JP5718614B2 - Autoinducer-2 inhibitor and preventive and / or therapeutic agent for periodontal disease or caries disease - Google Patents
Autoinducer-2 inhibitor and preventive and / or therapeutic agent for periodontal disease or caries disease Download PDFInfo
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- JP5718614B2 JP5718614B2 JP2010246117A JP2010246117A JP5718614B2 JP 5718614 B2 JP5718614 B2 JP 5718614B2 JP 2010246117 A JP2010246117 A JP 2010246117A JP 2010246117 A JP2010246117 A JP 2010246117A JP 5718614 B2 JP5718614 B2 JP 5718614B2
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicines Containing Plant Substances (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Cosmetics (AREA)
Description
本発明は、オートインデューサー−2阻害剤、並びに歯周病又は齲蝕病の予防及び/又は治療剤に関する。 The present invention relates to an autoinducer-2 inhibitor and a preventive and / or therapeutic agent for periodontal disease or caries disease.
自然界において、微生物は様々な環境下で生存しなければならない。貧栄養、低温度、高温、pH変化はもちろんのこと、生体内においては貪食細胞又は抗菌性液性因子(補体、抗体、リゾチーム等)が存在する環境での生存を余儀なくされる。このような状況下で、細菌は自らの存在環境の変化を敏感に感知する機構を獲得してきた。そのような機構の1つとして、微生物は特異的な情報伝達物質を介して環境における自らの密度を感知し、その密度に応じて自らの様々な生物活性を巧妙に制御していることが明らかとなっている。このような細胞間の情報伝達機構は、クオラムセンシングシステムと称される。 In nature, microorganisms must survive in various environments. In addition to oligotrophic, low temperature, high temperature, and pH change, living organisms are forced to survive in an environment where phagocytic cells or antibacterial humoral factors (complements, antibodies, lysozyme, etc.) are present. Under these circumstances, bacteria have acquired a mechanism for sensitively sensing changes in their environment. As one of such mechanisms, it is clear that microorganisms sense their own density in the environment through specific signaling substances and skillfully control their various biological activities according to their density. It has become. Such an information transmission mechanism between cells is called a quorum sensing system.
クオラムセンシングは、発光性海洋細菌であるビブリオ・フィシェリ及びビブリオ・ハーベイにおいて最初に報告された。しかし、最近では、多くの細菌における一般的な遺伝子調節機構であると認識されている。この現象により、細菌は、生物発光、スウォーミング、バイオフィルム形成、タンパク質分解酵素の産生、抗生物質の合成、遺伝子受容能の発達、プラスミド接合伝達、病原因子産生及び胞子形成などといった活動を一斉に行うことができる。 Quorum sensing was first reported in the luminescent marine bacteria Vibrio Fischeri and Vibrio Harvey. Recently, however, it has been recognized as a general gene regulatory mechanism in many bacteria. This phenomenon allows bacteria to perform activities such as bioluminescence, warming, biofilm formation, proteolytic enzyme production, antibiotic synthesis, gene acceptability development, plasmid conjugation transfer, virulence factor production and sporulation. Can be done.
クオラムセンシングシステムを有する細菌は、オートインデューサーと呼ばれるシグナル伝達分子を合成し、放出し、そのシグナル伝達分子に応答して、遺伝子発現を細胞密度の関数として制御する。これまで、アシルホモセリンラクトンがオートインデューサー−1として、4,5−ジヒドロキシ−2,3−ペンタンジオンがオートインデューサー−2として同定されている。 Bacteria with a quorum sensing system synthesize and release a signaling molecule called an autoinducer and respond to the signaling molecule to control gene expression as a function of cell density. So far, acyl homoserine lactone has been identified as autoinducer-1, and 4,5-dihydroxy-2,3-pentanedione as autoinducer-2.
ビブリオ属細菌、緑膿菌、セラチア、エンテロバクターなど臨床上重要な細菌がクオラムセンシングにオートインデューサー−1を利用することが報告されている。また、ビブリオ・ハーベイが、種内連絡には種特異性の高いオートインデューサー−1を利用し、種間連絡には種特異性の低いオートインデューサー−2を利用することが知られている。さらに最近の研究では、ある種の病原性細菌がオートインデューサー−2による種間でのクオラムセンシングにより、病原因子の産生を調節していることも示されている。このような病原性細菌としては、齲蝕原性菌であるストレプトコッカス・ミュータンス(Streptococcus mutans)、胃潰瘍及び胃ガンを惹起すると言われているヘリコバクター・ピロリ(Helicobacter pylori)、食中毒、ガス壊疽、出血性腸炎などの原因菌であるウェルシュ菌(Clostridium perfringens)等が挙げられる。従って、オートインデューサー−2を阻害する活性を有する物質が求められていた。 It has been reported that clinically important bacteria such as Vibrio bacteria, Pseudomonas aeruginosa, Serratia and Enterobacter use autoinducer-1 for quorum sensing. In addition, it is known that Vibrio Harvey uses autoinducer-1 with high species specificity for intra-species communication and uses autoinducer-2 with low species specificity for interspecies communication. . More recent studies have also shown that certain pathogenic bacteria regulate the production of virulence factors by quorum sensing between species with autoinducer-2. Such pathogenic bacteria include Streptococcus mutans , a cariogenic bacterium, Helicobacter pylori , which is said to cause gastric ulcer and gastric cancer, food poisoning, gas gangrene, hemorrhagic Examples include Clostridium perfringens, which is a causative bacterium such as enteritis. Therefore, a substance having an activity of inhibiting autoinducer-2 has been demanded.
オートインデューサー−2阻害剤としては、これまで、ダイズ抽出物を含むものなどが報告されている(例えば、非特許文献1参照)。しかし、非特許文献1記載のオートインデューサー−2阻害剤のオートインデューサー−2阻害活性は、十分なものではなかった。 As an autoinducer-2 inhibitor, what contains a soybean extract etc. is reported until now (for example, refer nonpatent literature 1). However, the autoinducer-2 inhibitory activity of the autoinducer-2 inhibitor described in Non-Patent Document 1 was not sufficient.
本発明は、優れたオートインデューサー−2阻害活性を有し、感染症の予防及び治療に有効な、オートインデューサー−2阻害剤の提供を課題とする。 An object of the present invention is to provide an autoinducer-2 inhibitor that has an excellent autoinducer-2 inhibitory activity and is effective in the prevention and treatment of infectious diseases.
本発明者等は、上記課題に鑑み鋭意検討を行った。その結果、ダイズ(Glycine max)発酵物のヘキサン抽出物が、オートインデューサー−2を阻害する活性を有するとともに、感染症に対して有効であることを見い出した。本発明はこの知見に基づいて完成するに至った。 The present inventors have conducted intensive studies in view of the above problems. As a result, it was found that a hexane extract of soybean ( Glycine max ) fermented product has an activity of inhibiting autoinducer-2 and is effective against infectious diseases. The present invention has been completed based on this finding.
本発明は、ダイズ(Glycine max)発酵物のヘキサン抽出物を有効成分とするオートインデューサー−2阻害剤に関する。
また、本発明は、ダイズ(Glycine max)発酵物のヘキサン抽出物を有効成分とする歯周病の予防及び/又は治療剤に関する。
また、本発明は、ダイズ(Glycine max)発酵物のヘキサン抽出物を有効成分とする齲蝕病の予防及び/又は治療剤に関する。
さらに、本発明は、前記オートインデューサー−2阻害剤を含有してなる、医薬組成物、食品組成物、口腔用組成物又は化粧料組成物に関する。
The present invention relates to an autoinducer-2 inhibitor comprising a hexane extract of fermented soybean ( Glycine max ) as an active ingredient.
The present invention also relates to a preventive and / or therapeutic agent for periodontal disease comprising a hexane extract of soybean ( Glycine max ) fermentation as an active ingredient.
The present invention also relates to a preventive and / or therapeutic agent for caries disease comprising a hexane extract of soybean ( Glycine max ) fermented product as an active ingredient.
Furthermore, the present invention relates to a pharmaceutical composition, a food composition, an oral composition or a cosmetic composition comprising the autoinducer-2 inhibitor.
本発明によれば、優れたオートインデューサー−2阻害活性を有し、感染症の予防及び治療に有効な、オートインデューサー−2阻害剤が提供される。 ADVANTAGE OF THE INVENTION According to this invention, the autoinducer-2 inhibitor which has the outstanding autoinducer-2 inhibitory activity and is effective in the prevention and treatment of an infectious disease is provided.
本発明に用いるダイズとは、マメ科(Fabaceae)マメ属(Glycine)の一年草であるダイズの種子をいう。 The soybean used in the present invention refers to soybean seeds that are annual plants of the genus Fabaceae ( Glycine ).
本発明に用いるダイズ発酵物の発酵に用いる菌としては特に制限はないが、発酵食品の製造に通常用いられる菌が好ましい。ダイズ発酵物の発酵に用いる菌としては、紅麹菌、テンペ菌、酵母菌、クモノスカビ(Rhizopus)、ケカビ(Mucor)、コウジ、乳酸菌等が挙げられる。本発明において、前記ダイズ発酵物が、紅麹菌、テンペ菌、酵母菌、クモノスカビ、ケカビ及びコウジよりなる群より選ばれる少なくとも1種による発酵物であることが好ましい。 Although there is no restriction | limiting in particular as microbe used for fermentation of the soybean fermented product used for this invention, The microbe normally used for manufacture of fermented food is preferable. Examples of bacteria used for fermentation of soybean fermented products include red koji, tempeh, yeast, Rhizopus , Mucor , koji, and lactic acid bacteria. In this invention, it is preferable that the said soybean fermented material is a fermented material by at least 1 sort (s) chosen from the group which consists of a red koji mold, a tempeh fungus, a yeast, a spider mold, a fungus, and a koji.
本発明に用いるダイズ発酵物を得るための発酵の条件としては、ダイズ発酵物のヘキサン抽出物がオートインデューサー−2を阻害する活性を有するものであれば特段の制限はなく、発酵原料と菌の組み合わせ毎に、加水条件、温度、pH、発酵時間、好気条件や嫌気条件といった発酵条件などを適宜調整することが出来る。 Fermentation conditions for obtaining the soybean fermented product used in the present invention are not particularly limited as long as the hexane extract of the soybean fermented product has an activity of inhibiting autoinducer-2. For each combination, fermentation conditions such as hydration conditions, temperature, pH, fermentation time, aerobic conditions and anaerobic conditions can be appropriately adjusted.
本発明に用いるダイズ発酵物としては、市販のものを用いてもよい。市販のダイズ発酵物としては、テンペ、豆ち醤、浜納豆、腐乳等が挙げられる。
なお、本明細書において、テンペとは、蒸煮した大豆と乳酸等の酸とを混合し、テンペ菌で発酵させたものをいう。豆ち醤とは、蒸煮した黒大豆を細かくきざみ、ニンニクやショウガなどと混合し発酵させたものをいう。浜納豆とは、蒸煮した黒大豆と食塩とを混合し、クモノスカビやケカビ等で発酵させたものをいう。腐乳とは、圧搾して水分を絞った豆腐と、塩やオカラ、香辛料等とを混合し、紅麹やケカビ等で発酵させたものをいう。
As the soybean fermented product used in the present invention, a commercially available product may be used. Commercially available soybean fermented products include tempeh, bean soy sauce, hama natto, and soy milk.
In addition, in this specification, tempeh means what mixed steamed soybeans and acids, such as lactic acid, and fermented with tempeh bacteria. “Mamechi soy sauce” means steamed black soybeans that are finely chopped and mixed with garlic or ginger and fermented. Hama Natto refers to a mixture of steamed black soybeans and salt and fermented with Kumonosukabi or Kakebi. “Tofu” refers to a mixture of tofu that has been squeezed and squeezed with water, salt, okara, spices, and the like, and fermented with red yeast rice, mildew, or the like.
本発明に用いるダイズ発酵物のヘキサン抽出物の製造方法に特に制限はなく、例えば、ダイズ発酵物の粉砕物、乾燥物若しくはその粉砕物、又はそれら自身を圧搾抽出することにより得られる搾汁を、ヘキサンで抽出することで得られる。また、このようにして得られる抽出物を、分配又はカラムクロマトなどの各種クロマトグラフィーなどで精製して得られた抽出物画分などを本発明におけるダイズ発酵物のヘキサン抽出物として用いることもできる。さらには、上記の方法により得られた抽出物からヘキサン等の溶媒を留去し、粉末としたものをダイズ発酵物のヘキサン抽出物としてもよい。
ダイズ発酵物のヘキサンによる抽出条件に特に制限はないが、0〜40℃(より好ましくは10〜30℃、さらにより好ましくは15〜25℃)で5〜720分(より好ましくは30〜300分、さらにより好ましくは60〜120分)で抽出することが好ましい。
There is no restriction | limiting in particular in the manufacturing method of the hexane extract of the soybean fermented product used for this invention, For example, the squeezed juice obtained by squeezing and extracting the pulverized product, dried product, or its pulverized product of soybean fermented product itself It is obtained by extracting with hexane. In addition, an extract fraction obtained by purifying the extract obtained in this way by various chromatographies such as distribution or column chromatography can also be used as a hexane extract of soybean fermented product in the present invention. . Furthermore, a solvent such as hexane is distilled off from the extract obtained by the above method, and the powder may be used as a hexane extract of soybean fermented product.
There is no particular limitation on the extraction conditions of soybean fermented product with hexane, but it is 5 to 720 minutes (more preferably 30 to 300 minutes) at 0 to 40 ° C. (more preferably 10 to 30 ° C., even more preferably 15 to 25 ° C.). And even more preferably 60 to 120 minutes).
本発明において、前記有効成分を溶媒に溶解/分散させ、オートインデューサー−2阻害剤、並びに歯周病又は齲蝕病の予防及び/又は治療剤としてもよい。本発明で用いることができる溶媒としては特に制限はないが、水、エタノール、プロピレングリコール、ジメチルスルホキサイド等が挙げられ、水及びエタノールが好ましい。 In the present invention, the active ingredient may be dissolved / dispersed in a solvent to serve as an autoinducer-2 inhibitor and a preventive and / or therapeutic agent for periodontal disease or caries disease. Although there is no restriction | limiting in particular as a solvent which can be used by this invention, Water, ethanol, propylene glycol, a dimethyl sulfoxide etc. are mentioned, Water and ethanol are preferable.
本発明におけるオートインデューサー−2(以下、「AI−2」ともいう)としては、細菌が産生するものでAI−2活性を有するものであれば特に制限はない。
本発明におけるAI−2の具体例としては、下記式で表される4,5−ジヒドロキシ−2,3−ペンタンジオン(本明細書において、DPDともいう)、及びDPDが有するAI−2活性と同等のAI−2活性を有する化合物が包含される。
The autoinducer-2 (hereinafter also referred to as “AI-2”) in the present invention is not particularly limited as long as it is produced by bacteria and has AI-2 activity.
Specific examples of AI-2 in the present invention include 4,5-dihydroxy-2,3-pentanedione (also referred to herein as DPD) represented by the following formula, and AI-2 activity possessed by DPD. Compounds having equivalent AI-2 activity are included.
前記DPDは、細菌のAI−2受容体と結合するときにボロンを取り込んで、フラノシルボレートジエステルに変換される。本発明におけるAI−2の別の具体例としては、前記フラノシルボレートジエステルが挙げられる。また、DPDはリン酸化されてリン酸化DPD(Phospho-DPD)となり、AI−2活性を発現することが知られている(例えば、Taga M.et al.,Mol.Microbiol.,42,p.777-793,2001参照)。本発明におけるAI−2は、リン酸化DPDも包含する。
前記フラノシルボレートジエステル及びPhospho-DPDの具体例を以下に示す。しかし、本発明はこれらに制限するものではない。
When DPD binds to the bacterial AI-2 receptor, it incorporates boron and is converted to furanosyl borate diester. Another specific example of AI-2 in the present invention is the furanosyl borate diester. It is also known that DPD is phosphorylated to become phosphorylated DPD (Phospho-DPD) and expresses AI-2 activity (see, for example, Taga M. et al., Mol. Microbiol., 42, p. 777-793, 2001). AI-2 in the present invention includes phosphorylated DPD.
Specific examples of the furanosyl borate diester and Phospho-DPD are shown below. However, the present invention is not limited to these.
本発明においてAI−2を阻害することは、AI−2がクオラムセンシングを介して細菌に及ぼす影響を阻害することをさし、AI−2活性を阻害すること、AI−2分解すること、AI−2のAI−2受容体への結合を阻害することなどが包含される。 Inhibiting AI-2 in the present invention refers to inhibiting the effect of AI-2 on bacteria via quorum sensing, inhibiting AI-2 activity, decomposing AI-2, Inhibiting the binding of AI-2 to the AI-2 receptor is included.
本発明においてAI−2活性は、AI−2がクオラムセンシングシステムを有する細菌に影響を及ぼす活性、すなわち、AI−2を介するクオラムセンシングによりもたらされる細菌の機能を促進する活性をさす。細菌は、AI−2を介するクオラムセンシングにより、発光、スウォーミング、バイオフィルム形成、タンパク質分解酵素の産生、抗生物質の合成、遺伝子受容能の発達、プラスミド接合伝達、病原因子産生及び胞子形成等を行うことが知られている。したがって、AI−2活性は、換言すれば、AI−2を認識する細菌、すなわちAI−2受容体を有する細菌による生物発光、スウォーミング、バイオフィルム形成、タンパク質分解酵素の産生、抗生物質の合成、遺伝子受容能の発達、プラスミド接合伝達、病原因子産生及び/又は胞子形成の活性ということができる。本発明においてAI−2活性は、特に、細菌の病原因子産生活性をさす。 In the present invention, AI-2 activity refers to an activity in which AI-2 affects bacteria having a quorum sensing system, that is, an activity that promotes the function of bacteria brought about by quorum sensing via AI-2. Bacteria can luminescence, warming, biofilm formation, proteolytic enzyme production, antibiotic synthesis, gene acceptability development, plasmid conjugation transfer, pathogenic factor production and spore formation by quorum sensing via AI-2 Etc. are known to perform. Thus, AI-2 activity is, in other words, bioluminescence, warming, biofilm formation, proteolytic enzyme production, antibiotic production by bacteria that recognize AI-2, ie, bacteria having an AI-2 receptor. It can be referred to as activity of synthesis, development of gene acceptability, plasmid conjugation transfer, pathogenic factor production and / or sporulation. In the present invention, AI-2 activity particularly refers to bacterial pathogen production activity.
前記病原因子としては、例えば、エンテロトキシン、アデニル酸シクラーゼ毒素、アドヘシン、アルカリプロテアーゼ、溶血毒、炭疽毒素、APX毒素、α毒素、β毒素、δ毒素、C2毒素、C3毒素、ボツリヌス毒素、束状線毛構造サブユニット、C5Aペプチダーゼ、心臓毒、走化性、コレラ毒素、毛様体毒素、クロストリジウム細胞毒、クロストリジウム神経毒、コラーゲン接着遺伝子、細胞溶解素、嘔吐毒素、内毒素、表皮剥脱毒素、外毒素、細胞外エラスターゼ、フィブリノゲン、フィブロネクチン結合タンパク質、線維状赤血球凝集素、フィンブリア、ゼラチナーゼ、赤血球凝集素、ロイコトキシン、リポタンパク質シグナルペプチダーゼ、リステリオリシンO、Mタンパク質、神経毒、非フィンブリアアドヘシン類、浮腫因子、透過酵素、百日咳毒素、ホスホリパーゼ、線毛、孔形成毒素、プロリンパーミアーゼ、セリンプロテアーゼ、志賀毒素、破傷風毒素、チオール活性化細胞溶解素、気管細胞溶解素、ウレアーゼなどが挙げられるが、本発明はこれらに制限されない。 Examples of the pathogenic factor include enterotoxin, adenylate cyclase toxin, adhesin, alkaline protease, hemolytic toxin, anthrax toxin, APX toxin, α toxin, β toxin, δ toxin, C2 toxin, C3 toxin, botulinum toxin, bundled line Hair structure subunit, C5A peptidase, cardiotoxin, chemotaxis, cholera toxin, ciliary toxin, clostridial cytotoxin, clostridial neurotoxin, collagen adhesion gene, cytolysin, vomiting toxin, endotoxin, exfoliating toxin, external Toxin, extracellular elastase, fibrinogen, fibronectin binding protein, fibrillar hemagglutinin, fimbria, gelatinase, hemagglutinin, leukotoxin, lipoprotein signal peptidase, listeriolysin O, M protein, neurotoxin, non-fimbria adhesin Edema factor, Examples include hyperenzyme, pertussis toxin, phospholipase, pili, pore forming toxin, proline permease, serine protease, Shiga toxin, tetanus toxin, thiol activated cytolysin, tracheal cell lysin, urease, etc. It is not limited to these.
本発明のAI−2阻害剤の有効成分で影響を及ぼすことができる細菌、換言すれば、本発明のAI−2阻害剤の有効成分で増殖・生育を抑制できる細菌は、AI−2によりその機能、例えば、生物発光、スウォーミング、バイオフィルム形成、タンパク質分解酵素の産生、抗生物質の合成、遺伝子受容能の発達、プラスミド接合伝達、病原因子産生及び胞子形成などが促進される細菌である。例えば、AI−2受容体を有する細菌、好ましくはAI−2受容体を有し、AI−2を産生する細菌を対象とすることができる。 Bacteria that can be affected by the active ingredient of the AI-2 inhibitor of the present invention, in other words, bacteria that can suppress the growth and growth of the active ingredient of the AI-2 inhibitor of the present invention are expressed by AI-2. Bacteria whose functions are promoted such as bioluminescence, warming, biofilm formation, proteolytic enzyme production, antibiotic synthesis, gene acceptability development, plasmid conjugation transfer, pathogenic factor production and sporulation . For example, a bacterium having an AI-2 receptor, preferably a bacterium having an AI-2 receptor and producing AI-2 can be used.
AI−2活性は、AI−2を認識することにより発光するレポーター細菌、好ましくはAI−2受容体及びルシフェラーゼを有する細菌を用いるバイオアッセイにより測定することができる(例えば、Keersmaecker S.C.J.et al.,J.Biol.Chem.,280(20),p.19563-19568,2005参照)。具体的には、ビブリオ・ハーベイ(Vibrio harveyi)BB170株をレポーター細菌とし、被検化合物の存在下で培養し、培養後の発光強度をケミルミネッセンス計などで測定することにより、AI−2活性を測定することができる。 AI-2 activity can be measured by a bioassay using a reporter bacterium that emits light by recognizing AI-2, preferably a bacterium having an AI-2 receptor and luciferase (eg, Keersmaecker S.C.J. Et al., J. Biol. Chem., 280 (20), p. 19563-19568, 2005). Specifically, Vibrio harveyi BB170 strain is used as a reporter bacterium, cultured in the presence of a test compound, and the luminescence intensity after the culture is measured with a chemiluminescence meter, etc. Can be measured.
AI−2を阻害することにより影響を及ぼす、又は増殖・生育を抑制することができる細菌としては、例えば、ビブリオ(Vibrio)属細菌、シュードモナス(Pseudomonas)属細菌、ポルフィロモナス(Porphyromonas)属細菌、エルシニア(Yersinia)属細菌、エシェリキア(Escherichia)属細菌、サルモネラ(Salmonella)属細菌、ヘモフィルス(Haemophilus)属細菌、ヘリコバクター(Helicobacter)属細菌、バシルス(Bacillus)属細菌、ボレリア(Borrelia)属細菌、ナイセリア(Neisseria)属細菌、カンピロバクター(Campylobacter)属細菌、デイノコックス(Deinococcus)属細菌、ミコバクテリウム(Mycobacterium)属細菌、エンテロコッカス(Enterococcus)属細菌、ストレプトコッカス(Streptococcus)属細菌、シゲラ(Shigella)属細菌、エロモナス(Aeromonas)属細菌、エイケネラ(Eikenella)属細菌、クロストリジウム(Clostridium)属細菌、スタフィロコッカス(Staphylococcus)属細菌、ラクトバチルス(Lactobacillus)属細菌、アクチノバチルス(Actinobacillus)属細菌、アクチノマイセス(Actinomyces)属細菌、バクテロイデス(Bacteroides)属細菌、カプノサイトファガ(Capnocytophaga)属細菌、クレブシエラ(Klebsiella)属細菌、ハロバチルス(Halobacillus)属細菌、フゾバクテリウム(Fusobacterium)属細菌、エルウィニア(Erwinia)属細菌、エルベネラ(Elbenella)属細菌、ラクトバチルス(Lactobacillus)属細菌、リステリア(Listeria)属細菌、マンヘイミア(Mannheimia)属細菌、ペプトコッカス(Peptococcus)属細菌、プレボテラ(Prevotella)属細菌、プロテウス(Proteus)属細菌、セラチア(Serratia)属細菌及びベイロネラ(Veillonella)属細菌などが挙げられる。より具体的には、ビブリオ・ハーベイ(Vibrio harveyi)、ビブリオ・フィシェリ(Vibrio fischeri)、コレラ菌(Vibrio cholerae)、腸炎ビブリオ(Vibrio parahaemolyticus)、ビブリオ・アルギノリチカス(Vibrio alginolyticus)、シュードモナス・ホスホレウム(Pseudomonas phosphoreum)、ポリフィロモナス・ジンジバリス(Porphyromonas gingivalis)、エルシニア・エンテロコリチカ(Yersinia enterocolitica)、大腸菌(Escherichia coli)、ネズミチフス菌(Salmonella typhimurium)、インフルエンザ菌(Haemophilus influenzae)、ヘリコバクター・ピロリ(Helicobacter pylori)、枯草菌(Bacillus subtilis)、ボレリア・ブルグドルフェリ(Borrelia burgfdorferi)、髄膜炎菌(Neisseria meningitidis)、淋菌(Neisseria gonorrhoeae)、ペスト菌(Yersinia pestis)、カンピロバクター・ジェジュニ(Campylobacter jejuni)、デイノコックス・ラジオデュランス(Deinococcus radiodurans)、結核菌(Mycobacterium tuberculosis)、エンテロコッカス・フェカリス(Enterococcus faecalis)、肺炎レンサ球菌(Streptococcus pneumoniae)、化膿レンサ球菌(Streptococcus pyogenes)、ストレプトコッカス・ミュータンス(Streptococcus mutans)、黄色ブドウ球菌(Staphylococcus aureus)、箕田赤痢菌(Shigella flexneri)、シゲラ・ボイデイ(Shigella boydii)、セレウス菌(Bacillus cereus)、バチルス・クブチリス(Bacillus cubtilis)、エロモナス・ハイドロフィラ(Aeromonas hydrophila)、チフス菌(Salmonella enterica)、エイケネラ・コロデンス(Eikenella corrodens)、ヘリコバクター・ヘパティカス(Helicobacter hepaticus)、ウェルシュ菌(Clostridium perfringens)、スタフィロコッカス・ハエモリティカス(Staphylococcus haemolyticus)、ラクトバチルス・ガセリ(Lactobacillus gasseri)、ラクトバチルス アシドフィラス(Lactobacillus acidophilus)、ラクトバチルス・ロイテリ(Lactobacillus reuteri)、ラクトバチルス・サリバリウス(Lactobacillus salivarius)、ラクトバチルス・カゼイ(Lactobacillus casei)、ストレプトコッカス・サンギニス(Streptococcus sanguinis)、ストレプトコッカス・アンギノーサス(Streptococcus anginosus)、ストレプトコッカス・オラリス(Streptococcus oralis)、ストレプトコッカス・ボビス(Streptococcus bovis)、ストレプトコッカス・ゴルドニ(Streptococcus gordonii)、ストレプトコッカス・ミティス(Streptococcus mitis)、アクチノバチルス・アクチノマイセテムコミタンス(Actinobacillus actinomycetemcomitans)、ビブリオ・ブルニフィカス(Vivrio vulnificus)、ビブリオ・ミミクス(Vibrio mimicus)、ビブリオ・アングイラルム(Vibrio anguillarum)、ラクトバチルス・ラムノサス(Lactobacillus rhamnosus)、エルウィニア・アミロボラ(Erwinia amylovora)、エルウィニア・カロトバラ(Erwinia carotovara)、ハロバチルス・ハロフィラス(Halabacilus halophilus)、セラチア・ピムチカ(Serratia pymuthica)、セラチア・マルセセンス(Serratia marcescens)、バクテロイデス・フラジリス(Bacteroides fragilis)、バクテロイデス・ブルガタス(Bacteroides vulgatus)、バクテロイデス・ディスタソニス(Bacteroides distasonis)、リステリア・モノサイトジェネス(Listeria monocytogenes)、スタフィロコッカス・エピデルミディス(Staphylococcus epidermidis)、クロストリジウム・ディフィシル(Clostridium difficile)、アエロモナス・ハイドロフィリア(Aeromonas hydrophilia)、マンヘイミア・ハエモライティカ(Mannhemia haemolytica)、クレブシエラ・ニューモニアエ(Klebsiella pneumoniae)、バチルス・アンスラシス(Bacillus anthracis)、カンピロバクター・コリ(Campylobacter coli)、カンピロバクター・レクタス(Campylobacter rectus)、プロテウス・ミラビリス(Proteus mirabilis)、アクチノマイセス・ナエスランディ(Actinomyces naeslundii)、ペプトコッカス・アナエロビウス(Peptococcus anaerobius)、フゾバクテリウム・ヌクレアタム(Fusobacterium nucleatum)、ベイロネラ・パルラ(Veillonella parvula)、カプノサイトファガ・スプティゲナ(Capnocytophaga sputigena)及びプレボテラ・インタメディア(Prevotella intermedia)などが挙げられる。 Examples of bacteria that can be affected by inhibiting AI-2 or that can suppress proliferation and growth include bacteria belonging to the genus Vibrio, bacteria belonging to the genus Pseudomonas, bacteria belonging to the genus Porphyromonas. , Yersinia (Yersinia) bacteria, Escherichia (Escherichia) bacteria, Salmonella (Salmonella) bacteria, Haemophilus (Haemophilus) bacteria, Helicobacter (Helicobacter) bacteria, Bacillus (Bacillus) bacteria, Borrelia (Borrelia) bacteria, Neisseria (Neisseria) bacteria belonging to the genus Campylobacter (Campylobacter) bacteria belonging to the genus, Day Roh Cox (Deinococcus) bacteria belonging to the genus Mycobacterium (Mycobacterium) bacteria belonging to the genus Enterococcus (Enterococcus) bacteria belonging to the genus Streptococcus (Streptococcus) bacteria belonging to the genus Shigella (Shigella) genus Bacteria, Aeromonas ( Ae romonas) bacteria belonging to the genus, Eikenera (Eikenella) bacteria belonging to the genus Clostridium (Clostridium) bacteria, Staphylococcus (Staphylococcus) bacteria belonging to the genus Lactobacillus (Lactobacillus) bacteria belonging to the genus Actinobacillus (Actinobacillus) bacteria belonging to the genus Actinomyces (Actinomyces) bacteria belonging to the genus Bacteroides (Bacteroides) bacteria belonging to the genus, Cap Roh site file moth (Capnocytophaga) bacteria belonging to the genus Klebsiella (Klebsiella) bacteria belonging to the genus, Harobachirusu (Halobacillus) bacteria, Fusobacterium (Fusobacterium) bacteria belonging to the genus Erwinia (Erwinia) bacteria belonging to the genus, Erubenera (Elbenella) bacteria belonging to the genus Lactobacillus (Lactobacillus) bacteria belonging to the genus Listeria (Listeria) bacteria belonging to the genus Mannheimia (Mannheimia) bacteria belonging to the genus, Peputokokkasu (Peptococcus) bacteria belonging to the genus Prevotella (Prevotella) bacteria belonging to the genus, Proteus (Proteus) bacteria belonging to the genus, Serachi Examples include bacteria of the genus Serratia and bacteria of the genus Veillonella. More specifically, Vibrio harveyi (Vibrio harveyi), Vibrio fischeri (Vibrio fischeri), cholera (Vibrio cholerae), Vibrio parahaemolyticus (Vibrio parahaemolyticus), Vibrio Aruginorichikasu (Vibrio alginolyticus), Pseudomonas Hosuhoreumu (Pseudomonas phosphoreum ), poly Philo Sphingomonas gingivalis (Porphyromonas gingivalis), Yersinia enterocolitica (Yersinia enterocolitica), E. (Escherichia coli), Salmonella typhimurium (Salmonella typhimurium), Haemophilus influenzae (Haemophilus influenzae), Helicobacter pylori (Helicobacter pylori), Bacillus subtilis (Bacillus subtilis), Borrelia burgdorferi (Borrelia burgfdorferi), meningococcal (Neisseria meningitidis), Neisseria gonorrhoeae (Neisseria gonorrhoeae), Yersinia pestis (Yersinia pestis), Campylobacter Jeji Two (Campylobacter jejuni), Day Roh Cox radiodurans (Deinococcus radiodurans), Mycobacterium tuberculosis (Mycobacterium tuberculosis), Enterococcus faecalis (Enterococcus faecalis), Streptococcus pneumoniae (Streptococcus pneumoniae), Streptococcus pyogenes (Streptococcus pyogenes), Streptococcus mu chest (Streptococcus mutans), Staphylococcus aureus (Staphylococcus aureus), Mita Shigella (Shigella flexneri), Shigella Boidei (Shigella boydii), Bacillus cereus (Bacillus cereus), Bacillus Kubuchirisu (Bacillus cubtilis), Aeromonas hydrophila ( Aeromonas hydrophila), Salmonella typhi (Salmonella enterica), Eikenera-Korodensu (Eikenella corrodens), Helicobacter Hepatikasu (Helicobacter hepaticus), Clostridium perfringens (Clostridium perfringens), staphylococcal · Haemoritikasu (Staphylococcus haemolyticus), Lactobacillus gasseri (Lactobacillus gasseri), Lactobacillus acidophilus (Lactobacillus acidophilus), Lactobacillus reuteri (Lactobacillus reuteri), Lactobacillus salivarius (Lactobacillus salivarius), Lactobacillus casei (Lactobacillus casei) , Streptococcus Sanginisu (Streptococcus sanguinis), Streptococcus anginosus (Streptococcus anginosus), Streptococcus oralis (Streptococcus oralis), Streptococcus bovis (Streptococcus bovis), Streptococcus Gorudoni (Streptococcus gordonii), Streptococcus mitis (Streptococcus mitis), actinolite Bacillus actinomycetemcomitans (Actinobacillus actinomycetemcomitans), Vibrio Vulnificus (Vivrio vulnificus), Vibrio Mimikusu (Vibrio mimicus), Vibrio Anguirarumu (Vibrio anguillarum), Lactobacillus rhamnosus (Lactobacillus rhamnosus), Erwinia Amirobora (Erwinia amylovora), Erwinia Karotobara (Erwinia carotovara), Harobachirusu-halophilus (Halabacilus halophilus), Serratia Pimuchika (Serratia pymuthica), Serratia marcescens (Serratia marcescens), Bacteroides fragilis (Bacteroides fragilis), Bacteroides vulgatus (Bacteroides vulgatus), Bacteroides Disutasonisu (Bacteroides distasonis), Listeria monocytogenes ( Listeria monocytogenes ), Staphylococcus epidermidis , Clostridium difficile ( Clo stridium difficile), Aeromonas hydrophila Philia (Aeromonas hydrophilia), Mannheimia Haemoraitika (Mannhemia haemolytica), Klebsiella pneumoniae (Klebsiella pneumoniae), Bacillus anthracis (Bacillus anthracis), Campylobacter coli (Campylobacter coli), Campylobacter rectus (Campylobacter rectus), Proteus mirabilis (Proteus mirabilis), Actinomyces Naesurandi (Actinomyces naeslundii), Peputokokkasu-Anaerobiusu (Peptococcus anaerobius), Fusobacterium nucleatum (Fusobacterium nucleatum), Beironera-Parla (Veillonella parvula), Cap Roh site file like moth-Suputigena (Capnocytophaga sputigena) and Prevotella inter media (Prevotella intermedia).
本発明のAI−2阻害剤の有効成分は、ストレプトコッカス・ミュータンス、ポリフィロモナス・ジンジバリス、ストレプトコッカス・オラリス、ストレプトコッカス・ゴルドニ、ストレプトコッカス・サングイニス、ストレプトコッカス・ミティス、アクチノマイセス・ナエスランディ、ペプトコッカス・アナエロビウス、アクチノバチルス・アクチノマイセテムコミタンス、フゾバクテリウム・ヌクレアタム、ベイロネラ・パルラ、カプノサイトファガ・スプティゲナ、プレボテラ・インタメディア及びラクトバチルス・サリバリウスなどに対するAI−2の阻害に対し、特に好ましく用いられる。 The active ingredients of the AI-2 inhibitor of the present invention include Streptococcus mutans, Polyphyromonas gingivalis, Streptococcus oralis, Streptococcus gordonii, Streptococcus sanguinis, Streptococcus mitis, Actinomyces naeslandi, Peptococcus anaerodia In particular, it is preferably used for the inhibition of AI-2 against Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum, Beironella parla, Capnocytofaga sputigena, Prevotella intermedia, Lactobacillus salivaius and the like.
生体内において、AI−2量とある種の感染症の症状とが相関関係を有し、本発明のAI−2阻害剤の有効成分を投与することにより歯周病や齲蝕病等の感染症の症状を低減できる。したがって、一実施形態において本発明は、ダイズ発酵物のヘキサン抽出物を有効成分とする、歯周病又は齲蝕病の予防及び/又は治療剤に関する。さらに、本発明のオートインデューサー−2阻害剤は、歯周病、齲蝕病等の感染症の予防及び/又は治療剤として用いることができる。さらには、本発明のオートインデューサー−2阻害剤は、歯周病、齲蝕病等の感染症の予防及び/又は治療剤などに含有させることができる。 In vivo, there is a correlation between the amount of AI-2 and the symptoms of certain infectious diseases, and infectious diseases such as periodontal diseases and caries diseases by administering the active ingredient of the AI-2 inhibitor of the present invention Can reduce the symptoms. Therefore, in one embodiment, the present invention relates to a preventive and / or therapeutic agent for periodontal disease or dental caries disease comprising a hexane extract of fermented soybean as an active ingredient. Furthermore, the autoinducer-2 inhibitor of the present invention can be used as a preventive and / or therapeutic agent for infectious diseases such as periodontal disease and caries disease. Furthermore, the autoinducer-2 inhibitor of the present invention can be contained in a preventive and / or therapeutic agent for infectious diseases such as periodontal disease and caries disease.
本発明のAI−2阻害剤の有効成分を投与することにより予防及び/又は治療することができる感染症は、AI−2を阻害することにより予防及び/又は治療することができる感染症であり、換言すれば、AI−2を利用するクオラムセンシングシステムを有する細菌、具体的にはAI−2を阻害することにより影響を及ぼすことができる上記のような細菌に関連する感染症である。 The infectious disease that can be prevented and / or treated by administering the active ingredient of the AI-2 inhibitor of the present invention is an infectious disease that can be prevented and / or treated by inhibiting AI-2. In other words, it is a bacterium having a quorum sensing system utilizing AI-2, specifically an infectious disease related to the above-mentioned bacterium that can be affected by inhibiting AI-2.
前記有効成分を投与することにより予防及び/又は治療することができる感染症の具体例として、口腔、皮膚、膣、消化(GI)管、食道及び気道等における感染症が挙げられる。より具体的には、ストレプトコッカス・ミュータンス等により引き起こされる齲蝕病;ポルフィロモナス・ジンジバリス等により引き起こされる歯周病(歯骨炎、歯肉炎を含む);日和見生物により引き起こされる日和見感染症;肺炎レンサ球菌及びインフルエンザ菌等により引き起こされる急性中耳炎(AOM)及び滲出性中耳炎(OME);インフルエンザ菌により引き起こされるインフルエンザ;ヘリコバクター・ピロリにより引き起こされる十二指腸潰瘍、胃ガン及び胃潰瘍;コレラ菌により引き起こされるコレラ;ペスト菌により引き起こされるペスト;髄膜炎菌により引き起こされる髄膜炎;ネズミチフス菌などのサルモネラ属細菌により引き起こされるサルモネラ中毒;ウェルシュ菌により引き起こされる食中毒、ガス壊疽及び出血性腸炎;及び大腸菌等により引き起こされる下痢症などが挙げられる(後述の実施例、並びに特開2009−114120号公報;Yoshida A.et al.,Appl.Environ.Microbiol.,71(5),p.2372-2380,2005;Wen Z.T.et al.,J.Bacteriol.,189(9),p.2682-2691,2004;Osaki T. et al.,J.Med.Microbiol.,55(Pt11),p.1477-1485,2006;及びOhtani K.et al.,Mol.Microbiol.,44(1),p.171-179,2002等参照)。 Specific examples of infectious diseases that can be prevented and / or treated by administering the active ingredient include infectious diseases in the oral cavity, skin, vagina, digestive (GI) tract, esophagus and respiratory tract. More specifically, caries disease caused by Streptococcus mutans, etc .; periodontal disease caused by Porphyromonas gingivalis etc. (including gingivitis and gingivitis); opportunistic infections caused by opportunistic organisms; pneumonia Acute otitis media (AOM) and exudative otitis media (OME) caused by streptococci and Haemophilus influenzae; influenza caused by Haemophilus influenzae; duodenal ulcer, gastric cancer and gastric ulcer caused by Helicobacter pylori; cholera caused by Vibrio cholerae; Plague caused by Plasmodium; meningitis caused by Neisseria meningitidis; Salmonella poisoning caused by Salmonella bacteria such as Salmonella typhimurium; Food poisoning, gas gangrene caused by Clostridium perfringens Hemorrhagic enteritis; and diarrhea caused by Escherichia coli and the like (Examples described later, and JP 2009-114120 A; Yoshida A. et al., Appl. Environ. Microbiol., 71 (5), Wen Z.T. et al., J. Bacteriol., 189 (9), p.2682-2691, 2004; Osaki T. et al., J. Med.Microbiol., 55 (Pt11), p. 1477-1485, 2006; and Ohtani K. et al., Mol. Microbiol., 44 (1), p. 171-179, 2002, etc.).
本明細書において感染症の予防には、感染症の発症を抑えること及び遅延させることが含まれ、感染症になる前の予防だけではなく、治療後の感染症の再発に対する予防も含まれる。本明細書において感染症の治療には、感染症を治癒すること、症状を改善すること及び症状の進行を抑えることが包含される。 In the present specification, prevention of infectious diseases includes suppressing and delaying the onset of infectious diseases, and includes not only prevention before infectious diseases but also prevention of recurrence of infectious diseases after treatment. In the present specification, treatment of an infectious disease includes curing an infectious disease, ameliorating symptoms, and suppressing progression of symptoms.
本発明のAI−2阻害剤、並びに前記感染症の予防及び/又は治療剤の投与対象は、好ましくは哺乳動物である。本明細書において哺乳動物は、温血脊椎動物をさし、例えば、ヒト及びサルなどの霊長類、マウス、ラット及びウサギなどの齧歯類、イヌ及びネコなどの愛玩動物、並びにウシ、ウマ及びブタなどの家畜が挙げられる。本発明のAI−2阻害剤、並びに前記感染症の予防及び/又は治療剤は、霊長類、特にヒトへの投与に好適である。感染症に罹患しているヒト、感染症と診断されているヒト、感染症に罹患する可能性があるヒト、感染症を予防する必要があるヒトに投与することが特に好ましい。 The subject of administration of the AI-2 inhibitor of the present invention and the preventive and / or therapeutic agent for the infectious disease is preferably a mammal. As used herein, mammals refer to warm-blooded vertebrates, such as primates such as humans and monkeys, rodents such as mice, rats and rabbits, companion animals such as dogs and cats, and cattle, horses and Examples include livestock such as pigs. The AI-2 inhibitor of the present invention and the preventive and / or therapeutic agent for the infectious disease are suitable for administration to primates, particularly humans. It is particularly preferred to administer to a human suffering from an infectious disease, a human being diagnosed with an infectious disease, a human being likely to suffer from an infectious disease, or a human in need of preventing the infectious disease.
本発明のAI−2阻害剤、並びに前記感染症の予防及び/又は治療剤の形態は、特に制限されないが、例えば、医薬組成物、食品組成物、口腔用組成物及び化粧料組成物とするか、又はこれらに含有させることができる。 The form of the AI-2 inhibitor of the present invention and the preventive and / or therapeutic agent for the infectious disease is not particularly limited, and for example, a pharmaceutical composition, a food composition, an oral composition and a cosmetic composition are used. Or can be contained in these.
医薬組成物を調製する場合は、通常、前記有効成分と好ましくは薬学的に許容される担体を含む製剤として調製する。薬学的に許容される担体とは、一般的に、前記有効成分とは反応しない、不活性の、無毒の、固体又は液体の、増量剤、希釈剤又はカプセル化材料等をいい、例えば、水、エタノール、ポリオール(例えば、グリセロール、プロピレングリコール、液体ポリエチレングリコールなど)、適切なそれらの混合物、植物性油などの溶媒又は分散媒体などが挙げられる。 When preparing a pharmaceutical composition, it is usually prepared as a preparation containing the active ingredient and preferably a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier generally refers to an inert, non-toxic, solid or liquid, bulking agent, diluent or encapsulating material that does not react with the active ingredient, eg, water. , Ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixtures thereof, solvents or dispersion media such as vegetable oils, and the like.
医薬組成物は、経口により、非経口により、例えば、皮膚に、皮下に、粘膜に、静脈内に、動脈内に、筋肉内に、腹腔内に、膣内に、肺に、脳内に、眼に、及び鼻腔内に投与される。経口投与製剤としては、錠剤、顆粒剤、細粒剤、散剤、カプセル剤、チュアブル剤、ペレット剤、シロップ剤、液剤、懸濁剤及び吸入剤などが挙げられる。非経口投与製剤としては、坐剤、保持型浣腸剤、点滴剤、点眼剤、点鼻剤、ペッサリー剤、注射剤、口腔洗浄剤並びに軟膏、クリーム剤、ゲル剤、制御放出パッチ剤及び貼付剤などの皮膚外用剤などが挙げられる。本発明の医薬組成物は、徐放性皮下インプラントの形態で、又は標的送達系(例えば、モノクローナル抗体、ベクター送達、イオン注入、ポリマーマトリックス、リポソーム及びミクロスフェア)の形態で、非経口で投与してもよい。 The pharmaceutical composition can be administered orally, parenterally, e.g., into the skin, subcutaneously, mucosal, intravenously, intraarterially, intramuscularly, intraperitoneally, intravaginally, into the lungs, into the brain, Administered to the eye and intranasally. Examples of the preparation for oral administration include tablets, granules, fine granules, powders, capsules, chewables, pellets, syrups, solutions, suspensions and inhalants. As parenteral preparations, suppositories, retention enemas, drops, eye drops, nasal drops, pessaries, injections, mouth washes, ointments, creams, gels, controlled release patches and patches Skin external preparations, and the like. The pharmaceutical compositions of the invention are administered parenterally in the form of sustained-release subcutaneous implants or in the form of targeted delivery systems (eg, monoclonal antibodies, vector delivery, ion implantation, polymer matrices, liposomes and microspheres). May be.
医薬組成物はさらに医薬分野において慣用の添加剤を含んでいてもよい。そのような添加剤には、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、抗酸化剤、着色剤、矯味剤などがあり、必要に応じて使用できる。長時間作用できるように徐放化するためには、既知の遅延剤等でコーティングすることもできる。賦形剤としては、例えば、カルボキシメチルセルロースナトリウム、寒天、軽質無水ケイ酸、ゼラチン、結晶セルロース、ソルビトール、タルク、デキストリン、デンプン、乳糖、白糖、ブドウ糖、マンニトール、メタ珪酸アルミン酸マグネシウム、リン酸水素カルシウム等が使用できる。結合剤としては、例えば、アラビアゴム、アルギン酸ナトリウム、エタノール、エチルセルロース、カゼインナトリウム、カルボキシメチルセルロースナトリウム、寒天、精製水、ゼラチン、デンプン、トラガント、乳糖、ヒドロキシセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルピロリドン等が挙げられる。崩壊剤としては、例えば、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ナトリウム、カルボキシメチルセルロースカルシウム、結晶セルロース、デンプン、ヒドロキシプロピルスターチ等が挙げられる。滑沢剤としては、例えば、ステアリン酸、ステアリン酸カルシウム、ステアリン酸マグネシウム、タルク、硬化油、ショ糖脂肪酸エステル、ロウ類等が挙げられる。抗酸化剤としては、トコフェロール、没食子酸エステル、ジブチルヒドロキシトルエン(BHT)、ブチルヒドロキシアニソール(BHA)、アスコルビン酸等が挙げられる。必要に応じてその他の添加剤や薬剤、例えば制酸剤(炭酸水素ナトリウム、炭酸マグネシウム、沈降炭酸カルシウム、合成ヒドロタルサイト等)、胃粘膜保護剤(合成ケイ酸アルミニウム、スクラルファート、銅クロロフィリンナトリウム等)を加えてもよい。 The pharmaceutical composition may further contain additives conventionally used in the pharmaceutical field. Such additives include, for example, excipients, binders, disintegrants, lubricants, antioxidants, colorants, flavoring agents, and the like, and can be used as necessary. In order to achieve sustained release so that it can act for a long time, it can also be coated with a known retarder or the like. Examples of excipients include sodium carboxymethylcellulose, agar, light anhydrous silicic acid, gelatin, crystalline cellulose, sorbitol, talc, dextrin, starch, lactose, sucrose, glucose, mannitol, magnesium aluminate metasilicate, calcium hydrogen phosphate Etc. can be used. Examples of the binder include gum arabic, sodium alginate, ethanol, ethyl cellulose, sodium caseinate, sodium carboxymethyl cellulose, agar, purified water, gelatin, starch, tragacanth, lactose, hydroxycellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc. Is mentioned. Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, crystalline cellulose, starch, hydroxypropyl starch and the like. Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, talc, hydrogenated oil, sucrose fatty acid ester, waxes and the like. Examples of the antioxidant include tocopherol, gallic acid ester, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbic acid and the like. Other additives and drugs as required, such as antacids (sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, synthetic hydrotalcite, etc.), gastric mucosa protective agents (synthetic aluminum silicate, sucralfate, copper chlorophyllin sodium, etc.) ) May be added.
口腔用組成物には、前記有効成分のほか、その形態に応じて種々の成分を配合することができる。配合可能な成分として、例えば研磨剤、湿潤剤、粘結剤、歯質強化剤、殺菌剤、pH調整剤、酵素類、抗炎症剤・血行促進剤、甘味剤、防腐剤、着色剤・色素類、香料等を適宜使用することができる。
口腔用組成物に配合することができる成分としては、具体的に、第2リン酸カルシウム、第3リン酸カルシウム、ピロリン酸カルシウム、リン酸マグネシウム、不溶性メタリン酸ナトリウム、無水ケイ酸、水酸化アルミニウム、アルミナ、ハイドロキシアパタイト、炭酸カルシウム、炭酸マグネシウム、硫酸カルシウム、ゼオライト、合成アルミノケイ酸塩、ベンガラ等の研磨剤;前記の研磨剤を結合剤を用いて造粒した顆粒状研磨剤;グリセリン、プロピレングリコール、1,3−ブチレングリコール、エチレングリコール、ポリエチレングリコール、ポリプロピレングリコール、エリスリトール、キシリトール、ソルビトール、マルチトール等の湿潤剤;カルボキシメチルセルロース及びその塩類、メチルセルロース、ヒドロキシエチルセルロース、カラギーナン、ポリアクリル酸ナトリウム、ヒドロキシプロピルセルロース、カルボキシメチルヒドロキシエチルセルロースナトリウム、アルギン酸ナトリウム、アルギン酸プロピレングリコールエステル、キサンタンガム、トラガカントガム、カラヤガム、アラビヤガム、ポリビニルアルコール、ポリビニルピロリドン、ビーガム、ラポナイト等の粘結剤;モノフルオルリン酸ナトリウム、フッ化スズ、フッ化ナトリウム等の歯質強化剤;クロルヘキシジン及びその塩類、トリクロサン、塩化セチルピリジニウム、チモール類、塩化ベンザルコニウム等の殺菌剤;リン酸ナトリウム等のpH調整剤;デキストラナーゼ、アミラーゼ、プロテアーゼ、リゾチーム、ムタナーゼ等の酵素類;塩化ナトリウム、ヒノキチオール、ε−アミノカプロン酸、トラネキサム酸、アラントイン類、トコフェロール類、オクチルフタリド、ニコチン酸エステル類、ジヒドロコレステロール、グリチルレチン酸、グリチルリチン酸及びその塩類、グリセロホスフェート、クロロフィル、水溶性無機リン酸化合物、アズレン類、カミツレ、センブリ、当帰、センキュウ、生薬類等の抗炎症剤・血行促進剤;サッカリンナトリウム、ステビオサイド、タウマチン、アスパラチルフェニルアラニンメチルエステル等の甘味剤;p−ヒドロキシ安息香酸、p−ヒドロキシ安息香酸エチル、p−ヒドロキシ安息香酸プロピル、p−ヒドロキシ安息香酸ブチル、安息香酸ナトリウム等の防腐剤;二酸化チタン等の着色剤・色素類;ペパーミント油、スペアミント油、メントール、カルボン、アネトール、オイゲノール、サリチル酸メチル、リモネン、オシメン、n−デシルアルコール、シトロネロール、α−テルピネオール、メチルアセテート、シトロネリルアセテート、メチルオイゲノール、シネオール、リナロール、エチルリナロール、ワニリン、チモール、アニス油、レモン油、オレンジ油、セージ油、ローズマリー油、桂皮油、ピメント油、桂葉油、冬緑油、丁子油、ユーカリ油等の香料等が挙げられる。
In addition to the active ingredient, various components can be blended in the oral composition depending on the form. Ingredients that can be incorporated include, for example, abrasives, wetting agents, binders, dentin enhancers, bactericides, pH adjusters, enzymes, anti-inflammatory agents / blood circulation promoters, sweeteners, preservatives, colorants / pigments , Fragrances and the like can be used as appropriate.
Specific components that can be blended in the oral composition include dicalcium phosphate, tricalcium phosphate, calcium pyrophosphate, magnesium phosphate, insoluble sodium metaphosphate, anhydrous silicic acid, aluminum hydroxide, alumina, hydroxyapatite Abrasives such as calcium carbonate, magnesium carbonate, calcium sulfate, zeolite, synthetic aluminosilicate, bengara, etc .; granular abrasives granulated from the above abrasives using a binder; glycerin, propylene glycol, 1,3- Wetting agents such as butylene glycol, ethylene glycol, polyethylene glycol, polypropylene glycol, erythritol, xylitol, sorbitol, maltitol; carboxymethylcellulose and its salts, methylcellulose, hydroxyethyl Binders such as roulose, carrageenan, sodium polyacrylate, hydroxypropylcellulose, sodium carboxymethylhydroxyethylcellulose, sodium alginate, propylene glycol alginate, xanthan gum, tragacanth gum, karaya gum, arabic gum, polyvinyl alcohol, polyvinyl pyrrolidone, bee gum, laponite; Dental strengthening agents such as sodium monofluorophosphate, tin fluoride, sodium fluoride; bactericides such as chlorhexidine and its salts, triclosan, cetylpyridinium chloride, thymols, benzalkonium chloride; pH of sodium phosphate, etc. Modifier: Enzymes such as dextranase, amylase, protease, lysozyme, mutanase; sodium chloride, hinokitiol, ε-a Minocaproic acid, tranexamic acid, allantoins, tocopherols, octylphthalide, nicotinic acid esters, dihydrocholesterol, glycyrrhetinic acid, glycyrrhizic acid and its salts, glycerophosphate, chlorophyll, water-soluble inorganic phosphate compounds, azulenes, camomile, Anti-inflammatory agents / blood circulation promoters such as assembly, Toki, Senkyu, herbal medicines; sweeteners such as saccharin sodium, stevioside, thaumatin, aspartylphenylalanine methyl ester; p-hydroxybenzoic acid, ethyl p-hydroxybenzoate, p- Preservatives such as propyl hydroxybenzoate, butyl p-hydroxybenzoate and sodium benzoate; colorants and pigments such as titanium dioxide; peppermint oil, spearmint oil, menthol, carvone, anethole Eugenol, methyl salicylate, limonene, ocimene, n-decyl alcohol, citronellol, α-terpineol, methyl acetate, citronellyl acetate, methyl eugenol, cineol, linalool, ethyl linalool, crocodile, thymol, anise oil, lemon oil, orange oil, Examples include sage oil, rosemary oil, cinnamon oil, pimento oil, cinnamon oil, winter green oil, clove oil, eucalyptus oil, and the like.
口腔用組成物には、本発明の効果を損なわない限り、界面活性剤を配合することもできる。界面活性剤としては特に制限はないが、アニオン系界面活性剤及びノニオン系界面活性剤を好ましく用いることができる。アニオン系界面活性剤としては、ラウリル硫酸ナトリウム、ミリスチル硫酸ナトリウム等のアルキル硫酸エステル塩;ラウロイルサルコシンナトリウム等のN−アシルアミノ酸塩;ラウロイルメチルタウリンナトリウム等のアシルタウリン塩;ヤシ油脂肪酸エチルエステルスルホン酸ナトリウム塩等の脂肪酸エステルスルホン酸塩等が挙げられる。ノニオン系界面活性剤としては、ポリオキシエチレン硬化ヒマシ油、ショ糖脂肪酸エステル、ソルビタン脂肪酸エステル、グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンソルビット脂肪酸エステル、ポリオキシエチレングリセリン脂肪酸エステル、ポリエチレングリコール脂肪酸エステル等の脂肪酸エステル類、ポリオキシエチレンフィトステロール、ポリオキシエチレンフィトスタノール、ポリオキシエチレンラノリン、ポリオキシエチレンラノリンアルコール、ポリオキシエチレンアルキルアミン、ポリオキシエチレン脂肪酸アミド、ポリオキシエチレンアルキルフェニルホルムアルデヒド縮合物、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンポリオキシプロピレンアルキルエーテル、ポリオキシエチレンポリオキシプロピレン共重合体、ポリオキシエチレンアルキルフェニルエーテル、ポリオキシエチレン脂肪酸エタノールアミドなどが挙げられる。 As long as the effects of the present invention are not impaired, a surfactant may be added to the oral composition. Although there is no restriction | limiting in particular as surfactant, Anionic surfactant and a nonionic surfactant can be used preferably. Examples of anionic surfactants include alkyl sulfate salts such as sodium lauryl sulfate and sodium myristyl sulfate; N-acyl amino acid salts such as sodium lauroyl sarcosine; acyl taurine salts such as sodium lauroyl methyl taurine; coconut oil fatty acid ethyl ester sulfonic acid Examples include fatty acid ester sulfonates such as sodium salts. Nonionic surfactants include polyoxyethylene hydrogenated castor oil, sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbite fatty acid ester, polyoxyethylene Fatty acid esters such as glycerin fatty acid ester and polyethylene glycol fatty acid ester, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene lanolin, polyoxyethylene lanolin alcohol, polyoxyethylene alkylamine, polyoxyethylene fatty acid amide, polyoxy Ethylene alkyl phenyl formaldehyde condensate, polyoxyethylene alkyl ether, polyoxye Ren polyoxypropylene alkyl ethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene alkyl phenyl ethers, polyoxyethylene fatty acid ethanol amides.
口腔用組成物は、前記有効成分を配合し、常法により製造することができる。口腔用組成物の形態は特に制限されず、粉歯磨、液状歯磨、練歯磨、潤製歯磨、口腔パスタ等のペースト状洗浄剤、洗口液、マウスウォッシュ等の液状洗浄剤、うがい用錠剤、歯肉マッサージクリーム、チューインガム、トローチ、キャンディ等の食品等の形態とすることができる。 The composition for oral cavity can be manufactured by a conventional method by blending the active ingredients. The form of the composition for oral cavity is not particularly limited, and is a powdery toothpaste, a liquid toothpaste, a toothpaste, a toothpaste, a paste-like cleaning agent such as oral pasta, a mouthwash, a liquid cleaning agent such as mouthwash, a gargle tablet, It can be in the form of food such as gingival massage cream, chewing gum, troche and candy.
食品組成物を調製する場合、その形態は特に制限されず、飲料も包含される。一般食品の他に、感染症(具体的には、歯肉炎や歯骨炎などの歯周病、齲蝕病等)の予防・改善等をコンセプトとしてその旨を表示した飲食品、すなわち、健康食品、機能性食品、病者用食品及び特定保健用食品なども包含される。健康食品、機能性食品、病者用食品及び特定保健用食品は、具体的には、細粒剤、錠剤、顆粒剤、散剤、カプセル剤、シロップ剤、液剤、流動食等の各種製剤形態として使用することができ、これら製剤のために使用することができる。製剤形態の食品組成物は、医薬製剤と同様に製造することができ、前記有効成分と、食品として許容できる担体、例えば適当な賦形剤(例えば、でん粉、加工でん粉、乳糖、ブドウ糖、水等)等とを混合した後、慣用の手段を用いて製造することができる。さらに、食品組成物は、スープ類、ジュース類、乳飲料、茶飲料、コーヒー飲料、ココア飲料、ゼリー状飲料などの液状食品組成物、プリン、ヨーグルトなどの半固形食品組成物、パン類、うどんなどの麺類、クッキー、チョコレート、キャンディ、ガム、せんべいなどの菓子類、ふりかけ、バター、ジャムなどのスプレッド類等の形態もとりうる。また、食品には、飼料も含まれる。 When preparing a food composition, the form in particular is not restrict | limited, A drink is also included. In addition to general foods, foods and drinks that indicate the concept of prevention and improvement of infectious diseases (specifically, periodontal diseases such as gingivitis and gingivitis, caries diseases, etc.), that is, health foods Functional foods, foods for sick people, foods for specified health use, and the like are also included. Health foods, functional foods, foods for patients and foods for specified health use are specifically formulated in various forms such as fine granules, tablets, granules, powders, capsules, syrups, liquids, and liquid foods. Can be used for these formulations. A food composition in the form of a preparation can be produced in the same manner as a pharmaceutical preparation. The active ingredient and a carrier acceptable as a food, for example, an appropriate excipient (eg, starch, processed starch, lactose, glucose, water, etc.) ) And the like, and then can be produced using conventional means. In addition, food compositions include soups, juices, milk beverages, tea beverages, coffee beverages, cocoa beverages, jelly-like beverages and other liquid food compositions, pudding, yogurt and other semi-solid food compositions, breads, udon Such as noodles such as cookies, chocolate, candy, gum, rice crackers and the like, spreads such as sprinkles, butter, jam and the like. The food also includes feed.
食品組成物には、種々の食品添加物、例えば、酸化防止剤、香料、各種エステル類、有機酸類、有機酸塩類、無機酸類、無機酸塩類、無機塩類、色素類、乳化剤、保存料、調味料、甘味料、酸味料、果汁エキス類、野菜エキス類、花蜜エキス類、pH調整剤、品質安定剤などの添加剤を単独、あるいは併用して配合してもよい。 Food compositions include various food additives such as antioxidants, fragrances, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, pigments, emulsifiers, preservatives, seasonings Additives such as additives, sweeteners, acidulants, fruit juice extracts, vegetable extracts, nectar extracts, pH adjusters, and quality stabilizers may be used alone or in combination.
化粧料組成物を調製する場合、その形態は特に制限されず、溶液、乳液、粉末、水−油二層系、水−油−粉末三層系、ゲル、エアゾール、ミスト及びカプセル等任意の形態とすることができる。また、化粧料組成物の製品形態も任意であり、例えば、マッサージ剤及びフットスプレー等のボディー化粧料、化粧水、乳液、クリーム及びパック等のフェーシャル化粧料、ファンデーション、おしろい、頬紅、口紅、アイシャドー、アイライナー、マスカラ及びサンスクリーン等のメーキャップ化粧料、メーク落とし、洗顔料及びボディーシャンプー等の皮膚洗浄料、ヘアーリンス及びシャンプー等の毛髪化粧料、浴用剤、軟膏、医薬部外品、あぶら取り紙、芳香化粧料等が挙げられる。 When preparing a cosmetic composition, the form is not particularly limited, and any form such as a solution, emulsion, powder, water-oil two-layer system, water-oil-powder three-layer system, gel, aerosol, mist, capsule, etc. It can be. The product form of the cosmetic composition is also arbitrary, for example, body cosmetics such as massage agents and foot sprays, facial cosmetics such as lotions, emulsions, creams and packs, foundations, funny, blushers, lipsticks, eye Makeup cosmetics such as shadows, eyeliners, mascaras and sunscreens, makeup removers, skin cleansers such as face wash and body shampoo, hair cosmetics such as hair rinses and shampoos, bath preparations, ointments, quasi drugs, oil Examples include papers and aromatic cosmetics.
化粧料組成物は、化粧品、医薬部外品及び医薬品等に慣用される他の成分、例えば、粉末成分、液体油脂、固体油脂、ロウ、炭化水素、高級脂肪酸、高級アルコール、エステル、シリコーン、アニオン界面活性剤、カチオン界面活性剤、両性界面活性剤、非イオン界面活性剤、保湿剤、水溶性高分子、増粘剤、皮膜剤、紫外線吸収剤、金属イオン封鎖剤、低級アルコール、多価アルコール、糖、アミノ酸、有機アミン、高分子エマルジョン、pH調整剤、皮膚栄養剤、ビタミン、酸化防止剤、酸化防止助剤、香料、水等を必要に応じて配合し、常法により製造することができる。 The cosmetic composition includes other components commonly used in cosmetics, quasi drugs and pharmaceuticals, such as powder components, liquid fats and oils, solid fats and oils, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, silicones, anions. Surfactant, cationic surfactant, amphoteric surfactant, nonionic surfactant, humectant, water-soluble polymer, thickener, film agent, UV absorber, sequestering agent, lower alcohol, polyhydric alcohol , Sugar, amino acids, organic amines, polymer emulsions, pH adjusters, skin nutrients, vitamins, antioxidants, antioxidant auxiliaries, fragrances, water, etc. may be blended as necessary and manufactured by conventional methods. it can.
その他の化粧料組成物に配合可能な成分としては、例えば、防腐剤(エチルパラベン、ブチルパラベン等)、消炎剤(例えば、グリチルリチン酸誘導体、グリチルレチン酸誘導体、サリチル酸誘導体、ヒノキチオール、酸化亜鉛、アラントイン等)、美白剤(例えば、胎盤抽出物、ユキノシタ抽出物、アルブチン等)、各種抽出物(例えば、オウバク、オウレン、シコン、シャクヤク、センブリ、バーチ、セージ、ビワ、ニンジン、アロエ、ゼニアオイ、アイリス、ブドウ、ヨクイニン、ヘチマ、ユリ、サフラン、センキュウ、ショウキュウ、オトギリソウ、オノニス、ニンニク、トウガラシ、チンピ、トウキ、海藻等)、賦活剤(例えば、ローヤルゼリー、感光素、コレステロール誘導体等)、血行促進剤(例えば、ノニル酸ワレニルアミド、ニコチン酸ベンジルエステル、ニコチン酸β−ブトキシエチルエステル、カプサイシン、ジンゲロン、カンタリスチンキ、イクタモール、タンニン酸、α−ボルネオール、ニコチン酸トコフェロール、イノシトールヘキサニコチネート、シクランデレート、シンナリジン、トラゾリン、アセチルコリン、ベラパミル、セファランチン、γ−オリザノール等)、抗脂漏剤(例えば、硫黄、チアントール等)、抗炎症剤(例えば、トラネキサム酸、チオタウリン、ヒポタウリン等)等が挙げられる。 Examples of other components that can be incorporated into the cosmetic composition include preservatives (ethyl paraben, butyl paraben, etc.), anti-inflammatory agents (eg, glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, etc. ), Whitening agents (for example, placenta extract, saxifrage extract, arbutin, etc.), various extracts (for example, buckwheat, auren, shikon, peonies, assembly, birch, sage, loquat, carrot, aloe, mallow, iris, grape , Yokuinin, Loofah, Lily, Saffron, Senkyu, Pepper, Hypericum, Onionis, Garlic, Pepper, Chimpi, Toki, Seaweed, etc.), Activator (for example, Royal Jelly, Photosensitizer, Cholesterol Derivative, etc.), Blood circulation promoter (for example, , Wallenylami nonylate Nicotinic acid benzyl ester, nicotinic acid β-butoxyethyl ester, capsaicin, zingerone, cantalis tincture, ictamol, tannic acid, α-borneol, nicotinic tocopherol, inositol hexanicotinate, cyclandrate, cinnarizine, trazoline, acetylcholine, And verapamil, cephalanthin, γ-oryzanol, etc.), antiseborrheic agents (eg, sulfur, thianthol, etc.), anti-inflammatory agents (eg, tranexamic acid, thiotaurine, hypotaurine, etc.).
本発明のAI−2阻害剤、並びに前記感染症の予防及び/又は治療剤の投与量は、AI−2を阻害しうる量、又は感染症を予防及び/又は治療しうる量であればよく、投与方法、年齢、症状等により適宜決定することができる。例えば、前記有効成分の質量に基づき、1日あたり、体重1kgあたり、経口投与で通常0.001〜100mg、好ましくは0.01〜10mgである。 The dose of the AI-2 inhibitor of the present invention and the preventive and / or therapeutic agent for the infectious disease may be an amount that can inhibit AI-2 or an amount that can prevent and / or treat an infectious disease. It can be appropriately determined depending on the administration method, age, symptoms and the like. For example, based on the mass of the active ingredient, the daily dose is usually 0.001 to 100 mg, preferably 0.01 to 10 mg per kg body weight per day.
本発明のAI−2阻害剤、並びに前記感染症の予防及び/又は治療剤における前記有効成分の含有量は、上記投与量を達成するように適宜決定できる。例えば、乾燥質量基準で、通常0.001〜5質量%、好ましくは0.05〜1質量%の量で前記有効成分を含む。 The content of the active ingredient in the AI-2 inhibitor of the present invention and the preventive and / or therapeutic agent for infectious diseases can be appropriately determined so as to achieve the above dose. For example, the active ingredient is usually contained in an amount of 0.001 to 5% by mass, preferably 0.05 to 1% by mass on a dry mass basis.
前記有効成分を投与することにより、AI−2を阻害することができ、ひいては、感染症を予防及び/又は治療することができる。 By administering the active ingredient, AI-2 can be inhibited, and thus infection can be prevented and / or treated.
従来の感染症の予防及び治療には抗生物質の投与が行われてきた。しかし細菌が薬剤耐性を獲得するため、抗生物質の効果が減弱してしまう。一方、AI−2を阻害すれば、細菌が本来持つシステムを使ってその病原性を制御することが可能となるため、薬剤耐性を持っている細菌にも効果が期待できる。 Antibiotics have been administered to prevent and treat conventional infections. However, since bacteria acquire drug resistance, the effectiveness of antibiotics is diminished. On the other hand, if AI-2 is inhibited, its pathogenicity can be controlled using a system originally possessed by the bacteria, and therefore, an effect can be expected for bacteria having drug resistance.
以下、本発明を実施例に基づきさらに詳細に説明するが、本発明はこれに限定されるものではない。 EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to this.
(製造例1−1)テンペのヘキサン抽出物の調製
テンペ(Mariza、市販品を購入)40gを細かく砕き、ヘキサン100mLを加えて室温(20℃)で2時間攪拌し、ヘキサン相を濾過した後ロータリーエバポレーターにより濃縮し、0.54gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 1-1) Preparation of Tempe Hexane Extract 40g Tempe (Mariza, purchased commercially) was finely crushed, added with 100mL of hexane, stirred at room temperature (20 ° C) for 2 hours, and filtered the hexane phase. Concentration by a rotary evaporator gave 0.54 g of extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例1−2)テンペの水抽出物の調製
テンペ(Mariza、市販品を購入)40gを細かく砕き、水100mLを加えて室温(20℃)で2時間攪拌し、ろ液を凍結乾燥により濃縮し、2.91gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 1-2) Preparation of Tempe aqueous extract Tempe (Mariza, purchase commercial product) 40 g finely crushed, add 100 mL of water, stir at room temperature (20 ° C.) for 2 hours, and freeze-dry the filtrate. Concentration gave 2.91 g of extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例1−3)テンペの50%エタノール抽出物の調製
テンペ(Mariza、市販品を購入)40gを細かく砕き、50%エタノール100mLを加えて室温(20℃)で2時間攪拌し、ろ液をロータリーエバポレーターにより濃縮し、1.65gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 1-3) Preparation of 50% ethanol extract of Tempe 40 g of Tempe (Mariza, commercially available product) was finely crushed, 100 mL of 50% ethanol was added, and the mixture was stirred at room temperature (20 ° C.) for 2 hours, and the filtrate. Was concentrated by a rotary evaporator to obtain 1.65 g of an extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例2−1)豆ち醤のヘキサン抽出物の調製
豆ち醤(味の素、市販品を購入)10gを細かく砕き、ヘキサン20mLを加えて室温(20℃)で2時間攪拌し、ヘキサン相を濾過した後ロータリーエバポレーターにより濃縮し、0.13gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Manufacture example 2-1) Preparation of hexane extract of bean soy sauce 10g of bean soy sauce (Ajinomoto, purchase commercially available product) is finely crushed, 20 mL of hexane is added, and the mixture is stirred at room temperature (20 ° C.) for 2 hours. Was filtered and then concentrated by a rotary evaporator to obtain 0.13 g of an extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例2−2)豆ち醤の水抽出物の調製
豆ち醤(味の素、市販品を購入)10gを細かく砕き、水20mLを加えて室温(20℃)で2時間攪拌し、ろ液を凍結乾燥により濃縮し、5.96gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Manufacture example 2-2) Preparation of water extract of Mamechi soy 10g of Mamechi soy (Ajinomoto, purchase a commercial product) is finely crushed, added with 20mL of water, stirred at room temperature (20 ° C) for 2 hours, and filtrated. Was concentrated by freeze-drying to obtain 5.96 g of extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例2−3)豆ち醤の50%エタノール抽出物の調製
豆ち醤(味の素、市販品を購入)10gを細かく砕き、50%エタノール20mLを加えて室温(20℃)で2時間攪拌し、ろ液をロータリーエバポレーターにより濃縮し、3.37gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Manufacture example 2-3) Preparation of 50% ethanol extract of Mamechi soy 10g Mamechi soy (Ajinomoto, purchase a commercial product) is finely crushed, added with 20mL of 50% ethanol and stirred at room temperature (20 ° C) for 2 hours. The filtrate was concentrated by a rotary evaporator to obtain 3.37 g of an extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例3−1)浜納豆のヘキサン抽出物の調製
浜納豆(鈴木醸造、市販品を購入)20gを細かく砕き、ヘキサン40mLを加えて室温(20℃)で2時間攪拌し、ヘキサン相を濾過した後ロータリーエバポレーターにより濃縮し、0.12gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 3-1) Preparation of Hama Natto hexane extract 20 g of Hama Natto (Suzuki brewed, purchased commercial product) was finely crushed, 40 mL of hexane was added, and the mixture was stirred at room temperature (20 ° C.) for 2 hours. After filtration, the filtrate was concentrated by a rotary evaporator to obtain 0.12 g of an extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例3−2)浜納豆の水抽出物の調製
浜納豆(鈴木醸造、市販品を購入)20gを細かく砕き、水40mLを加えて室温(20℃)で2時間攪拌し、ろ液を凍結乾燥により濃縮し、7.89gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 3-2) Preparation of Hama Natto Water Extract 20 g Hama Natto (Suzuki Brewery, purchase commercially available product) was finely crushed, added with 40 mL of water and stirred at room temperature (20 ° C.) for 2 hours, and the filtrate was removed. Concentration by lyophilization gave 7.89 g of extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例3−3)浜納豆の50%エタノール抽出物の調製
浜納豆(鈴木醸造、市販品を購入)20gを細かく砕き、50%エタノール40mLを加えて室温(20℃)で2時間攪拌し、ろ液をロータリーエバポレーターにより濃縮し、0.99gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Manufacture example 3-3) Preparation of 50% ethanol extract of Hama Natto 20 g of Hama Natto (Suzuki brewing, purchase a commercial product) is finely crushed, added with 40 mL of 50% ethanol, and stirred at room temperature (20 ° C.) for 2 hours. The filtrate was concentrated by a rotary evaporator to obtain 0.99 g of an extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例4−1)腐乳のヘキサン抽出物の調製
腐乳(興南貿易、市販品を購入)20gにヘキサン40mLを加えて室温(20℃)で2時間攪拌し、ヘキサン相を濾過した後ロータリーエバポレーターにより濃縮し、0.16gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Manufacture example 4-1) Preparation of hexane extract of humic milk 40 mL of hexane is added to 20 g of humic milk (Kingan Trading Co., Ltd., purchased commercially), stirred at room temperature (20 ° C.) for 2 hours, the hexane phase is filtered, and then the rotary evaporator. To give 0.16 g of extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例4−2)腐乳の水抽出物の調製
腐乳(興南貿易、市販品を購入)20gに水40mLを加えて室温(20℃)で2時間攪拌し、ろ液を凍結乾燥により濃縮し、5.48gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Manufacture example 4-2) Preparation of the water extract of humic milk 40mL of water is added to 20g of humic milk (Xingnan Trade, purchase a commercial product) and stirred at room temperature (20 ° C) for 2 hours, and the filtrate is concentrated by lyophilization. 5.48 g of extract was obtained.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例4−3)腐乳の50%エタノール抽出物の調製
腐乳(興南貿易、市販品を購入)20gに50%エタノール40mLを加えて室温(20℃)で2時間攪拌し、ろ液をロータリーエバポレーターにより濃縮し、3.13gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Manufacture example 4-3) Preparation of 50% ethanol extract of slaughtered milk 40 mL of 50% ethanol was added to 20 g of slaughtered milk (Kingan Trading, purchase a commercial product) and stirred for 2 hours at room temperature (20 ° C.). Concentration by an evaporator gave 3.13 g of extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例5−1)ダイズのヘキサン抽出物の調製
蒸煮した大豆40gにヘキサン100mLを加えて室温(20℃)で2時間攪拌し、ヘキサン相を濾過した後ロータリーエバポレーターにより濃縮し、0.10gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 5-1) Preparation of hexane extract of soybeans 100 mL of hexane was added to 40 g of steamed soybeans, stirred at room temperature (20 ° C.) for 2 hours, the hexane phase was filtered, and then concentrated by a rotary evaporator to obtain 0.10 g. An extract of was obtained.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例5−2)ダイズの水抽出物の調製
蒸煮した大豆40gに水100mLを加えて室温(20℃)で2時間攪拌し、ろ液を凍結乾燥により濃縮し、2.56gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 5-2) Preparation of Soybean Water Extract 100 g of water was added to 40 g of cooked soybean, stirred at room temperature (20 ° C.) for 2 hours, and the filtrate was concentrated by freeze-drying to obtain 2.56 g of extract. Got.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例5−3)ダイズの50%エタノール抽出物の調製
蒸煮した大豆40gに50%エタノール100mLを加えて室温(20℃)で2時間攪拌し、ろ液をロータリーエバポレーターにより濃縮し、1.45gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 5-3) Preparation of 50% ethanol extract of soybeans 100 mL of 50% ethanol was added to 40 g of steamed soybeans, stirred at room temperature (20 ° C.) for 2 hours, and the filtrate was concentrated by a rotary evaporator. 45 g of extract was obtained.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例6−1)碁石茶のヘキサン抽出物の調製
碁石茶(丸一横山商店から購入)10gを細かく砕き、ヘキサン40mLを加えて室温(20℃)で2時間攪拌し、ヘキサン相を濾過した後ロータリーエバポレーターの方法により濃縮し、0.28gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 6-1) Preparation of hexane extract of Goishi tea 10 g of Goishi tea (purchased from Maruichi Yokoyama Shoten) was finely crushed, 40 mL of hexane was added and stirred at room temperature (20 ° C.) for 2 hours, and the hexane phase was filtered. After that, it was concentrated by a rotary evaporator method to obtain 0.28 g of an extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例6−2)碁石茶の水抽出物の調製
碁石茶(丸一横山商店から購入)10gを細かく砕き、水40mLを加えて室温(20℃)で2時間攪拌し、ろ液を凍結乾燥により濃縮し、2.12gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Manufacture example 6-2) Preparation of water extract of Goishi tea 10g of Goishi tea (purchased from Maruichi Yokoyama store) is finely crushed, 40mL of water is added and stirred at room temperature (20 ° C) for 2 hours, and the filtrate is frozen. Concentration by drying gave 2.12 g of extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例6−3)碁石茶の50%エタノール抽出物の調製
碁石茶(丸一横山商店から購入)10gを細かく砕き、50%エタノール40mLを加えて室温(20℃)で2時間攪拌し、ろ液をロータリーエバポレーターにより濃縮し、2.04gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 6-3) Preparation of 50% ethanol extract of Goishi tea 10 g of Goishi tea (purchased from Maruichi Yokoyama Shoten) was finely crushed, added with 40 mL of 50% ethanol, and stirred at room temperature (20 ° C.) for 2 hours. The filtrate was concentrated by a rotary evaporator to obtain 2.04 g of extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例7−1)阿波番茶のヘキサン抽出物の調製
阿波番茶(山田産業から購入)10gを細かく砕き、ヘキサン40mLを加えて室温(20℃)で2時間攪拌し、ヘキサン相を濾過した後ロータリーエバポレーターにより濃縮し、0.17gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 7-1) Preparation of Awabancha Hexane Extract 10 g of Awabancha (purchased from Yamada Sangyo) was finely crushed, added with 40 mL of hexane, stirred at room temperature (20 ° C.) for 2 hours, and filtered the hexane phase. Concentration by a rotary evaporator gave 0.17 g of extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例7−2)阿波番茶の水抽出物の調製
阿波番茶(山田産業から購入)10gを細かく砕き、水40mLを加えて室温(20℃)で2時間攪拌し、ろ液を凍結乾燥により濃縮し、0.69gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 7-2) Preparation of Awabancha water extract 10 g of Awabancha (purchased from Yamada Sangyo) was finely crushed, 40 mL of water was added and stirred at room temperature (20 ° C.) for 2 hours, and the filtrate was freeze-dried. Concentration gave 0.69 g of extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例7−3)阿波番茶の50%エタノール抽出物の調製
阿波番茶(山田産業から購入)10gを細かく砕き、50%エタノール40mLを加えて室温(20℃)で2時間攪拌し、ろ液をロータリーエバポレーターにより濃縮し、1.12gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 7-3) Preparation of 50% ethanol extract of Awabancha Awabancha (purchased from Yamada Sangyo) 10 g is finely crushed, 40 mL of 50% ethanol is added, and the mixture is stirred at room temperature (20 ° C.) for 2 hours. Was concentrated by a rotary evaporator to obtain 1.12 g of an extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例8−1)ばたばた茶のヘキサン抽出物の調製
ばたばた茶(朝日町商工会から購入)10gを細かく砕き、ヘキサン40mLを加えて室温(20℃)で2時間攪拌し、ヘキサン相を濾過した後ロータリーエバポレーターにより濃縮し、0.13gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Manufacture example 8-1) Preparation of hexane extract of robata tea 10 gram of bataba tea (purchased from Asahimachi Chamber of Commerce and Industry) was finely crushed, 40 mL of hexane was added and stirred at room temperature (20 ° C.) for 2 hours, and the hexane phase was filtered Thereafter, the mixture was concentrated by a rotary evaporator to obtain 0.13 g of an extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例8−2)ばたばた茶の水抽出物の調製
ばたばた茶(朝日町商工会から購入)10gを細かく砕き、水40mLを加えて室温(20℃)で2時間攪拌し、ろ液を凍結乾燥により濃縮し、0.38gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Manufacture example 8-2) Preparation of water extract of robata tea 10g of bataba tea (purchased from Asahimachi Chamber of Commerce) is finely crushed, 40mL of water is added and stirred at room temperature (20 ° C) for 2 hours, and the filtrate is lyophilized. To give 0.38 g of extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例8−3)ばたばた茶の50%エタノール抽出物の調製
ばたばた茶(朝日町商工会から購入)10gを細かく砕き、50%エタノール40mLを加えて室温(20℃)で2時間攪拌し、ろ液をロータリーエバポレーターにより濃縮し、0.41gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 8-3) Preparation of 50% ethanol extract of batabata tea 10 g of batabata tea (purchased from Asahimachi Shokai), add 40 mL of 50% ethanol and stir at room temperature (20 ° C) for 2 hours. The liquid was concentrated by a rotary evaporator to obtain 0.41 g of an extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例9−1)緑茶のヘキサン抽出物の調製
緑茶(東海薬草研究所から購入)10gを細かく砕き、ヘキサン40mLを加えて室温(20℃)で2時間攪拌し、ヘキサン相を濾過した後ロータリーエバポレーターにより濃縮し、0.01gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 9-1) Preparation of Green Tea Hexane Extract 10 g of green tea (purchased from Tokai Herb Research Institute) was finely crushed, added with 40 mL of hexane, stirred at room temperature (20 ° C.) for 2 hours, and filtered the hexane phase. The mixture was concentrated by a rotary evaporator to obtain 0.01 g of an extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例9−2)緑茶の水抽出物の調製
緑茶(東海薬草研究所から購入)10gを細かく砕き、水40mLを加えて室温(20℃)で2時間攪拌し、ろ液を凍結乾燥により濃縮し、2.98gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 9-2) Preparation of water extract of green tea 10 g of green tea (purchased from Tokai Herb Research Institute) is finely crushed, 40 mL of water is added and stirred at room temperature (20 ° C.) for 2 hours, and the filtrate is freeze-dried. Concentration gave 2.98 g of extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例9−3)緑茶の50%エタノール抽出物の調製
緑茶(東海薬草研究所から購入)10gを細かく砕き、50%エタノール40mLを加えて室温(20℃)で2時間攪拌し、ろ液をロータリーエバポレーターにより濃縮し、3.65gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 9-3) Preparation of 50% ethanol extract of green tea 10 g of green tea (purchased from Tokai Herb Research Institute) was finely crushed, 40 mL of 50% ethanol was added, and the mixture was stirred at room temperature (20 ° C.) for 2 hours, and filtrated. Was concentrated by a rotary evaporator to obtain 3.65 g of an extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例10−1)紅茶のヘキサン抽出物の調製
紅茶(東海薬草研究所から購入)10gを細かく砕き、ヘキサン40mLを加えて室温(20℃)で2時間攪拌し、ヘキサン相を濾過した後ロータリーエバポレーターにより濃縮し、0.01gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 10-1) Preparation of black tea hexane extract 10 g of black tea (purchased from Tokai Herb Research Institute) was finely crushed, added with 40 mL of hexane, stirred at room temperature (20 ° C.) for 2 hours, and filtered the hexane phase. The mixture was concentrated by a rotary evaporator to obtain 0.01 g of an extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例10−2)紅茶の水抽出物の調製
紅茶(東海薬草研究所から購入)10gを細かく砕き、水40mLを加えて室温(20℃)で2時間攪拌し、ろ液を凍結乾燥により濃縮し、1.58gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 10-2) Preparation of black tea aqueous extract 10 g of black tea (purchased from Tokai Herb Research Institute), finely crushed, added with 40 mL of water and stirred at room temperature (20 ° C.) for 2 hours, and the filtrate was freeze-dried. Concentration gave 1.58 g of extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
(製造例10−3)紅茶の50%エタノール抽出物の調製
紅茶(東海薬草研究所から購入)10gを細かく砕き、50%エタノール40mLを加えて室温(20℃)で2時間攪拌し、ろ液をロータリーエバポレーターにより濃縮し、2.53gの抽出物を得た。
次いで、得られた抽出物を濃度が1%(w/v)となるようにエタノールに溶解した。
(Production Example 10-3) Preparation of 50% ethanol extract of black tea 10 g of black tea (purchased from Tokai Herb Research Institute), finely crushed, added 40 mL of 50% ethanol and stirred at room temperature (20 ° C.) for 2 hours, filtrate Was concentrated by a rotary evaporator to obtain 2.53 g of an extract.
Next, the obtained extract was dissolved in ethanol so as to have a concentration of 1% (w / v).
試験例1 AI−2活性の測定
AI−2バイオアッセイ系のためのレポーター菌株としてのビブリオ・ハーベイBB170株(ATCC BAA−1117)をMarine Agar 2216培地(商品名、Difco社製)で30℃、好気条件下で培養した。このように培養したビブリオ・ハーベイBB170株の一白金耳を、AB(Autoinducer Bioassay)培地(0.3M NaCl,0.05M MgSO4,0.2%vitamine-free casamino acidsに1Mリン酸カリウム〔pH7.0〕(0.42M KH2PO4、0.58M K2HPO4)10mL、0.1M L−アルギニン10mL、0.1mg/mL thiamin・HCl 1mL、10μg/mL リボフラビン1mL、グリセロール20mLを混合してフィルター滅菌したものをAB培地1Lに対して42mL加えたもの)培地3mLに植菌し、好気条件下で16時間、30℃、200rpmで振盪培養を行った。この菌液をAB培地で5000倍に希釈し、レポーター菌液とした。
Test Example 1 Measurement of AI-2 Activity Vibrio Harvey BB170 strain (ATCC BAA-1117) as a reporter strain for the AI-2 bioassay system was obtained at 30 ° C. in a Marine Agar 2216 medium (trade name, manufactured by Difco). Cultured under aerobic conditions. One platinum loop of Vibrio Harvey BB170 strain cultured in this way was added to AB (Autoinducer Bioassay) medium (0.3 M NaCl, 0.05 M MgSO 4 , 0.2% vitamine-free casamino acids, 1 M potassium phosphate [pH 7 0.0] (0.42M KH 2 PO 4 , 0.58M K 2 HPO 4 ) 10 mL, 0.1 M L-arginine 10 mL, 0.1 mg / mL thiamin · HCl 1 mL, 10 μg / mL riboflavin 1 mL, glycerol 20 mL The filter sterilized product was added to 42 mL of 1 L of AB medium) and inoculated into 3 mL of the medium, followed by shaking culture at 30 ° C. and 200 rpm for 16 hours under aerobic conditions. This bacterial solution was diluted 5000 times with AB medium to obtain a reporter bacterial solution.
前記レポーター菌液に、前記製造例にて調製した各抽出物のエタノール溶液をそれぞれ用いて、その終濃度が0.001%(w/v)になるように添加し、室温で10分プレインキュベートした。次いで、DPD(OMM Scientificに合成検討を依頼し、同社で合成したものを購入した)を終濃度が10μMとなるように添加し、30℃にて好気振盪培養を行った。4時間後の発光強度をケミルミネッセンス計(ベルトールド社製、Mitharas LB940(商品名))で測定した。なお、発光強度は、DPDのみ添加したものの発光強度をコントロールとし、各抽出物を添加したときの発光強度をコントロールに対する相対値として表した。このように算出した発光強度の相対値をAI−2相対活性とし、各抽出物を添加したときのAI−2活性を測定した。さらに、ポジティブコントロールとして、AI−2阻害化合物として既知の化合物(4−ブロモ−5−(4−メトキシフェニル)−2(5H)−フラノン、Sigma社製)を用い、同様にAI−2活性を測定した。
その結果を表1に示す。
Using the ethanol solution of each extract prepared in the above production example, add to the reporter bacterial solution so that the final concentration is 0.001% (w / v), and preincubate at room temperature for 10 minutes did. Next, DPD (OMM Scientific was asked to investigate synthesis and purchased by the company) was added so that the final concentration was 10 μM, and aerobic shaking culture was performed at 30 ° C. The light emission intensity after 4 hours was measured with a chemiluminescence meter (Mitharas LB940 (trade name), manufactured by Bertoold). In addition, the luminescence intensity was expressed as a relative value with respect to the control, with the luminescence intensity when only DPD was added as a control, and when each extract was added. The relative value of the luminescence intensity calculated in this way was defined as AI-2 relative activity, and the AI-2 activity when each extract was added was measured. Further, as a positive control, a known compound (4-bromo-5- (4-methoxyphenyl) -2 (5H) -furanone, manufactured by Sigma) was used as an AI-2 inhibitory compound, and AI-2 activity was similarly measured. It was measured.
The results are shown in Table 1.
表1の結果から明らかなように、本発明のAI−2阻害剤を添加することで、AI−2相対活性が、既知のAI−2阻害化合物に比して同等もしくはそれ以下まで低下した。したがって、本発明のAI−2阻害剤は、既知のAI−2阻害化合物に比して、同等もしくはそれ以上のAI−2阻害活性を有することが示された。
さらに、AI−2阻害剤に用いる抽出物の抽出方法に関して、ダイズ製品を出発原料として用いる場合、カビを用いてダイズ製品を発酵させ、発酵物をヘキサンで抽出することが有効であることが示された。
As is apparent from the results in Table 1, by adding the AI-2 inhibitor of the present invention, the relative activity of AI-2 was reduced to the same level or lower than that of known AI-2 inhibitory compounds. Therefore, it was shown that the AI-2 inhibitor of the present invention has an AI-2 inhibitory activity equal to or higher than that of known AI-2 inhibitory compounds.
Furthermore, regarding the extraction method of the extract used for the AI-2 inhibitor, when using a soybean product as a starting material, it is effective to ferment the soybean product using mold and extract the fermentation product with hexane. It was done.
試験例2 殺菌試験
試験例1と同様に調製したレポーター菌液と、前記製造例にて調製したテンペ、豆ち醤、浜納豆又は腐乳のヘキサン抽出物とを混合し、30℃で10分間プレインキュベートした。次いで、AB培地で1000倍に希釈し、Marine Agar培地(Difco社製)に播種し、30℃で1日培養した。培養後、寒天培地に発生したコロニーをカウントし生菌数を算出した。
その結果は、AI−2阻害活性を示す濃度及びこれの10倍濃度では殺菌作用を示さず、本発明のAI−2阻害剤の有効成分は、歯周病、齲蝕病の原因菌に対する殺菌作用を示すものではなかった。
Test Example 2 Bactericidal Test The reporter bacterial solution prepared in the same manner as in Test Example 1 and the tempe, bean soy sauce, Hama natto or humic hexane extract prepared in the above production example were mixed and pre-treated at 30 ° C. for 10 minutes. Incubated. Next, the resultant was diluted 1000 times with AB medium, seeded on Marine Agar medium (manufactured by Difco), and cultured at 30 ° C. for 1 day. After cultivation, the number of colonies generated on the agar medium was counted and the number of viable bacteria was calculated.
The results show that the concentration of AI-2 inhibitory activity and 10 times the concentration thereof do not show bactericidal action, and the active ingredient of the AI-2 inhibitor of the present invention is bactericidal action against the causative bacteria of periodontal disease and caries disease. It did not indicate.
以上の結果は、本発明のAI−2阻害剤の有効成分は、歯周病、齲蝕病の原因菌等の病原性細菌に対する殺菌能を示すものではなく、病原性細菌の種間連絡に利用されるAI−2の活性を阻害するものであることを示すものである。 The above results show that the active ingredient of the AI-2 inhibitor of the present invention does not show bactericidal ability against pathogenic bacteria such as periodontal disease and caries disease, and is used for interspecific communication of pathogenic bacteria. It shows that it inhibits the activity of AI-2.
試験例3 歯垢中AI−2量と齲蝕病との関係
ビブリオ・ハーベイBB152株(ATCC BAA−1119)をMarine Agar2216培地で30℃、好気条件下で培養した。このように培養したビブリオ・ハーベイBB152株の一白金耳をMarine Broth2216培地に植菌し、好気条件下8時間、30℃、200rpmで振盪培養を行った。
上記菌液をAB培地に植菌し、さらに好気条件下16時間、30℃、200rpmで振盪培養を行った。遠心分離(8000rpm、15分、4℃)後の上清を取り出し、カットオフ値1Kのスピンカラム(ポール社製)を用いて分子量1000以下の画分を得、AI−2溶液とした(AI−2濃度:約0.1μM)。
Test Example 3 Relationship between the amount of AI-2 in dental plaque and caries disease Vibrio Harvey BB152 strain (ATCC BAA-1119) was cultured in Marine Agar 2216 medium at 30 ° C. under aerobic conditions. One platinum loop of Vibrio Harvey BB152 strain cultured in this way was inoculated into Marine Broth 2216 medium, followed by shaking culture at 30 ° C. and 200 rpm for 8 hours under aerobic conditions.
The above bacterial solution was inoculated into AB medium, and further cultured with shaking at 30 ° C. and 200 rpm for 16 hours under aerobic conditions. The supernatant after centrifugation (8000 rpm, 15 minutes, 4 ° C.) was taken out, and a fraction having a molecular weight of 1000 or less was obtained using a spin column (manufactured by Pall) with a cut-off value of 1K to obtain an AI-2 solution (AI -2 concentration: about 0.1 μM).
齲蝕原性細菌であるストレプトコッカス・ミュータンスJCM5705株をBHI寒天培地(Difco社製)に播種・培養(嫌気条件下で37℃、1日)した。このようにして培養したストレプトコッカス・ミュータンスJCM5705株の一白金耳をBHI液体培地(Difco社製)に植菌し、嫌気条件下で37℃、16時間培養した。PBSにて洗浄後、2×1010個/mLになるように菌液を調製した。 Streptococcus mutans JCM5705 strain, which is a cariogenic bacterium, was seeded and cultured (37 ° C., 1 day under anaerobic condition) on BHI agar medium (manufactured by Difco). One platinum loop of Streptococcus mutans JCM5705 strain thus cultured was inoculated into a BHI liquid medium (manufactured by Difco) and cultured at 37 ° C. for 16 hours under anaerobic conditions. After washing with PBS, a bacterial solution was prepared at 2 × 10 10 cells / mL.
抗生物質水溶液(アンピシリン、カナマイシン各2mg/mL)をSDラット(雄性、3週齢)に5日間自由飲水させた後、ストレプトコッカス・ミュータンス菌液をラットの左右下顎臼歯部に各50μL、1回/日で5日間滴下した。食餌は齲蝕誘導食であるDiet2000(商品名、オリエンタルバイオサービス社製)を与えた。その後、AI−2溶液又はAB培地(コントロール)を2回/日、1回当たり200μLを臼歯部に1ヶ月間滴下した(各群N=5)。また、ストレプトコッカス・ミュータンス菌液を滴下しない群も設定した(N=5)。 An antibiotic aqueous solution (ampicillin and kanamycin 2 mg / mL each) was allowed to freely drink in SD rats (male, 3 weeks old) for 5 days, and then Streptococcus mutans bacteria solution was applied to the left and right lower molars of rats 50 μL each time. Per day for 5 days. Diet was Diet2000 (trade name, manufactured by Oriental Bioservice) which is a caries induction diet. Thereafter, AI-2 solution or AB medium (control) was dropped twice a day at 200 μL per dose to the molar part for 1 month (each group N = 5). In addition, a group in which Streptococcus mutans solution was not dropped was also set (N = 5).
各群のSDラットの齲蝕の程度を示す齲蝕スコアを、Keyes P.H.et al.,J.Dent.Res.,37,6,p.1958に記載の方法に準じて測定した。その結果を表2に示す。 The caries score indicating the degree of caries in each group of SD rats was measured by Keyes P.M. H. et al., J. et al. Dent. Res., 37, 6, p. Measurement was performed according to the method described in 1958. The results are shown in Table 2.
表2の結果から、歯垢中AI−2量と齲蝕病とが相関関係を有し、従って、歯垢中のAI−2が齲蝕亢進に関与し、AI−2活性の阻害が齲蝕病の予防・改善に有効であることが示された。 From the results in Table 2, there is a correlation between the amount of AI-2 in dental plaque and caries disease. Therefore, AI-2 in dental plaque is involved in caries enhancement, and inhibition of AI-2 activity is a cause of caries disease. It was shown to be effective for prevention and improvement.
(処方例)
ダイズ発酵物のヘキサン抽出物を有効成分とする歯周病又は齲蝕病の予防及び/又は治療剤として、下記に示す組成のチューブ入り練歯磨、練歯磨、樹脂製容器入りマウスウォッシュを常法により各々調製した。
(Prescription example)
As a preventive and / or therapeutic agent for periodontal disease or caries disease containing hexane extract of fermented soybeans as an active ingredient, toothpaste in tubes, toothpaste and resin-washed mouthwash with the composition shown below are used in a conventional manner. Each was prepared.
処方例1 チューブ入り練歯磨の調製
ソルビトール 35質量%
無水ケイ酸 20質量%
濃グリセリン 5質量%
ダイズ発酵物ヘキサン抽出物 5質量%
カルボキシメチルセルロースナトリウム 1質量%
歯磨き用香料 1質量%
フッ化ナトリウム 0.2質量%
サッカリンナトリウム 0.2質量%
塩化セチルピリジニウム 0.05質量%
精製水 残余
計100質量%
Formulation Example 1 Preparation of toothpaste with tube Sorbitol 35% by mass
Silica anhydride 20% by mass
Concentrated glycerin 5% by mass
Soybean fermented hexane extract 5% by mass
Carboxymethylcellulose sodium 1% by mass
Toothpaste fragrance 1% by mass
Sodium fluoride 0.2% by mass
Saccharin sodium 0.2% by mass
Cetylpyridinium chloride 0.05% by mass
Purified water residue
100% by mass in total
処方例2 チューブ入り練歯磨の調製
炭酸カルシウム 30質量%
ソルビトール 28質量%
無水ケイ酸 8質量%
濃グリセリン 5質量%
ラウリル硫酸ナトリウム 1.2質量%
カルボキシメチルセルロースナトリウム 1質量%
歯磨き用香料 1質量%
ダイズ発酵物ヘキサン抽出物 0.5質量%
酢酸dl−α−トコフェロール 0.2質量%
フッ化ナトリウム 0.2質量%
サッカリンナトリウム 0.2質量%
塩化セチルピリジニウム 0.05質量%
精製水 残余
計100質量%
Formulation Example 2 Preparation of toothpaste with tube Calcium carbonate 30% by mass
Sorbitol 28% by mass
Silica anhydride 8% by mass
Concentrated glycerin 5% by mass
Sodium lauryl sulfate 1.2% by mass
Carboxymethylcellulose sodium 1% by mass
Toothpaste fragrance 1% by mass
Soybean fermented product hexane extract 0.5% by mass
Dl-α-Tocopherol acetate 0.2% by mass
Sodium fluoride 0.2% by mass
Saccharin sodium 0.2% by mass
Cetylpyridinium chloride 0.05% by mass
Purified water residue
100% by mass in total
処方例3 練歯磨の調製
ソルビトール 25質量%
無水ケイ酸 20質量%
プロピレングリコール 6質量%
ラクチトール 5質量%
カルボキシメチルセルロースナトリウム 1質量%
歯磨き用香料 1質量%
ダイズ発酵物ヘキサン抽出物 0.5質量%
フッ化ナトリウム 0.2質量%
サッカリンナトリウム 0.2質量%
塩化セチルピリジニウム 0.05質量%
精製水 残余
計100質量%
Formulation Example 3 Preparation of Toothpaste Sorbitol 25% by mass
Silica anhydride 20% by mass
Propylene glycol 6% by mass
Lactitol 5% by mass
Carboxymethylcellulose sodium 1% by mass
Toothpaste fragrance 1% by mass
Soybean fermented product hexane extract 0.5% by mass
Sodium fluoride 0.2% by mass
Saccharin sodium 0.2% by mass
Cetylpyridinium chloride 0.05% by mass
Purified water residue
100% by mass in total
処方例4 練歯磨の調製
ソルビトール 28質量%
ポリオキシエチレン(200)ポリオキシプロピレン(40)共重合体 16質量%
無水ケイ酸 12質量%
パラチニット 10質量%
濃グリセリン 8質量%
ラウリル硫酸ナトリウム 1.2質量%
カルボキシメチルセルロースナトリウム 1.5質量%
歯磨き用香料 1質量%
ダイズ発酵物ヘキサン抽出物 0.8質量%
モノフルオロリン酸ナトリウム 0.7質量%
サッカリンナトリウム 0.2質量%
塩化セチルピリジニウム 0.05質量%
精製水 残余
計100質量%
Formulation Example 4 Preparation of toothpaste sorbitol 28% by mass
16% by mass of polyoxyethylene (200) polyoxypropylene (40) copolymer
Silica anhydride 12% by mass
Palatinit 10% by mass
Concentrated glycerin 8% by mass
Sodium lauryl sulfate 1.2% by mass
Sodium carboxymethylcellulose 1.5% by mass
Toothpaste fragrance 1% by mass
Soybean fermented product hexane extract 0.8% by mass
Sodium monofluorophosphate 0.7% by mass
Saccharin sodium 0.2% by mass
Cetylpyridinium chloride 0.05% by mass
Purified water residue
100% by mass in total
処方例5 練歯磨の調製
ソルビトール 28質量%
無水ケイ酸 15質量%
ポリエチレングリコール400 8質量%
エリスリトール 5質量%
ラウリル硫酸ナトリウム 1.2質量%
カルボキシメチルセルロースナトリウム 1質量%
歯磨き用香料 1質量%
ダイズ発酵物ヘキサン抽出物 0.1質量%
酢酸dl−α−トコフェロール 0.2質量%
フッ化ナトリウム 0.2質量%
サッカリンナトリウム 0.2質量%
塩化セチルピリジニウム 0.05質量%
精製水 残余
計100質量%
Formulation Example 5 Preparation of toothpaste Sorbitol 28% by mass
Silica anhydride 15% by mass
Polyethylene glycol 400 8% by mass
Erythritol 5% by mass
Sodium lauryl sulfate 1.2% by mass
Carboxymethylcellulose sodium 1% by mass
Toothpaste fragrance 1% by mass
Soybean fermented product hexane extract 0.1% by mass
Dl-α-Tocopherol acetate 0.2% by mass
Sodium fluoride 0.2% by mass
Saccharin sodium 0.2% by mass
Cetylpyridinium chloride 0.05% by mass
Purified water residue
100% by mass in total
処方例6 樹脂製容器入りマウスウォッシュの調製
エタノール 15質量%
エリスリトール 7質量%
ポリオキシエチレン硬化ヒマシ油 2質量%
サッカリンナトリウム 0.5質量%
ダイズ発酵物ヘキサン抽出物 0.2質量%
洗口剤用香料 0.2質量%
安息香酸ナトリウム 0.1質量%
酢酸dl−α−トコフェロール 0.05質量%
トリクロサン 0.02質量%
精製水 残余
計100質量%
Formulation Example 6 Preparation of mouthwash in resin container Ethanol 15% by mass
Erythritol 7% by mass
Polyoxyethylene hydrogenated castor oil 2% by mass
Saccharin sodium 0.5% by mass
Soybean fermented product hexane extract 0.2% by mass
Fragrance for mouthwash 0.2% by mass
Sodium benzoate 0.1% by mass
Dl-α-tocopherol acetate 0.05% by mass
Triclosan 0.02% by mass
Purified water residue
100% by mass in total
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