、ゼリー状、半固体のプリン状等の剤型に、公知の方法で製剤化される。フィルム状、ドロップ状、ゼリー状、半固体のプリン状の剤型等により、経口投与の場合は、本発明の免疫調節用組成物は、水無しにより摂取されることが可能である。または、ハマアザミ又はその抽出物若しくは精製物の乾燥粉末を生薬又は漢方薬製剤として経口投与することも可能である。 When the immunomodulatory composition of the present invention is orally administered, the immunomodulatory composition of the present invention may be, for example, tablets, capsules, granules, syrups, powders, films, drops, jellies, etc. It is formulated into a semi-solid syrup-like dosage form by a known method. The immunomodulatory composition of the present invention can be ingested without water in the case of oral administration due to a film-like, drop-like, jelly-like, semi-solid pudding-like dosage form or the like. Alternatively, the dried powder of Cirsium maritimum or its extract or purified product can be orally administered as a crude drug or a Chinese herbal medicine preparation.
非経口投与する場合は、例えば、皮下注射、静脈内注射、筋肉注射、髄腔内注射、経皮吸収剤、吸入薬、坐剤、点眼剤、点鼻剤等の剤型に公知の方法で製剤化することが可能である。 In the case of parenteral administration, for example, by a method known for the dosage form such as subcutaneous injection, intravenous injection, intramuscular injection, intrathecal injection, transdermal absorbent, inhalant, suppository, eye drops, nasal drops, etc. It can be formulated.
投与形態の一態様として、ハマアザミ又はその抽出物又はその精製物の安定性及び生体利用性を高め、あるいは患者の服薬コンプライアンスを向上するため、又はこれらを組み合わせた目的のために、公知の薬物送達システムを利用して、吸収部位まで本発明の免疫調節用組成物を送達することが可能である。 As one aspect of the dosage form, known drug delivery for the purpose of enhancing the stability and bioavailability of Cirsium maritimum or its extract or its purified product, or improving the patient's medication compliance, or for a combined purpose. The system can be used to deliver the immunomodulatory compositions of the invention to the site of absorption.
薬物送達システムとしては、限定されないが、例えばセルロース、デキストラン、澱粉、ポリビニルアルコール、アセチル化若しくはメタクリル化されたポリマー、ポリ乳酸及びポリグリコール酸及びそのブロック共重合体、ポリエチレングリコール等のポリマーを利用する方法、アルブミン等の輸送タンパク質を利用する方法、その他ミセル、リポソーム、ミクロスフェア、ナノ粒子、複合エマルジョン、デンドリマー等を利用する方法が挙げられる。これらの薬物送達システムは、吸収部位等の目的の部位へ本発明の免疫調節用組成物を運搬する目的だけでなく、適時に本発明の免疫調節用組成物を放出する放出制御の目的にも用いられ得る。 The drug delivery system utilizes, for example, but not limited to, polymers such as cellulose, dextran, starch, polyvinyl alcohol, acetylated or methacrylicated polymers, polylactic acid and polyglycolic acid and their block copolymers, polyethylene glycol and the like. Methods, methods using transport proteins such as albumin, and other methods using micelles, liposomes, microspheres, nanoparticles, composite emulsions, dendrimers and the like can be mentioned. These drug delivery systems are used not only for the purpose of transporting the immunomodulatory composition of the present invention to a target site such as an absorption site, but also for the purpose of release control for releasing the immunomodulatory composition of the present invention in a timely manner. Can be used.
本発明の免疫調節用組成物は、本発明の効果を損なわない範囲で、固形の製剤においては、賦形剤、滑沢剤、結合剤、崩壊剤等を、液状の製剤においては、溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤等を適宜配合することが可能である。 The immunomodulatory composition of the present invention contains excipients, lubricants, binders, disintegrants, etc. in solid formulations and solvents in liquid formulations, as long as the effects of the present invention are not impaired. It is possible to appropriately add a solubilizing agent, a suspending agent, an isotonic agent, a buffering agent, a pain-relieving agent and the like.
賦形剤としては、例えば、乳糖、白糖、D−マンニトール、ぶどう糖、デンプン、炭酸カルシウム、カオリン、結晶セルロース、軽質無水ケイ酸などが挙げられる。 Examples of excipients include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, light anhydrous silicic acid and the like.
滑沢剤の好適な例としては、例えばステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、精製タルク、コロイドシリカ、ホウ砂、ポリエチレングリコール等が挙げられる。 Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, purified talc, colloidal silica, borax, polyethylene glycol and the like.
結合剤としては、例えば、水、エタノール、プロパノール、単シロップ、ブドウ糖液、デンプン液、ゼラチン液、結合セルロース、白糖、D−マンニトール、デキストリン、カルボキシメチルセルロース、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、ヒドロキシプロピルスターチ、メチルセルロース、エチルセルロース、シェラック、リン酸カルシウム、ポリビニルピロリドン等が挙げられる。 Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, bound cellulose, sucrose, D-mannitol, dextrin, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl starch. , Methyl cellulose, ethyl cellulose, shelac, calcium phosphate, polyvinylpyrrolidone and the like.
崩壊剤としては、例えば、デンプン、乾燥デンプン、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、カルメロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、アルギン酸ナトリウム、カンテン末、炭酸水素ナトリウム、炭酸カルシウム、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、乳糖等が挙げられる。 Examples of the disintegrant include starch, dried starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, sodium alginate, canten powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, and the like. Examples include stearic acid monoglyceride and lactose.
溶剤としては、例えば、注射用水、アルコール、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油等が挙げられる。 Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
溶解補助剤としては、例えば、ポリエチレングリコール、プロピレングリコール、D−マンニトール、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム等が挙げられる。 Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
懸濁化剤としては、例えば、ステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリン等の界面活性剤や、例えば、ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース等の親水性高分子等が挙げられる。 Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate, and for example, polyvinyl alcohol and polyvinyl. Examples thereof include hydrophilic polymers such as pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
等張化剤としては、例えば、塩化ナトリウム、グリセリン、D−マンニトール等が挙げられる。 Examples of the tonicity agent include sodium chloride, glycerin, D-mannitol and the like.
緩衝剤としては、例えば、リン酸塩、酢酸塩、炭酸塩、クエン酸塩などの緩衝液等が挙げられる。 Examples of the buffer include a buffer solution such as phosphate, acetate, carbonate, and citrate.
無痛化剤としては、例えば、ベンジルアルコール等が挙げられる。 Examples of the soothing agent include benzyl alcohol and the like.
防腐剤としては、例えば、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸等が挙げられる。 Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
本発明の免疫調節用組成物を経口により投与する場合のハマアザミ又はその抽出物の有効投与量は、限定はされないが、固形分換算で、ヒト及び動物であれば、一般に1日あたり0.00001〜5000mg/kg体重であり、好ましくは0.01〜200mg/kg体重であり、より好ましくは0.1〜100mg/kg体重である。本発明の免疫調節用組成物を非経口投与する場合のハマアザミ又はその抽出物の有効投与量は、限定はされないが、固形分換算で、ヒト及び動物であれば、一般に一日あたり0.000001〜50mg/kg体重、好ましくは、0.00001〜5mg/kg体重、より好ましくは、0.00001〜1mg/kg体重である。投与回数は、通常は1日1〜4回程度であるが、投与経路によって、適宜調整することができる。 The effective dose of Cirsium maritimum or its extract when the immunomodulatory composition of the present invention is orally administered is not limited, but is generally 0.00001 per day for humans and animals in terms of solid content. It has a body weight of ~ 5000 mg / kg, preferably 0.01 to 200 mg / kg body weight, and more preferably 0.1 to 100 mg / kg body weight. The effective dose of Cirsium maritimum or its extract when the immunomodulatory composition of the present invention is orally administered is not limited, but is generally 0.000001 per day for humans and animals in terms of solid content. ~ 50 mg / kg body weight, preferably 0.00001-5 mg / kg body weight, more preferably 0.00001-1 mg / kg body weight. The number of administrations is usually about 1 to 4 times a day, but can be appropriately adjusted depending on the administration route.
次に、実施例により本発明を具体的に説明するが、本発明は以下の実施例に限定されるものではない。 Next, the present invention will be specifically described with reference to Examples, but the present invention is not limited to the following Examples.
(実施例1)乾燥粉砕物からの酢酸エチルによる抽出方法
ハマアザミの葉及び花の乾燥粉砕物、それぞれ100gを、それぞれ100%酢酸エチル1000mlに分散、撹拌させ、室温にて1週間抽出した。抽出上清を濾別したのち、残渣を再び酢酸エチルに分散させ、加熱還流後、抽出上清を濾別した。上清を順次減圧濃縮、窒素ガス雰囲気下で減圧乾燥、凍結乾燥を行い、ハマアザミの葉による抽出物1(4g)及びハマアザミの花による抽出物2(4g)を得た。
(Example 1) Extraction method with ethyl acetate from dried ground product 100 g of each dried ground product of Cirsium maritimum leaves and flowers was dispersed in 1000 ml of 100% ethyl acetate, stirred, and extracted at room temperature for 1 week. The extract supernatant was filtered off, the residue was dispersed again in ethyl acetate, heated under reflux, and the extract supernatant was filtered off. The supernatant was sequentially concentrated under reduced pressure, dried under reduced pressure and freeze-dried under a nitrogen gas atmosphere to obtain Extract 1 (4 g) from Cirsium maritimum leaves and Extract 2 (4 g) from Cirsium maritimum flowers.
(実施例2)乾燥粉砕物からの水による抽出方法
ハマアザミの葉の乾燥粉砕物100gに水1.5Lを加え、ミキサーで粉砕後、撹拌及び超音波付与を行い、抽出上清を濾別及び脱水することにより、水と併せて抽出液(2L)を得た。更に、順次減圧濃縮、窒素ガス雰囲気下で減圧乾燥、凍結乾燥を行い、抽出物3(15g)を得た。
(Example 2) Extraction method with water from dried crushed product 1.5 L of water was added to 100 g of dried crushed product of Cirsium maritimum leaf, crushed with a mixer, stirred and ultrasonically applied, and the extraction supernatant was filtered and separated. By dehydration, an extract (2 L) was obtained together with water. Further, the mixture was sequentially concentrated under reduced pressure, dried under reduced pressure and freeze-dried under a nitrogen gas atmosphere to obtain Extract 3 (15 g).
(実施例3)搾汁による抽出方法
ハマアザミの生葉及び生茎の混合物(1kg)に水1Lを加え、ミキサーで粉砕後、撹拌及び超音波付与を行い、抽出上清を濾別、洗浄、及び脱水する事により、水と併せて抽出液(2L)を得た。更に、順次減圧濃縮、窒素ガス雰囲気下で減圧乾燥、凍結乾燥を行い、抽出物4(15g)を得た。
(Example 3) Extraction method by squeezing 1 L of water is added to a mixture (1 kg) of fresh leaves and fresh stems of Cirsium maritimum, crushed with a mixer, stirred and ultrasonically applied, and the extracted supernatant is filtered, washed, and subjected to ultrasonic waves. By dehydration, an extract (2 L) was obtained together with water. Further, the mixture was sequentially concentrated under reduced pressure, dried under reduced pressure and freeze-dried under a nitrogen gas atmosphere to obtain Extract 4 (15 g).
(実施例4)圧搾による抽出方法
ハマアザミの生葉及び生茎の混合物(1kg)に水1Lを加え、ミキサーで粉砕後、撹拌及び超音波付与を行い、抽出上清を濾別及び脱水後、圧搾する事により、抽出液(1.5L)を得た。更に、順次減圧濃縮、窒素ガス雰囲気下で減圧乾燥、凍結乾燥を行い、抽出物(20g)を得た。
(Example 4) Extraction method by squeezing 1 L of water is added to a mixture (1 kg) of fresh leaves and stalks of Cirsium maritimum, crushed with a mixer, stirred and ultrasonically applied, and the extracted supernatant is filtered and dehydrated and then squeezed. By doing so, an extract (1.5 L) was obtained. Further, the mixture was sequentially concentrated under reduced pressure, dried under reduced pressure and freeze-dried under a nitrogen gas atmosphere to obtain an extract (20 g).
(実施例5)乾燥粉末の製造方法
ハマアザミの生葉、生茎(1kg)を、40℃冷風乾燥機で一晩乾燥後、粉砕機で微粉砕し、ハマアザミ乾燥粉末(100g)を得た。
(Example 5) Method for producing dry powder Cirsium maritimum leaves and stems (1 kg) were dried overnight in a 40 ° C. cold air dryer and then finely pulverized in a crusher to obtain dried Cirsium maritimum powder (100 g).
(実施例6)乾燥粉砕物からの熱水による抽出方法
実施例5で得られたハマアザミの葉及び茎の乾燥粉砕物100gに熱水1.5Lを加え、抽出上清を濾別することにより、水と併せて抽出液(2L)を得た。更に、順次減圧濃縮、窒素ガス雰囲気下で減圧乾燥、凍結乾燥を行い、抽出物3(20g)を得た。
(Example 6) Extraction method with hot water from dried crushed product By adding 1.5 L of hot water to 100 g of dried crushed product of Cirsium maritimum leaves and stems obtained in Example 5, and filtering the extraction supernatant. , An extract (2 L) was obtained together with water. Further, the mixture was sequentially concentrated under reduced pressure, dried under reduced pressure and freeze-dried under a nitrogen gas atmosphere to obtain Extract 3 (20 g).
(実施例7)生葉及び生茎からの熱水による抽出方法
ハマアザミの生葉及び生茎の混合物(1kg)に熱水1Lを加え、抽出上清を濾別することにより、水と併せて抽出液(1.5L)を得た。更に、順次減圧濃縮、窒素ガス雰囲気下で減圧乾燥、凍結乾燥を行い、抽出物3(15g)を得た。
(Example 7) Extraction method from fresh leaves and fresh stems with hot water 1 L of hot water is added to a mixture (1 kg) of fresh leaves and fresh stems of Cirsium maritimum, and the extraction supernatant is filtered to extract the extract together with water. (1.5 L) was obtained. Further, the mixture was sequentially concentrated under reduced pressure, dried under reduced pressure and freeze-dried under a nitrogen gas atmosphere to obtain Extract 3 (15 g).
(実施例8)ハマアザミ抽出物の画分分離
ハマアザミの葉から実施例1のようにして得られた酢酸エチル抽出物500mgをシリカゲルクロマトグラフィーに供した。条件は、下記の通りである。
・シリカゲル:和光純薬製、Wakosil C−200、25g
・カラムサイズ;20mmφ×100cm
・溶離液:アセトン/ヘキサン+メタノール(濃度0w/w%〜100w/w%)、各500mL
このような条件で、0、5−1、5−2、10、20、30、50、100%アセトン画分及び100%メタノール画分の計9画分(図1)の試料を分取して、それぞれ試験例1によって分析した。
(Example 8) Fraction separation of Cirsium maritimum extract 500 mg of ethyl acetate extract obtained from the leaves of Cirsium maritimum as in Example 1 was subjected to silica gel chromatography. The conditions are as follows.
-Silica gel: Wakosil C-200, 25g, manufactured by Wako Pure Chemical Industries, Ltd.
-Column size: 20 mmφ x 100 cm
-Eluent: Acetone / Hexane + Methanol (concentration 0w / w% -100w / w%), 500mL each
Under these conditions, a total of 9 fractions (Fig. 1) of 0, 5-1, 5-2, 10, 20, 30, 50, 100% acetone fraction and 100% methanol fraction were sampled. Each was analyzed according to Test Example 1.
(実施例9)
さらに、実施例8で得られた画分のうちで試験例1の評価結果の高かった30%アセトン画分の精製を進めた。
すなわち、実施例8で得られた30%アセトン画分70mgを、以下の条件のHPLCに供した。
・析装置: 島津製作所製、LC−10A
・カラム: ナカライテスク社製、Cosmosil C18−AR−II
・カラムサイズ;10mmφ×250mm
・溶離液:80%メタノール
・流量: 1.5 ml/min
・入口圧: MPa
・検出器:紫外分光検出器(UV)
・カラム温度:35℃
・注入量:50μl
(Example 9)
Further, among the fractions obtained in Example 8, the 30% acetone fraction, which had the highest evaluation result in Test Example 1, was purified.
That is, 70 mg of the 30% acetone fraction obtained in Example 8 was subjected to HPLC under the following conditions.
・ Analysis device: LC-10A manufactured by Shimadzu Corporation
-Column: Cosmosil C18-AR-II manufactured by Nacalai Tesque
-Column size: 10 mmφ x 250 mm
-Eluent: 80% methanol-Flow rate: 1.5 ml / min
・ Inlet pressure: MPa
-Detector: Ultraviolet spectroscopic detector (UV)
-Column temperature: 35 ° C
・ Injection amount: 50 μl
上記の条件でHPLCを行い、紫外線吸収のあったピークを分取し、活性成分(シルシマリチン)を12mg得た。
1H NMR:(500 MHz, CDCl3): dH 7.90 (1H, d), 7.81 (1H, d), 6.97 (1H, m), 6.56, dd), 3.96(3H,s) 3.92(3H,s)
HPLC was performed under the above conditions, and the peaks that had absorbed ultraviolet rays were separated to obtain 12 mg of the active ingredient (silcimaritin).
1 H NMR: (500 MHz, CDCl 3 ): dH 7.90 (1H, d), 7.81 (1H, d), 6.97 (1H, m), 6.56, dd), 3.96 (3H, s) 3.92 (3H, s) )
(試験例1)β‐ヘキソサミニダーゼ遊離抑制の評価
1.細胞培養
RBL−2H3細胞を、10%(v/v)ウシ胎児血清(FBS:Sigma−Aldrich社製)、100U/mlのペニシリン(ナカライテスク社製)、および100μg/mlのストレプトマイシン(ナカライテスク社製)を含む、ダルベッコ改変イーグル培地(ナカライテスク社製、DMEM)中で培養した。この時、5%CO2を含む加湿雰囲気中で37℃の条件であった。
(Test Example 1) Evaluation of β-
2.βーヘキソサミニダーゼ遊離活性
上記1で培養したRBL−2H3細胞を、10%FBSを含むDMEM中に、2.5×105細胞/ウェルで、24ウェルプレートに播種し、37℃で一晩培養した。次いで、細胞をPBSで2回洗浄した。この細胞を、2時間50ng/mLのDNP特異的IgE(Sigma−Aldrich社製)を用いて感作した。細胞を、MT緩衝液で洗浄した後、MT緩衝液中に希釈したハマアザミ抽出試料または精製物を添加した。ここで、ハマアザミ抽出試料は、実施例1と同様の方法で、100%の酢酸エチルでハマアザミの葉または花を抽出処理後、濃縮したサンプルを10mg/mLの濃度になるようにジメチルスルホキシド(DMSO)に溶解し、MT緩衝液中に0.5%濃度になるよう希釈して使用した。実施例8および9で得られたハマアザミの抽出物から精製して得られたシルシマリチンは、濃縮したサンプルを10mg/mLの濃度になるようにジメチルスルホキシド(DMSO)に溶解し、MT緩衝液中に0.5%濃度になるよう希釈して使用した。同様に市販されているシルシマリチンも参考のため試験に供した。10分間のインキュベーション後、DNP−HSA(最終濃度50ng/mL)を添加し、そして培養物を30分間インキュベートした。上清を回収し、そして細胞を、0.1%ポリエチレングリコールモノ−p−イソオクチルフェニルエーテル(トリトンX100、ナカライテスク社製)を含むMT緩衝液で溶解した。各上清および細胞溶解物のアリコートを37℃で30分間、0.1 Mクエン酸緩衝液(pH 4.5)中で可溶化した、1mMのp−ニトロフェニルN−アセチル−D−グルコサミド(和光純薬社製)と共にインキュベートした。酵素反応を、2Mグリシン緩衝液(pH 10.4)を添加することにより停止し、吸光度を405nmで測定した。ハマアザミ抽出試料によるRBL−2H3細胞からβ−ヘキソサミニダーゼ放出活性の割合を、以下の式を用いて計算した。
酵素放出活性(%)={(細胞上清の吸収/細胞上清の吸収+細胞溶解物の吸収)×100}
2. β-hexosaminidase free activity The RBL-2H3 cells cultured in 1 above were seeded in a 24-well plate at 2.5 × 10 5 cells / well in DMEM containing 10% FBS, and 1 at 37 ° C. It was cultured in the evening. The cells were then washed twice with PBS. The cells were sensitized with 50 ng / mL DNP-specific IgE (manufactured by Sigma-Aldrich) for 2 hours. After washing the cells with MT buffer, diluted Cirsium maritimum extract sample or purified product was added to MT buffer. Here, the Cirsium maritimum extract sample is prepared by extracting the leaves or flowers of Cirsium maritimum with 100% ethyl acetate in the same manner as in Example 1, and then the concentrated sample is dimethylsulfoxide (DMSO) so as to have a concentration of 10 mg / mL. ), Diluted in MT buffer to a concentration of 0.5% and used. Silcimaritin obtained by purifying from the Cirsium maritimum extract obtained in Examples 8 and 9 was prepared by dissolving the concentrated sample in dimethyl sulfoxide (DMSO) to a concentration of 10 mg / mL in MT buffer. It was diluted to a concentration of 0.5% and used. Similarly, commercially available silcimaritin was also used in the test for reference. After 10 minutes of incubation, DNP-HSA (
Enzyme release activity (%) = {(absorption of cell supernatant / absorption of cell supernatant + absorption of cell lysate) x 100}
その結果をそれぞれ図2〜図5に示す。データは、3回の実験の平均±標準偏差で示している。 The results are shown in FIGS. 2 to 5, respectively. The data are shown as the mean ± standard deviation of the three experiments.
図2および図3からわかるように、ハマアザミの葉および花の抽出物に、特に優れたβ−ヘキソサミニザーゼ遊離抑制作用が見出された。 As can be seen from FIGS. 2 and 3, a particularly excellent β-hexosaminize release inhibitory effect was found in the leaf and flower extracts of Cirsium maritimum.
また、ハマアザミの葉の酢酸エチル抽出物カラムクロマトグラフィーによって分画した実施例8の試料について、図4に示すように、いくつかの分画(D.C.C.30、50、100)は、有意にβ‐ヘキソサミニダーゼの放出を減弱することがわかった。特に、D.C.C.30とD.C.C.50は50μg/mLで、86.1から88.6パーセント阻害、ポジティブコントロールとの比較でβ−ヘキソサミニダーゼの放出に対する強力な阻害効果を有していることがわかった。
In addition, as shown in FIG. 4, some fractions (
さらに、実施例9で得られたハマアザミ精製物または市販のシルシマリチンを用いた試験により、図5Aおよび図5Bに示す通り、濃度依存的なβ−ヘキソサミニダーゼの放出に対する強力な阻害効果が見られた。ここで、図5Aは、ハマアザミ精製物を使用した結果を示し、図5Bは、市販のシルシマリチンを使用した結果を示す。 Furthermore, tests using the purified Cirsium maritimum obtained in Example 9 or commercially available silcimaritin showed a strong inhibitory effect on the release of β-hexosaminidase in a concentration-dependent manner, as shown in FIGS. 5A and 5B. Was done. Here, FIG. 5A shows the result of using the purified Cirsium maritimum product, and FIG. 5B shows the result of using the commercially available cirsium maritimum.
(試験例2)生体を用いた抗体産生評価
1.動物と抗原
5週齢の雌C3H/HeJマウス(体重15〜20g)は、日本SLC(浜松、静岡県、日本)から購入した。動物を、室温24±3℃、12/12h(A.M.7:00−P.M.7:00)の明暗サイクルの条件で飼育した。実験計画は、高知県立大学の動物実験委員会(承認番号:2015−006)によって承認されている、動物実験のためのガイドラインに従った。抗原は、LHEであり、和光純薬から購入した。
(Test Example 2) Evaluation of antibody production using a
2.給餌、感作およびサンプリング
マウスは水とAIN−93G食餌を自由に摂取できるようにした。次いで、マウスを体重に応じて、10匹ずつからなる3グループに割り当て、4週間、以下の食餌を自由に供給した。
非感作グループ:AIN−93G
LHE感作グループ:AIN−93G
LHE感作−ハマアザミグループ:1%ハマアザミ(CMM)を添加したAIN−93G。
2. Feeding, Sensitization and Sampling Mice were given free access to water and an AIN-93G diet. Then, the mice were assigned to 3 groups consisting of 10 mice according to their body weights, and the following diets were freely supplied for 4 weeks.
Non-sensitized group: AIN-93G
LHE Sensitization Group: AIN-93G
LHE Sensitization-Cirsium maritimum group: AIN-93G with 1% Cirsium maritimum (CMM) added.
実験期間を通して、マウスの体重を3回/週記録した。1つの感作群のマウスは、14日目および21日目に、LHE50μgおよび4mgの水酸化アルミニウムを含む0.2mLのPBSを腹腔内投与した(LHE感作グループおよびLHE感作‐ハマアザミグループの両方)。非感作グループは、4mgの水酸化アルミニウムを含む0.2mLのPBSのみを腹腔内投与した。抗体レベルを評価するために、27日目に軽い麻酔下において、血液をマウスの眼窩静脈から得た。糞ペレットは、31日目に採取した。次に、糞ペレットをALPHA 2−4 LDplus(クリスト社製、オステロード、ドイツ)により乾燥した。これらのサンプルは、酵素結合免疫吸着アッセイ(ELISA)に供し、総抗体およびLHEに対する特異的抗体を測定した。 Mice body weight was recorded 3 times / week throughout the experiment. Mice in one sensitization group received intraperitoneally 0.2 mL PBS containing 50 μg LHE and 4 mg aluminum hydroxide on days 14 and 21 (LHE sensitization group and LHE sensitization-thistle group). Both). The non-sensitized group received only 0.2 mL PBS containing 4 mg aluminum hydroxide intraperitoneally. To assess antibody levels, blood was obtained from the orbital veins of mice on day 27 under light anesthesia. Fecal pellets were collected on day 31. The fecal pellets were then dried with ALPHA 2-4 LDplus (Cristo, Osterode, Germany). These samples were subjected to an enzyme-linked immunosorbent assay (ELISA) to measure total antibody and specific antibody against LHE.
3.血清LHE特異的IgE、IgA、IgG1、およびIgG2aの測定
LHE特異的IgE、IgA、IgG1、およびIgG2aのレベルは、酵素結合免疫吸着アッセイ(ELISA)を用いて測定した。具体的には、ヌンク‐イムノプレート(サーモサイエンティフィック社製、ロスキレ、デンマーク)を、LHEを含む0.1M炭酸緩衝液(pH 9.6)100μLでコーティングし、そして4℃で一晩インキュベートした。ウェルを、0.05%ポリオキシエチレン(20)ソルビタンモノラウレート(Tween20、和光純薬、大阪、日本)を含有するPBS(PBST)で洗浄した後、1%BSA/PBST溶液にて37℃で1時間インキュベートした。各血清試料の100μL量(IgEとIgAでは1:50、IgG1、IgG2aでは、1:250の割合で、1%BSAを含むPBSTにて希釈)を各ウェルに適用し、そして混合物を37℃にて1時間インキュベートした。200μLのPBSTで各ウェルを5回洗浄後、HRP結合ウサギ抗マウスIgE(1%BSAを含有するPBSTにて1:1000希釈、サンタクルーズバイオテクノロジー社製)100μL、HRP結合ウサギ抗マウスIgA(1%BSAを含有するPBSTにて1:1000希釈、サンタクルーズバイオテクノロジー社製)、HRP結合ウサギ抗マウスIgG1(1%BSAを含有するPBSTにて1:5000希釈、サンタクルーズバイオテクノロジー社製)、およびHRP結合ウサギ抗マウスIgG2a(1%BSAを含有するPBSTにて1:5000希釈、サンタクルーズバイオテクノロジー社製)を各ウェルに添加し、そして37℃にて1時間インキュベートした。各ウェルを200μLのPBSTで5回洗浄後、合成基質であるο−phenylendiamine(一級;和光純薬工業)2mgを5mlのクエン酸バッファーに加え、さらにH2O2(特級;和光純薬工業)を0.006%加えたものを、各ウェルに100μlずつ入れ、室温にて1−5分以内の反応後、2.5M H2SO4(ナカライテスク社製)50μLで反応を終了させ、そして490nmでの吸光度をxMarkTMマイクロプレートリーダー(バイオラッドラボラトリー社製)で測定した。
3. 3. Serum LHE-Specific IgE, IgA, IgG1, and IgG2a Measurements LHE-specific IgE, IgA, IgG1, and IgG2a levels were measured using an enzyme-linked immunosorbent assay (ELISA). Specifically, Nunk-Imnoplate (Thermo Scientific, Roskilde, Denmark) is coated with 100 μL of 0.1 M carbonate buffer (pH 9.6) containing LHE and incubated overnight at 4 ° C. did. Wells are washed with PBS (PBST) containing 0.05% polyoxyethylene (20) sorbitan monolaurate (
4.血清総IgE、IgA、IgGの測定
総IgE、IgGおよびIgAレベルを、製造業者の説明書に従ってELISAキット(eBioscience社製)を用いて定量した。
4. Measurement of Serum Total IgE, IgA, IgG Total IgE, IgG and IgA levels were quantified using an ELISA kit (manufactured by eBioscience) according to the manufacturer's instructions.
5.糞便中の総IgAとLHE特異的IgAの測定
糞ペレットの抽出物は、以下のようにして調製した。すなわち、糞ペレット100mgを、PBS 1mLに混合し、そして一晩4℃でインキュベートした。その後、ペレットを5分間ボルテックスした。この混合物を遠心分離(4,000×gで、15分間)後、上清を回収し、−30℃で保存した。総IgAおよびLHE特異的IgAの検出のための手順は、上述と同様に行った。
5. Measurement of total IgA and LHE-specific IgA in feces Extracts of fecal pellets were prepared as follows. That is, 100 mg of fecal pellets were mixed with 1 mL of PBS and incubated overnight at 4 ° C. The pellet was then vortexed for 5 minutes. The mixture was centrifuged (4,000 xg for 15 minutes), the supernatant was collected and stored at -30 ° C. The procedure for detecting total IgA and LHE-specific IgA was the same as described above.
3つのグループの間に体重差は認められなかった。 No weight difference was observed between the three groups.
血清中のLHE特異的IgE、IgA、IgG1、およびIgG2aの産生の確認の結果(図6〜図8)、以下のことが分かった。なお、図6および図7においては、データは、10匹のマウスの平均±標準誤差で示され、星印は、p<0.05を表わし、十字印は、p<0.10を表わす。また、図8においては、データは、7匹のマウスの平均±標準誤差で示され、星印は、p<0.05を表わし、十字印は、p<0.10を表わす。 As a result of confirming the production of LHE-specific IgE, IgA, IgG1 and IgG2a in serum (FIGS. 6 to 8), the following was found. In addition, in FIG. 6 and FIG. 7, the data is shown by the average ± standard error of 10 mice, the star mark represents p <0.05, and the cross mark represents p <0.10. Also, in FIG. 8, the data are shown as mean ± standard error of 7 mice, where the stars represent p <0.05 and the crosses represent p <0.10.
食餌によって1%ハマアザミ抽出物を与えた場合は、抗原特異IgEの産生を抑える傾向があることが示唆された。(図6A) It was suggested that when 1% Cirsium maritimum extract was fed by diet, it tended to suppress the production of antigen-specific IgE. (Fig. 6A)
食餌によって1%ハマアザミ抽出物を与えた場合は、抗原特異IgAの産生を促進することが示唆された(図6B)。 It was suggested that feeding 1% Cirsium maritimum extract by diet promotes the production of antigen-specific IgA (Fig. 6B).
食餌によって1%ハマアザミ抽出物を与えた場合は、抗原特異IgG1の産生に影響しないと考えられた(図6C)。 It was considered that feeding 1% Cirsium maritimum extract by diet did not affect the production of antigen-specific IgG1 (Fig. 6C).
食餌によって1%ハマアザミ抽出物を与えた場合は、抗原特異IgG2aの産生に影響しないと考えられた(図6D)。 It was considered that feeding 1% Cirsium maritimum extract by diet did not affect the production of antigen-specific IgG2a (Fig. 6D).
ThバランスでみるとIgG1/IgG2a比に違いの変化は認められず、IgGにおいてはTh2(免疫抑制)へシフトしないことが示唆された。 No change in the IgG1 / IgG2a ratio was observed in the Th balance, suggesting that IgG does not shift to Th2 (immunosuppressive drug).
また、1%ハマアザミ抽出物投与では、抗原特異IgEの産生を抑える傾向があるが、総IgEを抑えるわけではないことが明らかとなった。1%ハマアザミ抽出物投与では血清中の抗原特異IgA産生を促進するが、総IgAを促進するわけではないことが明らかとなった。ハマアザミ群の血清中の総IgG1は、ポジディブコントロールであるLHE感作群及びネガティブコントロールである非感作群と比較し同程度であった。一方、LHE感作群では非感作群と比較し、有意な上昇が認められた。(図6および図7)
このことは、ハマアザミにアレルギーを抑制する作用があることを意味すると考えられる。
It was also revealed that administration of 1% Cirsium maritimum extract tends to suppress the production of antigen-specific IgE, but does not suppress the total IgE. It was revealed that administration of 1% Cirsium maritimum extract promotes antigen-specific IgA production in serum, but does not promote total IgA. The total IgG1 in the serum of the Cirsium maritimum group was comparable to that of the positive control LHE sensitized group and the negative control non-sensitized group. On the other hand, a significant increase was observed in the LHE sensitized group as compared with the non-sensitized group. (Fig. 6 and Fig. 7)
This is considered to mean that Cirsium maritimum has an effect of suppressing allergies.
1%ハマアザミ抽出物投与では、糞便中抗原特異IgAの産生を促進することが示唆された。1%ハマアザミ抽出物投与では糞便中抗原特異IgAの産生を促進するが、総IgAを促進するわけではないことが明らかとなった。(図8)。このことは、ハマアザミに粘膜免疫の上昇作用があることを意味すると考えられる。 It was suggested that administration of 1% Cirsium maritimum extract promotes the production of antigen-specific IgA in feces. It was revealed that administration of 1% Cirsium maritimum extract promotes the production of antigen-specific IgA in feces, but does not promote total IgA. (Fig. 8). This is considered to mean that Cirsium maritimum has an effect of increasing mucosal immunity.
(試験例3)脾臓リンパ球を用いた抗体産生評価
卵白オボアルブミン(OVA)感作したマウスを用いて、特に抗体を産生する組織である脾臓からリンパ球を分離し、酢酸エチル抽出したハマアザミの抗体産生に及ぼす影響を評価した。さらに、抗アレルギー効果についてTh1/Th2バランスについて検討した。
1.動物と抗原
5週齢の雌BALB/cマウス(体重15〜20g)は、日本SLC(浜松、静岡県、日本)から購入した。動物を、24±3℃で維持し、12時間の明/暗サイクルで部屋に収容した。実験計画は、高知県立大学の動物実験委員会によって承認されている、動物実験のためのガイドラインに従った。抗原は、卵白オボアルブミン(OVA)であり、和光純薬から購入した。
(Test Example 3) Evaluation of antibody production using spleen lymphocytes Lymphocytes were isolated from the spleen, which is an antibody-producing tissue, using egg white ovoalbumin (OVA) -sensitized mice, and ethyl acetate-extracted Hama thistle The effect on antibody production was evaluated. Furthermore, the Th1 / Th2 balance was examined for the anti-allergic effect.
1. 1. Animals and Antigens 5-week-old female BALB / c mice (body weight 15-20 g) were purchased from Japan SLC (Hamamatsu, Shizuoka Prefecture, Japan). Animals were maintained at 24 ± 3 ° C. and housed in the room with a 12 hour light / dark cycle. The experimental design followed the guidelines for animal experiments approved by the Animal Experiment Committee of Kochi Prefectural University. The antigen was egg white ovalbumin (OVA), which was purchased from Wako Junyaku.
2.給餌、感作およびサンプリング
マウスは水とMF飼料(オリエンタル酵母工業)を自由に摂取できるようにした。
2. Feeding, Sensitization and Sampling Mice were given free access to water and MF feed (Oriental Yeast Co., Ltd.).
マウスの感作は、1週間間隔で合計3回の腹腔免疫を行うことで実行した。すなわち、それぞれ、OVA50μgおよび水酸化アルミニウムの4mgを含む0.2mLのPBSを腹腔内投与した。抗体産生の状況を評価するために、27日目に軽い麻酔下において、血液をマウスの眼窩静脈から得た。抗体産生が確認できたマウスから、脾臓を取りだした。 Mice sensitization was performed by performing a total of 3 peritoneal immunizations at weekly intervals. That is, 0.2 mL of PBS containing 50 μg of OVA and 4 mg of aluminum hydroxide was intraperitoneally administered, respectively. To assess the status of antibody production, blood was obtained from the orbital veins of mice on day 27 under light anesthesia. The spleen was taken out from the mouse in which antibody production was confirmed.
まず、5mLのチューブにRPMI1640培地を3mL入れ、取りだした脾臓を浸した。その後、5mLディッシュにRPMI1640培地を5mL入れ、脾臓をすりガラス2枚ですり潰した。ナイロンメッシュ(グライナー:70μmメッシュ)を使い、50mLの遠沈管に細胞懸濁液を作り、400×gで5分間遠心分離した。遠心分離後の上清を除去し、新しいRPMI1640培地を10mL加えて懸濁した。この操作を2回繰り返した。その後、RPMI1640培地を10mL加えて細胞懸濁液を作った。 First, 3 mL of RPMI1640 medium was placed in a 5 mL tube, and the removed spleen was immersed. Then, 5 mL of RPMI1640 medium was placed in a 5 mL dish, and the spleen was ground with two frosted glasses. Using a nylon mesh (Gliner: 70 μm mesh), a cell suspension was prepared in a 50 mL centrifuge tube and centrifuged at 400 × g for 5 minutes. The supernatant after centrifugation was removed, and 10 mL of fresh RPMI1640 medium was added and suspended. This operation was repeated twice. Then, 10 mL of RPMI1640 medium was added to prepare a cell suspension.
別の15mL遠沈管にLympholyte(コスモ・バイオ)を4mL入れておき、この上に細胞懸濁液を静かに重層し、1000×gで30分間遠心した。中間層に集まったリンパ球をピペットで取り出し、15mLの遠沈管に移した後、新しいRPMI1640培地を10mL加えて懸濁した。さらに、350×gで5分間遠心した。遠心分離後の上清を除去し、新しいRPMI1640培地を10mL加えて懸濁した。この操作を2回繰り返した。その後、RPMI1640培地を10mL加えて細胞懸濁液を作った。 4 mL of Lymfluorite (Cosmo Bio) was placed in another 15 mL centrifuge tube, and the cell suspension was gently layered on this and centrifuged at 1000 × g for 30 minutes. Lymphocytes collected in the middle layer were pipetted out, transferred to a 15 mL centrifuge tube, and then 10 mL of fresh RPMI1640 medium was added and suspended. Further, it was centrifuged at 350 × g for 5 minutes. The supernatant after centrifugation was removed, and 10 mL of fresh RPMI1640 medium was added and suspended. This operation was repeated twice. Then, 10 mL of RPMI1640 medium was added to prepare a cell suspension.
このようにして得られた脾臓リンパ球溶液(2×106cells/ml)を、24穴プレートに4×106cells/mlの脾臓リンパ球溶液をそれぞれ0.5ml播いた。培地で添加した濃度の2倍量のハマアザミ抽出物(0.2、2、10、20、100、200、1000mg/ml)を0.5ml添加し、2.5 mg/mLのアレルゲン(OVA)を10μL(25μgのアレルゲン)添加し、抗原刺激した。そのまま脾臓リンパ球を72時間培養した。 The spleen lymphocyte solution thus obtained (2 × 10 6 cells / ml) was seeded on a 24-well plate with 0.5 ml each of 4 × 10 6 cells / ml of the spleen lymphocyte solution. Add 0.5 ml of Cirsium maritimum extract (0.2, 2, 10, 20, 100, 200, 1000 mg / ml) at twice the concentration added in the medium, and add 2.5 mg / mL allergen (OVA). Was added in an amount of 10 μL (25 μg of allergen) and stimulated with an antigen. The spleen lymphocytes were cultured as they were for 72 hours.
この後、培地上清中に含まれるOVA特異的抗体IgE、IgG1、およびIgG2aの量を測定した。測定結果を図9に示す。さらに、測定結果から得られたIg2a/IgG1の割合を図10に示す。 After that, the amounts of OVA-specific antibodies IgE, IgG1, and IgG2a contained in the culture medium supernatant were measured. The measurement results are shown in FIG. Furthermore, the ratio of Ig2a / IgG1 obtained from the measurement results is shown in FIG.
この結果から、IgEおよびIgG1は濃度依存的に抗体価が低下していることがわかった。抗体産生が活発な脾臓においてアレルギーに関係する抗体価が低下したことから、ハマアザミ抽出物は、血清中の抗体量に加え、抗体産生の中心である脾臓リンパ球においてもアレルギーを抑制する可能性が示唆された。 From this result, it was found that the antibody titers of IgE and IgG1 decreased in a concentration-dependent manner. Since the antibody titer related to allergy decreased in the spleen where antibody production is active, the Hama thistle extract may suppress allergies not only in the amount of antibody in serum but also in spleen lymphocytes, which are the center of antibody production. It was suggested.
Th1/Th2バランスに関しては、ハマアザミ抽出物の濃度依存的に、Th1値が上昇し、Th1/Th2がバランスの取れた良好な状態になっていることがわかる。このことからも、ハマアザミ抽出物が、アレルギーを抑制する可能性が示唆される。 Regarding the Th1 / Th2 balance, it can be seen that the Th1 value increases depending on the concentration of the Cirsium maritimum extract, and Th1 / Th2 is in a well-balanced and good state. This also suggests that Cirsium maritimum extract may suppress allergies.
(試験例4)
試験例1と同様に調製したRBL−2H3細胞を、96ウェルのブラックマイクロプレートに6.0×104細胞/ウェルとなるよう播種し、37℃で一晩培養した。次いで、細胞をPBSで2回洗浄した。この細胞に、2時間、50ng/mLのDNP特異的IgE(抗DNP−IgE抗体、Sigma−Aldrich社製)を用いて感作した。その後、細胞をPBSで2回洗浄した後、Fluo−3AM(アセトキシメチル)とともに1時間反応させた。反応後、さらにPBSで2回洗浄し、PBSで溶解した100μlの試料を添加し10分間反応させた。その後、MTバッファーで0.625μg/mlに調整したDNP−HSAを10μl加え、ただちに蛍光・発光マイクロプレートリーダー(Thermo)で、485nm、538nmの吸光度を測定した。
ここで、試料としては、実施例1で調製したハマアザミの葉の抽出物(1μg/ml、10μg/mlに濃度を調整)、ブランク(DNP−HSAを含まないMTバッファー)、およびコントロール(ハマアザミを含まないPBS)を使用した。
(Test Example 4)
The RBL-2H3 cells prepared in the same manner as in Test Example 1, were inoculated to a 96-well black microplate 6.0 × 10 4 cells / well and cultured overnight at 37 ° C.. The cells were then washed twice with PBS. The cells were sensitized with 50 ng / mL DNP-specific IgE (anti-DNP-IgE antibody, manufactured by Sigma-Aldrich) for 2 hours. The cells were then washed twice with PBS and then reacted with Fluo-3AM (acetoxymethyl) for 1 hour. After the reaction, the mixture was further washed twice with PBS, 100 μl of the sample dissolved in PBS was added, and the reaction was carried out for 10 minutes. Then, 10 μl of DNP-HSA adjusted to 0.625 μg / ml with MT buffer was added, and the absorbance at 485 nm and 538 nm was immediately measured with a fluorescence / emission microplate reader (Thermo).
Here, as samples, the extract of Cirsium maritimum leaf prepared in Example 1 (concentration was adjusted to 1 μg / ml and 10 μg / ml), blank (MT buffer containing no DNP-HSA), and control (Cirsium maritimum) were used. PBS) not included was used.
データは、平均±標準偏差(n=4)で表わす。コントロールと比較して、ハマアザミを添加した場合には、顕著な抑制効果が見られた(図11)。 Data are represented by mean ± standard deviation (n = 4). Compared with the control, when Cirsium maritimum was added, a remarkable inhibitory effect was observed (Fig. 11).
(試験例5)
PBSで1μg/20μL(50μg/mL)に調整した抗−DNP IgE抗体(Sigma)を麻酔下のBALB/cマウスの耳介に皮内投与した。23時間後、PBSで5%に調整した試料溶液を強制経口投与(5mg/100μg/匹(20g);250mg/5mL/kg)した。コントロールはPBSを同様に強制経口投与した。1時間後、1%エバンスブルーを含むPBSで100μg/200μL(500μg/mL)に調整したDNP−HSA(Sigma)を静脈に投与した。DNP−HASを投与30分後、マウスの両耳介厚をthickness gaugeで3回測定した後、頸椎脱臼によりマウスを屠殺し、耳介を採取した。採取した耳介は、1mLのホルムアミドで63℃、48hインキュベートし耳から色素が抽出されたことを確認し、試験管から耳を取り除き、上清の吸光度を610nmで測定した。
(Test Example 5)
Anti-DNP IgE antibody (Sigma) adjusted to 1 μg / 20 μL (50 μg / mL) with PBS was intradermally administered to the auricle of anesthetized BALB / c mice. After 23 hours, the sample solution adjusted to 5% with PBS was orally administered by gavage (5 mg / 100 μg / animal (20 g); 250 mg / 5 mL / kg). Controls were similarly gavage orally administered PBS. One hour later, DNP-HSA (Sigma) adjusted to 100 μg / 200 μL (500 μg / mL) with PBS containing 1% Evans blue was intravenously administered. Thirty minutes after administration of DNP-HAS, the thickness of both auricles of the mice was measured three times with a tickness gauge, and then the mice were killed by cervical dislocation and the auricles were collected. The collected auricle was incubated with 1 mL of formamide at 63 ° C. for 48 hours to confirm that the pigment was extracted from the ear, the ear was removed from the test tube, and the absorbance of the supernatant was measured at 610 nm.
その結果を図12に示す。図12における説明は以下を意味する。
Untreated control:抗体感作なし‐抗原投与
Anti DNP−HSA:抗体感作有‐抗原投与
Anti DNP−HSA‐CMM:抗体感作有‐ハマアザミ溶液投与‐抗原投与
Ear swellingは、耳介厚測定結果を指す。
Ear dye intensityは、Untreated controlの色素量を1とした時の相対的値で示す。
The result is shown in FIG. The description in FIG. 12 means the following.
United control: No antibody sensitization-Antigen administration Anti DNP-HSA: Antibody sensitization Yes-Antigen administration Anti DNP-HSA-CMM: Antibodies sensitization-Cirsium maritimum solution administration-Antigen administration
Ear swelling refers to the result of auricle thickness measurement.
Ear dye intensity is shown as a relative value when the amount of dye in the United control is 1.
ハマアザミの経口投与により、耳介の膨張が抑えられ、色素量も抑制できていることがわかる。 It can be seen that oral administration of Cirsium maritimum suppresses the swelling of the auricle and the amount of pigment.
(処方例)
以下の各処方例中の数値の単位は、全体量を100とした、「w/w%」で示す。
(Prescription example)
The unit of the numerical value in each of the following prescription examples is indicated by "w / w%" with the total amount as 100.
(処方例1)アレルギーの予防または治療のための組成物(錠剤)
上記の実施例で得られた抽出物を用いて、常法により下記組成のアレルギー予防又は治療のための錠剤を製造することができる。ここで、ハマアザミ抽出物としては、実施例1で得られるような試料を用いる。
Using the extract obtained in the above example, tablets having the following composition for prevention or treatment of allergies can be produced by a conventional method. Here, as the Cirsium maritimum extract, a sample as obtained in Example 1 is used.
(処方例2)アレルギー予防または治療のための組成物(顆粒剤)
上記の実施例1で得られた抽出物を用いて、下記組成を混合及び撹拌して均一に調製し、流動層造粒装置により顆粒を得ることができる。顆粒剤は、飲料と共に服用することが可能である。
(Prescription example 2) Composition for prevention or treatment of allergies (granule)
Using the extract obtained in Example 1 above, the following composition can be mixed and stirred to uniformly prepare the granules, and granules can be obtained by a fluidized bed granulator. Granules can be taken with beverages.
(処方例3)アレルギー予防または治療のための飲料
上記の実施例1で得られた抽出物を用いて、常法により下記組成のアレルギー予防又は治療のための飲料を製造することができる。
(Prescription Example 3) Beverage for Allergy Prevention or Treatment A beverage for allergy prevention or treatment having the following composition can be produced by a conventional method using the extract obtained in Example 1 above.
(処方例5)お茶
(処方例):粉末茶
成 分 配合量
ハマアザミ水抽出物(粉末) 22
香料 3
デキストリン 75
合 計 100
(処方例):粉末茶
成 分 配合量
ハマアザミ熱水抽出物(粉末) 22
香料 3
デキストリン 75
合 計 100
(Prescription example 5) Tea (Prescription example): Powdered tea
Cirsium maritimum water extract (powder) 22
Total 100
(Prescription example): Powdered tea
Cirsium maritimum hot water extract (powder) 22
Total 100
(処方例)
水900mlを60℃まで加熱し、これにハマアザミ葉または茎、または葉及び茎の混合物30gを加え6分間抽出した。これを30メッシュのストレーナーで残渣を除去し、濾紙濾過(工業用濾紙No.26:ADVANTEC社製、捕集粒子径=3μm)により清澄化を行い、茶760mlを得た。
(Prescription example)
900 ml of water was heated to 60 ° C., and 30 g of Cirsium maritimum leaves or stems or a mixture of leaves and stems was added thereto, and the mixture was extracted for 6 minutes. The residue was removed with a 30-mesh strainer and clarified by filter paper filtration (industrial filter paper No. 26: manufactured by ADVANTEC, collected particle size = 3 μm) to obtain 760 ml of tea.
(処方例)
ハマアザミ葉及び茎部100gを長さ3mm程度に刻んだものを常法により100℃において1時間撹拌して焙煎した。
この組成物を浸透性の良い薄紙製袋に詰めてティ−パック等の袋部を得た。この袋部1個当たりに含まれるハマアザミ葉及び茎部粉砕物は、1.2gである。
(Prescription example)
100 g of Cirsium maritimum leaves and stems were chopped to a length of about 3 mm and roasted by stirring at 100 ° C. for 1 hour by a conventional method.
This composition was packed in a thin paper bag having good permeability to obtain a bag portion such as a tea pack. The amount of Cirsium maritimum leaf and stalk crushed product contained in each bag is 1.2 g.
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