JP2020109071A - Agent for inhibiting activity of periodontal pathogen-producing cysteine protease - Google Patents
Agent for inhibiting activity of periodontal pathogen-producing cysteine protease Download PDFInfo
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- JP2020109071A JP2020109071A JP2019160972A JP2019160972A JP2020109071A JP 2020109071 A JP2020109071 A JP 2020109071A JP 2019160972 A JP2019160972 A JP 2019160972A JP 2019160972 A JP2019160972 A JP 2019160972A JP 2020109071 A JP2020109071 A JP 2020109071A
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- hinokitiol
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- peony
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Abstract
Description
本発明は、歯周病原因菌が産生するシステインプロテアーゼの活性を抑制するために用いられる組成物に関する。 The present invention relates to a composition used for suppressing the activity of cysteine protease produced by periodontal disease-causing bacteria.
歯周病は、歯周病原因菌の感染により生じる慢性感染性疾患である。原因菌の感染により炎症が進行すると、歯肉が腫れて血や膿が出るだけでなく、歯を支える歯槽骨が破壊されやがては歯を喪失する。更に歯周病は、糖尿病、心疾患、そして、妊婦の低体重児出産などの全身疾患のリスクファクターであることが知られている。そのため、歯周病の予防又は治療は、健康な口腔機能の維持及び回復だけではなく、全身疾患のリスク低減という面からも非常に重要である。 Periodontal disease is a chronic infectious disease caused by infection with periodontal disease-causing bacteria. When the inflammation progresses due to the infection of the causative bacteria, not only the gingiva swells and blood and pus are produced, but also the alveolar bone that supports the teeth is destroyed and eventually the teeth are lost. Furthermore, periodontal disease is known to be a risk factor for diabetes, heart disease, and systemic diseases such as birth of a low-birth weight pregnant woman. Therefore, prevention or treatment of periodontal disease is very important not only for maintaining and recovering healthy oral function, but also for reducing the risk of systemic diseases.
近年、歯周病原因菌のなかでもグラム陰性嫌気性桿菌のポルフィロモナス・ジンジバリス(Porphyromonas gingivalis、以下「P.ジンジバリス」と称する)が最も重要な病因菌であり、それが産生するプロテアーゼ群がコラーゲンを始めとする歯周組織成分や生体防御系に関与する血清蛋白質を分解することが知られ、歯周病の病原性に深く関係していることが明らかになっている。特にアルギニン−ジンジパイン(Arg-gingipain)等の塩基性アミノ酸−ジンジパインは、P.ジンジバリスが産生するトリプシン様プロテアーゼ活性を有するシステインプロテアーゼであり、最も有力な歯周病の病原性因子であるとされている。具体的には、塩基性アミノ酸−ジンジパインは、菌自身の栄養素獲得に重要な機能をもち、更に、歯周組織を構成する細胞間マトリックス、例えばコラーゲンやフィブロネクチンなどを分解し、菌を排除する生体反応の重要な要素である抗体や補体を分解し、更に、好中球の機能を阻害することで感染を持続し、炎症を慢性化させることが知られている。そこで、歯周病を治療又は予防するために、塩基性アミノ酸−ジンジパインの活性を抑制する製剤の開発が期待されている。 In recent years, among the bacteria causing periodontal disease, the gram-negative anaerobic bacterium Porphyromonas gingivalis (P. gingivalis, hereinafter referred to as "P. gingivalis") is the most important causative bacterium, and the protease group produced by it is It is known to degrade periodontal tissue components such as collagen and serum proteins involved in the biological defense system, and it has been clarified that they are closely related to the pathogenicity of periodontal disease. In particular, basic amino acids such as arginine-gindipain (Arg-gingipain)-gingipain are cysteine proteases having trypsin-like protease activity produced by P. gingivalis, and are considered to be the most potent virulence factors for periodontal disease. There is. Specifically, the basic amino acid-Zindipain has an important function for the nutrient acquisition of the bacterium itself, and further decomposes the intercellular matrix that constitutes the periodontal tissue, such as collagen and fibronectin, to eliminate the bacterium. It is known that by degrading antibodies and complements, which are important elements of the reaction, and further inhibiting the function of neutrophils, infection is sustained and inflammation becomes chronic. Therefore, in order to treat or prevent periodontal disease, it is expected to develop a preparation that suppresses the activity of the basic amino acid zingipain.
塩基性アミノ酸−ジンジパインのうち、アルギニン−ジンジパインの活性を阻害する物質としては、アンチパイン、ロイペプチン、TLCK(トシル−リシン−クロロメチルケトン塩酸塩)またはE−64等のシステインプロテアーゼ阻害剤が知られている。また、アルギニン−ジンジパインがアルギニン末端を選択的に分解する基質特性に着目して、その拮抗的阻害剤としてのペプチド誘導体が提案されている(特許文献1または2参照)。しかし、いずれも安全性が確認されておらず、実用化には至っていない。また、膵炎や汎発性血管内血液凝固症の治療薬として用いられているメシル酸ガベキサートがアルギニン−ジンジパインに対して高い特異的活性阻害作用を発揮することから、それを用いた各種のアルギニン−ジンジパイン活性阻害剤が提案されている(特許文献3〜6参照)。 Among the basic amino acid-gindipain, as a substance that inhibits the activity of arginine-gindipain, cysteine protease inhibitors such as antipain, leupeptin, TLCK (tosyl-lysine-chloromethylketone hydrochloride) or E-64 are known. ing. In addition, focusing on the substrate property in which arginine-gindipain selectively decomposes the arginine terminal, peptide derivatives have been proposed as competitive inhibitors thereof (see Patent Document 1 or 2). However, none of them have been confirmed to be safe and have not been put to practical use. In addition, since gabexate mesylate, which is used as a therapeutic agent for pancreatitis and generalized intravascular coagulation, exerts a high specific activity inhibitory action on arginine-gindipain, various arginine-containing compounds are used. Gingipain activity inhibitors have been proposed (see Patent Documents 3 to 6).
一方、ヒノキチオールは、従来より抗菌作用が知られており、その広範な抗菌スペクトルにより防腐用食品添加物、育毛剤、化粧品などの添加物として広く使用されている。またマトリクスメタロプロテアーゼ活性阻害作用を有することが知られているが、歯周病原因菌が産生するトリプシン様プロテアーゼ活性を有するシステインプロテアーゼ、特に塩基性アミノ酸−ジンジパインの活性を阻害する作用を有することは知られていない。また、シャクヤクには筋緊張緩和、血管拡張、抗炎症作、鎮静及び鎮痛等の作用があることが知られており、その根は生薬(日本薬局方)の原料として使用されている。またシャクヤクエキスは医薬品部外品原料規格に記載されており、従来より医薬品部外品の原料として使用されている。しかし、シャクヤクまたはそのエキスが歯周病原因菌産生システインプロテアーゼ、特に塩基性アミノ酸−ジンジパインの活性を阻害する作用を有することは知られていない。 On the other hand, hinokitiol has hitherto been known to have an antibacterial action, and due to its broad antibacterial spectrum, it is widely used as an additive for antiseptic food additives, hair restorers, cosmetics and the like. It is also known to have a matrix metalloprotease activity inhibitory action, but it is known that it has an action to inhibit the activity of cysteine protease having trypsin-like protease activity produced by periodontal disease-causing bacteria, especially the activity of basic amino acid-gindipain. unknown. In addition, it is known that peony has actions such as muscle tone relaxation, vasodilation, anti-inflammatory action, sedation and analgesia, and its root is used as a raw material for crude drugs (Japanese Pharmacopoeia). In addition, peony extract is described in the standard for quasi-drug raw materials and has been used as a raw material for quasi-drugs. However, it is not known that peony or its extract has an action of inhibiting the activity of cysteine protease produced by periodontal disease-causing bacteria, particularly the basic amino acid zingipain.
本発明は、歯周病の病原性因子である歯周病原因菌産生システインプロテアーゼ、特に塩基性アミノ酸−ジンジパインが有する蛋白質分解活性を抑制するために用いる組成物を提供することを課題とする。また、本発明はヒノキチオールやシャクヤクについて見出された新たな作用に基づいて、その新たな用途を提供することを課題とする。 An object of the present invention is to provide a composition used for suppressing the proteolytic activity of periodontal disease-causing bacterium-produced cysteine protease, which is a virulence factor of periodontal disease, in particular, a basic amino acid-gingipain. Another object of the present invention is to provide a new use of hinokitiol and peony based on the new action found.
本発明者らは、前記課題を解決すべく鋭意検討を重ねていたところ、後述する実施例に示すように、ヒノキチオールおよびシャクヤクエキスに歯周病原因菌産生システインプロテアーゼが有する蛋白質分解活性を抑制する作用があることを見出し、この知見に基づいてさらに検討を重ねて、本発明を完成するに至った。本発明は下記の実施態様を有するものである。 The present inventors have conducted extensive studies to solve the above-mentioned problems, and as shown in Examples described later, suppress the proteolytic activity of cystein protease produced by periodontal disease-causing bacteria in hinokitiol and peony extract. The present invention has been found to have an action, and further investigations have been carried out based on this finding to complete the present invention. The present invention has the following embodiments.
(I)歯周病原因菌産生システインプロテアーゼの活性抑制用組成物
(I−1)ヒノキチオール及びシャクヤク加工物よりなる群より選択される少なくとも1種を有効成分とする、歯周病原因菌産生システインプロテアーゼの活性抑制用組成物。
(I−2)ヒノキチオール及びシャクヤク加工物よりなる群より選択される少なくとも1種を有効成分とするジンジパイン活性抑制用組成物。
(I−3)ヒノキチオール及びシャクヤク加工物よりなる群より選択される少なくとも1種を有効成分とする塩基性アミノ酸−ジンジパイン活性抑制用組成物。
(I−4)前記塩基性アミノ酸がアルギニンまたはリジンである、(I−3)に記載する塩基性アミノ酸−ジンジパイン活性抑制用組成物。
(I−5)口腔用組成物である(I−1)〜(I−4)のいずれかに記載する活性抑制用組成物。
(I−6)活性抑制用組成物中のヒノキチオールの割合が0.001〜0.5質量%、好ましくは0.05〜0.2質量%、より好ましくは0.01〜0.2質量%である、(I−1)〜(I−5)のいずれかに記載する活性抑制用組成物。
(I−7)活性抑制用組成物中のシャクヤク加工物の割合が乾燥物換算で0.00001〜1質量%、好ましくは0.00005〜0.1質量%、より好ましくは0.0001〜0.01質量%である、(I−1)〜(I−6)のいずれかに記載する活性抑制用組成物。
(I) Composition for suppressing activity of cysteine protease produced by periodontal disease-causing bacteria (I-1) Cysteine produced by periodontal disease-causing bacteria, which contains at least one selected from the group consisting of hinokitiol and peony processed product as an active ingredient A composition for suppressing protease activity.
(I-2) A composition for suppressing zingipain activity, comprising at least one selected from the group consisting of hinokitiol and processed peonies as an active ingredient.
(I-3) A composition for suppressing a basic amino acid-gingipain activity, which comprises, as an active ingredient, at least one selected from the group consisting of hinokitiol and processed peonies.
(I-4) The basic amino acid-gingipain activity suppressing composition according to (I-3), wherein the basic amino acid is arginine or lysine.
(I-5) The composition for suppressing activity described in any one of (I-1) to (I-4), which is a composition for oral cavity.
(I-6) The proportion of hinokitiol in the composition for suppressing activity is 0.001 to 0.5% by mass, preferably 0.05 to 0.2% by mass, more preferably 0.01 to 0.2% by mass. The composition for suppressing activity according to any one of (I-1) to (I-5), which is
(I-7) The ratio of the peony processed product in the activity suppressing composition is 0.00001 to 1% by mass, preferably 0.00005 to 0.1% by mass, and more preferably 0.0001 to 0 in terms of dry matter. The composition for suppressing activity according to any one of (I-1) to (I-6), which is 0.01% by mass.
(II)歯周病原因菌産生システインプロテアーゼの活性抑制作用を付与する方法
(II−1)口腔用組成物にヒノキチオール及びシャクヤク加工物よりなる群より選択される少なくとも1種を配合する工程を有する、口腔用組成物に歯周病原因菌産生システインプロテアーゼの活性抑制作用を付与する方法。なお、当該方法は、「口腔用組成物にヒノキチオール及びシャクヤク加工物よりなる群より選択される少なくとも1種を配合する工程を有する、歯周病原因菌産生システインプロテアーゼの活性抑制作用を有する口腔用組成物の製造方法」と言い換えることができる。
(II−2)前記歯周病原因菌産生システインプロテアーゼがジンジパイン、好ましくは塩基性アミノ酸−ジンジパインである(II−1)に記載する方法。
(II−3)前記塩基性アミノ酸がアルギニンまたはリジンである、(II−2)に記載する方法。
(II−4)口腔用組成物にヒノキチオールの含有量が0.001〜0.5質量%、好ましくは0.05〜0.2質量%、より好ましくは0.01〜0.2質量%になるように配合する工程を有する、(II−1)〜(II−3)のいずれかに記載する方法。
(II−5)口腔用組成物にシャクヤク加工物の含有量が乾燥含量で0.00001〜1質量%、好ましくは0.00005〜0.1質量%、より好ましくは0.0001〜0.01質量%になるように配合する工程を有する、(II−1)〜(II−4)のいずれかに記載する方法。
(II) Method of imparting activity suppressing action of cysteine protease produced by periodontal disease-causing bacteria (II-1) having a step of adding at least one selected from the group consisting of hinokitiol and peony processed products to the oral composition A method for imparting an activity suppressing action of cysteine protease produced by periodontal disease-causing bacteria to a composition for oral cavity. In addition, the said method has the process of mix|blending at least 1 sort(s) selected from the group which consists of a hinokitiol and a peony processed product to the composition for oral cavity, for the oral cavity which has the activity suppression activity of the cysteine protease which causes periodontal disease-causing bacteria. In other words, it can be referred to as a “method for producing a composition”.
(II-2) The method according to (II-1), wherein the cysteine protease produced by the periodontal disease-causing bacterium is zingipain, preferably basic amino acid-gingipain.
(II-3) The method according to (II-2), wherein the basic amino acid is arginine or lysine.
(II-4) The content of hinokitiol in the oral composition is 0.001 to 0.5% by mass, preferably 0.05 to 0.2% by mass, more preferably 0.01 to 0.2% by mass. The method described in any of (II-1) to (II-3), which comprises a step of blending so that
(II-5) The content of the peony processed product in the oral composition is 0.00001 to 1% by mass, preferably 0.00005 to 0.1% by mass, and more preferably 0.0001 to 0.01% by dry content. The method according to any one of (II-1) to (II-4), which has a step of blending so as to be mass%.
本発明の歯周病原因菌産生システインプロテアーゼ、ジンジパインまたは塩基性アミノ酸−ジンジパインの活性抑制用組成物によれば、歯周病原因菌であるP.ジンジバリスが産生するこれらの蛋白質分解酵素の活性を抑制することができる。また本発明の方法によれば、歯周病原因菌であるP.ジンジバリスが産生するシステインプロテアーゼ、ジンジパインまたは塩基性アミノ酸−ジンジパインの活性を抑制する作用を口腔用組成物に付与することができる。 The composition for inhibiting the activity of periodontal disease-causing bacteria cysteine protease, zingipain, or basic amino acid-gingipain according to the present invention can be used as P. It is possible to suppress the activity of these proteolytic enzymes produced by Gingivalis. Further, according to the method of the present invention, P. The composition for oral cavity can be imparted with the action of suppressing the activity of cysteine protease, zingipain, or basic amino acid-gingipain produced by Gingivalis.
(I)歯周病原因菌産生システインプロテアーゼの活性抑制用組成物
本発明が対象とする組成物は、ヒノキチオール及びシャクヤク加工物よりなる群より選択される少なくとも1種を有効成分とする組成物であり、歯周病原因菌産生システインプロテアーゼの活性を抑制するために使用されることを特徴とする。ここで本発明が対象とする歯周病原因菌は、ポルフィロモナス・ジンジバリス(Porphyromonas gingivalis)(P.ジンジバリス)である。また、当該P.ジンジバリスが産生するシステインプロテアーゼとしては、好ましくはジンジパイン、特にアルギニン残基のC末端を切断する作用を有するアルギニン−ジンジパインやリジン残基のC末端を切断する作用を有するリジン−ジンジパイン等の塩基性アミノ酸−ジンジパインを挙げることができる。このため、本発明の組成物は、好ましくはジンジパインの活性抑制用組成物であり、より好ましくは塩基性アミノ酸−ジンジパインの活性抑制用組成物であり、特に好ましくはアルギニン−ジンジパインまたはリジン−ジンジパインである。なお、塩基性アミノ酸とは、側鎖にプロトン(H+)を受け取ることができるアミノ基またはイミノ基を有するアミノ酸を指し、アルギニン、リジン、ヒスチジン、トリプトファン、及びオルニチンを挙げることができる。好ましくはアルギニン、及びリジンである。本明細書において、以下、ジンジパイン、及び塩基性アミノ酸−ジンジパインを含むシステインプロテアーゼの総称として「Cysプロテアーゼ」という用語を使用する。
(I) Composition for inhibiting activity of cysteine protease produced by periodontal disease-causing bacterium A composition targeted by the present invention is a composition containing at least one selected from the group consisting of hinokitiol and peony processed product as an active ingredient. And is used for suppressing the activity of cysteine protease produced by periodontal disease-causing bacteria. The periodontal disease-causing bacterium targeted by the present invention is Porphyromonas gingivalis (P. gingivalis). The cysteine protease produced by P. gingivalis is preferably gindipain, particularly arginine-gindipain having an action of cleaving the C-terminal of arginine residue or lysine-gindipine having an action of cleaving the C-terminal of lysine residue. And basic amino acid-gingipain. Therefore, the composition of the present invention is preferably a composition for suppressing the activity of zingipain, more preferably a composition for suppressing the activity of basic amino acid-jinzipain, particularly preferably arginine-ginzipain or lysine-ginzipain. is there. The basic amino acid refers to an amino acid having an amino group or an imino group capable of receiving a proton (H + ) in its side chain, and examples thereof include arginine, lysine, histidine, tryptophan, and ornithine. Arginine and lysine are preferred. In the present specification, hereinafter, the term "Cys protease" is used as a general term for cysteine protease containing zingipain and basic amino acid-gingipain.
本発明においてCysプロテアーゼ活性抑制とは、P.ジンジバリスが産生するCysプロテアーゼが有する蛋白質分解活性(トリプシン様プロテアーゼ活性)を減弱または消失させることを意味する。当該Cysプロテアーゼ活性の抑制作用は、後述する実験例1で示すように、被験試料の存在下または非存在下で、Cysプロテアーゼを、その基質として使用するBz-L-Arg-pNA・HCl(Benzoyl-L-arginine p-nitroanilide monohydrochloride)(アルギニン−ジンジパイン用基質)またはAc-Lys-pNA・HCl(N-α-Acetyl-L-lysine p-nitroanilide monohydrochloride)(リジン−ジンジパイン用基質)に反応させて、生じるパラニトロアニリン(pNA)に由来する発光を吸光度で測定することで評価することができる。被験試料の存在下で反応させた場合の反応液の吸光度が非存在下で反応させた場合の反応液の吸光度よりも低い場合、または被験試料の存在下で反応させた場合の反応前後の吸光度の差が非存在下で反応させた場合の反応前後の吸光度の差よりも低い場合は、当該被験試料はCysプロテアーゼ活性抑制作用があると判断することができる。 In the present invention, suppression of Cys protease activity means to reduce or eliminate the proteolytic activity (trypsin-like protease activity) of Cys protease produced by P. gingivalis. The inhibitory action on the Cys protease activity is, as shown in Experimental Example 1 described later, in the presence or absence of a test sample, Cys protease is used as a substrate for Bz-L-Arg-pNA.HCl (Benzoyl -L-arginine p-nitroanilide monohydrochloride) (substrate for arginine-gindipine) or Ac-Lys-pNA.HCl (N-α-Acetyl-L-lysine p-nitroanilide monohydrochloride) (substrate for lysine-gindipine) Can be evaluated by measuring the luminescence derived from the generated para-nitroaniline (pNA) by absorbance. The absorbance before and after the reaction when the absorbance of the reaction solution when reacted in the presence of the test sample is lower than the absorbance of the reaction solution when reacted in the absence of the test sample, or before and after the reaction when reacted in the presence of the test sample When the difference between the values is smaller than the difference in absorbance before and after the reaction when the reaction is performed in the absence, it can be determined that the test sample has a Cys protease activity inhibitory action.
本発明のCysプロテアーゼ活性抑制用組成物が有効成分として含有するヒノキチオールは、台湾ヒノキやヒバに含まれている不飽和七員環化合物であり、別名β-ツヤプリシン、及び4-イソプロピルトロポロンとも称される。従来より抗菌作用が知られており、防腐用食品添加物、育毛剤、化粧品などの添加物として広く使用されている公知の化合物である。金属イオンと接触すると塩を形成するが、本発明をそれらの塩も含めて、ヒノキチオールと総称する。ヒノキチオールは台湾ヒノキやヒバから抽出された精油から単離することもできるが、簡便には商業的に入手することができる。 Hinokitiol contained in the composition for suppressing Cys protease activity of the present invention as an active ingredient is an unsaturated seven-membered ring compound contained in Taiwan cypress and Hiba, and is also known as β-tsuyapricin and 4-isopropyltropolone. It It is a well-known compound which has been conventionally known for its antibacterial action and has been widely used as an additive for antiseptic food additives, hair restorers, cosmetics and the like. Although forming a salt upon contact with a metal ion, the present invention, including those salts, is collectively referred to as hinokitiol. Hinokitiol can also be isolated from essential oils extracted from Taiwan cypress and hiba, but it can be conveniently obtained commercially.
本発明のCysプロテアーゼ活性抑制用組成物中のヒノキチオールの含有量は、Cysプロテアーゼ活性抑制作用を発揮することを限度として特に制限されず、目的及び用途によって適宜設定することができる。例えば、本発明のCysプロテアーゼ活性抑制用組成物がそのまま口腔内に適用される口腔用組成物である場合は、例えば0.001〜0.5質量%の範囲から適宜設定することができる。好ましくは0.005〜0.2質量%であり、より好ましくは0.01〜0.2質量%である。また本発明のCysプロテアーゼ活性抑制用組成物が、用時に水で希釈して口腔内に適用される口腔用組成物である場合は、希釈後の濃度が前記範囲になるようにヒノキチオールを含有するものであればよい。例えば、制限されないものの、一例を挙げると、用時に水で10倍に希釈して使用する場合、例えばヒノキチオールを0.01〜5質量%の濃度で含むように口腔用組成物を調製することができる。さらに本発明のCysプロテアーゼ活性抑制用組成物が、前述する口腔用組成物(そのまま使用、用時希釈使用のものを含む)にCysプロテアーゼ活性抑制用を付与するための添加剤として使用されるものである場合、前記口腔用組成物が調製できることを限度としてヒノキチオールの含有量は特に制限されることなく、例えば0.1〜100質量%の範囲から適宜設定することができる。 The content of hinokitiol in the composition for suppressing Cys protease activity of the present invention is not particularly limited as long as it exhibits a Cys protease activity suppressing effect, and can be appropriately set depending on the purpose and application. For example, when the composition for suppressing Cys protease activity of the present invention is an oral composition that is directly applied to the oral cavity, it can be appropriately set within the range of 0.001 to 0.5% by mass, for example. It is preferably 0.005 to 0.2% by mass, and more preferably 0.01 to 0.2% by mass. Moreover, when the composition for suppressing Cys protease activity of the present invention is an oral composition that is diluted with water before use and applied to the oral cavity, it contains hinokitiol so that the concentration after dilution falls within the above range. Anything will do. For example, although not limited, as an example, when used by diluting 10-fold with water at the time of use, it is possible to prepare an oral composition so as to contain, for example, hinokitiol at a concentration of 0.01 to 5% by mass. it can. Further, the composition for suppressing Cys protease activity of the present invention is used as an additive for imparting the composition for suppressing Cys protease activity to the above-described oral composition (including those used as it is and diluted before use) In this case, the content of hinokitiol is not particularly limited as long as the composition for oral cavity can be prepared, and can be appropriately set, for example, in the range of 0.1 to 100 mass %.
本発明のCysプロテアーゼ活性抑制用組成物が有効成分として含有するシャクヤク加工物は、ボタン科(Paeoniaceae)のシャクヤク(Paeonia lactiflora Pallas)又はその他近縁植物の根の加工物であり、根の粉砕物、細切物及びこれらの乾燥物、並びに溶媒抽出物(シャクヤクエキス)のいずれであってもよい。好ましくはシャクヤクエキスである。シャクヤクエキスの抽出に使用される抽出溶媒としては、例えば、水、有機溶媒(エタノール、メタノール、イソプロパノール等の低級アルコール:プロピレングリコール、1,3−ブチレングリコール等の多価アルコール;エーテル、ヘキサン、ベンゼン、クロロホルム、アセトン、ペンタン、酢酸エチル等)等またはこれらの混合物を挙げることができる。好ましくは水、エタノール、1,3−ブチレングリコール、又はこれらの混合溶媒(例えば含水エタノールなど)である。 The peony processed product which the composition for suppressing Cys protease activity of the present invention contains as an active ingredient is a peony (Paeonia lactiflora Pallas) of the family Botanicale (Paeoniaceae) or a processed product of roots of other closely related plants. , Shredded products and dried products thereof, and solvent extracts (peony extract). Peony extract is preferred. Examples of the extraction solvent used for the extraction of the peony extract include water, organic solvents (lower alcohols such as ethanol, methanol, isopropanol: polyhydric alcohols such as propylene glycol and 1,3-butylene glycol; ethers, hexane, benzene. , Chloroform, acetone, pentane, ethyl acetate, etc.) or a mixture thereof. Water, ethanol, 1,3-butylene glycol, or a mixed solvent thereof (for example, water-containing ethanol) is preferable.
シャクヤクエキスの製造にて採用される抽出方法については、特に制限されず、植物抽出物の製造に使用される一般的な抽出手法であればよい。例えば抽出溶媒中にシャクヤクの根(好ましくは乾燥粉砕物)を冷浸、温浸等によって浸漬し、必要に応じて撹拌する方法;パーコレーション法;水蒸気蒸留法等を挙げることができる。得られた抽出液を、必要に応じてろ過または遠心分離によって固形物を除去することにより、シャクヤクエキスが回収できる。本発明のCysプロテアーゼ活性抑制用組成物では、上記抽出処理により得られた液状のシャクヤクエキスをそのまま使用してもよいが、必要に応じて、一部又は全ての溶媒を除去して濃縮液若しくは乾燥物(エキス末、乾燥エキス)として使用してもよい。また、これらの濃縮物若しくは乾燥物を更に精製処理に供してもよく、更にこれらを適当な溶剤に溶解もしくは懸濁して用いることもできる。 The extraction method used in the production of the peony extract is not particularly limited, and any general extraction method used in the production of plant extracts may be used. For example, a method of immersing a peony root (preferably a dry pulverized product) in an extraction solvent by cold soaking, warm soaking, and stirring as necessary; a percolation method; a steam distillation method and the like can be mentioned. The peony extract can be recovered by removing the solid matter from the obtained extract by filtration or centrifugation as necessary. In the composition for inhibiting Cys protease activity of the present invention, the liquid peony extract obtained by the above extraction treatment may be used as it is, but if necessary, a part or all of the solvent may be removed to obtain a concentrated solution or It may be used as a dried product (extract powder, dried extract). In addition, these concentrates or dried products may be subjected to further purification treatment, and these may be dissolved or suspended in an appropriate solvent and used.
シャクヤク加工物(シャクヤクの根の粉砕物やシャクヤクエキスなど)については、商業的に販売されているので、本発明では商業的に入手したものを使用してもよい。 Since the processed peonies (crushed peonies roots, peonies extracts, etc.) are commercially available, commercially available products may be used in the present invention.
本発明のCysプロテアーゼ活性抑制用組成物中のシャクヤク加工物の含有量は、Cysプロテアーゼ活性抑制作用を発揮することを限度として特に制限されず、目的及び用途によって適宜設定することができる。例えば、本発明のCysプロテアーゼ活性抑制用組成物がそのまま口腔内に適用される口腔用組成物である場合は、シャクヤク加工物の乾燥物に換算して、例えば0.00001〜1質量%の範囲から適宜設定することができる。好ましくは0.00005〜0.1質量%であり、より好ましくは0.0001〜0.01質量%である。また本発明のCysプロテアーゼ活性抑制用組成物が、用時に水で希釈して口腔内に適用される口腔用組成物である場合は、希釈後の濃度が前記範囲になるようにシャクヤク加工物を含有するものであればよい。例えば、制限されないものの、一例を挙げると、用時に水で10倍に希釈して使用する場合、例えばシャクヤク加工物を0.000001〜0.1質量%の濃度で含むように口腔用組成物を調製することができる。さらに本発明のCysプロテアーゼ活性抑制用組成物が、前述する口腔用組成物(そのまま使用、用時希釈使用のものを含む)にCysプロテアーゼ活性抑制作用を付与するための添加剤として使用されるものである場合、前記口腔用組成物が調製できることを限度としてシャクヤク加工物の含有量は特に制限されることなく、例えば0.1〜100質量%の範囲から適宜設定することができる。 The content of the peony processed product in the composition for suppressing Cys protease activity of the present invention is not particularly limited as long as it exhibits the Cys protease activity suppressing effect, and can be appropriately set depending on the purpose and application. For example, when the composition for suppressing Cys protease activity of the present invention is an oral composition that is directly applied to the oral cavity, it is converted to a dried product of peony, for example, in the range of 0.00001 to 1% by mass. Can be set as appropriate. It is preferably 0.00005 to 0.1% by mass, and more preferably 0.0001 to 0.01% by mass. When the composition for suppressing Cys protease activity of the present invention is an oral composition which is diluted with water before use and applied to the oral cavity, a peony processed product is prepared so that the concentration after dilution is within the above range. It may be contained. For example, although not limited, when used as a 10-fold dilution with water when used, for example, a composition for oral cavity containing a peony processed product at a concentration of 0.000001 to 0.1 mass% is used. It can be prepared. Furthermore, the composition for suppressing Cys protease activity of the present invention is used as an additive for imparting a Cys protease activity suppressing action to the above-described oral composition (including those used as it is and diluted before use) In this case, the content of the peony processed product is not particularly limited as long as the composition for oral cavity can be prepared, and can be appropriately set, for example, in the range of 0.1 to 100% by mass.
本発明のCysプロテアーゼ活性抑制用組成物は、前述するように、そのまままたは水で希釈して口腔内に適用される口腔用組成物として使用されるものであってもよいし、またこれらの口腔用組成物に添加してCysプロテアーゼ活性抑制作用を有する口腔用組成物を調製するための添加剤として使用されるものであってもよい。 As described above, the composition for suppressing Cys protease activity of the present invention may be used as an oral composition to be applied to the oral cavity as it is or diluted with water, or these oral cavity compositions may be used. It may be used as an additive for preparing an oral composition having a Cys protease activity-suppressing action by being added to the oral composition.
ヒノキチオールは水に微溶性の結晶であるため、本発明のCysプロテアーゼ活性抑制用組成物を口腔用組成物への添加剤として使用する場合(以下、この場合の本発明の組成物を「本発明の添加剤」と称する)は、ヒノキチオールをエタノールまたはプロピレングリコール等の可溶性溶媒に溶解した液剤の状態として調製されることが好ましい。 Since hinokitiol is a crystal that is slightly soluble in water, when the composition for suppressing Cys protease activity of the present invention is used as an additive to a composition for oral cavity (hereinafter, the composition of the present invention in this case is referred to as “the present invention”). Is referred to as "additive of") is preferably prepared as a liquid preparation in which hinokitiol is dissolved in a soluble solvent such as ethanol or propylene glycol.
本発明のCysプロテアーゼ活性抑制用組成物をそのまままたは水で希釈して口腔用組成物として使用する場合(以下、この場合の本発明の組成物を「本発明の口腔用組成物」と称する)、その剤型としては、歯磨剤(練り歯磨剤、粉歯磨剤、ジェル歯磨剤、液体歯磨剤)、洗口液(マウスリンス、マウスウォッシュ、デンタルリンス)、口腔用軟膏剤、および口中清涼剤(マウススプレー等の液剤、錠剤(錠菓を含む)、口腔衛生剤、カプセル剤、顆粒剤、グミ、ガムなど)等を制限なく例示することができる。洗口液などの液状の剤型については、原液のまま使用するタイプであっても、また濃縮タイプであって使用時に希釈して使用するタイプであってもよい。これらは、Cysプロテアーゼの活性を抑制する目的に加えて、歯磨きなど口腔内を洗浄・清掃する目的、口腔内に清涼感を付与する目的、口腔内を殺菌する目的、及び/または口臭を除去または防止する目的で使用されるものであってもよい。 When the composition for suppressing Cys protease activity of the present invention is used as it is or diluted with water as an oral composition (hereinafter, the composition of the present invention in this case is referred to as "oral composition of the present invention") , Its formulations include toothpaste (toothpaste, powdered dentifrice, gel dentifrice, liquid dentifrice), mouthwash (mouth rinse, mouthwash, dental rinse), oral ointment, and mouth refreshing agent. (Liquids such as mouth spray, tablets (including tablet confectionery), oral hygiene agents, capsules, granules, gummies, gums, etc.) can be exemplified without limitation. The liquid dosage form such as mouth rinse may be a type that is used as a stock solution or a concentrated type that is diluted at the time of use. In addition to suppressing the activity of Cys protease, these are for cleaning and cleaning the oral cavity such as toothpaste, for imparting a refreshing feeling to the oral cavity, for sterilizing the oral cavity, and/or for removing bad breath or It may be used for the purpose of prevention.
本発明の口腔用組成物は、本発明の効果を損なわない範囲で、口腔用組成物の種類、剤型及び目的に応じて通常配合され得る研磨剤、発泡剤、増粘剤、香料、甘味剤、湿潤剤、抗酸化剤、pH調整剤、着色剤、防腐剤等の添加剤や、薬理活性成分、溶剤等を添加し、従来公知の手法に従って所望の剤型に調製することができる。 The oral composition of the present invention, as long as the effect of the present invention is not impaired, a polishing agent, a foaming agent, a thickener, a fragrance, and a sweetness which can be usually added according to the type, dosage form and purpose of the oral composition. Additives such as agents, wetting agents, antioxidants, pH adjusters, coloring agents, preservatives, etc., pharmacologically active ingredients, solvents and the like can be added to prepare desired dosage forms according to conventionally known methods.
研磨剤としては、口腔用組成物に一般的に使用される種々の研磨剤を配合することができる。特に限定されないが、例えば、第1リン酸カルシウム、第2リン酸カルシウム・2水和物及び無水和物、第3リン酸カルシウム、炭酸カルシウム、ピロリン酸カルシウム、水酸化アルミニウム、アルミナ、シリカゲル、無水ケイ酸、ケイ酸アルミニウム、沈降性シリカ、不溶性メタリン酸ナトリウム、第3リン酸マグネシウム、炭酸マグネシウム、硫酸カルシウム、ポリメタクリル酸メチル、ベントナイト、ケイ酸ジルコニウム、チタニウム結合ケイ酸塩等が挙げられる。 As the abrasive, various abrasives generally used in oral compositions can be blended. Although not particularly limited, for example, monocalcium phosphate, dicalcium phosphate dihydrate and anhydrate, tricalcium phosphate, calcium carbonate, calcium pyrophosphate, aluminum hydroxide, alumina, silica gel, anhydrous silicic acid, aluminum silicate, Precipitable silica, insoluble sodium metaphosphate, tribasic magnesium phosphate, magnesium carbonate, calcium sulfate, polymethylmethacrylate, bentonite, zirconium silicate, titanium-bonded silicate and the like can be mentioned.
発泡剤としては、口腔用組成物に一般的に使用される種々の発泡剤(発泡性界面活性剤)を配合することができる。特に限定されないが、アニオン界面活性剤、ノニオン界面活性剤、カチオン界面活性剤、及び/または両性界面活性剤を配合することができる。より具体的には、アニオン界面活性剤としては、例えば、ラウロイルメチルタウリン又はその塩、ラウロイルグルタミン酸又はその塩、ラウロイルサルコシン又はその塩等のアミノ酸系界面活性剤;ドデシルベンゼンスルホン酸ナトリウム、水素添加ココナッツ脂肪酸モノグリセリドモノ硫酸ナトリウム、α−オレフィンスルホン酸ナトリウム等が挙げられる。ノニオン界面活性剤としては、例えば、ショ糖脂肪酸エステル、マルトース脂肪酸エステル、マルチトール脂肪酸エステル、ラクトール脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシエチレンソルビタンモノステアレート、ポリオキシエチレン高級アルコールエーテル、ポリオキシエチレン硬化ヒマシ油、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ポリオキシプロピレン脂肪酸エステル、ポリグリセリン脂肪酸エステル等が挙げられる。カチオン界面活性剤としては、例えば、塩化ラウリルトリメチルアンモニウム、塩化ステアリルトリメチルアンモニウム、塩化ベンゼトニウム、塩化セチルピリジニウム、塩化ベンザルコニウム、塩化ステアリルジメチルベンジルアンモニウム等が挙げられる。両性界面活性剤としては、例えば、ヤシ油脂肪酸アミドプロピルベタイン、ラウリルジメチルアミノ酢酸ベタイン、ラウリルジメチルアミンオキシド、2-アルキル−N−カルボキシメチル−N−ヒドロキシエチルイミダゾリウムベタイン、N−ラウリルジアミノエチルグリシン、N−ミリスチルジアミノエチルグリシン、N−アルキル−1−ヒドロキシエチルイミダゾリンベタインナトリウム等が挙げられる。 As the foaming agent, various foaming agents (foaming surfactants) generally used in oral compositions can be blended. Although not particularly limited, an anionic surfactant, a nonionic surfactant, a cationic surfactant, and/or an amphoteric surfactant can be blended. More specifically, examples of the anionic surfactant include amino acid surfactants such as lauroylmethyl taurine or a salt thereof, lauroyl glutamic acid or a salt thereof, lauroyl sarcosine or a salt thereof; sodium dodecylbenzenesulfonate, hydrogenated coconut. Examples thereof include fatty acid monoglyceride sodium monosulfate and sodium α-olefin sulfonate. Examples of nonionic surfactants include sucrose fatty acid ester, maltose fatty acid ester, maltitol fatty acid ester, lactol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan monostearate, polyoxyethylene higher alcohol ether, and polyoxyethylene curing agent. Castor oil, polyoxyethylene polyoxypropylene copolymer, polyoxyethylene polyoxypropylene fatty acid ester, polyglycerin fatty acid ester and the like can be mentioned. Examples of the cationic surfactant include lauryltrimethylammonium chloride, stearyltrimethylammonium chloride, benzethonium chloride, cetylpyridinium chloride, benzalkonium chloride, stearyldimethylbenzylammonium chloride and the like. Examples of the amphoteric surfactant include coconut oil fatty acid amide propyl betaine, lauryl dimethyl amino acetic acid betaine, lauryl dimethyl amine oxide, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolium betaine, N-lauryl diaminoethyl glycine. , N-myristyldiaminoethylglycine, N-alkyl-1-hydroxyethylimidazoline sodium betaine and the like.
増粘剤としては、口腔用組成物に一般的に使用される種々の増粘剤を配合することができる。特に限定されないが、キサンタンガム、アルギン酸ナトリウム、ポリビニルアルコール、ヒドロキシエチルセルロース、ポリアクリル酸ナトリウム、カラギナン、カルボキシメチルセルロースナトリウム、ポリビニルピロリドン等が挙げられる。 As the thickener, various thickeners commonly used in oral compositions can be blended. Examples include, but are not limited to, xanthan gum, sodium alginate, polyvinyl alcohol, hydroxyethyl cellulose, sodium polyacrylate, carrageenan, sodium carboxymethyl cellulose, and polyvinylpyrrolidone.
香料としては、口腔用組成物に一般的に使用される種々の香料を配合することができる。特に限定されないが、l−メントール、l−カルボン、シンナミックアルデヒド、オレンジオイル、アネトール、1,8−シネオール、メチルサリシレート、オイゲノール、チモール、リナロール、リモネン、メントン、メンチルアセテート、シトラール、カンファー、ボルネオール、ピネン、スピラントール、エチルアセテート、エチルブチレート、イソアミルアセテート、ヘキサナール、ヘキセナール、メチルアンスラニレート、エチルメチルフェニルグリシデート、ベンズアルデヒド、バニリン、エチルバニリン、フラネオール、マルトール、エチルマルトール、ガンマ/デルタデカラクトン、ガンマ/デルタウンデカラクトン、N−エチル−p−メンタン−3−カルボキサミド、メンチルラクテート、エチレングリコール−l−メンチルカーボネート等の香料成分;ペパーミント油、スペアミント油、ユーカリ油、クローブ油、タイム油、セージ油、カルダモン油、ローズマリー油、マジョラム油、レモン油、ナツメグ油、ラベンダー油、パラクレス油等の天然精油;アップル、バナナ、ストロベリー、ブルーベリー、メロン、ピーチ、パイナップル、グレープ、マスカット、ワイン、チェリー、スカッシュ、コーヒー、ブランデー、ヨーグルト等の調合フレーバーが挙げられる。 As the fragrance, various fragrances commonly used in oral compositions can be blended. Although not particularly limited, 1-menthol, 1-carvone, cinnamic aldehyde, orange oil, anethole, 1,8-cineole, methyl salicylate, eugenol, thymol, linalool, limonene, menthol, menthyl acetate, citral, camphor, borneol, Pinene, spilanthol, ethyl acetate, ethyl butyrate, isoamyl acetate, hexanal, hexenal, methyl anthranilate, ethyl methyl phenylglycidate, benzaldehyde, vanillin, ethyl vanillin, furaneol, maltol, ethyl maltol, gamma/delta decalactone, gamma /Deltown Decalactone, N-Ethyl-p-menthane-3-carboxamide, Menthyl lactate, Ethylene glycol-1-menthyl carbonate and other fragrance ingredients; peppermint oil, spearmint oil, eucalyptus oil, clove oil, thyme oil, sage oil , Cardamom oil, rosemary oil, marjoram oil, lemon oil, nutmeg oil, lavender oil, paracles oil and other natural essential oils; apple, banana, strawberry, blueberry, melon, peach, pineapple, grape, muscat, wine, cherry, squash , Coffee, brandy, yogurt, and other mixed flavors.
甘味剤としては、口腔用組成物に一般的に使用される種々の甘味料を配合することができる。特に限定されないが、サッカリンナトリウム、アセスルファームK、ステビオサイド、ネオヘスポリジルジヒドロカルコン、グリチルリチン、ペリラルチン、タウマチン、アスパルチルフェニルアラニンメチルエステル、p−メトキシシンナミックアルデヒド、アスパルテーム、キシリトール、エリスリトール等が挙げられる。 As the sweetener, various sweeteners generally used in oral compositions can be blended. Specific examples thereof include, but are not limited to, saccharin sodium, acesulfame K, stevioside, neohesporidyl dihydrochalcone, glycyrrhizin, perillartine, taumatine, aspartyl phenylalanine methyl ester, p-methoxycinnamic aldehyde, aspartame, xylitol, erythritol and the like.
湿潤剤としては、口腔用組成物に一般的に使用される種々の湿潤剤を配合することができる。特に限定されないが、ソルビット、グリセリン、濃グリセリン、エチレングリコール、プロピレングリコール、1,3−ブチレングリコール、ポリエチレングリコール、ポリプロピレングリコール等が挙げられる。 As the wetting agent, various wetting agents generally used in oral compositions can be blended. Although not particularly limited, sorbit, glycerin, concentrated glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, polyethylene glycol, polypropylene glycol and the like can be mentioned.
抗酸化剤としては、口腔用組成物に一般的に使用される種々の抗酸化剤を配合することができる。特に限定されないが、ローズマリー抽出物、ステビア抽出物、ヒマワリ種子抽出物、没食子酸プロピル、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、L−システイン塩酸塩、フィチン酸、ハイドロキノン及びその配糖体、ノルジヒドログアヤレチン酸、グアヤク脂、ポリフェノール、トコフェロール酢酸エステル、マツエキス、アスコルビン酸等が挙げられる。 As the antioxidant, various antioxidants generally used in oral compositions can be blended. Although not particularly limited, rosemary extract, stevia extract, sunflower seed extract, propyl gallate, dibutylhydroxytoluene, butylhydroxyanisole, L-cysteine hydrochloride, phytic acid, hydroquinone and its glycosides, nordihydro group Examples thereof include ayaletic acid, guaiac fat, polyphenol, tocopherol acetate, pine extract, and ascorbic acid.
pH調整剤としては、口腔用組成物に一般的に使用される種々のpH調整剤を配合することができる。特に限定されないが、フタル酸、リン酸、クエン酸、コハク酸、酢酸、フマル酸、リンゴ酸、炭酸やそれらのカリウム塩、ナトリウム塩又はアンモニウム塩、水酸化ナトリウムなどが挙げられる。本発明の口腔用組成物のpHは、口腔内及び人体に安全性上問題ない範囲であれば特に限定されるものではないが、例えば口腔用組成物30gを25℃70mLの水に溶解させた場合のpHの範囲としてpH3〜9が挙げられる。本発明の口腔用組成物のpHは、必要に応じて前記pH調整剤を使用して当該範囲に調整され得る。 As the pH adjuster, various pH adjusters generally used in oral compositions can be blended. Although not particularly limited, phthalic acid, phosphoric acid, citric acid, succinic acid, acetic acid, fumaric acid, malic acid, carbonic acid and their potassium salts, sodium salts or ammonium salts, sodium hydroxide and the like can be mentioned. The pH of the oral composition of the present invention is not particularly limited as long as it does not cause a safety problem in the oral cavity and the human body. For example, 30 g of the oral composition was dissolved in water at 25°C and 70 mL. In this case, the range of pH includes pH 3 to 9. The pH of the oral composition of the present invention can be adjusted to the range using the pH adjuster, if necessary.
着色剤としては、口腔用組成物に一般的に使用される種々の着色剤を配合することができる。特に限定されないが、例えば、赤色2号、赤色3号、赤色225号、赤色226号、黄色4号、黄色5号、黄色205号、青色1号、青色2号、青色201号、青色204号、緑色3号、雲母チタン、酸化チタン等が挙げられる。 As the colorant, various colorants generally used in oral compositions can be blended. Although not particularly limited, for example, Red No. 2, Red No. 3, Red No. 225, Red No. 226, Yellow No. 4, Yellow No. 5, Yellow No. 205, Blue No. 1, Blue No. 2, Blue No. 201, Blue No. 204 , Green No. 3, titanium mica, titanium oxide and the like.
防腐剤としては、口腔用組成物に一般的に使用される種々の防腐剤を配合することができる。特に限定されないが、例えば安息香酸ナトリウム、メチルパラベン、エチルパラベン、プロピルパラベン、ブチルパラベン等のパラベン類、塩化セチルピリジニウム、塩酸アルキルジアミノエチルグリシン、ソルビン酸カリウム等が挙げられる。 As the preservative, various preservatives generally used in oral compositions can be blended. Although not particularly limited, examples thereof include parabens such as sodium benzoate, methylparaben, ethylparaben, propylparaben and butylparaben, cetylpyridinium chloride, alkyldiaminoethylglycine hydrochloride, potassium sorbate and the like.
薬理活性成分としては、口腔用組成物に一般的に使用される種々の薬理活性成分を配合することができる。特に限定されないが、例えばクロロヘキシジン、トリクロサン、イソプロピルメチルフェノール、塩化セチルピリジニウム、グルコン酸亜鉛、クエン酸亜鉛等の殺菌又は抗菌剤;トラネキサム酸、グリチルリチン酸ジカリウム塩等の抗炎症剤;アラントイン、アラントインクロルヒドロキシアルミニウム、アスコルビン酸、塩化リゾチーム、グリチルリチン酸及びその塩類、塩化ナトリウム、乳酸アルミニウム等の収斂剤;デキストラナーゼ、アミラーゼ、プロテアーゼ、ムタナーゼ、リゾチーム等の酵素;塩化ストロンチウム、硝酸カリウム等の知覚過敏抑制剤などが挙げられ、これらを薬剤学的に許容できる範囲で使用することができる。 As the pharmacologically active ingredient, various pharmacologically active ingredients generally used in oral compositions can be blended. Although not particularly limited, for example, bactericidal or antibacterial agents such as chlorohexidine, triclosan, isopropylmethylphenol, cetylpyridinium chloride, zinc gluconate, zinc citrate; anti-inflammatory agents such as tranexamic acid, dipotassium glycyrrhizinate; allantoin, allantoin chlorhydroxy Astringents such as aluminum, ascorbic acid, lysozyme chloride, glycyrrhizic acid and its salts, sodium chloride and aluminum lactate; enzymes such as dextranase, amylase, protease, mutanase, lysozyme; hypersensitivity inhibitors such as strontium chloride and potassium nitrate And these can be used in a pharmaceutically acceptable range.
溶剤としては、エタノールやイソプロピルアルコール等を使用することができる。 As the solvent, ethanol or isopropyl alcohol can be used.
本発明の口腔用組成物中の任意成分の含有量としては、配合される各成分の量、担体、添加剤の種類等に応じて適宜設定され得るが、総量として1〜80重量%が挙げられる。 The content of the optional component in the composition for oral cavity of the present invention can be appropriately set according to the amount of each component to be blended, the carrier, the type of additive, etc., but the total amount is 1 to 80% by weight. To be
また、本発明の口腔用組成物は、薬理学的に許容される従来公知の担体を含んでいてもよい。このような担体としては、例えば水(イオン交換水、蒸留水、精製水等)、生理食塩水等の水性担体;高級脂肪酸、植物油、動物油、シリコーン油類、金属石鹸等の油性担体が挙げられる。本発明において、これらの担体の含有量は、口腔用組成物において有効成分であるヒノキチオールと、その他の任意成分以外の残部に相当するように調整される。 The oral composition of the present invention may contain a conventionally known carrier that is pharmacologically acceptable. Examples of such carriers include water (ion-exchanged water, distilled water, purified water, etc.), aqueous carriers such as physiological saline, and higher fatty acids, vegetable oils, animal oils, silicone oils, oily carriers such as metal soaps. .. In the present invention, the content of these carriers is adjusted so as to correspond to the balance other than hinokitiol, which is an active ingredient in the oral composition, and other optional ingredients.
本発明の口腔用組成物の使用量/回は特に限定されず、用途に応じて適宜調整され得るが、例えば、練歯磨剤の場合には0.2〜1gが挙げられ、液体歯磨剤や洗口剤の場合には5〜20mLが挙げられる。また本発明の口腔用組成物の適用者は好ましくは成人であり、より好ましくは歯周病に罹患した人または歯周病に罹患しやすい人である。 The amount of the oral composition of the present invention to be used/time is not particularly limited and may be appropriately adjusted depending on the application. For example, in the case of a toothpaste, 0.2 to 1 g may be mentioned. In the case of a mouthwash, 5-20 mL is mentioned. Further, the applicator of the composition for oral cavity of the present invention is preferably an adult, and more preferably a person suffering from periodontal disease or a person susceptible to periodontal disease.
(II)Cysプロテアーゼの活性抑制作用を付与する方法
後述する実験例1に示すようにヒノキチオール及びシャクヤク加工物には歯周病原因菌であるP.ジンジバリスが産生するCysプロテアーゼの活性を抑制する作用がある。このため、口腔用組成物にヒノキチオール及びシャクヤク加工物から選択される少なくとも1種を配合することで、当該口腔用組成物にP.ジンジバリスが産生するCysプロテアーゼの活性を抑制する作用を付与することができる。
(II) Method for imparting activity suppressing activity of Cys protease As shown in Experimental Example 1 described below, hinokitiol and peony processed products have an activity of suppressing the activity of Cys protease produced by P. gingivalis, which is a periodontal disease-causing bacterium. There is. Therefore, by adding at least one selected from hinokitiol and peony processed products to the oral composition, the oral composition is provided with an action of suppressing the activity of Cys protease produced by P. gingivalis. You can
従って、本発明は口腔用組成物にヒノキチオール及びシャクヤク加工物から選択される少なくとも1種を配合する工程を有する、口腔用組成物に歯周病原因菌産生Cysプロテアーゼの活性抑制作用を付与する方法を提供する。口腔用組成物にはヒノキチオール単独で配合してもよいし、シャクヤク加工物を単独または形態が異なるシャクヤク加工物を2種以上組み合わせて配合してもよいし、さらにヒノキチオールとシャクヤク加工物とを組み合わせて配合してもよい。ここで配合する好適なシャクヤク加工物としては、シャクヤクエキスを例示することができる。 Therefore, the present invention has a step of adding at least one selected from hinokitiol and peony processed products to the oral composition, and a method for imparting an activity suppressing action of periodontal disease-causing bacteria-produced Cys protease to the oral composition. I will provide a. The composition for oral cavity may be blended with hinokitiol alone, or may be blended with peony processed products alone or in combination of two or more peony processed products having different morphology, and further combined hinokitiol and peony processed product. You may mix it. An example of a suitable peony product to be blended here is peony extract.
ここでヒノキチオール及び/またはシャクヤク加工物を添加配合する対象の口腔用組成物は、その剤型及び含有成分として、ヒノキチオール及びシャクヤク加工物を含有していないことを除いて、前述する口腔用組成物を挙げることができる。当該口腔用組成物に対するヒノキチオールの配合量は、調製する口腔用組成物の種類や剤型及び目的によって相違するものの、例えば、調製する口腔用組成物がそのまま口腔内に適用される口腔用組成物である場合は、例えば0.001〜0.5質量%の範囲から適宜設定することができる。好ましくは0.005〜0.2質量%であり、より好ましくは0.01〜0.2質量%である。また調製する口腔用組成物が、用時に水で希釈して口腔内に適用される口腔用組成物である場合は、希釈後の口腔用組成物中のヒノキオールの濃度が前記範囲になるようにヒノキチオールを配合すればよい。例えば、制限されないものの、一例を挙げると、用時に水で10倍に希釈して使用される口腔用組成物の場合、例えばヒノキチオールを0.01〜5質量%の割合で配合して口腔用組成物を調製することができる。 Here, the oral composition to be added and blended with hinokitiol and/or peony processed product has the above-mentioned oral composition except that it does not contain hinokitiol and peony processed product as its dosage form and contained components. Can be mentioned. The blending amount of hinokitiol with respect to the oral composition varies depending on the type and dosage form of the oral composition to be prepared and the purpose, but for example, the oral composition to be prepared is directly applied to the oral cavity. When it is, it can be appropriately set from the range of 0.001 to 0.5 mass %, for example. It is preferably 0.005 to 0.2% by mass, and more preferably 0.01 to 0.2% by mass. When the oral composition to be prepared is an oral composition which is diluted with water before use and applied to the oral cavity, the concentration of hinokiol in the oral composition after dilution is in the above range. Hinokitiol may be blended with. For example, although not limited, in the case of an oral composition that is used by diluting 10 times with water at the time of use, for example, hinokitiol is blended at a ratio of 0.01 to 5% by mass, and the oral composition is used. Can be prepared.
口腔用組成物に対するシャクヤク加工物の配合量は、調製する口腔用組成物の種類や剤型及び目的によって相違するものの、例えば、調製する口腔用組成物がそのまま口腔内に適用される口腔用組成物である場合は、乾燥物換算で、例えば0.00001〜1質量%の範囲から適宜設定することができる。好ましくは0.00005〜0.1質量%であり、より好ましくは0.0001〜0.01質量%である。また調製する口腔用組成物が、用時に水で希釈して口腔内に適用される口腔用組成物である場合は、希釈後の口腔用組成物中のシャクヤク加工物の濃度が前記範囲になるようにシャクヤク加工物を配合すればよい。例えば、制限されないものの、一例を挙げると、用時に水で10倍に希釈して使用される口腔用組成物の場合、例えばシャクヤク加工物を0.000001〜10質量%の割合で配合して口腔用組成物を調製することができる。 The blended amount of the peony processed product with respect to the oral composition varies depending on the type and dosage form of the oral composition to be prepared and the purpose, but for example, the oral composition to be prepared is directly applied to the oral cavity. When it is a product, it can be appropriately set in the range of 0.00001 to 1% by mass in terms of dry matter. It is preferably 0.00005 to 0.1% by mass, and more preferably 0.0001 to 0.01% by mass. When the oral composition to be prepared is an oral composition that is diluted with water at the time of use and applied to the oral cavity, the concentration of the peony processed product in the diluted oral composition is in the above range. Thus, the peony processed product may be blended. For example, although not limited, in the case of an oral composition that is used by diluting it 10 times with water at the time of use, for example, a peony processed product is blended at a ratio of 0.000001 to 10% by mass to the oral cavity. A composition for use can be prepared.
以上、本明細書において、「含む」及び「含有する」の用語には、「からなる」及び「から実質的になる」という意味が含まれる。 As described above, in the present specification, the terms “including” and “containing” include the meanings of “consisting of” and “consisting essentially of”.
以下、本発明の構成及び効果について、その理解を助けるために、実験例を用いて本発明を説明する。但し、本発明はこれらの実験例によって何ら制限を受けるものではない。以下の実験は、特に言及しない限り、室温(25±5℃)、及び大気圧条件下で実施した。また、特に言及しない限り、「%」は質量%を意味する。 Hereinafter, in order to help understanding of the constitution and effect of the present invention, the present invention will be explained using experimental examples. However, the present invention is not limited to these experimental examples. The following experiments were performed at room temperature (25±5° C.) and atmospheric pressure unless otherwise stated. Further, "%" means% by mass unless otherwise specified.
実験例1 ジンジパイン活性抑制効果の評価
ポルフィロモナス・ジンジバリス(Porphyromonas gingivalis)(P.ジンジバリス)が産生するプロテアーゼ(ジンジパイン)の蛋白質分解活性(ジンジパイン活性)に対するヒノキチオール及びシャクヤクエキスの抑制効果を、以下の試験により評価した。
Experimental Example 1 Evaluation of gingipain activity inhibitory effect The inhibitory effects of hinokitiol and peony extract on the proteolytic activity (gingipain activity) of the protease (jinzipain) produced by Porphyromonas gingivalis (P. gingivalis) are described below. It was evaluated by a test.
(1)試験方法
(1−1)P.ジンジバリス産生プロテアーゼの精製
P.ジンジバリス(JCM 12257)を50μg/mLヘミン及び1μg/mLメナジオン含有GAM液体培地にて、37℃で2日間嫌気培養した。培養後、培養液を遠心分離(10000rpm、4℃、10分間)した後、回収した上清に80%飽和になるように硫酸アンモニウムを添加し、4℃条件下で2時間スターラーで撹拌した。次いでこれを遠心分離(10000rpm、4℃、30分間)した後、得られた沈殿物にBuffer(20mM Tris-HCl(pH7.4)、150mM NaCl、10mM CaCl2)を加えて溶解し、これを透析膜に入れて、Buffer(20mM Tris-HCl(pH7.4)、150mM NaCl、10mM CaCl2、0.05% Tween20)(4℃)にて1日間透析した。透析後、透析膜から回収した透析液を、遠心分離(10000rpm、4℃、30分間)し、得られた上清に終濃度が25%になるようにグリセリンを添加して、これをP.ジンジバリス産生プロテアーゼ液(粗酵素液)とした。
(1) Test method (1-1) P. Purification of Gingivalis Protease P. Gingivalis (JCM 12257) was anaerobically cultured in a GAM liquid medium containing 50 μg/mL hemin and 1 μg/mL menadione at 37° C. for 2 days. After culturing, the culture solution was centrifuged (10000 rpm, 4° C., 10 minutes), ammonium sulfate was added to the collected supernatant to 80% saturation, and the mixture was stirred with a stirrer at 4° C. for 2 hours. Then, this was centrifuged (10000 rpm, 4°C, 30 minutes), and the resulting precipitate was dissolved by adding Buffer (20 mM Tris-HCl (pH7.4), 150 mM NaCl, 10 mM CaCl 2 ). The sample was placed in a dialysis membrane and dialyzed against Buffer (20 mM Tris-HCl (pH 7.4), 150 mM NaCl, 10 mM CaCl 2 , 0.05% Tween 20) (4° C.) for 1 day. After dialysis, the dialysate collected from the dialysis membrane was centrifuged (10000 rpm, 4° C., 30 minutes), and glycerin was added to the resulting supernatant so that the final concentration was 25%. It was used as a gingivalis-producing protease solution (crude enzyme solution).
(1−2)ジンジパイン活性の測定
0.1M Tris−HCl(pH7.4)の中で、終濃度0.05mM システイン、表1に示す組成からなる被験試料(実施例用、比較例用)、上記方法で調製したP.ジンジバリス産生プロテアーゼ液(粗酵素液)の100倍希釈液、及び1mM Bz-L-Arg-pNA・HCl[L-BAPA](Benzoyl-L-arginine p-nitroanilide monohydrochloride)(アルギニン−ジンジパイン用基質)または1mM Ac-Lys-pNA・HCl(N-α-Acetyl-L-lysine p-nitroanilide monohydrochloride)(リジン−ジンジパイン用基質)を混合し、37℃で5時間インキュベートした。なお、ここに記載する各成分の濃度は、添加混合後の終濃度である。インキュベート前後で、反応液0.5mLを48ウェルマイクロプレートに移し、波長430nmにおける吸光度を測定した。インキュベート前の吸光度(初期値)とインキュベート後の吸光度との差から反応により分解生成したパラニトロアニリン(pNA)の量、つまり基質の分解活性(ジンジパイン活性)を評価した。
(1-2) Measurement of gingipain activity In 0.1 M Tris-HCl (pH 7.4), a final concentration of 0.05 mM cysteine, a test sample having the composition shown in Table 1 (for Examples and Comparative Examples), P. cerevisiae prepared by the above method A 100-fold dilution of Gingivalis-produced protease solution (crude enzyme solution), and 1 mM Bz-L-Arg-pNA.HCl [L-BAPA] (Benzoyl-L-arginine p-nitroanilide monohydrochloride) (substrate for arginine-gindipine) or 1 mM Ac-Lys-pNA.HCl (N-α-Acetyl-L-lysine p-nitroanilide monohydrochloride) (substrate for lysine-gindipine) was mixed and incubated at 37°C for 5 hours. The concentration of each component described here is the final concentration after addition and mixing. Before and after the incubation, 0.5 mL of the reaction solution was transferred to a 48-well microplate, and the absorbance at a wavelength of 430 nm was measured. From the difference between the absorbance before the incubation (initial value) and the absorbance after the incubation, the amount of para-nitroaniline (pNA) decomposed and produced by the reaction, that is, the decomposition activity of the substrate (gingipain activity) was evaluated.
(2)試験結果
基質としてアルギニン−ジンジパイン用基質を用いた場合の結果を表2及び図1に、リジン−ジンジパイン用基質を用いた場合の結果を表3及び図2に、それぞれ示す。
(2) Test Results The results when the substrate for arginine-gindipain is used as the substrate are shown in Table 2 and FIG. 1, and the results when the substrate for lysine-gindipine is used are shown in Table 3 and FIG. 2, respectively.
表2及び図1に示すように、ヒノキチオール及びシャクヤクエキスのいずれも含有しない比較例1では、pNA由来の発光が確認され、アルギニン−ジンジパイン活性を示したのに対し、ヒノキチオールを0.01%含有する実施例1、0.02%含有する実施例2、及び0.04%含有する実施例3では、いずれもその活性が用量依存的に抑制されることが確認された。この結果より、ヒノキチオールには、アルギニン−ジンジパイン活性を抑制する作用があることが判明した。またシャクヤクエキスを0.0001%含有する実施例4、0.001%含有する実施例5、及び0.01%含有する実施例6でもその活性が用量依存的に抑制されることが確認された。この結果より、シャクヤクエキスを始めとするシャクヤク加工物には、アルギニン−ジンジパイン活性を抑制する作用があることが判明した。また実施例7及び8の結果から、ヒノキチオールにシャクヤクエキスを併用すると、ヒノキチオールのアルギニン−ジンジパイン活性抑制作用は損なわれることなく、維持または増強することが確認された。 As shown in Table 2 and FIG. 1, in Comparative Example 1 containing neither hinokitiol nor peony extract, pNA-derived luminescence was confirmed, and arginine-gindipain activity was shown, while 0.01% hinokitiol was contained. In Example 1, Example 2 containing 0.02%, and Example 3 containing 0.04%, it was confirmed that the activity was suppressed in a dose-dependent manner. From this result, it was revealed that hinokitiol has an action of suppressing arginine-gindipain activity. It was also confirmed that the activity was suppressed in a dose-dependent manner in Example 4 containing 0.0001% of peony extract, Example 5 containing 0.001%, and Example 6 containing 0.01%. .. From these results, it was revealed that processed peonies such as peony extract have an action of suppressing arginine-gindipine activity. In addition, from the results of Examples 7 and 8, it was confirmed that when peony extract was used in combination with hinokitiol, the arginine-gindipain activity suppressing action of hinokitiol was maintained or enhanced without being impaired.
また表3及び図2に示すように、ヒノキチオール及びシャクヤクエキスのいずれも含有しない比較例2では、pNA由来の発光が確認され、リジン−ジンジパイン活性を示したのに対し、ヒノキチオールを0.01%含有する実施例9、0.02%含有する実施例102、及び0.04%含有する実施例11では、いずれもその活性が用量依存的に抑制されることが確認された。この結果より、ヒノキチオールには、アルギニン−ジンジパイン活性だけでなくリジン−ジンジパイン活性をも抑制する作用があることが判明した。またシャクヤクエキスを0.0001%含有する実施例12、0.001%含有する実施例13、及び0.01%含有する実施例14でもその活性が用量依存的に抑制されることが確認された。この結果より、シャクヤク加工物にも、アルギニン−ジンジパイン活性だけでなくリジン−ジンジパイン活性を抑制する作用があることが判明した。これらの実験結果から、ヒノキチオール及びシャクヤクエキスには、塩基性アミノ酸−ジンジパイン活性を抑制する作用があることが明らかになった。 Further, as shown in Table 3 and FIG. 2, in Comparative Example 2 containing neither hinokitiol nor peony extract, pNA-derived luminescence was confirmed, and lysine-gindipain activity was shown, whereas hinokitiol was 0.01%. It was confirmed that the activity was suppressed in a dose-dependent manner in Example 9 containing 0.02%, Example 102 containing 0.02%, and Example 11 containing 0.04%. From this result, it was revealed that hinokitiol has an action of suppressing not only arginine-gindipain activity but also lysine-gindipain activity. It was also confirmed that the activity was suppressed in a dose-dependent manner in Example 12 containing 0.0001% of peony extract, Example 13 containing 0.001%, and Example 14 containing 0.01%. .. From this result, it was revealed that the processed peonies also have an action of suppressing not only the arginine-gindipine activity but also the lysine-gindipine activity. From these experimental results, it was revealed that hinokitiol and peony extract have an action of suppressing the basic amino acid-gindipain activity.
歯磨き剤の形態を有する本発明の歯周病原因菌産生システインプロテアーゼの活性抑制用組成物を表4に例示する。 Table 4 exemplifies a composition for suppressing the activity of cysteine protease produced by periodontal disease-causing bacteria of the present invention in the form of a dentifrice.
洗口液の形態を有する本発明の歯周病原因菌産生システインプロテアーゼの活性抑制用組成物を表5に例示する。 Table 5 illustrates the composition for inhibiting the activity of cysteine protease produced by periodontal disease-causing bacteria of the present invention in the form of mouthwash.
ゲル状軟膏剤(半固形剤)の形態を有する本発明の歯周病原因菌産生システインプロテアーゼの活性抑制用組成物を表6に例示する。 Table 6 exemplifies the composition for suppressing the activity of periodontal disease-causing bacterium-produced cysteine protease of the present invention in the form of a gel-like ointment (semisolid).
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