JP2007254333A - Microbial cell-containing composition having inflammation suppressive action - Google Patents
Microbial cell-containing composition having inflammation suppressive action Download PDFInfo
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- JP2007254333A JP2007254333A JP2006079369A JP2006079369A JP2007254333A JP 2007254333 A JP2007254333 A JP 2007254333A JP 2006079369 A JP2006079369 A JP 2006079369A JP 2006079369 A JP2006079369 A JP 2006079369A JP 2007254333 A JP2007254333 A JP 2007254333A
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Abstract
Description
発明の分野
本発明は、炎症抑制作用のある菌体含有組成物に関する。より詳しくは、本発明は、ヒトを含む動物腸内または発酵食品から分離される細菌であって、特定の属に属するグラム陽性細菌からなる群より選択される細菌を含んでなる組成物に関する。また本発明は、炎症抑制作用を有する飲食品に関する。
The present invention relates to a fungus-containing composition having an anti-inflammatory action. More particularly, the present invention relates to a composition comprising bacteria selected from the group consisting of gram-positive bacteria belonging to a specific genus, wherein the bacteria are isolated from animal intestines including humans or fermented foods. Moreover, this invention relates to the food-drinks which have an inflammation suppression effect.
背景技術
関節炎は、関節滑膜付近において発症する炎症性疾患である。特に、関節リウマチ（Rheumatoid arthritis, RA）（または、リウマチ性関節炎）は関節の滑膜の慢性炎症により骨組織が傷害される、原因不明の慢性炎症疾患である。その有病率は、世界人口の１％（約５０００万人）であり、最も頻度の高い膠原病である。
BACKGROUND ART Arthritis is an inflammatory disease that develops near the synovial membrane. In particular, rheumatoid arthritis (RA) (or rheumatoid arthritis) is a chronic inflammatory disease of unknown cause in which bone tissue is damaged by chronic inflammation of the joint synovium. Its prevalence is 1% of the world population (about 50 million people) and is the most common collagen disease.
一般に、関節リウマチの患者は、罹病年数とともに関節の機能障害を来たし、日常生活に支障を来たすことが多い。しかしながら、現行の薬物治療では、根本的な治癒をもたらすことは困難であると言われている。このために、治療では通常、その症状に応じてステロイド剤、非ステロイド剤系抗炎症剤、免疫調整剤、免疫抑制剤が用いられる。これらの薬剤は、継続使用が必要とされ、副作用も現れることがあるために、慎重な薬剤療法が必要とされる。 In general, patients with rheumatoid arthritis often suffer from joint dysfunction with the morbidity, and often interfere with daily life. However, current medications are said to be difficult to bring about radical healing. For this reason, steroids, non-steroidal anti-inflammatory agents, immunomodulators, and immunosuppressants are usually used in treatment depending on the symptoms. These drugs require continued drug use and may cause side effects, necessitating careful drug therapy.
このため、薬剤使用の軽減と炎症症状改善を伴うものであって、副作用が少なく、より安全に使用することができる薬剤または食品の提供が望まれている。このような薬剤または食品の提供は、患者のＱＯＬ（クオリティ・オブ・ライフ）の向上に役立つことが期待される。 Therefore, it is desired to provide a drug or food that is accompanied by reduction of drug use and improvement of inflammatory symptoms, has few side effects, and can be used more safely. Providing such drugs or foods is expected to help improve the quality of life (QOL) of patients.
一方で、近年、腸内フローラの研究が進展し、腸内フローラが宿主の健康や疾病に密接に関係していることが明らかとなり、乳酸菌やビフィズス菌等をプロバイオティクスなどの様式で様々な疾病の予防や症状改善のために用いる試みが盛んに行われている。 On the other hand, in recent years, research on intestinal flora has progressed, and it has become clear that intestinal flora is closely related to the health and diseases of the host, and lactic acid bacteria and bifidobacteria have been used in various forms such as probiotics. There are many attempts to use it to prevent disease and improve symptoms.
例えば、特開２０００−１２５８１０号公報（特許文献１）には、酵母菌と乳酸菌とからなる、炎症抑制作用及び感染症防御作用のある濃縮飲料が開示されている。また特開２００４−９１４３３号公報（特許文献２）には、３〜８種の乳酸菌と酵母菌との混合菌体を含む、炎症性疾患改善用組成物が開示されている。しかしながら、これらの効果は必ずしも満足できるものではなく、また使用する菌も複数必要であり、工程も煩雑である。またエンテロコッカス属を使用することについても何等開示されていない。 For example, Japanese Unexamined Patent Publication No. 2000-125810 (Patent Document 1) discloses a concentrated beverage having an anti-inflammatory action and an infectious disease-protecting action, comprising yeast and lactic acid bacteria. Japanese Patent Application Laid-Open No. 2004-91433 (Patent Document 2) discloses an inflammatory disease-improving composition containing a mixed cell of 3 to 8 lactic acid bacteria and yeast. However, these effects are not always satisfactory, and a plurality of bacteria to be used are necessary, and the process is complicated. There is also no disclosure about the use of Enterococcus.
また特開平１１−２５９２８１号公報（特許文献３）には、特定のエンテロコッカス属菌の死菌体を使用した免疫調整剤が開示されている。しかしながら、ここでは単に細胞等に対する大腸菌感染の防御効果が確認されているにすぎない。 JP-A-11-259281 (Patent Document 3) discloses an immunomodulator using a dead cell of a specific Enterococcus genus. However, here, only the protective effect of E. coli infection on cells and the like has been confirmed.
乳酸菌の一つであるエンテロコッカス・フェカリス・ＥＣ−１２株（Enterococcus faecalis EC-12）（以下において「ＥＣ−１２株」と略すことがある）は、その死菌体に、整腸作用、抗腫瘍作用、皮膚アレルギー改善作用等があることが報告されている（例えば、「食品と開発」、Vol.39、No.10、６１〜６３頁（非特許文献１）。しかしながら、関節炎等の炎症性疾患への効果に関しては本発明者らの知る限り、何等報告されていない。 Enterococcus faecalis EC-12 (hereinafter referred to as “EC-12 strain”), which is one of lactic acid bacteria, has an intestinal action and antitumor effect on its dead cells. It has been reported that there are effects, skin allergy improving action, etc. (for example, “Food and Development”, Vol. 39, No. 10, pp. 61-63 (Non-patent Document 1). As far as the present inventors know about the effect on the disease, nothing has been reported.
本発明者らは今般、ヒトを含む動物腸内または発酵食品から分離されるグラム陽性細菌の一つである、ＥＣ−１２菌株の摂取により、コラーゲン誘発関節炎（collagen-induced arthritis, CIA）が顕著に改善されることを予想外にも見出した。本発明はかかる知見に基づくものである。 The present inventors are prominent in collagen-induced arthritis (CIA) due to ingestion of EC-12 strain, one of Gram-positive bacteria isolated from animal intestines including human and fermented foods. Unexpectedly found that it is improved. The present invention is based on such knowledge.
本発明の目的は、日常生活において容易に摂取することができ、かつ、副作用の極めて少ない、医薬または飲食品として使用可能な、炎症の進行抑制またはその症状の改善効果を有する組成物を提供することにある。 An object of the present invention is to provide a composition that can be easily ingested in daily life and that can be used as a medicine or a food or drink with extremely few side effects and that has an effect of suppressing the progression of inflammation or improving the symptoms thereof. There is.
本発明による組成物は、ヒトを含む動物腸内または発酵食品から分離される細菌であって、エンテロコッカス属（Enterococcus）、ビフィドバクテリウム属（Bifidobacterium）、ラクトバシルス属（Lactobacillus）、ストレプトコッカス属（Streptococcus）、および、ラクトコッカス属（Lactococcus）に属する細菌からなる群より選択される少なくとも１種以上の細菌を有効成分として含んでなるものであって、炎症またはこれに関連する状態の進行抑制または改善に用いられる。 The composition according to the present invention is a bacterium isolated from the animal intestinal or fermented foods including human, Enterococcus (Enterococcus), bifidobacteria (Bifidobacterium), Lactobacillus (Lactobacillus), Streptococcus (Streptococcus ) And at least one bacterium selected from the group consisting of bacteria belonging to the genus Lactococcus as an active ingredient, which suppresses or improves the progress of inflammation or a condition related thereto Used for.
本発明の好ましい態様によれば、前記細菌は死菌体である。 According to a preferred embodiment of the present invention, the bacterium is a dead cell.
本発明の別の態様によれば、前記有効成分を有効量含んでなる、飲食品であって、炎症またはこれに関連する状態の進行抑制または改善に用いられる飲食品が提供される。 According to another aspect of the present invention, there is provided a food or drink comprising an effective amount of the active ingredient, which is used for suppressing or improving the progression of inflammation or a state related thereto.
本発明のさらに別の態様によれば、前記有効成分を有効量含んでなる、飲食品であって、炎症またはこれに関連する状態の進行抑制または改善する機能が表示された飲食品が提供される。 According to still another aspect of the present invention, there is provided a food or drink comprising an effective amount of the active ingredient, wherein the food or drink displays a function for suppressing or improving the progress of inflammation or a state related thereto. The
本発明によれば、有効成分を医薬品または飲食品として摂取することによって、炎症またはこれに関連する状態の進行を抑制するか、または炎症またはこれに関連する状態を改善することができる。本発明における有効成分は、ヒトを含む動物腸内または発酵食品から分離される細菌またはその死菌体であり、これまでの報告から、副作用がほとんど無く安全性が高いことは明らかである。このため、本発明による組成物、または飲食品は、副作用が殆ど無く、安全性に優れたものである。よって、これらは日常生活において容易に摂取することができる。さらに、本発明による組成物または飲食品は、リウマチ性関節炎の治療におけるサポート食品として用いることで関節破壊により生じる関節痛や関節の変形を抑制し、日常生活での動作障害を軽減できる。またリウマチ性関節炎の影響による生活習慣病の併発も抑制することが期待できる。 ADVANTAGE OF THE INVENTION According to this invention, by taking an active ingredient as a pharmaceutical or food / beverage products, progress of inflammation or the state relevant to this can be suppressed, or inflammation or the state relevant to this can be improved. The active ingredient in the present invention is bacteria isolated from animal intestines including humans or fermented foods or dead cells thereof, and it is clear from previous reports that there are almost no side effects and high safety. For this reason, the composition or food-drinks by this invention have few side effects, and are excellent in safety. Therefore, they can be easily taken in daily life. Furthermore, the composition or the food or drink according to the present invention can be used as a support food in the treatment of rheumatoid arthritis, thereby suppressing joint pain and joint deformation caused by joint destruction, and reducing operational disturbances in daily life. It can also be expected to suppress the complication of lifestyle-related diseases due to the effects of rheumatoid arthritis.
微生物の寄託
エンテロコッカス・フェカリス・ＥＣ−１２株（Enterococcus faecalis EC-12）は、平成１７年（２００５年）２月２５日（原寄託日）付で独立行政法人産業技術総合研究所 特許生物寄託センター（〒305-5466 日本国茨城県つくば市東１丁目１番地１ 中央第６）に寄託された。受託番号は、ＦＥＲＭ ＢＰ−１０２８４である。
Deposit of Microorganisms Enterococcus faecalis · EC-12 strain (Enterococcus faecalis EC-12), the 2005 (2005) February 25, National Institute of Advanced Industrial Science and Technology, International Patent Organism Depositary dated (original deposit date) Deposited at 1-6 Higashi 1-chome, Tsukuba City, Ibaraki Prefecture 305-5466, Japan. The accession number is FERM BP-10284.
有効成分
本発明による組成物および飲食品の有効成分は、前記したように、ヒトを含む動物腸内または発酵食品から分離される細菌であって、エンテロコッカス属、ビフィドバクテリウム属、ラクトバシルス属、ストレプトコッカス属、および、ラクトコッカス属に属する細菌からなる群より選択される少なくとも１種以上の細菌である。この細菌は、乳酸を生成するグラム陽性細菌である。
Active ingredient The active ingredient of the composition and food and drink according to the present invention, as described above, is a bacterium isolated from animal intestines including humans or fermented foods, Enterococcus, Bifidobacterium, Lactobacillus, At least one bacterium selected from the group consisting of Streptococcus and bacteria belonging to the genus Lactococcus. This bacterium is a Gram-positive bacterium that produces lactic acid.
ここで、エンテロコッカス属に属する細菌としては、例えば、エンテロコッカス・フェカリス（Enterococcus faecalis）、エンテロコツカス・フェシウム（Enterococcus faecium）等が挙げられる。ビフィドバクテリウム属に属する細菌としては、例えば、ビフィドバクテリウム・ロンガム（Bifidobacterium longum）、ビフィドバクテリウム・プレーべ（Bifidobacterium breve）、ビフィドバクテリウム・ビフィダム（Bifidobacterium bifidum）等が挙げられる。ラクトバシルス属に属する細菌としては、ラクトバシルス・アシドフィラス（Lactobacillus acidophilus）、ラクトバシルス・カゼイ（Lactobacillus casei）、ラクトバシルス・サリバリウス（Lactobacillus salivarius）等が挙げられる。 Here, examples of bacteria belonging to the genus Enterococcus include Enterococcus faecalis , Enterococcus faecium, and the like. Examples of the bacteria belonging to the genus Bifidobacterium include Bifidobacterium longum , Bifidobacterium breve , Bifidobacterium bifidum, and the like. . Examples of bacteria belonging to the genus Lactobacillus include Lactobacillus acidophilus , Lactobacillus casei , Lactobacillus salivarius and the like.
また、ストレプトコッカス属に属する細菌としては、例えば、ストレプトコッカス・サーモフィラス（Streptococcus thermophilus）等が挙げられる。ラクトコッカス属に属する細菌としては、例えば、ラクトコッカス・クレモリス（Lactococcus cremoris）、ラクトコッカス・ラクティス（Lactococcus lactis）等が挙げられる。 Examples of bacteria belonging to the genus Streptococcus include Streptococcus thermophilus . Examples of bacteria belonging to the genus Lactococcus include Lactococcus cremoris and Lactococcus lactis .
本発明の好ましい態様によれば、有効成分として用いられる細菌は、エンテロコッカス属に属する菌である。より好ましくは、該細菌は、エンテロコッカス・フェカリス（Enterococcus faecalis）である。 According to a preferred embodiment of the present invention, the bacterium used as an active ingredient is a bacterium belonging to the genus Enterococcus. More preferably, the bacterium is Enterococcus faecalis .
エンテロコッカス・フェカリスとしては、例えば、エンテロコッカス・フェカリス・ＥＣ−１２株（受託番号ＦＥＲＭ ＢＰ−１０２８４）、ATCC 19433、ATCC 14508、ATCC 23655、IFO 16803、IFO 16804等の菌株またはその変異株が例示できる。有効成分として用いられる細菌としては、このうち、前記ＥＣ−１２株が最も好ましい。
なおここで「変異株」とは、特定の菌株に対し、当業者に周知の方法により当業者がその性質に変化を及ぼさない範囲で変異させたもの、あるいは、それと同等であると当業者が確認できるものを包含する意味である。
Examples of Enterococcus faecalis include strains such as Enterococcus faecalis EC-12 (accession number FERM BP-10284), ATCC 19433, ATCC 14508, ATCC 23655, IFO 16803, IFO 16804, and mutants thereof. Of these, the EC-12 strain is most preferred as the bacterium used as the active ingredient.
Here, the term “mutant strain” means that a specific strain has been mutated by a method well known to those skilled in the art within a range that does not change the properties thereof, or is equivalent to that. The meaning includes things that can be confirmed.
有効成分として用いられる細菌は、生菌および／または死菌体を用いることができるが、好ましくは死菌体が用いられ、より好ましくは、前記細菌を公知の加熱処理手段で殺菌して得られる加熱殺菌菌体が用いられる。加熱殺菌菌体は、前記細菌を常法に従って培養して得られた培養物から、例えば、濾過、遠心分離等の方法により菌体を回収し、水洗後、水等に懸濁して１２０℃以下（好ましくは８０〜１２０℃）、３０分以内（３秒〜３０分間）加熱処理した後、必要に応じて濃縮、乾燥することにより調製できる。また菌体を焼成、蒸煮（例えば１７０℃以下、６０分以内）に付すことによって調製してもよい。なお、エンテロコッカス・フェカリス・前記ＥＣ−１２株の加熱処理による殺菌菌体粉末は、商品名「ＥＣ−１２」（コンビ株式会社製）として市販されている。このため、本発明においては、有効成分として用いられる細菌として、このような市販品を用いてもよい。 Bacteria used as an active ingredient can be live bacteria and / or dead cells, preferably dead cells, more preferably obtained by sterilizing the bacteria with a known heat treatment means. Heat sterilized cells are used. The heat-sterilized bacterial cell is collected from the culture obtained by culturing the bacterium according to a conventional method, for example, by filtration, centrifugation, or the like, washed with water, suspended in water or the like and 120 ° C. or lower. (Preferably 80 to 120 ° C.) Heat treatment within 30 minutes (3 seconds to 30 minutes), followed by concentration and drying as necessary. Moreover, you may prepare by attaching | subjecting a microbial cell to baking and steaming (for example, 170 degrees C or less and less than 60 minutes). Note that enterococcus faecalis and bactericidal cell powder by heat treatment of the EC-12 strain are commercially available under the trade name “EC-12” (manufactured by Combi Corporation). For this reason, in this invention, you may use such a commercial item as bacteria used as an active ingredient.
用途
本発明による有効成分は、炎症の進行抑制または改善する効果を有する。すなわち、後述する実施例に示されるように、本発明による有効成分は、関節リウマチの一般的な病態モデルであるコラーゲン誘発関節炎（collagen-induced arthritis、以下「ＣＩＡ」と略すことがある）に対して実際に抑制作用を有することが実際に確認されている（実施例、図１、図２および図３）。すなわち、本発明による有効成分の投与群と非投与群のマウスの所見より、本発明による組成物によって病態の進行が軽減されたことが確認された。このように、本発明による有効成分は、炎症の進行を抑制しまたは改善する効果を実際に示した。よって、本発明における有効成分は、炎症性疾患の患者に対し、炎症の低減等といった症状の進行抑制、症状の緩和、改善効果をもたらすことができ、さらには治療効果も期待できる。また本発明の有効成分は、毒性も低く、哺乳動物に対し安全に用いることができる。
Use The active ingredient according to the present invention has an effect of suppressing or improving the progression of inflammation. That is, as shown in Examples described later, the active ingredient according to the present invention is effective against collagen-induced arthritis (hereinafter sometimes abbreviated as “CIA”), which is a general model of rheumatoid arthritis. In fact, it has been confirmed that it actually has a suppressive action (Example, FIGS. 1, 2 and 3). That is, it was confirmed from the findings of the mice in the active ingredient administration group and the non-administration group according to the present invention that the progression of the disease state was reduced by the composition according to the present invention. Thus, the active ingredient according to the present invention actually showed the effect of suppressing or improving the progression of inflammation. Therefore, the active ingredient in the present invention can bring about symptom progression suppression, symptom alleviation, improvement effects such as reduction of inflammation, etc., and a therapeutic effect can be expected for patients with inflammatory diseases. Further, the active ingredient of the present invention has low toxicity and can be used safely for mammals.
したがって、本発明による有効成分は、炎症またはこれに関連する状態の進行抑制または改善に用いることができる。ここで、症状または状態の「進行抑制または改善」とは、症状または状態の、調節、進行の抑制、遅延、緩和、改善、症状等の再進行の予防などを包含する意味で使用される。 Therefore, the active ingredient according to the present invention can be used for suppressing or improving the progression of inflammation or a condition related thereto. Here, the “progression suppression or improvement” of a symptom or condition is used in the meaning including regulation, suppression of progression, delay, alleviation, improvement, prevention of re-progression of symptoms, etc.
本発明において、「炎症」は、物理的、化学的又は生物学的な要因による損傷もしくは刺激に対する生体の免疫反応の結果生ずす現象をいい、多くの場合、炎症組織における痛み、発熱、赤化、腫脹等を伴い、炎症組織の機能低下や機能喪失を伴うこともある。炎症を伴う疾患としては、細菌感染症、ウイルス感染症、自己免疫疾患、アレルギー疾患、悪性腫瘍等が含まれるが、本発明においては好ましくは、自己免疫疾患によるものである。より具体的には、本発明における炎症性の疾患は、関節炎、さらに好ましくは、リウマチ性関節炎である。 In the present invention, “inflammation” refers to a phenomenon that occurs as a result of the body's immune response to damage or irritation caused by physical, chemical, or biological factors, and in many cases, pain, fever, redness in inflamed tissues. In addition, it may be accompanied by a decrease in function or loss of function of the inflamed tissue accompanied by swelling and the like. Diseases accompanied by inflammation include bacterial infections, viral infections, autoimmune diseases, allergic diseases, malignant tumors, etc., but preferably in the present invention, they are caused by autoimmune diseases. More specifically, the inflammatory disease in the present invention is arthritis, more preferably rheumatoid arthritis.
自己免疫疾患などでは、Ｔｈ１／Ｔｈ２バランスが変調していることが知られており、Ｔｈ１／Ｔｈ２バランスを回復することにより病態を改善することが期待できる。本発明における有効成分の使用は、このようなバランスの回復に役立つものと考えられる。実際に、コラーゲン誘発関節炎（collagen-induced arthritis）は、Ｔｈ１優位な状態で発症するが、ＥＣ−１２株の投与により、コラーゲン誘発関節炎を悪化させることなく病状を改善できている（実施例）。 In autoimmune diseases and the like, it is known that the Th1 / Th2 balance is modulated, and it can be expected to improve the disease state by restoring the Th1 / Th2 balance. The use of the active ingredient in the present invention is considered to help restore such balance. Actually, collagen-induced arthritis develops in a state predominantly Th1, but administration of the EC-12 strain has improved the pathology without exacerbating collagen-induced arthritis (Example).
本発明において、有効成分の効果の確認試験に実際に使用しているII型コラーゲンによるコラーゲン誘導関節炎マウスは、マウスにII型コラーゲンを注射することにより、コラーゲン誘導関節炎を発症させる自己免疫疾患の関節炎の病態モデルマウスである。具体的には、マウスにII型コラーゲンを注射することにより、II型コラーゲンが、関節滑膜細胞およびマクロファージに取り込まれ、その断片が、ＭＨＣ クラスＩＩ分子によって自己抗原として提示される。これにより、自己反応性ヘルパーＴ細胞が、マクロファージおよび滑膜細胞を活性化させ、炎症性サイトカインを放出する。また、自己反応性ヘルパーＴ細胞は、Ｂ細胞に抗II型コラーゲン抗体を産生させ、この抗II型コラーゲン抗体が、自己の関節軟骨のII型コラーゲンと抗原抗体反応をし、補体が活性化され炎症を起こす。なおこれらは仮定であってこれによって本発明が限定的に解釈されるものではない。 In the present invention, a collagen-induced arthritis mouse caused by type II collagen that is actually used in a test for confirming the effect of an active ingredient is arthritis of an autoimmune disease that causes collagen-induced arthritis by injecting type II collagen into the mouse. It is a disease state model mouse. Specifically, when type II collagen is injected into a mouse, type II collagen is taken up by articular synoviocytes and macrophages, and fragments thereof are presented as autoantigens by MHC class II molecules. Thereby, autoreactive helper T cells activate macrophages and synoviocytes and release inflammatory cytokines. In addition, self-reactive helper T cells cause B cells to produce anti-type II collagen antibodies that react with type II collagen in their articular cartilage and activate complement. It causes inflammation. These are assumptions, and the present invention is not construed as being limited thereto.
したがって、本発明による有効成分の効果は、四肢の腫脹の程度、後肢のフットパッドの厚さ、炎症性サイトカイン値、II型コラーゲンに対する抗体価等を経時的に測定することにより確認することができる。 Therefore, the effect of the active ingredient according to the present invention can be confirmed by measuring the degree of swelling of the limbs, the footpad thickness of the hind limbs, the inflammatory cytokine value, the antibody titer against type II collagen, etc. over time. .
よって本発明の他の態様によれば、ヒトを含む動物腸内または発酵食品から分離される細菌であって、エンテロコッカス属、ビフィドバクテリウム属、ラクトバシルス属、ストレプトコッカス属、および、ラクトコッカス属に属する細菌からなる群より選択される少なくとも１種以上の細菌を有効成分として含んでなる、炎症またはこれに関連する状態の進行抑制剤または改善剤が提供される。 Therefore, according to another aspect of the present invention, there is a bacterium isolated from the intestinal or fermented foods including humans, wherein the genus Enterococcus, Bifidobacterium, Lactobacillus, Streptococcus, and Lactococcus Provided is an agent for suppressing or improving the progression of inflammation or a condition related thereto, comprising at least one bacterium selected from the group consisting of the bacterium belonging thereto as an active ingredient.
また本発明によれば、前記したように、炎症またはこれに関連する状態を発症しているか、またはその発症の疑いのある患者に、有効量の前記有効成分を投与するかまたは摂取させることを含んでなる、炎症の症状もしくはこれに関連する状態の進行を抑制するかまたはそれを改善する方法が提供される。ここで「有効量」とは、症状または状態の進行を抑制するか、または改善するために、その効果を発揮する上で少なくとも必要とされる有効成分の量を意味する。また「患者」は、本発明の組成物または飲食品を、投与または摂取する対象となるヒトまたはヒトを除く哺乳動物（例えば、マウス、ラット、ウサギ、イヌ、ネコ、ウシ、ウマ、ブタ、サル等）を意味する。「投与」および「摂取」とは、対象となる患者に対し、目的とする物質を経口的または非経口的に生体内に取り込ませることを意味する。 Further, according to the present invention, as described above, a patient who develops or is suspected of developing inflammation or a condition related thereto is administered or ingested an effective amount of the active ingredient. A method of inhibiting or ameliorating the progression of symptoms of inflammation or conditions associated therewith is provided. As used herein, “effective amount” means the amount of an active ingredient that is required at least to exert its effect in order to suppress or improve the progression of symptoms or conditions. “Patient” refers to a human or a mammal other than a human (for example, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey) to which the composition or food or drink of the present invention is to be administered or ingested. Etc.). “Administration” and “intake” mean that a target substance is taken into a living body orally or parenterally to a subject patient.
組成物または飲食品
本発明による組成物は、前記した有効成分として含んでなるものである。
Composition or food or drink The composition according to the present invention comprises the above-mentioned active ingredient.
ここで「有効成分として含んでなる」とは、所望する製品形態に応じた生理学的に許容されうる担体を含んでいてもよいことは当然として、併用可能な他の補助成分を含有する場合も包含する意味である。すなわち、本発明による組成物は、有効成分である菌体または死菌体を用いて、必要に応じて、生理学的に許容されうる担体、賦形剤、結合剤、希釈剤などと混合することにより製造できる。本発明による組成物は、経口または非経口的に投与または摂取することができる。経口用の形態としては、食品、顆粒剤、散剤、錠剤（糖衣錠を含む）、丸剤、カプセル剤、シロップ剤、乳剤、懸濁剤が挙げられる。非経口用の形態としては、注射剤、点滴剤、外用剤、坐剤が挙げられる。これらの製剤は、当該技術分野で通常行われている手法により、薬学的に許容される担体（例えば、賦形剤、添加剤）とともに製剤化することができる。薬学的に許容される担体としては、賦形剤、結合剤、香料、緩衝剤、増粘剤、着色剤、安定剤、乳化剤、分散剤、懸濁化剤、崩壊剤、滑沢剤、防腐剤等が挙げられる。具体例としては、例えば、炭酸マグネシウム、ステアリン酸マグネシウム、タルク、砂糖、ラクトース、ペクチン、デキストリン、澱粉、ゼラチン、トラガント、メチルセルロース、ナトリウムカルボキシメチルセルロース、低融点ワックス等が挙げられる。 As used herein, “comprising as an active ingredient” may contain a physiologically acceptable carrier according to the desired product form, and may contain other auxiliary ingredients that can be used in combination. It means to include. That is, the composition according to the present invention is mixed with physiologically acceptable carriers, excipients, binders, diluents, etc., if necessary, using bacterial cells or dead cells which are active ingredients. Can be manufactured. The composition according to the present invention can be administered or ingested orally or parenterally. Examples of oral forms include foods, granules, powders, tablets (including sugar-coated tablets), pills, capsules, syrups, emulsions, and suspensions. Examples of parenteral forms include injections, drops, external preparations, and suppositories. These preparations can be formulated together with a pharmaceutically acceptable carrier (for example, an excipient or an additive) by a method commonly used in the art. Pharmaceutically acceptable carriers include excipients, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, disintegrants, lubricants, preservatives. Agents and the like. Specific examples include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting point wax, and the like.
また併用可能な他の補助成分としては、例えば、ビタミン成分（例えば、ビタミンＣ、ビタミンＥ）、抗生物質、グリコーゲン、アミノ酸類、ペプチド類、ミネラル類（例えば、亜鉛、鉄、銅、マンガンなど）などが挙げられる。 Other auxiliary components that can be used in combination include, for example, vitamin components (eg, vitamin C, vitamin E), antibiotics, glycogen, amino acids, peptides, minerals (eg, zinc, iron, copper, manganese, etc.) Etc.
製剤の内、例えば経口剤は、下記のようにして製造できる。有効成分に、例えば賦形剤（例えば、乳糖、白糖、デンプン、マンニトール）、崩壊剤（例えば、炭酸カルシウム、カルボキシメチルセルロースカルシウム）、結合剤（例えば、α化デンプン、アラビアゴム、カルボキシメチルセルロース、ポリビニールピロリドン、ヒドロキシプロピルセルロース）、または滑沢剤（例えば、タルク、ステアリン酸マグネシウム、ポリエチレングリコール）を添加して圧縮成形し、次いで必要により、味のマスキング、腸溶性もしくは持続性の目的のために慣用の方法でコーティングすることによって、経口剤を製造することができる。コーティング剤としては、例えば、エチルセルロース、ヒドロキシメチルセルロース、ポリオキシエチレングリコールなどを用いることができる。 Among the preparations, for example, oral preparations can be produced as follows. Active ingredients include, for example, excipients (eg lactose, sucrose, starch, mannitol), disintegrants (eg calcium carbonate, carboxymethylcellulose calcium), binders (eg pregelatinized starch, gum arabic, carboxymethylcellulose, polyvinyl) Pyrrolidone, hydroxypropylcellulose), or lubricant (eg talc, magnesium stearate, polyethylene glycol) and compression molded, then used for taste masking, enteric or sustained purposes as needed An oral preparation can be produced by coating with the above method. As the coating agent, for example, ethyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol, or the like can be used.
本発明おいて、組成物は経口摂取されるものであることが好ましい。 In the present invention, the composition is preferably taken orally.
また例えば、注射剤は、有効成分を、分散剤、保存剤、等張化剤などと共に水性溶剤（例えば、蒸留水、生理的食塩水等）または油性溶剤（例えば、植物油、プロピレングリコール）などに溶解、懸濁または乳化することにより製造することができる。外用剤や坐剤等の他の製剤も慣用の方法により製造することができる。 In addition, for example, in the injection, the active ingredient is mixed with an aqueous solvent (for example, distilled water, physiological saline, etc.) or an oily solvent (for example, vegetable oil, propylene glycol) together with a dispersing agent, a preservative, an isotonic agent and the like. It can be produced by dissolving, suspending or emulsifying. Other preparations such as external preparations and suppositories can also be produced by conventional methods.
製剤化にあたっては、本発明による有効成分以外の１種以上の医療上有効な有効成分をさらに添加し配合してもよい。また本発明による有効成分の投与にあたっては、本発明による有効成分以外の１種以上の医療上有効な有効成分を組み合わせて投与してもよい。このような他の有効成分としては、例えば、成長ホルモン、カルシウム拮抗剤、プロテアーゼ阻害剤、ステロイド剤等が挙げられる。 In formulating, one or more medically effective active ingredients other than the active ingredient according to the present invention may be further added and blended. In administration of the active ingredient according to the present invention, one or more kinds of medically effective active ingredients other than the active ingredient according to the present invention may be administered in combination. Examples of such other active ingredients include growth hormones, calcium antagonists, protease inhibitors, steroids and the like.
本発明による組成物は、医薬品への適用のみならず、食品への適用も意図されている。よって、本発明による飲食品は、本発明による有効成分を有効量含んでなるものである。 The composition according to the invention is intended not only for pharmaceutical applications but also for foods. Therefore, the food / beverage products according to the present invention comprise an effective amount of the active ingredient according to the present invention.
ここで「有効成分を有効量含んでなる」とは、個々の飲食品を通常喫食される量摂取した結果、有効成分としての効果を発揮しうるような量で有効成分を含有することをいう。本発明による飲食品には、本発明による有効成分をそのまままたは上記のような組成物の形態で、飲食品に配合してもよい。また、本発明による飲食品は、本発明による有効成分に安定剤等の慣用の添加成分を加えて飲食品として調製したもの、各種タンパク質、糖類、脂肪、微量元素、ビタミン類等をそれらにさらに配合して調製したもの、液状、半液体状若しくは固体状にしたもの、ペースト状にしたもの、または、一般の飲食品へ添加したものであってもよい。 As used herein, “comprising an effective amount of an active ingredient” means containing an active ingredient in such an amount that an effect as an active ingredient can be exhibited as a result of ingesting the amount of each food or drink normally consumed. . You may mix | blend the active ingredient by this invention with the food / beverage products by this invention as it is or in the form of the above compositions. In addition, the food and drink according to the present invention are prepared as food and drink by adding conventional additive components such as stabilizers to the active ingredient according to the present invention, various proteins, sugars, fats, trace elements, vitamins and the like. It may be prepared by blending, liquid, semi-liquid or solid, paste, or added to a general food or drink.
本発明において、「飲食品」は、医薬以外のものであって、哺乳動物が摂取可能なものであれば特に制限はなく、その形態も液状、半液体状または固体状のいずれのものであってもよい。このため飲食品には、例えば飲料の形態も包含される。飲食品はまた、サプリメントのような栄養補助食品の錠剤形態であってもよい。 In the present invention, the “food or drink” is not a drug and is not particularly limited as long as it is ingestible by mammals, and the form thereof is any of liquid, semi-liquid or solid. May be. For this reason, the form of a drink is also included by food-drinks, for example. The food or drink may also be in the form of a dietary supplement tablet such as a supplement.
本発明において「飲食品」には、健康食品、機能性食品、特定保健用食品、栄養補助食品、疾病リスク低減表示を付した食品、または、病者用食品のような分類のものも包含される。さらに「飲食品」という用語は、ヒト以外の哺乳動物を対象として使用される場合には、飼料を含む意味でここで用いてもよい。ここでいう特定保健用食品とは、高血圧性の臓器障害、またはそれらに伴う疾患または状態の予防、改善、状態の緩和等を目的として食品の製造または販売等を行う場合に、保健上の観点から、各国において法上の何らかの制限を受けることがある食品をいう。このような食品は、食品が疾病リスクを低減する可能性があること表示した食品、すなわち、疾病リスク低減表示を付した食品であることもできる。ここで、疾病リスク低減表示とは、疾病リスクを低減する可能性のある食品の表示であって、ＦＡＯ／ＷＨＯ合同食品規格委員会（コーデックス委員会）の定める規格に基づいて、またはその規格を参考にして、定められた表示または認められた表示であることができる。 In the present invention, the “food and beverage” includes foods classified as health foods, functional foods, foods for specified health use, dietary supplements, foods with a disease risk reduction label, or foods for the sick. The Furthermore, the term “food or drink” may be used herein to include feed when used for mammals other than humans. As used herein, the food for specified health use refers to a health perspective when manufacturing or selling foods for the purpose of preventing, improving, or alleviating the condition of hypertensive organ disorders or diseases or conditions associated therewith. To food that may be subject to some legal restrictions in each country. Such foods can also be foods that indicate that the foods may reduce disease risk, i.e., foods with a disease risk reduction label. Here, the disease risk reduction label is a label for foods that may reduce the disease risk, and is based on or based on the standard established by the FAO / WHO Joint Food Standards Committee (Codex Committee). The display can be a defined or recognized display with reference to FIG.
本発明による有効成分は、リウマチ性関節炎のような炎症の症状またはこれに関連する状態の進行抑制または改善作用を有する。このため、日常生活で摂取する食品、健康食品、機能性食品、サプリメント（例えば、カルシウム、マグネシウム等のミネラル類、ビタミンＫ等のビタミン類を１種以上含有する食品）に本発明の有効成分を配合することにより、前記作用に基づく機能を併せ持つ食品を提供することができる。 The active ingredient according to the present invention has an effect of suppressing or improving the progression of symptoms of inflammation such as rheumatoid arthritis or a condition related thereto. For this reason, the active ingredient of the present invention is added to foods, health foods, functional foods and supplements (for example, foods containing one or more vitamins such as minerals such as calcium and magnesium and vitamin K) taken in daily life. By mix | blending, the foodstuff which has the function based on the said effect | action can be provided.
本発明によれば、前記したように、本発明における有効成分を有効量含んでなる飲食品であって、リウマチ性関節炎のような炎症の症状またはこれに関連する状態の進行抑制または改善に用いられる飲食品が提供される。 According to the present invention, as described above, it is a food or drink comprising an effective amount of the active ingredient in the present invention, and used for suppressing or improving the progress of symptoms of inflammation such as rheumatoid arthritis or a condition related thereto. Food and drink is provided.
本発明の別の態様によれば、本発明における有効成分を有効量含んでなる飲食品であって、リウマチ性関節炎のような炎症の症状またはこれに関連する状態の進行抑制または改善する機能が表示された飲食品が提供される。ここで飲食品に付される機能表示は、例えば、製品の本体、容器、包装、説明書、添付文書、または宣伝物のいずれかにすることができる。 According to another aspect of the present invention, there is provided a food or beverage product comprising an effective amount of the active ingredient in the present invention, which has a function of suppressing or improving the progression of symptoms of inflammation such as rheumatoid arthritis or a condition related thereto. The displayed food or drink is provided. Here, the function display attached to the food or drink can be, for example, any of the main body of the product, the container, the packaging, the instruction manual, the attached document, or the promotional material.
本発明による飲食品の具体例としては、ジュース、清涼飲料水、茶飲料、ドリンク剤、ゼリー状飲料、機能性飲料等の各種飲料；ビール等のアルコール飲料；飯類、麺類、パン類およびパスタ類等の炭水化物含有食品；魚肉ハム、ソーセージ、水産練り製品等の練製品；カレー、あんかけ、中華スープ等のレトルト製品；スープ類；牛乳、乳飲料、アイスクリーム、チーズ、ヨーグルト等の乳製品；みそ、ヨーグルト、乳酸菌、発酵飲料、漬け物等の発酵物；豆製品；ビスケット、クッキーなどの洋菓子類、饅頭や羊羹等の和菓子類、キャンディー類、ガム類、グミ、ゼリー、プリンなどの冷菓や氷菓などの各種菓子類；インスタントスープ、インスタントみそ汁等のインスタント食品、電子レンジ対応食品等が挙げられる。さらには、粉末、穎粒、錠剤、カプセル剤、液状、ペースト状またはゼリー状に調製された健康飲食品も挙げられる。 Specific examples of the food and drink according to the present invention include juices, soft drinks, tea beverages, drinks, jelly-like beverages, functional beverages and other beverages; beer and other alcoholic beverages; rice, noodles, breads and pasta Carbohydrate-containing foods such as seafood; paste products such as fish ham, sausage and fish paste products; retort products such as curry, sauce, and Chinese soup; soups; dairy products such as milk, milk drinks, ice cream, cheese, and yogurt; miso Fermented products such as yogurt, lactic acid bacteria, fermented beverages, pickles; bean products; Western confectionery such as biscuits and cookies; Japanese confectionery such as buns and sheep candy; Various kinds of confectionery; instant food such as instant soup and instant miso soup, food for microwave oven, and the like. Furthermore, health foods and drinks prepared in the form of powder, granules, tablets, capsules, liquid, paste or jelly are also included.
本発明による飲食品の製造に当たっては、通常の飲食品の処方設計に用いられている糖類、香料、果汁、食品添加剤、安定剤などを適宜添加することができる。飲食品の製造は、当該技術分野に公知の製造技術を参照して実施することができる。本発明による飲食品は様々な形態を取ることができ、公知の医薬品の製造技術に準じて本発明による飲食品を製造してもよい。その場合には、本発明による組成物の製造の項目において述べたような担体や製剤用添加剤を用いて製造することができ、具体的には、経口剤の欄に記載された担体や製造用添加剤を用いて製造することができる。また、本発明における機能以外の機能を発揮する他の成分あるいは他の機能性食品と組み合わせることによって、多機能性の飲食品としてもよい。 In the production of foods and drinks according to the present invention, sugars, fragrances, fruit juices, food additives, stabilizers and the like that are used in normal food and drink formulation design can be added as appropriate. Manufacture of food-drinks can be implemented with reference to a manufacturing technique well-known in the said technical field. The food / beverage products according to the present invention can take various forms, and the food / beverage products according to the present invention may be produced according to known pharmaceutical production techniques. In that case, it can be produced using a carrier or formulation additive as described in the item of production of the composition according to the present invention, specifically, the carrier or production described in the column of oral preparation. Can be produced using additives. Moreover, it is good also as multifunctional food / beverage products by combining with the other component which exhibits functions other than the function in this invention, or another functional food.
本発明による組成物および飲食品はまた、コラーゲン、コンドロイチン、またはグルコサミンから選択される１種以上をさらに含んでなることができる。これらをさらに含むことは、副作用の無しに関節の痛み、腫脹、変形を抑制する上で有利である。 The composition and food and drink according to the present invention may further comprise one or more selected from collagen, chondroitin, or glucosamine. Further inclusion thereof is advantageous in suppressing joint pain, swelling and deformation without side effects.
本発明による組成物は、有効成分を、組成物全量に対して、０．０１〜１００重量％含んでなることが好ましく、０．１〜５０重量％含んでなることがより好ましい。 The composition according to the present invention preferably contains 0.01 to 100% by weight, more preferably 0.1 to 50% by weight, of the active ingredient relative to the total amount of the composition.
本発明による組成物を飲食品に添加して使用する場合、飲食品中への該組成物の添加量は、０．０１〜８０質量％とすることが好ましく、０．１〜５０質量％とすることがより好ましい。 When the composition according to the present invention is used by adding to a food or drink, the amount of the composition added to the food or drink is preferably 0.01 to 80% by mass, and 0.1 to 50% by mass. More preferably.
本発明による組成物および飲食品を投与または摂取する場合、本発明による有効成分の投与量または摂取量は、受容者、受容者の年齢および体重、症状、投与時間、剤形、投与方法、薬剤の組み合わせ等に依存して決定できる。例えば、本発明による有効成分を経口投与または経口摂取する場合、細菌の死菌体粉末量として、成人１人の一日当たり摂取量が、５０〜５０００ｍｇの範囲であることが好ましく、１００〜４０００ｍｇであることがより好ましい。これらは、一日１または数回の投与単位に分割して投与することができる。なお、これらの投与量または摂取量は、成人の体重を６０ｋｇと仮定して、体重６０ｋｇの成人１人１日あたりの有効成分の投与量もしくは摂取量として、必要に応じて計算することによって算出ことができる。 When administering or ingesting the composition and food and drink according to the present invention, the dose or intake of the active ingredient according to the present invention is as follows: recipient, age and weight of recipient, symptoms, administration time, dosage form, administration method, drug It can be determined depending on the combination of. For example, when the active ingredient according to the present invention is orally administered or ingested, the daily intake amount per adult is preferably in the range of 50 to 5000 mg as the amount of dead bacterial powder of bacteria, More preferably. These can be administered in one or several daily dosage units. These doses or intakes are calculated by calculating as necessary the dose or intake of the active ingredient per day for an adult with a body weight of 60 kg, assuming that the weight of an adult is 60 kg. be able to.
なお、組成物または飲食品への有効成分である菌体の添加方法は、菌体の死菌体を用いる場合は、特に制限はなく、各飲食品に用いられる他の原料と一緒に最初から添加することができる。したがって、加熱処理（加熱殺菌、焼成、蒸煮等の菌体が死滅するような温度条件下での処理）が必要な飲食品に添加しても効果が損われることがない。 In addition, the addition method of the microbial cell which is an active ingredient to a composition or food / beverage products has no restriction | limiting in particular, when using the dead cell body of a microbial cell, from the beginning with other raw materials used for each food / beverage product Can be added. Therefore, even if it adds to the food / beverage products which require heat processing (process under the temperature conditions which kill cells, such as heat sterilization, baking, and steaming), an effect is not impaired.
本発明を以下の例によって詳細に説明するが、本発明はこれらに限定されるものではない The present invention is illustrated in detail by the following examples, but the present invention is not limited thereto.
材料と方法：
コラーゲン誘発関節炎の誘導とＥＣ−１２の投与
供試動物として、９週齢の雄性ＤＢＡ／１Ｊ（日本クレア株式会社より入手可能）マウスを用いた。
また試薬として、ＥＣ−１２株の加熱処理による殺菌菌体粉末としてＥＣ−１２（商品名）（コンビ株式会社製）、および、II型コラーゲン（chick sternal cartilage由来、ｓｉｇｍａ社Ｂ製）を用いた。
Materials and methods:
As a test animal for induction of collagen-induced arthritis and EC-12 administration , 9-week-old male DBA / 1J mice (available from Claire Japan) were used.
In addition, as a reagent, EC-12 (trade name) (manufactured by Combi Co., Ltd.) and type II collagen (derived from chick internal cartilage, manufactured by Sigma B) were used as bactericidal cell powder by heat treatment of EC-12 strain. .
II型コラーゲン／１０ｍＭ酢酸（２ｍｇ／ｍｌ）と完全フロイントアジュバントを等量混合してｗ／ｏエマルジョンを作成し、これをＤＢＡ／１Ｊマウスの尾基部に各０．１ｍｌ皮内投与した（０日目：ｐｒｉｍｉｎｇ）。
２１日目にも同様の操作を行った（ｂｏｏｓｔ）。
A w / o emulsion was prepared by mixing equal amounts of type II collagen / 10 mM acetic acid (2 mg / ml) and complete Freund's adjuvant, and each 0.1 ml was administered intradermally to the tail base of DBA / 1J mice (day 0) Eye: priming).
The same operation was performed on the 21st day (boost).
ＥＣ−１２投与については、０．２ｍｇまたは２．０ｍｇのＥＣ−１２を０．５ｍｌの蒸留水にそれぞれ懸濁し、０日目より連日７週間経口投与した。対照群には同量の蒸留水を投与した。 Regarding EC-12 administration, 0.2 mg or 2.0 mg of EC-12 was suspended in 0.5 ml of distilled water, and orally administered from the 0th day for 7 consecutive days. The same amount of distilled water was administered to the control group.
試験１： コラーゲン誘発関節炎に対するＥＣ−１２の臨床的抑制効果の確認
関節炎の症状は２５日から目視により週３回観察し、下記の基準に従ってクリニカルスコアを測定して、数値化した。
クリニカルスコアの判定基準：
０＝正常、
１＝発赤、
２＝軽い腫れ、
３＝中程度の腫れ、
４＝重篤な腫れ、
５＝関節の硬直／機能の消失。
測定の際には、四肢それぞれにスコアを与え、結果は１匹あたりの合計として表した。
Test 1: Confirmation of Clinical Inhibitory Effect of EC-12 on Collagen-Induced Arthritis Symptoms of arthritis were observed visually three times a week from the 25th, and the clinical score was measured according to the following criteria and digitized.
Clinical score criteria:
0 = normal,
1 = redness,
2 = mild swelling,
3 = moderate swelling,
4 = severe swelling,
5 = joint stiffness / loss of function.
In the measurement, a score was given to each limb, and the result was expressed as a total per animal.
結果は、図１に示される通りであった。
対照群およびＥＣ−１２投与群のクリニカルスコアは共に、２１日目以降上昇したが、対照群のピーク時（３５日目）に対照群と比較して有意に症状を改善した。
The result was as shown in FIG.
The clinical scores of the control group and the EC-12 administration group both increased after the 21st day, but the symptoms improved significantly compared to the control group at the peak time of the control group (35th day).
試験２： コラーゲン誘発関節炎に対するＥＣ−１２の病理組織学的抑制効果の確認
４９日目にマウスを解剖し、関節組織の病理学的解析を行った。
具体的には、後部膝関節を４％パラホルムアルデヒド・リン酸緩衝液で固定後、ＥＤＴＡ−ナトリウム水溶液（ｐＨ７．４）で脱灰した。その後、パラフィンに包埋後、厚さ３μｍの連続切片を作成し、ヘマトキシリン・エオジン（ＨＥ）染色を行い観察した。
コラーゲン誘発関節炎発症の判定は、各マウスの関節の組織学的所見により行った。また下記の組織学的基準に沿ってそれをスコア化した。
Test 2: Confirmation of Histopathological Inhibitory Effect of EC-12 on Collagen-Induced Arthritis On day 49, mice were dissected and pathological analysis of joint tissue was performed.
Specifically, the posterior knee joint was fixed with 4% paraformaldehyde / phosphate buffer, and then decalcified with an EDTA-sodium aqueous solution (pH 7.4). Then, after embedding in paraffin, a continuous section having a thickness of 3 μm was prepared, and stained with hematoxylin and eosin (HE) and observed.
Determination of the onset of collagen-induced arthritis was performed based on the histological findings of the joints of each mouse. It was also scored according to the following histological criteria.
・「関節軟骨の障害」：関節軟骨の破壊と膠原線維増生の頻度により、下記の基準に従ってスコア０〜４から判定した。
クリニカルスコアの判定基準：
０＝軟骨に障害が認められない、
１＝軟骨表層部一部が破壊している、
２＝軟骨の一部が破壊脱落している、
３＝軟骨が破壊し、表面に膠原線維が増生している、
４＝バンヌスが軟骨表面を覆い侵食している。
"Articular cartilage damage": Judgment was made from scores 0 to 4 according to the following criteria according to the frequency of articular cartilage destruction and collagen fiber hyperplasia.
Clinical score criteria:
0 = no damage to the cartilage
1 = part of cartilage surface layer is broken,
2 = A part of cartilage is broken and dropped.
3 = Cartilage is destroyed and collagen fibers are growing on the surface,
4 = Vanus erodes the cartilage surface.
・「滑膜増生」：滑膜増生の範囲と程度により、下記の基準に従ってスコア０〜４から判定した。
クリニカルスコアの判定基準：
０＝滑膜増殖が認められない、
１＝滑膜増殖が一部に認められる、
２＝滑膜増殖が薄く広範囲に認められる。あるいは、厚いが狭い範囲に認められる、
３＝滑膜増殖が厚く広範囲に認められる、
４＝滑膜増殖が厚く広範囲に認められ、バンヌスの増殖を伴う。
-"Synovial membrane augmentation": Judged from scores 0 to 4 according to the following criteria depending on the range and extent of synovial membrane augmentation.
Clinical score criteria:
0 = no synovial proliferation observed
1 = synovial proliferation is observed in part,
2 = Synovial growth is thin and widely observed. Or, it ’s thick but narrow,
3 = Synovial proliferation is thick and widespread,
4 = Synovial proliferation is thick and widespread, accompanied by Vannus proliferation.
・「炎症細胞浸潤」：炎症細胞出現の頻度とリンパ濾胞の形成により、下記の基準に従ってスコア０〜４から判定した。
クリニカルスコアの判定基準：
０＝炎症細胞は認められない、
１＝滑膜ひだに炎症細胞がわずかに認められる、
２＝滑膜ひだ、滑膜面の一部に炎症細胞が認められる、
３＝滑膜ひだ、滑膜面に炎症細胞が多数認められる、
４＝滑膜ひだ、滑膜面に炎症細胞が多数認められ、滑膜にリンパ瀘胞の形成を認める。
"Inflammatory cell infiltration": Based on the frequency of appearance of inflammatory cells and the formation of lymphoid follicles, a score of 0 to 4 was determined according to the following criteria.
Clinical score criteria:
0 = no inflammatory cells observed
1 = slight inflammatory cells are found in synovial folds,
2 = Synovial folds, inflammatory cells are found in part of the synovial surface,
3 = Synovial folds, many inflammatory cells are observed on the synovial surface,
4 = Synovial folds, many inflammatory cells are observed on the synovial surface, and formation of lymphocysts is observed in the synovium.
・「パンヌスの増生」：パンヌス形成、脂肪組織消失の程度により、下記の基準に従ってスコア０〜４から判定した。
クリニカルスコアの判定基準：
０＝パンヌスが認められない、
１＝滑膜ひだの一部に肉芽細胞の増生が認められる、
２＝滑膜ひだ、滑膜面の一部にパンヌスが認められる、
３＝滑膜ひだ、滑膜面全体にパンヌスが認められる、
４＝滑膜ひだ、滑膜面に多数パンヌスが認められ、脂肪細胞が消失し、軟骨の破壊を伴っている。
-“Increase of pannus”: Judged from scores 0 to 4 according to the following criteria, depending on the extent of pannus formation and adipose tissue loss.
Clinical score criteria:
0 = Pannus is not allowed,
1 = proliferation of granulation cells is observed in part of synovial folds,
2 = synovial folds, pannus is observed in part of the synovial surface,
3 = synovial folds, pannus is observed throughout the synovial surface,
4 = Synovial folds, many pannus were observed on the synovial surface, adipocytes disappeared, and cartilage was destroyed.
結果は図２および図３に示される通りであった。
ＥＣ−１２をｐｒｉｍｉｎｇの７日前から投与した場合（図２）、およびｐｒｉｍｉｎｇの日から投与した場合（図３）のいずれの場合にも、関節軟骨の障害、滑膜増生、炎症細胞浸潤およびパンヌスの増生共に、ＥＣ−１２投与群において改善が認められた。
The results were as shown in FIG. 2 and FIG.
When EC-12 was administered from 7 days before priming (FIG. 2) and from the day of priming (FIG. 3), articular cartilage damage, synovial hyperplasia, inflammatory cell infiltration and pannus were observed. Improvement was observed in the EC-12 administration group.
Claims (12)
炎症またはこれに関連する状態の進行抑制または改善に用いられる、飲食品。 A food or drink comprising an effective amount of the active ingredient according to claim 1,
A food or drink used for suppressing or improving the progression of inflammation or a condition related thereto.
炎症またはこれに関連する状態の進行抑制または改善する機能が表示された、飲食品。 A food or drink comprising an effective amount of the active ingredient according to claim 1,
A food or drink with a function of suppressing or improving the progression of inflammation or a related condition.
Priority Applications (1)
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| JP2010195700A (en) * | 2009-02-24 | 2010-09-09 | Combi Corp | Oral ingestion composition |
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| JP2012526748A (en) * | 2009-05-11 | 2012-11-01 | ネステク ソシエテ アノニム | Short-time high-temperature treatment results in a microbial preparation with an anti-inflammatory profile |
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| WO2011105403A1 (en) * | 2010-02-26 | 2011-09-01 | コンビ株式会社 | Composition having bedsore-relieving effect |
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| KR20190099360A (en) * | 2018-01-31 | 2019-08-27 | 주식회사 비피도 | Composition for prevention or treatment of rheumatoid arthritis with Bifidobacterium |
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