JP2021098679A - Method for stabilizing non-polymer catechin - Google Patents
Method for stabilizing non-polymer catechin Download PDFInfo
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- JP2021098679A JP2021098679A JP2019232316A JP2019232316A JP2021098679A JP 2021098679 A JP2021098679 A JP 2021098679A JP 2019232316 A JP2019232316 A JP 2019232316A JP 2019232316 A JP2019232316 A JP 2019232316A JP 2021098679 A JP2021098679 A JP 2021098679A
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- Prior art keywords
- agent
- polymer catechins
- cationic
- polymer
- catechins
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- 235000005487 catechin Nutrition 0.000 title claims abstract description 130
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- 238000000034 method Methods 0.000 title claims abstract description 40
- 230000000087 stabilizing effect Effects 0.000 title claims abstract description 15
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Abstract
Description
本発明は、非重合体カテキン類の安定化方法に関する。 The present invention relates to a method for stabilizing non-polymer catechins.
非重合体カテキン類は、例えば、抗がん作用、抗ガン転移作用、抗腫瘍作用、抗菌作用、抗ウイルス作用、血圧調節作用、血中コレステロール調節作用、抗肥満作用、抗酸化作用、消臭作用、老化予防作用、認知症予防作用（アミロイドβ蓄積予防・産生抑制）、インフルエンザ予防作用、歯周病予防作用等の様々な化学的・生理的活性作用を有することが知られている（非特許文献１〜３４）。しかしながら、非重合体カテキン類は、抗酸化物質であるため、時間の経過とともに酸素などの作用を受けて劣化しやすいという性質を有する。そのため、保存時において非重合体カテキン類量が徐々に減少してしまう。 Non-polymer catechins are, for example, anticancer action, anticancer metastasis action, antitumor action, antibacterial action, antiviral action, blood pressure regulating action, blood cholesterol regulating action, antiobesity action, antioxidant action, deodorant action. It is known to have various chemically and physiologically active actions such as action, anti-aging action, dementia preventive action (prevention of amyloid β accumulation / production suppression), preventive action against influenza, and preventive action against periodontal disease (non-). Patent Documents 1 to 34). However, since non-polymer catechins are antioxidants, they have the property of being easily deteriorated by the action of oxygen and the like over time. Therefore, the amount of non-polymer catechins gradually decreases during storage.
しかしながら、非重合体カテキン類の劣化抑制に有効な手段がなく、非重合体カテキン類の安定化が求められていた。
本発明は、非重合体カテキン類の安定化方法、非重合体カテキン類の安定化剤、それを含有する製剤を提供するものである。
However, there is no effective means for suppressing the deterioration of non-polymer catechins, and stabilization of non-polymer catechins has been required.
The present invention provides a method for stabilizing non-polymer catechins, a stabilizer for non-polymer catechins, and a preparation containing the same.
本発明者は、上記課題に鑑み検討した結果、非重合体カテキン類を特定のカチオン性物質と共存させることで、非重合体カテキン類の安定性を向上できることを見出した。 As a result of studying in view of the above problems, the present inventor has found that the stability of non-polymer catechins can be improved by coexisting non-polymer catechins with a specific cationic substance.
すなわち、本発明は、非重合体カテキン類を、該非重合体カテキン類に対する結合定数が１．０×１０4Ｍ-1以上であるカチオン性物質と共存させる、非重合体カテキン類の安定化方法を提供するものである。 That is, the present invention is a method for stabilizing non-polymer catechins, in which the non-polymer catechins are allowed to coexist with a cationic substance having a binding constant to the non-polymer catechins of 1.0 × 10 4 M -1 or more. Is to provide.
本発明はまた、非重合体カテキン類に対する結合定数が１．０×１０4Ｍ-1以上であるカチオン性物質を有効成分とする、非重合体カテキン類の安定化剤を提供するものである。 The present invention also provides a stabilizer for non-polymeric catechins, which comprises a cationic substance having a binding constant to non-polymeric catechins of 1.0 × 10 4 M -1 or more as an active ingredient. ..
本発明は更に、非重合体カテキン類を安定化するための、非重合体カテキン類に対する結合定数が１．０×１０4Ｍ-1以上であるカチオン性物質の使用を提供するものである。 The present invention further provides the use of a cationic substance having a binding constant to non-polymeric catechins of 1.0 × 10 4 M -1 or more for stabilizing non-polymeric catechins.
本発明はまた更に、上記安定化剤と、非重合体カテキン類を含有する、抗がん剤、抗ガン転移剤、抗腫瘍剤、抗菌剤、抗ウイルス剤、血圧調節剤、血中コレステロール調節剤、抗肥満剤、抗酸化剤、消臭剤、老化予防剤、認知症予防剤、インフルエンザ予防剤及び歯周病予防剤から選択される製剤を提供するものである。 The present invention further comprises the above stabilizer and non-polymer catechins, such as an anticancer agent, an anticancer metastatic agent, an antitumor agent, an antibacterial agent, an antiviral agent, a blood pressure regulator, and a blood cholesterol regulator. It provides a preparation selected from an agent, an anti-obesity agent, an anti-oxidant agent, a deodorant agent, an anti-aging agent, a dementia preventive agent, an influenza preventive agent and a periodontal disease preventive agent.
本発明は更にまた、抗がん剤、抗ガン転移剤、抗腫瘍剤、抗菌剤、抗ウイルス剤、血圧調節剤、血中コレステロール調節剤、抗肥満剤、抗酸化剤、消臭剤、老化予防剤、認知症予防剤、インフルエンザ予防剤及び歯周病予防剤から選択される製剤の製造のための、上記方法により安定化された非重合体カテキン類の使用を提供するものである。 The present invention further relates to anticancer agents, anticancer metastatic agents, antitumor agents, antibacterial agents, antiviral agents, blood pressure regulators, blood cholesterol regulators, antiobesity agents, antioxidants, deodorants, and aging. It provides the use of non-polymer catechins stabilized by the above method for the manufacture of formulations selected from prophylactics, dementia prophylaxis, influenza prophylaxis and periodontal disease prophylaxis.
本発明によれば、非重合体カテキン類の安定化方法、非重合体カテキン類の安定化剤を提供することができる。また、本発明により安定化された非重合体カテキン類を用いることで、非重合体カテキン類自体が有する化学的・生理的活性作用を十分に発現できる製剤を提供することができる。 According to the present invention, it is possible to provide a method for stabilizing non-polymer catechins and a stabilizer for non-polymer catechins. Further, by using the non-polymer catechins stabilized by the present invention, it is possible to provide a preparation capable of sufficiently expressing the chemically and physiologically active actions of the non-polymer catechins themselves.
〔安定化方法〕
本発明の非重合体カテキン類の安定化方法は、非重合体カテキン類を、該非重合体カテキン類に対する結合定数が１．０×１０4Ｍ-1以上であるカチオン性物質と共存させることを特徴とするものである。
[Stabilization method]
The method for stabilizing non-polymer catechins of the present invention is to allow the non-polymer catechins to coexist with a cationic substance having a binding constant to the non-polymer catechins of 1.0 × 10 4 M -1 or more. It is a feature.
（安定化）
本明細書において「非重合体カテキン類の安定化」とは、非重合体カテキン類量の減少を抑制することをいう。非重合体カテキン類量の減少の要因としては、例えば、非重合体カテキン類の酸化重合や酸化分解を挙げることができる。例えば、保存前後における非重合体カテキン類の残存率（％）を算出することにより、非重合体カテキン類の安定化の指標とすることができる。
(Stabilization)
As used herein, the term "stabilization of non-polymer catechins" means suppressing a decrease in the amount of non-polymer catechins. Examples of factors for reducing the amount of non-polymer catechins include oxidative polymerization and oxidative decomposition of non-polymer catechins. For example, by calculating the residual ratio (%) of non-polymer catechins before and after storage, it can be used as an index for stabilizing non-polymer catechins.
（非重合体カテキン類）
本明細書において「非重合体カテキン類」とは、カテキン、ガロカテキン、エピカテキン及びエピガロカテキン等の非ガレート体と、カテキンガレート、ガロカテキンガレート、エピカテキンガレート及びエピガロカテキンガレート等のガレート体を併せての総称である。本発明においては、上記８種の非重合体カテキン類のうち少なくとも１種を含有すればよい。
(Non-polymer catechins)
As used herein, the term "non-polymer catechins" refers to non-gallates such as catechin, gallocatechin, epicatechin and epigallocatechin, and gallates such as catechin gallate, gallocatechin gallate, epicatechin gallate and epigallocatechin gallate. Is a general term for all of them. In the present invention, at least one of the above eight types of non-polymer catechins may be contained.
非重合体カテキン類は、例えば、市販の試薬でも、非重合体カテキン類を含む植物抽出物の形態でもよい。
植物としては、非重合体カテキン類を含むものであれば特に限定されないが、例えば、Camellia属、例えば、C. sinensis var.sinensis（やぶきた種を含む）、C. sinensis var.assamica及びそれらの雑種から選択される茶葉（Camellia sinensis）が挙げられる。茶葉は、その加工方法により、不発酵茶、半発酵茶、発酵茶に分類されるが、これらのうちの１種又は２種以上を適宜選択して使用することができる。不発酵茶葉としては、例えば、煎茶、番茶、碾茶、釜入り茶、茎茶、棒茶、芽茶等の緑茶葉が挙げられ、火入れ加工が施されていてもよい。また、半発酵茶葉としては、例えば、鉄観音、色種、黄金桂、武夷岩茶等の烏龍茶葉が挙げられる。更に、発酵茶葉としては、ダージリン、アッサム、スリランカ等の紅茶葉が挙げられる。茶葉は１種又は２種以上を使用することができる。中でも、非重合体カテキン類含量、風味の点から、不発酵茶葉が好ましく、緑茶が更に好ましい。なお、抽出方法及び抽出条件は特に限定されず、公知の方法を採用することができる。
Non-polymer catechins may be, for example, commercially available reagents or in the form of plant extracts containing non-polymer catechins.
The plant is not particularly limited as long as it contains non-polymer catechins, but for example, Camellia genus, for example, C. sinensis var.sinensis (including tea plant species), C. sinensis var. Assamica and theirs. Examples include tea leaves (Camellia sinensis) selected from hybrids. Tea leaves are classified into non-fermented tea, semi-fermented tea, and fermented tea according to the processing method, and one or more of these can be appropriately selected and used. Examples of the non-fermented tea leaves include green tea leaves such as sencha, bancha, tencha, potted tea, kukicha, bar tea, and mecha, which may be fired. Examples of semi-fermented tea leaves include oolong tea leaves such as Tieguanyin, color species, golden katsura, and Wuyi tea. Further, examples of fermented tea leaves include black tea leaves such as Darjeeling, Assam and Sri Lanka. One kind or two or more kinds of tea leaves can be used. Among them, unfermented tea leaves are preferable, and green tea is more preferable, from the viewpoint of non-polymer catechin content and flavor. The extraction method and extraction conditions are not particularly limited, and a known method can be adopted.
なお、非重合体カテキン類として植物抽出物を用いる場合、そのまま用いてもよく、適宜な溶媒で希釈した希釈液として用いても、濃縮エキスや乾燥粉末としたり、ペースト状に調製したものを用いてもよい。また、凍結乾燥し、用時に、通常抽出に用いられる溶媒で希釈して用いることもできる。 When a plant extract is used as the non-polymer catechins, it may be used as it is, or it may be used as a diluted solution diluted with an appropriate solvent, or it may be a concentrated extract, a dry powder, or a paste prepared. You may. It can also be freeze-dried and diluted with a solvent usually used for extraction before use.
（カチオン性物質）
本明細書において「カチオン性物質」とは、水と接触したときに正電荷を帯びる物質をいう。カチオン性物質は、通常分子内にカチオン性基を有しており、かかるカチオン性基としては、例えば、１級アミノ基、２級アミノ基、３級アミノ基等のアミノ基、４級アンモニウム基、ホスホニウム基等のオニウム塩基、アルギニル基、リシル基、ヒスチジル基、グアニジル基等のアミノ酸残基、イミダゾール基等の複素環基を挙げることができる。なお、カチオン性物質がカチオン性基とアニオン性基の両方を有する場合には、分子全体で正電荷を帯びていればよい。
(Cationic substance)
As used herein, the term "cationic substance" refers to a substance that becomes positively charged when in contact with water. A cationic substance usually has a cationic group in the molecule, and examples of such a cationic group include an amino group such as a primary amino group, a secondary amino group and a tertiary amino group, and a quaternary ammonium group. , Onium groups such as phosphonium groups, amino acid residues such as arginyl groups, lysyl groups, histidyl groups and guanidyl groups, and heterocyclic groups such as imidazole groups can be mentioned. When the cationic substance has both a cationic group and an anionic group, the entire molecule may be positively charged.
ここで、本発明者が、非重合体カテキン類の安定化の観点で、「カチオン性物質」に着眼したのは、次の理由からである。すなわち、非重合体カテキン類は、Ｂ環を起点に酸化され、テアフラビン等の多量体に変化することが知られている。本発明者は、このような酸化メカニズムに着目し、非重合体カテキン類のＢ環の電子密度を低下させることで、非重合体カテキン類を安定化できるのではないかと考えた。そして、非重合体カテキン類のＢ環の電子密度を低下させる目的においては、電子求引性を有するカチオン性物質が特に有効であると考えた。
また、本発明者は、かかるカチオン性物質の中でも、非重合体カテキン類の安定化を達成するためには、非重合体カテキン類に対する結合定数が１．０×１０4Ｍ-1以上であるものが、非重合体カテキン類と分子間で相互作用しやすく、特に有効であることを見出した。本明細書において「結合定数」とは、非重合体カテキン類に対するカチオン性物質の結合親和力を表す指標であり、結合定数の値が大きいほど、非重合体カテキン類との相互作用が強いことを意味する。
Here, the present inventor focused on "cationic substances" from the viewpoint of stabilizing non-polymer catechins for the following reasons. That is, it is known that non-polymer catechins are oxidized starting from the B ring and changed into multimers such as theaflavin. The present inventor paid attention to such an oxidation mechanism and thought that the non-polymer catechins could be stabilized by lowering the electron density of the B ring of the non-polymer catechins. Then, it was considered that a cationic substance having an electron-attracting property is particularly effective for the purpose of reducing the electron density of the B ring of the non-polymer catechins.
Further, in order to achieve stabilization of non-polymer catechins among such cationic substances, the present inventor has a binding constant to non-polymer catechins of 1.0 × 10 4 M -1 or more. It has been found that those are particularly effective because they easily interact with non-polymer catechins between molecules. In the present specification, the "binding constant" is an index showing the binding affinity of a cationic substance with respect to non-polymer catechins, and the larger the value of the binding constant, the stronger the interaction with non-polymer catechins. means.
本発明においては、結合定数を、非重合体カテキン類とカチオン性物質との相互作用を熱力学的に解析し、等温滴定熱量測定（ＩＴＣ）により求める。等温滴定熱量測定では、２５℃、ｐＨ６．０の条件で、非重合体カテキン類とカチオン性物資を用いて滴定を行い、分子同士が結合する時に発生する微小な熱量変化を計測する。そして、得られた滴定曲線から、非重合体カテキン類とカチオン性物資との結合比（ｎ）、結合定数（Ｋａ）、結合のエンタルピー変化（ΔＨ）を求めることができる。更に、下記式（１）から結合の自由エネルギー変化（ΔＧ）を、下記式（２）から結合のエントロピー変化（ΔＳ）を、それぞれ算出することができる。具体的には、後掲の実施例に記載の方法が挙げられる。なお、等温滴定熱量測定では、例えば、ＭＩＣＲＯＣＡＬ社製の等温滴定型熱量計（ＶＰ−ＩＴＣ）を用いることができる。 In the present invention, the binding constant is determined by thermodynamically analyzing the interaction between the non-polymer catechins and the cationic substance and isothermal titration calorimetry (ITC). In the isothermal titration calorific value measurement, titration is performed using non-polymer catechins and cationic materials under the conditions of 25 ° C. and pH 6.0, and minute changes in calorific value generated when molecules are bonded to each other are measured. Then, from the obtained titration curve, the binding ratio (n) of the non-polymer catechins and the cationic material, the binding constant (Ka), and the enthalpy change of the bond (ΔH) can be obtained. Further, the free energy change (ΔG) of the bond can be calculated from the following formula (1), and the entropy change (ΔS) of the bond can be calculated from the following formula (2). Specifically, the method described in the examples described later can be mentioned. In the isothermal titration calorimeter measurement, for example, an isothermal titration calorimeter (VP-ITC) manufactured by MICROCAL can be used.
ΔＧ＝−ＲＴｌｎＫａ （１）
ΔＧ＝ΔＨ−ＴΔＳ （２）
〔式中、Ｒは気体定数を示し、Ｔは絶対温度を示し、Ｋａは結合定数を示す。〕
を解析することにより、
ΔG = -RTlnKa (1)
ΔG = ΔH−TΔS (2)
[In the equation, R indicates the gas constant, T indicates the absolute temperature, and Ka indicates the coupling constant. ]
By analyzing
カチオン性物質は、非重合体カテキン類に対する結合定数が１．０×１０4Ｍ-1以上であるが、非重合体カテキン類の安定性向上の観点から、２，０×１０4Ｍ-1以上が好ましく、３．０×１０4Ｍ-1以上がより好ましく、４．０×１０4Ｍ-1以上が更に好ましい。なお、かかる結合定数の上限は特に限定されないが、１０００×１０4Ｍ-1以下が好ましく、１００×１０4Ｍ-1以下が更に好ましい。 The cationic substance has a binding constant to non-polymer catechins of 1.0 × 10 4 M -1 or more, but from the viewpoint of improving the stability of non-polymer catechins, it is 2,0 × 10 4 M -1. The above is preferable, 3.0 × 10 4 M -1 or more is more preferable, and 4.0 × 10 4 M -1 or more is further preferable. The upper limit of the coupling constant is not particularly limited , but is preferably 1000 × 10 4 M -1 or less, and more preferably 100 × 10 4 M -1 or less.
カチオン性物質としては結合定数が１．０×１０4Ｍ-1以上であれば特に限定されないが、例えば、カチオン性タンパク質、カチオン性ポリマー、カチオン性界面活性剤が挙げられ、非重合体カテキン類に対する結合定数が１．０×１０4Ｍ-1以上であるものを適宜選択すればよい。カチオン性物質は、１種又は２種以上含有することができる。なお、カチオン性物の由来は特に限定されず、例えば、化学合成品でも、市販品でもよい。 The cationic substance is not particularly limited as long as the binding constant is 1.0 × 10 4 M -1 or more, and examples thereof include cationic proteins, cationic polymers, and cationic surfactants, and non-polymer catechins. A polymer having a coupling constant of 1.0 × 10 4 M -1 or more may be appropriately selected. The cationic substance can be contained alone or in combination of two or more. The origin of the cationic substance is not particularly limited, and may be, for example, a chemically synthesized product or a commercially available product.
本明細書において「カチオン性タンパク質」とは、正電荷を有する二以上のアミノ酸から形成され、生理学的ｐＨ等の選択したｐＨにおいて正味の正電荷を有するタンパク質をいい、ペプチド（オリゴマー）、ポリペプチドも包含する概念である。
カチオン性タンパク質は、正電荷を有する同種のアミノ酸からなるタンパク質であっても、正電荷を有する２以上の異種アミノ酸からなるタンパク質であってもよい。また、カチオン性タンパク質は、正電荷を有するアミノ酸と、負電荷を有するアミノ酸とをいずれも含むものであってもよいが、等電点が８以上であることを要する。なお、正電荷を有するアミノ酸としては、例えば、アルギニン、リシン、ヒスチジン、グアニジン等が挙げられ、また負電荷を有するアミノ酸としては、例えば、アスパラギン酸、グルタミン酸、システイン、チロシン等を挙げることができる。
As used herein, the term "cationic protein" refers to a protein formed from two or more amino acids having a positive charge and having a net positive charge at a selected pH such as physiological pH, and is a peptide (oligomer) or polypeptide. It is also a concept that includes.
The cationic protein may be a protein consisting of the same kind of amino acids having a positive charge, or a protein consisting of two or more heterologous amino acids having a positive charge. Further, the cationic protein may contain both a positively charged amino acid and a negatively charged amino acid, but it is required to have an isoelectric point of 8 or more. Examples of positively charged amino acids include arginine, lysine, histidine, and guanidine, and examples of negatively charged amino acids include aspartic acid, glutamic acid, cysteine, and tyrosine.
カチオン性タンパク質の具体例としては、例えば、プロタミン、ラクトフェリン、ポリリジン、ポリアルギニン、ポリオルニチン、ヌクレオリン、スペルミン、ヒストン、メリチン、マガイニンＩＩ、ディフェンシン、プロテグリン、セクロピン、ポリエチレンイミン、リゾチーム、パパイン、酸処理ゼラチン、ＨＩＶ−Ｔａｔ、ｐＶＥＣ等を挙げることができる。 Specific examples of cationic proteins include, for example, protamine, lactoferrin, polylysine, polyarginine, polyornithine, nucleoline, spermine, histones, meritin, maginin II, defensins, protegrins, seclopines, polyethyleneimine, lysozyme, papaine, acid-treated gelatin. , HIV-Tat, pVEC and the like.
本明細書において「カチオン性ポリマー」とは、カチオン性基を主鎖又は側鎖に有する高分子化合物をいい、「カチオン性タンパク質」は包含されない。
カチオン性ポリマーには、カチオン性基のみを有し、アニオン性基を有さないカチオン性ポリマーの他、カチオン性基及びアニオン性基を有し、かつ全体としてカチオン性を示す両性ポリマーもある。なお、カチオン性ポリマーは、ホモポリマーであっても、コポリマーであってもよい。
As used herein, the term "cationic polymer" refers to a polymer compound having a cationic group in the main chain or side chain, and does not include "cationic protein".
Cationic polymers include cationic polymers having only cationic groups and no anionic groups, as well as amphoteric polymers having cationic and anionic groups and exhibiting cationicity as a whole. The cationic polymer may be a homopolymer or a copolymer.
カチオン性ポリマーとしては、分子全体で正電荷を有する限り特に限定されないが、例えば、ポリアリルアミン塩酸塩、ポリアミンスルホン塩酸塩、ポリビニルアミン塩酸塩、キトサン酢酸塩、カチオン化澱粉、カチオン化グアーガム、カチオン化タラガム、カチオン化ローカストビーンガム、カチオン化ポリビニルアルコール、カチオン化セルロース、４級化ポリビニルピロリドン、ポリジアリル４級アンモニウム塩（例えば、ジアリルジメチルアンモニウムクロライド）等を挙げることができる。 The cationic polymer is not particularly limited as long as it has a positive charge in the whole molecule, and for example, polyallylamine hydrochloride, polyaminesulfone hydrochloride, polyvinylamine hydrochloride, chitosan acetate, cationized starch, cationized guar gum, and cationization. Examples thereof include tara gum, cationized locust bean gum, cationized polyvinyl alcohol, cationized cellulose, quaternized polyvinylpyrrolidone, and polydiallyl quaternary ammonium salt (for example, diallyldimethylammonium chloride).
本明細書において「カチオン性界面活性剤」とは、分子内に親油基部分と親水基部分を有し、水に溶かしたときに親水基部分がイオンに解離し、正電荷に帯電する化合物をいう。
カチオン性界面活性剤としては、非重合体カテキン類の安定性向上の観点から、不飽和炭化水素基を分子内に１以上有するカチオン性界面活性剤、長鎖飽和炭化水素基を分子内に１以上有するカチオン性界面活性剤が好ましく、例えば、下記式（Ａ）で表されるものを挙げることができる。
As used herein, the term "cationic surfactant" is a compound that has a lipophilic group portion and a hydrophilic group portion in the molecule, and when dissolved in water, the hydrophilic group portion dissociates into ions and is charged to a positive charge. To say.
As the cationic surfactant, from the viewpoint of improving the stability of non-polymer catechins, a cationic surfactant having one or more unsaturated hydrocarbon groups in the molecule and one long-chain saturated hydrocarbon group in the molecule are used. The cationic surfactant having the above is preferable, and examples thereof include those represented by the following formula (A).
（式中、Ｒ1、Ｒ2は、相互に独立に、炭素数１〜３の飽和炭化水素基を示す。
Ｒ3、Ｒ4は、相互に独立に、炭素数３〜２０の飽和又は不飽和の炭化水素基を示す。
Ａ-は、アニオンを示す。）
(In the formula, R 1 and R 2 represent saturated hydrocarbon groups having 1 to 3 carbon atoms independently of each other.
R 3 and R 4 independently represent saturated or unsaturated hydrocarbon groups having 3 to 20 carbon atoms.
A - indicates an anion. )
Ｒ1〜Ｒ4に係る飽和炭化水素基としては、例えば、アルキル基が挙げられ、直鎖状及び分岐状のいずれでもよい。
Ｒ4に係る不飽和飽和炭化水素基としては、例えば、アルケニル基が挙げられ、直鎖状及び分岐状のいずれの形態であってもよい。なお、不飽和炭化水素基の不飽和結合の位置は、分子鎖内及び分子鎖末端のいずれでもよく、任意の位置に有することができる。
Ａ-に係るアニオンとしては特に限定されないが、例えば、ハロゲン化物イオン、ホウ素アニオン、リンアニオン、カルボン酸アニオン、硫酸アニオン、有機スルホン酸アニオンを挙げることができる。
Examples of the saturated hydrocarbon group according to R 1 to R 4 include an alkyl group, which may be linear or branched.
Examples of the unsaturated saturated hydrocarbon group according to R 4 include an alkenyl group, which may be in either a linear form or a branched form. The position of the unsaturated bond of the unsaturated hydrocarbon group may be either within the molecular chain or at the end of the molecular chain, and may be held at any position.
A - is not particularly limited as anion according to, for example, can be exemplified halide ion, a boron anion, phosphate anion, a carboxylate anion, a sulfate anion, an organic sulfonic acid anion.
カチオン性界面活性剤の具体例としては、例えば、ジアリルジメチルアンモニウムクロライド、塩化セチ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、塩化イソステアリルトリメチルアンモニウム、塩化ラウリルトリメチルアンモニウム、塩化ベヘニルトリメチルアンモニウム、塩化オクタデシルトリメチルアンモニウム、塩化ココイルトリメチルアンモニウム、臭化セチルトリメチルアンモニウム、臭化ステアリルトリメチルアンモニウム、臭化ラウリルトリメチルアンモニウム、塩化イソステアリルラウリルジメチルアンモニウム、塩化ジセチルジメチルアンモニウム、塩化ジステアリルジメチルアンモニウム、塩化ジココイルジメチルアンモニウム等を挙げることができる。 Specific examples of the cationic surfactant include diallyldimethylammonium chloride, cetyltrimethylammonium chloride, stearyltrimethylammonium chloride, isostearyltrimethylammonium chloride, lauryltrimethylammonium chloride, behenyltrimethylammonium chloride, octadecyltrimethylammonium chloride, and chloride. Cocoyltrimethylammonium, cetyltrimethylammonium bromide, stearyltrimethylammonium bromide, lauryltrimethylammonium bromide, isostearyllauryldimethylammonium chloride, disetyldimethylammonium chloride, distearyldimethylammonium chloride, dicocoyldimethylammonium chloride and the like. Can be done.
本発明で使用するカチオン性物質の分子量としては、非重合体カテキン類の安定性向上、ハンドリング性の観点から、１００Ｄａ以上が好ましく、２００Ｄａ以上がより好ましく、３００Ｄａ以上が更に好ましく、そして１０００００Ｄａ以下が好ましく、９５０００Ｄａ以下がより好ましく、９００００Ｄａ以下が更に好ましい。かかる分子量の範囲としては、好ましくは１００〜１０００００であり、より好ましくは２００〜９５００００であり、更に好ましくは３００〜９００００である。なお、カチオン性物質の分子量は、ゲル浸透クロマトグラフィーにより測定するものとする。 The molecular weight of the cationic substance used in the present invention is preferably 100 Da or more, more preferably 200 Da or more, further preferably 300 Da or more, and 100,000 Da or less from the viewpoint of improving the stability and handling of non-polymer catechins. Preferably, 95,000 Da or less is more preferable, and 90000 Da or less is further preferable. The range of such a molecular weight is preferably 100 to 100,000, more preferably 200 to 950000, and even more preferably 300 to 90000. The molecular weight of the cationic substance shall be measured by gel permeation chromatography.
中でも、カチオン性物質としては、非重合体カテキン類の安定性向上の観点から、カチオン性タンパク質、カチオン化ポリマー及びカチオン性界面活性剤から選択される１以上が好ましく、カチオン性タンパク質及びカチオン性界面活性剤から選択される１以上がより好ましく、カチオン性タンパク質が更に好ましく、プロタミン及びラクトフェリンから選択される１以上がより更に好ましい。 Among them, as the cationic substance, one or more selected from a cationic protein, a cationic polymer and a cationic surfactant is preferable from the viewpoint of improving the stability of non-polymer catechins, and the cationic protein and the cationic surfactant are preferable. One or more selected from activators is more preferred, cationic proteins are even more preferred, and one or more selected from protamine and detergents are even more preferred.
（共存）
非重合体カテキン類と、カチオン性物質を共存させる方法としては、非重合体カテキン類とカチオン性物質とを混合すればよく、溶媒を用いてもよい。溶媒としては、非重合体カテキン類及びカチオン性物質を分散又は溶解し、かつこれら成分と反応しないものである限り、適宜選択して使用することができる。例えば、水、生理食塩水、緩衝剤、有機溶媒、有機溶媒水溶液が挙げられ、用途に応じて適宜選択することができる。水としては、例えば、イオン交換水、蒸留水、天然水が挙げられる。緩衝剤としては、例えば、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤、クエン酸緩衝剤、酢酸緩衝剤、グリシン緩衝剤、グリシルグリシン緩衝剤、トリス緩衝剤、アスパラギン酸、アスパラギン酸塩、イプシロン−アミノカプロン酸が挙げられる。有機溶媒としては、エタノール等のアルコールの他、炭化水素、エーテル等を使用することができる。なお、有機溶媒水溶液中の有機溶媒濃度は、適宜選択することができる。
(Coexistence)
As a method for coexisting the non-polymer catechins and the cationic substance, the non-polymer catechins and the cationic substance may be mixed, or a solvent may be used. As the solvent, as long as it disperses or dissolves non-polymer catechins and cationic substances and does not react with these components, it can be appropriately selected and used. Examples thereof include water, physiological saline, a buffer, an organic solvent, and an aqueous solution of an organic solvent, which can be appropriately selected depending on the intended use. Examples of water include ion-exchanged water, distilled water, and natural water. Examples of the buffer include borate buffer, phosphate buffer, carbon dioxide buffer, citric acid buffer, acetate buffer, glycine buffer, glycylglycine buffer, tris buffer, aspartic acid, and aspartate. , Epsilon-aminocaproic acid. As the organic solvent, in addition to alcohol such as ethanol, hydrocarbons, ether and the like can be used. The concentration of the organic solvent in the aqueous solution of the organic solvent can be appropriately selected.
なお、非重合体カテキン類とカチオン性物質との共存は、両者が最終的に同一系内に存在する状態になればよく、非重合体カテキン類とカチオン性物質とを共存させるタイミングや混合順序は特に限定されない。また、共存させるときの温度は、通常常温（２０℃±１５℃）であるが、必要により冷却してもよい。 The coexistence of the non-polymer catechins and the cationic substance may be such that both are finally present in the same system, and the timing and mixing order of the non-polymer catechins and the cationic substance coexisting. Is not particularly limited. The temperature at the time of coexistence is usually room temperature (20 ° C. ± 15 ° C.), but may be cooled if necessary.
カチオン性物質の使用量は、非重合体カテキン類の安定性向上の観点から、（Ａ）非重合体カテキン類に対する（Ｂ）カチオン性物質の質量比[（Ｂ）／（Ａ）]として、０．０００８以上が好ましく、０．００１以上がより好ましく、０．０９９以上が更に好ましく、そして１０以下が好ましく、０．６以下がより好ましく、０．５以下が更に好ましい。かかる質量比[（Ｂ）／（Ａ）]の範囲としては、好ましくは０．０００８〜１０であり、より好ましくは０．００１〜０．６であり、更に好ましくは０．０９９〜０．５である。 The amount of the cationic substance used is defined as (A) the mass ratio of the cationic substance to the non-polymer catechins [(B) / (A)] from the viewpoint of improving the stability of the non-polymer catechins. 0.0008 or more is preferable, 0.001 or more is more preferable, 0.099 or more is further preferable, 10 or less is preferable, 0.6 or less is more preferable, and 0.5 or less is further preferable. The range of the mass ratio [(B) / (A)] is preferably 0.0008 to 10, more preferably 0.001 to 0.6, and further preferably 0.099 to 0.5. Is.
〔安定化剤〕
本発明の非重合体カテキン類の安定化剤は、非重合体カテキン類に対する結合定数が１．０×１０4Ｍ-1以上であるカチオン性物質を有効成分とするものである。なお、非重合体カテキン類及びカチオン性物質の具体的態様、カチオン性物質の使用量は、上記において説明したとおりである。
[Stabilizer]
The stabilizer for non-polymer catechins of the present invention contains a cationic substance having a binding constant to non-polymer catechins of 1.0 × 10 4 M -1 or more as an active ingredient. The specific aspects of the non-polymer catechins and the cationic substance and the amount of the cationic substance used are as described above.
〔製剤〕
非重合体カテキン類は、例えば、抗がん作用、抗ガン転移作用、抗腫瘍作用、抗菌作用、抗ウイルス作用、血圧調節作用、血中コレステロール調節作用、抗肥満作用、抗酸化作用、消臭作用、老化予防作用、認知症予防作用（アミロイドβ蓄積予防・産生抑制）、インフルエンザ予防作用、歯周病予防作用等の様々な化学的・生理的活性作用を有することが報告されている。その一例を下記に示す。
[Preparation]
Non-polymer catechins have, for example, anti-cancer action, anti-cancer metastasis action, anti-tumor action, antibacterial action, antiviral action, blood pressure regulating action, blood cholesterol regulating action, anti-obesity action, antioxidant action, deodorization It has been reported to have various chemically and physiologically active actions such as action, anti-aging action, dementia preventive action (amyloid β accumulation prevention / production suppression), influenza preventive action, and periodontal disease preventive action. An example is shown below.
抗がん作用
（１）Nakamura Y, et al. The past and future of studies on tea and cancer prevention. Genes and Environment. 2010, 32: 67-74（非特許文献１）
（２）Yang CS, et al. Antioxidative and anti-carcinogenic activities of tea polyphenols. Arch Toxicol. 2009, 83: 11-21（非特許文献２）
Anti-cancer effect (1) Nakamura Y, et al. The past and future of studies on tea and cancer prevention. Genes and Environment. 2010, 32: 67-74 (Non-Patent Document 1)
(2) Yang CS, et al. Antioxidative and anti-carcinogenic activities of tea polyphenols. Arch Toxicol. 2009, 83: 11-21 (Non-Patent Document 2)
抗ガン転移作用
（１）Taniguchi S, et al. Effect of (-)-epigallocatechin gallate, the main constituent of green tea,on lung metastasis with mouse B16 melanoma cell lines. Cancer Lett. 1992, 65: 51-54（非特許文献３）
（２）Sazuka M, et al. Inhibitory effects of green tea infusion on in vitro invasion and in vivo metastasis of mouse lung carcinoma cells. Cancer Lett. 1995, 98: 27-31（非特許文献４）
（３）Cao Y, et al. Angiogenesis inhibited by drinking tea. Nature. 1999, 398: 381（非特許文献５）
Anti-cancer metastasis (1) Taniguchi S, et al. Effect of (-)-epigallocatechin gallate, the main constituent of green tea, on lung metastasis with mouse B16 melanoma cell lines. Cancer Lett. 1992, 65: 51-54 ( Non-Patent Document 3)
(2) Sazuka M, et al. Inhibitory effects of green tea infusion on in vitro invasion and in vivo metastasis of mouse lung carcinoma cells. Cancer Lett. 1995, 98: 27-31 (Non-Patent Document 4)
(3) Cao Y, et al. Angiogenesis inhibited by drinking tea. Nature. 1999, 398: 381 (Non-Patent Document 5)
抗腫瘍作用
（１）Suzuki Y, et al. Health-promoting effects of green tea. Proc Jpn Acad Ser B Phys BiolSci. 2012, 88: 88-101（非特許文献６）
（２）Pan MH, et al. Multistage carcinogenesis process as molecular targets in cancer chemoprevention by epicatechin-3-gallate. Food Funct. 2011, 2: 101-110（非特許文献７）
Antitumor effect (1) Suzuki Y, et al. Health-promoting effects of green tea. Proc Jpn Acad Ser B Phys BiolSci. 2012, 88: 88-101 (Non-Patent Document 6)
(2) Pan MH, et al. Multistage carcinogenesis process as molecular targets in cancer chemoprevention by epicatechin-3-gallate. Food Funct. 2011, 2: 101-110 (Non-Patent Document 7)
抗菌作用
（１）White DO, et al. Orthomyxoviridae. Medical Virology (Academic Press, Inc), 1994, 489-499（非特許文献８）
（２）Matrosovich MN, et al. Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J Virol. 2004 78: 12665-12667（非特許文献９）
Antibacterial activity (1) White DO, et al. Orthomyxoviridae. Medical Virology (Academic Press, Inc), 1994, 489-499 (Non-Patent Document 8)
(2) Matrosovich MN, et al. Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J Virol. 2004 78: 12665-12667 (Non-Patent Document 9)
抗ウイルス作用
（１）Nakayama M, et al. Inhibition of influenza virus infection by tea. Lett Appl Microbiol, 1990, 11: 38-40（非特許文献１０）
（２）Nakayama M, et al. Inhibition of the infectivity of influenza virus by tea polyphenols, Antiviral Research. 1993, 21: 289-299（非特許文献１１）
（３）中山幹男他、茶カテキンと特異抗体のインフルエンザウイルスに対する効果. 感染症誌. 1996,70: 1190-1192（非特許文献１２）
Antiviral action (1) Nakayama M, et al. Inhibition of influenza virus infection by tea. Lett Appl Microbiol, 1990, 11: 38-40 (Non-Patent Document 10)
(2) Nakayama M, et al. Inhibition of the infectivity of influenza virus by tea polyphenols, Antiviral Research. 1993, 21: 289-299 (Non-Patent Document 11)
(3) Effect of tea catechin and specific antibody on influenza virus by Mikio Nakayama et al. 1996,70: 1190-1192 (Non-Patent Document 12)
血圧調節作用
（１）Kurita I, et al. Antihypertensive effect of Benifuuki tea containing O-methylated EGCG, J Agri Food Chem. 2010, 58: 1903-1908（非特許文献１３）
（２）原征彦他、茶成分のアンジオテンシンI変換酵素阻害能について. 農化誌. 1987, 61: 803-808（非特許文献１４）
Blood pressure regulation effect (1) Kurita I, et al. Antihypertensive effect of Benifuuki tea containing O-methylated EGCG, J Agri Food Chem. 2010, 58: 1903-1908 (Non-Patent Document 13)
(2) Yasuhiko Hara et al., Angiotensin I-converting enzyme inhibitory ability of tea ingredients. Agricultural Chemicals. 1987, 61: 803-808 (Non-Patent Document 14)
血中コレステロール調節作用
（１）Muramatsu K, et al. Effect of green tea catechins on plasma cholesterol level in cholesterol-fed rats. J Nutr Sci Vitaminol. 1986, 32: 613-622（非特許文献１５）
（２）福興眞弓他、茶葉カテキンの構成成分である(-)エピガロカテキンガレートの血中コレステロール低下作用. 栄食誌. 1989, 39: 495-500（非特許文献１６）
（３）Ikeda I, et al. Tea catechins decrease micellar solubility and intestinal absorption of cholesterol in rats. Biochim Biophys Acta. 1992, 1127: 141-146（非特許文献１７）
（４）Ikeda I, et al. Tea catechins with a galloyl moiety suppress postprandial hypertriacylglycerolemia by delaying lymphatic transport of dietary fat in rats. J Nutr. 2005, 135: 155-159（非特許文献１８）
Blood cholesterol regulating action (1) Muramatsu K, et al. Effect of green tea catechins on plasma cholesterol level in cholesterol-fed rats. J Nutr Sci Vitaminol. 1986, 32: 613-622 (Non-Patent Document 15)
(2) Mayumi Fukuko et al. (-) Epigallocatechin gallate, which is a component of tea leaf catechin, has a blood cholesterol-lowering effect. Eishoku Magazine. 1989, 39: 495-500 (Non-Patent Document 16)
(3) Ikeda I, et al. Tea catechins decrease micellar solubility and intestinal absorption of cholesterol in rats. Biochim Biophys Acta. 1992, 1127: 141-146 (Non-Patent Document 17)
(4) Ikeda I, et al. Tea catechins with a galloyl moiety suppress postprandial hypertriacylglycerolemia by delaying lymphatic transport of dietary fat in rats. J Nutr. 2005, 135: 155-159 (Non-Patent Document 18)
抗肥満作用
（１）Hase T, et al. Anti-obesity effects of tea catechins in humans. J Oleo Sci. 2001, 50: 599-605（非特許文献１９）
（２）Tsuchida T, et al. Reduction of body fat in humans by long-term ingestion of catechins.Prog Med. 2002, 22: 2189-2203（非特許文献２０）
Anti-obesity effects (1) Hase T, et al. Anti-obesity effects of tea catechins in humans. J Oleo Sci. 2001, 50: 599-605 (Non-Patent Document 19)
(2) Tsuchida T, et al. Reduction of body fat in humans by long-term ingestion of catechins.Prog Med. 2002, 22: 2189-2203 (Non-Patent Document 20)
抗酸化作用
佐野満昭他, 茶の抗酸化性. フードケミカル. 1993, 9: 24-31（非特許文献２１）
Antioxidant effect Mitsuaki Sano et al., Antioxidant property of tea. Food Chemicals. 1993, 9: 24-31 (Non-Patent Document 21)
消臭作用
Biosci Biotechnol Biochem. 2002 Feb;66(2):373-377（非特許文献２２）
Deodorant effect
Biosci Biotechnol Biochem. 2002 Feb; 66 (2): 373-377 (Non-Patent Document 22)
老化予防作用
（１）Unno K, et al. Suppressive effect of green tea catechins on morphologic and functional regression of the brain in aged mice with accelerated senescence (SAMP10). Exp Gerontol. 2004, 39: 1027-1034（非特許文献２３）
（２）Unno K, et al. Daily consumption of green tea catechin delays memory regression in aged mice. Biogerontology. 2007, 8: 89-95（非特許文献２４）
（３）Unno K, et al. Daily ingestion of green tea catechins from adulthood suppressed brain dysfunction in aged mice. Biofactors. 2008, 34: 263-271（非特許文献２５）
Anti-aging effect (1) Unno K, et al. Suppressive effect of green tea catechins on morphologic and functional regression of the brain in aged mice with accelerated senescence (SAMP10). Exp Gerontol. 2004, 39: 1027-1034 (Non-patent literature) 23)
(2) Unno K, et al. Daily consumption of green tea catechin delays memory regression in aged mice. Biogerontology. 2007, 8: 89-95 (Non-Patent Document 24)
(3) Unno K, et al. Daily ingestion of green tea catechins from adulthood suppressed brain dysfunction in aged mice. Biofactors. 2008, 34: 263-271 (Non-Patent Document 25)
認知症予防作用（アミロイドβ蓄積予防・産生抑制）
（１）Kuriyama S, et al. Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya Project 1. Am J Clin Nutr. 2006, 83: 355-361（非特許文献２６）
（２）Lee S, et al. Protective effects of the green tea polyphenol (-)-epigallocatechingallate against hippocampal neuronal damage after transient global ischemia in gerbils. Neurosci Lett. 2000, 287: 191-194（非特許文献２７）
（３）Wei IH, et al. Green tea polyphenol (-)-epigallocatechin gallate attenuates the neuronal NADPH-d/nNOS expression in the nodose ganglion of acute hypoxic rats. Brain Res. 2004, 999: 73-80（非特許文献２８）
Dementia preventive action (prevention of amyloid β accumulation / suppression of production)
(1) Kuriyama S, et al. Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya Project 1. Am J Clin Nutr. 2006, 83: 355-361 (Non-Patent Document 26)
(2) Lee S, et al. Protective effects of the green tea polyphenol (-)-epigallocatechingallate against hippocampal neuronal damage after transient global ischemia in gerbils. Neurosci Lett. 2000, 287: 191-194 (Non-Patent Document 27)
(3) Wei IH, et al. Green tea polyphenol (-)-epigallocatechin gallate meters the neuronal NADPH-d / nNOS expression in the nodose ganglion of acute hypoxic rats. Brain Res. 2004, 999: 73-80 (Non-patent documents) 28)
インフルエンザ予防作用
（１）Nakayama M, et al. Inhibition of the infectivity of influenza virus by tea polyphenols. Antiviral Res. 1993, 21: 289-299（非特許文献２９）
（２）Song JM, et al. Antiviral effect of catechins in green tea on influenza virus. Antiviral Res. 2005, 68: 66-74（非特許文献３０）
（３）Kuzuhara T, et al. Green tea catechins inhibit the endonuclease activity of influenza A virus RNA polymerase. PLoS Curr Influenza 2009, RRN1052（非特許文献３１）
Influenza prophylaxis (1) Nakayama M, et al. Inhibition of the infectivity of influenza virus by tea polyphenols. Antiviral Res. 1993, 21: 289-299 (Non-Patent Document 29)
(2) Song JM, et al. Antiviral effect of catechins in green tea on influenza virus. Antiviral Res. 2005, 68: 66-74 (Non-Patent Document 30)
(3) Kuzuhara T, et al. Green tea catechins inhibit the endonuclease activity of influenza A virus RNA polymerase. PLoS Curr Influenza 2009, RRN1052 (Non-Patent Document 31)
歯周病予防作用
（１）Tajima T, et al. Preventive effects of tea polyphenols (sunphenon) on plaque formation in men. Nihon Univ Dent J. 1993, 71: 654-659（非特許文献３２）
（２）Sakanaka S, et al. Effects of green tea polyphenols on glucan synthesis and cellular adherence of cariogenic streptococci. Agric Biol Chem. 1990, 54: 2925-2929（非特許文献３３）
（３）Nishihara Y, et al. Inhibitory effects of food containing sucrose added tea catechins on dental caries in rats. Nihon Univ J Oral Sci. 1993, 19: 217-221（非特許文献３４）
Periodontal disease preventive effects (1) Tajima T, et al. Preventive effects of tea polyphenols (sunphenon) on plaque formation in men. Nihon Univ Dent J. 1993, 71: 654-659 (Non-Patent Document 32)
(2) Sakanaka S, et al. Effects of green tea polyphenols on glucan synthesis and cellular adherence of cariogenic streptococci. Agric Biol Chem. 1990, 54: 2925-2929 (Non-Patent Document 33)
(3) Nishihara Y, et al. Inhibitory effects of food containing sucrose added tea catechins on dental caries in rats. Nihon Univ J Oral Sci. 1993, 19: 217-221 (Non-Patent Document 34)
非重合体カテキン類自体が有する、このような化学的・生理的活性作用を十分に発現させるためには、有効量の非重合体カテキン類が製剤中に含まれていることが必要である。本発明においては、非重合体カテキン類に対して本発明の安定化方法を適用又は本発明の安定化剤を添加することにより、非重合体カテキン類の安定性が向上するため、非重合体カテキン類自体が有する様々な化学的・生理的活性作用を十分に発現することができる。 例えば、本発明の安定化方法を適用した非重合体カテキン類、あるいは本発明の安定化剤を含有する非重合体カテキン類を、下記のα群から選択される製剤として使用することができる。 In order to sufficiently express such a chemically and physiologically active action of the non-polymer catechins themselves, it is necessary that an effective amount of the non-polymer catechins is contained in the preparation. In the present invention, the stability of the non-polymer catechins is improved by applying the stabilizing method of the present invention to the non-polymer catechins or adding the stabilizer of the present invention. It can fully express various chemically and physiologically active actions of catechins themselves. For example, non-polymer catechins to which the stabilizing method of the present invention is applied, or non-polymer catechins containing the stabilizer of the present invention can be used as a preparation selected from the following α group.
〔α群〕
抗がん剤、抗ガン転移剤、抗腫瘍剤、抗菌剤、抗ウイルス剤、血圧調節剤、血中コレステロール調節剤、抗肥満剤、抗酸化剤、消臭剤、老化予防剤、認知症予防剤、インフルエンザ予防剤、歯周病予防剤
[Α group]
Anti-cancer agent, anti-cancer metastasis agent, anti-tumor agent, antibacterial agent, anti-virus agent, blood pressure regulator, blood cholesterol regulator, anti-obesity agent, antioxidant, deodorant, anti-aging agent, dementia prevention Drugs, influenza preventives, periodontal disease preventives
本明細書において「予防」とは、個体における疾患若しくは症状の発症の防止又は遅延、あるいは個体の疾患若しくは症状の発症の危険性を低下させることをいう。また、抗がん剤等の薬理学的製剤として使用する場合、当該使用は、ヒト若しくは非ヒト動物、又はそれらに由来する検体における使用であり得、また治療的使用であっても非治療的使用であってもよい。なお、「非治療的」とは、医療行為を含まない概念、すなわち人間を手術、治療又は診断する方法を含まない概念、より具体的には医師又は医師の指示を受けた者が人間に対して手術、治療又は診断を実施する方法を含まない概念である。 As used herein, the term "prevention" means preventing or delaying the onset of a disease or symptom in an individual, or reducing the risk of developing a disease or symptom in an individual. When used as a pharmacological preparation such as an anticancer drug, the use may be in humans or non-human animals, or in a sample derived from them, and even if it is a therapeutic use, it is non-therapeutic. It may be used. The term "non-therapeutic" means a concept that does not include medical practice, that is, a concept that does not include a method of surgery, treatment, or diagnosis of a human being, and more specifically, a doctor or a person who has been instructed by a doctor to treat a human being. It is a concept that does not include a method of performing surgery, treatment, or diagnosis.
製剤中の非重合体カテキン類の含有量は、有効量が含まれるように製剤の種類により適宜選択することができる。なお、非重合体カテキン類の含有量は、通常知られている測定法のうち測定試料の状況に適した分析法により測定することが可能であり、例えば、液体クロマトグラフィで分析することが可能である。具体的には、後掲の実施例に記載の方法が挙げられる。なお、測定の際には装置の検出域に適合させるため、試料を凍結乾燥したり、装置の分離能に適合させるため試料中の夾雑物を除去したりする等、必要に応じて適宜処理を施してもよい。 The content of the non-polymer catechins in the preparation can be appropriately selected depending on the type of the preparation so that the effective amount is included. The content of the non-polymer catechins can be measured by an analysis method suitable for the condition of the measurement sample among the commonly known measurement methods, and can be analyzed by, for example, liquid chromatography. is there. Specifically, the method described in the examples described later can be mentioned. At the time of measurement, appropriate treatment is performed as necessary, such as freeze-drying the sample to match the detection range of the device and removing impurities in the sample to match the separability of the device. May be given.
本発明の製剤は、一般製剤の製造に用いられる種々の添加剤を含んでいてもよい。添加剤は製剤の種類により適宜選択可能であるが、例えば、賦形剤、滑沢剤、崩壊剤、結合剤、着色剤、甘味剤、矯味剤、吸着剤、防腐剤、安定化剤、湿潤剤、帯電防止剤、ｐＨ調節剤、界面活性剤、デンプン、溶剤、懸濁化剤を挙げることができる。 The pharmaceutical product of the present invention may contain various additives used in the production of general pharmaceutical products. Additives can be appropriately selected depending on the type of formulation, and are, for example, excipients, starches, disintegrants, binders, colorants, sweeteners, flavoring agents, adsorbents, preservatives, stabilizers, and wetting agents. Examples thereof include agents, antistatic agents, pH adjusters, surfactants, starches, solvents, and suspending agents.
本発明の製剤の剤型は、その種類により適宜選択可能であるが、例えば、液剤、ゼリー剤、グミ剤、シロップ剤、ドライシロップ剤、錠剤、散剤、丸剤、トローチ剤顆粒剤、細粒剤、チュアブル製剤、口腔内崩壊剤、スプレーを挙げることができる。 The dosage form of the formulation of the present invention can be appropriately selected depending on the type thereof, and for example, a liquid agent, a jelly agent, a gummy agent, a syrup agent, a dry syrup agent, a tablet, a powder, a pill, a troche granule, or a fine granule. , Chewable formulations, orally disintegrants, sprays.
本発明の製剤の製造方法は特に限定されず、製剤の種類に応じて適宜の方法を採用し得る。例えば、非重合体カテキン類、カチオン性物質、必要により他の成分を混合して製造することができる。混合方法としては、撹拌、震盪等の適宜の方法を採用することが可能であり、混合装置を使用しても構わない。混合装置の混合方式は、容器回転型でも、容器固定型でもよい。容器回転型として、例えば、水平円筒型、Ｖ型、ダブルコーン型、立方体型等を採用することができる。また、容器固定型として、例えば、リボン型、スクリュー型、円錐形スクリュー型、パドル型、流動層型、フィリップスブレンダ−等を採用することができる。造粒物とする場合には、例えば、噴霧造粒、流動層造粒、圧縮造粒、転動造粒、撹拌造粒、押出造粒、粉末被覆造粒を採用することが可能であり、錠剤とする場合には、湿式打錠及び乾式打錠のいずれでもよい。濃縮液状とする場合には、例えば、常圧にて溶媒の蒸発を行う常圧濃縮法、減圧にて溶媒の蒸発を行う減圧濃縮法、膜分離により溶媒を除去する膜濃縮法等の公知の方法を採用することができる。 The method for producing the pharmaceutical product of the present invention is not particularly limited, and an appropriate method can be adopted depending on the type of the pharmaceutical product. For example, it can be produced by mixing non-polymer catechins, cationic substances, and if necessary, other components. As a mixing method, an appropriate method such as stirring or shaking can be adopted, and a mixing device may be used. The mixing method of the mixing device may be a container rotating type or a container fixed type. As the container rotating type, for example, a horizontal cylindrical type, a V type, a double cone type, a cubic type and the like can be adopted. Further, as the container fixing type, for example, a ribbon type, a screw type, a conical screw type, a paddle type, a fluidized bed type, a Philips blender and the like can be adopted. In the case of granulating products, for example, spray granulation, fluidized layer granulation, compression granulation, rolling granulation, stirring granulation, extrusion granulation, and powder-coated granulation can be adopted. In the case of tablets, either wet tableting or dry tableting may be used. In the case of making a concentrated liquid, for example, a known atmospheric concentration method in which the solvent is evaporated at normal pressure, a vacuum concentration method in which the solvent is evaporated under reduced pressure, a membrane concentration method in which the solvent is removed by membrane separation, and the like are known. The method can be adopted.
１．非重合体カテキン類の分析
試料溶液をフィルター（０．４５μｍ）で濾過し、高速液体クロマトグラフ（型式ＳＣＬ−１０ＡＶＰ、島津製作所製）を用い、オクタデシル基導入液体クロマトグラフ用パックドカラム（Ｌ−カラムＴＭ ＯＤＳ４．６ｍｍφ×２５０ｍｍ、５μｍ：財団法人 化学物質評価研究機構製）を装着し、カラム温度４０℃にてグラジエント法により分析した。非重合体カテキン類の標準品として、栗田工業製のものを使用し、検量線法で定量した。移動相Ａ液は酢酸を０．１ｍｏｌ／Ｌ含有する蒸留水溶液、Ｂ液は酢酸を０．１ｍｏｌ／Ｌ含有するアセトニトリル溶液とし、試料注入量は１０μＬ、ＵＶ検出器波長は２８０ｎｍの条件で行った。なお、グラジエントの条件は、以下のとおりである。
1. 1. Analysis of non-polymer catechins The sample solution is filtered through a filter (0.45 μm), and a packed column (L-column) for an octadecyl group-introduced liquid chromatograph using a high performance liquid chromatograph (model SCL-10AVP, manufactured by Shimadzu Corporation) TM ODS 4.6 mmφ × 250 mm, 5 μm: manufactured by Chemical Substance Evaluation and Research Organization) was attached, and the analysis was performed by the gradient method at a column temperature of 40 ° C. As a standard product of non-polymer catechins, one manufactured by Kurita Water Industries was used and quantified by the calibration curve method. The mobile phase A solution was a distilled aqueous solution containing 0.1 mol / L of acetic acid, and the B solution was an acetonitrile solution containing 0.1 mol / L of acetic acid. The sample injection amount was 10 μL and the UV detector wavelength was 280 nm. .. The conditions for the gradient are as follows.
濃度勾配条件
時間（分） Ａ液濃度（体積％） Ｂ液濃度（体積％）
０ ９７％ ３％
５ ９７％ ３％
３７ ８０％ ２０％
４３ ８０％ ２０％
４３．５ ０％ １００％
４８．５ ０％ １００％
４９ ９７％ ３％
６０ ９７％ ３％
Concentration gradient condition Time (minutes) Liquid A concentration (volume%) Liquid B concentration (volume%)
0 97% 3%
5 97% 3%
37 80% 20%
43 80% 20%
43.50% 100%
48.5% 100%
49 97% 3%
60 97% 3%
２．カチオン性物質の分析
（１）プロタミン
試料約０．１〜０．１５ｇを量り、窒素定量法のケルダール法により定量する。そして、次式により含量を求める。なお、ケルダール法による定量は、第８版食品添加物公定書を参照することができる。また、０．０５ｍｏ／Ｌ硫酸１ｍｌ＝１．４０１ｍｇＮとする。
2. Analysis of cationic substances (1) Weigh about 0.1 to 0.15 g of protamine sample and quantify it by the Kjeldahl method of nitrogen quantification method. Then, the content is calculated by the following formula. For the quantification by the Kjeldahl method, refer to the 8th edition Food Additives Official Standard. Further, 0.05 mo / L sulfuric acid 1 ml = 1.401 mgN.
プロタミンの含量（％）＝
〔窒素量(ｍｇ)×３．１９〕/〔乾燥物換算した試料の採取量(ｇ)×１０００〕×１００
Protamine content (%) =
[Nitrogen amount (mg) x 3.19] / [Dried sample collection amount (g) x 1000] x 100
（２）ラクトフェリン
ラクトフェリン含量は、ラテックス凝集法により測定できる。ラテックス凝集法は、抗ラクトフェリン抗体感作ラテックスを用いたラテックス凝集比濁法であり、抗原抗体反応の活性を有するラクトフェリンを定量する方法である。試料中のラクトフェリンは、ラテックス粒子に結合した抗ラクトフェリン抗体と抗原抗体反応を示し、凝集を生じる。この凝集を一定波長にて吸光度変化を測定し、これを換算してラクトフェリンの含量を市販のキット及び光学分析装置を用いて実施する。市販のキットとして、例えば、ラクトフェリン測定試薬（ヒト・ウシ用）（株式会社インフィニータ製）を使用することができる。光学分析装置として、自動生化学分析機ＢＩＯＬＩＳ２４ｉ（東京貿易メディシス株式会社）を使用することができる。
(2) Lactoferrin The lactoferrin content can be measured by the latex agglutination method. The latex agglutination method is a latex agglutination turbidimetric method using an anti-lactoferrin antibody-sensitized latex, and is a method for quantifying lactoferrin having an activity of an antigen-antibody reaction. The lactoferrin in the sample shows an antigen-antibody reaction with the anti-lactoferrin antibody bound to the latex particles and causes agglutination. This aggregation is carried out by measuring the change in absorbance at a constant wavelength and converting it to determine the content of lactoferrin using a commercially available kit and an optical analyzer. As a commercially available kit, for example, a lactoferrin measuring reagent (for humans and cattle) (manufactured by Infinita Co., Ltd.) can be used. As the optical analyzer, an automatic biochemical analyzer BIOLIS24i (Tokyo Boeki Medicis Co., Ltd.) can be used.
（３）ＨＩＶ−ｔａｔ
試料中のＨＩＶ−Ｔａｔは、抗ＨＩＶ−Ｔａｔ抗体と抗原抗体反応を示し、ＥＬＩＳＡ法にてＨＩＶ−Ｔａtの含量を市販のキットを用いて測定する。市販のキットとして、抗ＴＡＴイムノグロブリン測定ＥＬＩＳＡキット（コスモ・バイオ株式会社製）を使用することができる。
(3) HIV-tat
HIV-Tat in the sample shows an anti-HIV-Tat antibody and an antigen-antibody reaction, and the content of HIV-Tat is measured by an ELISA method using a commercially available kit. As a commercially available kit, an anti-TAT immunoglobulin measurement ELISA kit (manufactured by Cosmo Bio Co., Ltd.) can be used.
（４）ｐＶＥＣ
試料中のｐＶＥＣは液体クロマトグラフィー質量分析（ＬＣ／ＭＳ／ＭＳ）により、ＨＰＬＣカラム及び移動相を用いて測定する。
(4) pVEC
The pVEC in the sample is measured by liquid chromatography-mass spectrometry (LC / MS / MS) using an HPLC column and mobile phase.
（５）セチルトリメチルアンモニウムクロライド
試料中のセチルトリメチルアンモニウムクロライドは、液体クロマトグラフィー質量分析法（ＬＣ／ＭＳ／ＭＳ）により、ＨＰＬＣカラム及び移動相を用いて測定する。
・ＬＣ／ＭＳ／ＭＳ：ＬＣＭＳ ８０３０（島津製作所）
・ＨＰＬＣカラム ：Ｓｈｉｍ ｐａｃｋ ＦＣ ＯＤＳ（７５ｍｍ×２．０ｍｍ i.d., 粒子径 ３μｍ)（島津製作所）
・移動相 ：５ｍＭ酢酸アンモニウム水溶液、５ｍＭ酢酸アンモニウムメタノール溶液
(5) Cetyltrimethylammonium chloride The cetyltrimethylammonium chloride in the sample is measured by liquid chromatography-mass spectrometry (LC / MS / MS) using an HPLC column and a mobile phase.
・ LC / MS / MS: LCMS 8030 (Shimadzu Corporation)
-HPLC column: Sim pack FC ODS (75 mm x 2.0 mm id, particle size 3 μm) (Shimadzu Corporation)
-Mobile phase: 5 mM ammonium acetate aqueous solution, 5 mM ammonium acetate methanol solution
（６）ポリジアリルジメチルアンモニウムクロライド
試料中のポリジアリルジメチルアンモニウムクロライドは、液体クロマトグラフィー質量分析法（ＬＣ／ＭＳ／ＭＳ）により、ＨＰＬＣカラム及び移動相を用いて測定する。
(6) Polydiallyl dimethylammonium chloride The polydiallyl dimethylammonium chloride in the sample is measured by liquid chromatography-mass spectrometry (LC / MS / MS) using an HPLC column and a mobile phase.
３．カチオン性物質の結合定数の分析
溶媒として１０ｍＭリン酸Ｂｕｆｆｅｒ（ｐＨ６．０）を用い、カチオン性物質水溶液又はデキストリン（β−シクロデキストリン、γ−シクロデキストリン）水溶液を、等温滴定型熱量計（ＩＴＣ、ＭｉｃｌｏＣａｌ社製、機種名：ＶＰ−ＩＴＣ）の試料セル（容量１．４ｍＬ）に満たし、２５℃条件下にて、３１０ｒｐｍで回転しているシリンジから、エピガロカテキンガレート（ＥＧＣｇ）を一定間隔で滴下し、生じた熱量変化を繰り返し測定した。カチオン性物質又はデキストリン水溶液を含まない１０ｍＭリン酸ＢｕｆｆｅｒへのＥＧＣｇ水溶液滴下時の熱量変化も同様に測定し、希釈熱のデータとした。ＥＧＣｇ水溶液のカチオン性高分子水溶液又はデキストリン水溶液への熱滴定データから希釈熱のデータを差し引いた後、解析ソフトウェア（Ｏｒｉｇｉｎ７）を用いて、１サイト結合モデルで解析した。
3. 3. Analysis of binding constants of cationic substances Using 10 mM Buffer phosphate (pH 6.0) as a solvent, an aqueous solution of a cationic substance or an aqueous solution of dextrin (β-cyclodextrin, γ-cyclodextrin) is used as an isothermal titration calorimeter (ITC, Epigallocatechin gallate (EGCg) is dispensed at regular intervals from a syringe that fills a sample cell (capacity 1.4 mL) of MicroCal, model name: VP-ITC) and rotates at 310 rpm under 25 ° C. conditions. It was dropped and the change in the amount of heat generated was repeatedly measured. The change in calorific value when the EGCg aqueous solution was added dropwise to the 10 mM buffer phosphate containing no cationic substance or dextrin aqueous solution was also measured in the same manner and used as the data of the heat of dilution. After subtracting the dilution heat data from the thermal titration data of the EGCg aqueous solution into the cationic polymer aqueous solution or the dextrin aqueous solution, analysis was performed using a one-site binding model using analysis software (Origin7).
４．ｐＨの測定
試料を２０℃に温度調整し、ｐＨメータ（ＨＯＲＩＢＡ コンパクトｐＨメータ、堀場製作所製）を用いて測定した。
4. pH measurement The temperature of the sample was adjusted to 20 ° C., and measurement was performed using a pH meter (HORIBA compact pH meter, manufactured by HORIBA, Ltd.).
５．非重合体カテキン類の安定性評価
保存前（製造直後）の試料中の非重合体カテキン類の含有量、及び５５℃で７日間保存後の試料中の非重合体カテキン類の含有量から、下記式により非重合体カテキン類の残存率を求めた。
5. Evaluation of stability of non-polymer catechins Based on the content of non-polymer catechins in the sample before storage (immediately after production) and the content of non-polymer catechins in the sample after storage at 55 ° C. for 7 days. The residual ratio of non-polymer catechins was determined by the following formula.
非重合体カテキン類の残存率（％）＝Ｘ／Ｙ×１００
（Ｘは、保存後の試料中の非重合体カテキン類の含有量を示し、Ｙは、保存前の試料中の非重合体カテキン類の含有量を示す。）
Residual rate of non-polymer catechins (%) = X / Y × 100
(X indicates the content of non-polymer catechins in the sample after storage, and Y indicates the content of non-polymer catechins in the sample before storage.)
実施例１及び比較例１
表１に示す各成分を均一に混合し、各液体組成物を調製した。得られた液体組成物について分析及び非重合体カテキン類の安定性評価を行った。その結果を表１に併せて示す。
Example 1 and Comparative Example 1
Each component shown in Table 1 was uniformly mixed to prepare each liquid composition. The obtained liquid composition was analyzed and the stability of non-polymer catechins was evaluated. The results are also shown in Table 1.
表１から、非重合体カテキン類に対して特定のカチオン性物質を共存させることで、非重合体カテキン類の安定性を向上できることが分かる。 From Table 1, it can be seen that the stability of the non-polymer catechins can be improved by coexisting a specific cationic substance with the non-polymer catechins.
本発明の安定化剤を含有する製剤の調製例を下記に示す。 An example of preparation of the preparation containing the stabilizer of the present invention is shown below.
調製例１
（質量部）
粉末緑茶抽出物*3 ０．３８
プロタミン ０．０１
イオン交換水 ９９．６１
計 １００．００
*3：非重合体カテキン類３８質量％
Preparation Example 1
(Mass part)
Powdered green tea extract * 3 0.38
Protamine 0.01
Ion-exchanged water 99.61
100.00 in total
* 3: 38% by mass of non-polymer catechins
調製例２
（質量部）
非重合体カテキン類*1 ０．１０
ラクトフェリン*4 ０．０１
イオン交換水 ９９．８９
計 １００．００
*1：Teavigo（太陽化学株式会社）：非重合体カテキン類９４％
*4：Lactotransferrin, Sigma-Aldrich Co. LLC.
Preparation Example 2
(Mass part)
Non-polymer catechins * 1 0.10.
Lactoferrin * 4 0.01
Ion-exchanged water 99.89
100.00 in total
* 1: Teavigo (Taiyo Kagaku Co., Ltd.): Non-polymer catechins 94%
* 4: Lactotransferrin, Sigma-Aldrich Co. LLC.
調製例３
（質量部）
非重合体カテキン類*1 ０．１０
ＨＩＶ−ｔａｔ*5 ０．０１
イオン交換水 ９９．８９
計 １００．００
*1：Teavigo（太陽化学株式会社）：非重合体カテキン類９４％
*5：HIV-Tat(47-57), Jena Bioscience
Preparation Example 3
(Mass part)
Non-polymer catechins * 1 0.10.
HIV-tat * 5 0.01
Ion-exchanged water 99.89
100.00 in total
* 1: Teavigo (Taiyo Kagaku Co., Ltd.): Non-polymer catechins 94%
* 5: HIV-Tat (47-57), Jena Bioscience
調製例４
（質量部）
非重合体カテキン類*1 ０．１０
ｐＶＥＣ*6 ０．０１
イオン交換水 ９９．８９
計 １００．００
*1：Teavigo（太陽化学株式会社）：非重合体カテキン類９４％
*6：pVEC (Cadherin-5), c AnaSpec, Inc
Preparation Example 4
(Mass part)
Non-polymer catechins * 1 0.10.
pVEC * 6 0.01
Ion-exchanged water 99.89
100.00 in total
* 1: Teavigo (Taiyo Kagaku Co., Ltd.): Non-polymer catechins 94%
* 6: pVEC (Cadherin-5), c AnaSpec, Inc
調製例５
（質量部）
非重合体カテキン類*1 ０．１０
セチルトリメチルアンモニウムクロライド*7 ０．０１
イオン交換水 ９９．８９
計 １００．００
*1：Teavigo（太陽化学株式会社）：非重合体カテキン類９４％
*7：コータミン60W（花王（株））
Preparation Example 5
(Mass part)
Non-polymer catechins * 1 0.10.
Cetyltrimethylammonium chloride * 7 0.01
Ion-exchanged water 99.89
100.00 in total
* 1: Teavigo (Taiyo Kagaku Co., Ltd.): Non-polymer catechins 94%
* 7: Kotamin 60W (Kao Corporation)
調製例６
（質量部）
非重合体カテキン類*1 ０．１０
ポリジアリルジメチルアンモニウムクロライド*8 ０．０１
イオン交換水 ９９．８９
計 １００．００
*1：Teavigo（太陽化学株式会社）：非重合体カテキン類９４％
*8：マーコート100（花王（株））
Preparation Example 6
(Mass part)
Non-polymer catechins * 1 0.10.
Polydiallyl dimethylammonium chloride * 8 0.01
Ion-exchanged water 99.89
100.00 in total
* 1: Teavigo (Taiyo Kagaku Co., Ltd.): Non-polymer catechins 94%
* 8: Marcourt 100 (Kao Corporation)
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