JP7413005B2 - Method for stabilizing non-polymer catechins - Google Patents
Method for stabilizing non-polymer catechins Download PDFInfo
- Publication number
- JP7413005B2 JP7413005B2 JP2019232316A JP2019232316A JP7413005B2 JP 7413005 B2 JP7413005 B2 JP 7413005B2 JP 2019232316 A JP2019232316 A JP 2019232316A JP 2019232316 A JP2019232316 A JP 2019232316A JP 7413005 B2 JP7413005 B2 JP 7413005B2
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- JP
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- Prior art keywords
- polymer catechins
- cationic
- catechins
- tea
- polymer
- Prior art date
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- 235000005487 catechin Nutrition 0.000 title claims description 126
- 150000001765 catechin Chemical class 0.000 title claims description 123
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- 238000000034 method Methods 0.000 title claims description 33
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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-polymeric 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 have, for example, anticancer effect, anticancer metastasis effect, antitumor effect, antibacterial effect, antiviral effect, blood pressure regulation effect, blood cholesterol regulation effect, antiobesity effect, antioxidant effect, and deodorizing effect. It is known to have various chemical and physiological active effects, such as anti-aging effect, anti-dementia effect (prevention of amyloid β accumulation and production suppression), anti-influenza effect, and periodontal disease preventive effect (non- Patent Documents 1 to 34). However, since non-polymer catechins are antioxidants, they tend to deteriorate over time due to the effects of oxygen and the like. 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 there has been a demand for stabilization of non-polymer catechins.
The present invention provides a method for stabilizing non-polymer catechins, a stabilizer for non-polymer catechins, and a formulation 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 studies in view of the above-mentioned problems, the present inventors have found that the stability of non-polymer catechins can be improved by allowing the non-polymer catechins to coexist 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 provides 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 for the non-polymer catechins of 1.0×10 4 M -1 or more. It provides:
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-polymer catechins, which contains as an active ingredient a cationic substance having a binding constant for non-polymer catechins of 1.0×10 4 M -1 or more. .
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 for 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 provides an anticancer agent, an anticancer metastasis agent, an antitumor agent, an antibacterial agent, an antiviral agent, a blood pressure regulating agent, and a blood cholesterol regulating agent containing the above-mentioned stabilizer and non-polymer catechins. The present invention provides a formulation selected from a pharmaceutical agent, an anti-obesity agent, an antioxidant, a deodorant, an anti-aging agent, an agent for preventing dementia, an agent for preventing influenza, and an agent for preventing periodontal disease.
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 metastasis agents, antitumor agents, antibacterial agents, antiviral agents, blood pressure regulators, blood cholesterol regulators, antiobesity agents, antioxidants, deodorants, and anti-aging agents. The present invention provides the use of non-polymer catechins stabilized by the above method for producing a preparation selected from a preventive agent, a dementia preventive agent, an influenza preventive agent, and a periodontal disease preventive agent.
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 according to the present invention, it is possible to provide a preparation that can sufficiently exhibit the chemical and physiological activity 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 includes coexisting non-polymer catechins with a cationic substance having a binding constant for the non-polymer catechins of 1.0×10 4 M -1 or more. This is a characteristic 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, "stabilization of non-polymer catechins" refers to suppressing a decrease in the amount of non-polymer catechins. Examples of factors contributing to the decrease in the amount of non-polymer catechins include oxidative polymerization and oxidative decomposition of non-polymer catechins. For example, by calculating the residual rate (%) of non-polymer catechins before and after storage, it can be used as an index of stabilization of 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, "non-polymer catechins" refer to non-gallate forms such as catechin, gallocatechin, epicatechin and epigallocatechin, and gallate forms such as catechin gallate, gallocatechin gallate, epicatechin gallate and epigallocatechin gallate. It is a general term that includes the following. In the present invention, at least one of the eight non-polymer catechins mentioned above 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。
The non-polymeric catechins may be in the form of, for example, a commercially available reagent or a plant extract containing the non-polymeric catechins.
Plants are not particularly limited as long as they contain non-polymer catechins, but include, for example, Camellia, C. sinensis var.sinensis (including Yabukita species), C. sinensis var.assamica, and their like. Tea leaves (Camellia sinensis) are selected from hybrids. Tea leaves are classified into unfermented tea, semi-fermented tea, and fermented tea depending on the processing method, and one or more of these can be appropriately selected and used. Examples of unfermented tea leaves include green tea leaves such as sencha, bancha, tencha, kettle tea, stem tea, stick tea, and bud tea, which may also be pasteurized. In addition, examples of semi-fermented tea leaves include oolong tea leaves such as Tieguanyin, Irotane, Golden Gui, and Wuyiyan tea. Furthermore, examples of fermented tea leaves include black tea leaves from Darjeeling, Assam, Sri Lanka, and the like. One type or two or more types of tea leaves can be used. Among these, unfermented tea leaves are preferred, and green tea is more preferred, from the viewpoint of non-polymer catechin content and flavor. Note that the extraction method and extraction conditions are not particularly limited, and known methods 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 using plant extracts as non-polymer catechins, they may be used as they are, as a diluted solution diluted with an appropriate solvent, as a concentrated extract, as a dry powder, or as a paste. You can. Alternatively, it can be lyophilized and diluted with a solvent commonly 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 it comes into contact with water. Cationic substances usually have a cationic group in their molecules, and examples of such cationic groups include amino groups such as primary amino groups, secondary amino groups, and tertiary amino groups, and quaternary ammonium groups. , onium bases such as a phosphonium group, amino acid residues such as an arginyl group, lysyl group, histidyl group, and guanidyl group, and heterocyclic groups such as an imidazole group. In addition, when a cationic substance has both a cationic group and an anionic group, it is sufficient that the entire molecule is 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 reason why the present inventor focused on "cationic substances" from the viewpoint of stabilizing non-polymer catechins is as follows. That is, it is known that non-polymer catechins are oxidized starting from the B ring and change into multimers such as theaflavin. The present inventor focused on such an oxidation mechanism and considered that non-polymer catechins could be stabilized by lowering the electron density of the B ring of non-polymer catechins. And, for the purpose of lowering the electron density of the B ring of non-polymer catechins, it was considered that cationic substances having electron-withdrawing properties are particularly effective.
The present inventor also found that among such cationic substances, in order to achieve stabilization of non-polymer catechins, the binding constant for non-polymer catechins is 1.0×10 4 M -1 or more. It has been found that catechins easily interact intermolecularly with non-polymer catechins, making them particularly effective. In this specification, "binding constant" is an index expressing the binding affinity of a cationic substance 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 thermodynamic analysis of the interaction between non-polymer catechins and a cationic substance and by isothermal titration calorimetry (ITC). In isothermal titration calorimetry, titration is performed using non-polymer catechins and cationic substances under conditions of 25° C. and pH 6.0, and minute changes in calorific value that occur when molecules bond together are measured. Then, from the obtained titration curve, the binding ratio (n), binding constant (Ka), and change in enthalpy of binding (ΔH) between the non-polymer catechins and the cationic substance can be determined. 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 Examples below may be mentioned. In the isothermal titration calorimetry, 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 formula, R represents a gas constant, T represents an absolute temperature, and Ka represents a binding 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 of 1.0×10 4 M -1 or more for non-polymer catechins, but from the viewpoint of improving the stability of non-polymer catechins, the binding constant is 2.0×10 4 M -1 It is preferably at least 3.0×10 4 M −1 , more preferably at least 4.0×10 4 M −1 , and even more preferably at least 4.0×10 4 M −1 . The upper limit of the coupling constant is not particularly limited, but is preferably 1000×10 4 M −1 or less, 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 it has a binding constant of 1.0×10 4 M -1 or more, but examples include cationic proteins, cationic polymers, and cationic surfactants, and non-polymer catechins. A material having a binding constant of 1.0×10 4 M −1 or more may be appropriately selected. One or more types of cationic substances can be contained. Note that the origin of the cationic substance is not particularly limited, and for example, it may be 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 that is formed from two or more positively charged amino acids and has a net positive charge at a selected pH such as physiological pH, and includes peptides (oligomers), polypeptides, etc. It is a concept that also includes
The cationic protein may be a protein consisting of positively charged homologous amino acids, or a protein consisting of two or more positively charged heterologous amino acids. Furthermore, the cationic protein may contain both positively charged amino acids and negatively charged amino acids, but is required to have an isoelectric point of 8 or more. In addition, 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 protamine, lactoferrin, polylysine, polyarginine, polyornithine, nucleolin, spermine, histones, melittin, magainin II, defensin, protegrin, cecropin, polyethyleneimine, lysozyme, papain, and acid-treated gelatin. , HIV-Tat, pVEC, etc.
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 its main chain or side chain, and does not include "cationic protein."
Cationic polymers include cationic polymers that have only cationic groups and no anionic groups, as well as amphoteric polymers that have cationic groups and anionic groups and exhibit cationic properties as a whole. Note that 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。 Cationic polymers are not particularly limited as long as the entire molecule has a positive charge, but examples include polyallylamine hydrochloride, polyamine sulfone hydrochloride, polyvinylamine hydrochloride, chitosan acetate, cationized starch, cationized guar gum, and cationized polymers. Examples include tara gum, cationized locust bean gum, cationized polyvinyl alcohol, cationized cellulose, quaternized polyvinylpyrrolidone, polydiallyl quaternary ammonium salt (for example, diallyldimethylammonium chloride), and the like.
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" refers to a compound that has a lipophilic group and a hydrophilic group in its molecule, and when dissolved in water, the hydrophilic group dissociates into ions and becomes positively charged. means.
As cationic surfactants, from the viewpoint of improving the stability of non-polymer catechins, cationic surfactants having one or more unsaturated hydrocarbon groups in the molecule, and cationic surfactants having one or more long-chain saturated hydrocarbon groups in the molecule. Cationic surfactants having the above are preferred, and examples 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 each independently represent a saturated hydrocarbon group having 1 to 3 carbon atoms.
R 3 and R 4 each independently represent a saturated or unsaturated hydrocarbon group having 3 to 20 carbon atoms.
A - represents 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 groups for R 1 to R 4 include alkyl groups, which may be either linear or branched.
Examples of the unsaturated hydrocarbon group for R 4 include alkenyl groups, which may be in either a linear or branched form. The unsaturated bond of the unsaturated hydrocarbon group may be located at any position within the molecular chain or at the end of the molecular chain.
The anion related to A - is not particularly limited, but includes, for example, a halide ion, a boron anion, a phosphorus anion, a carboxylic acid anion, a sulfuric acid anion, and 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 cationic surfactants 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, dicetyldimethylammonium chloride, distearyldimethylammonium chloride, dicocoyldimethylammonium chloride, etc. I can do it.
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, still more preferably 300 Da or more, and 100,000 Da or less, from the viewpoint of improving the stability of non-polymer catechins and handling properties. It is preferably 95,000 Da or less, more preferably 90,000 Da or less. The molecular weight range is preferably 100 to 100,000, more preferably 200 to 950,000, and still more preferably 300 to 90,000. Note that the molecular weight of the cationic substance is 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 these, the cationic substance is preferably one or more selected from cationic proteins, cationic polymers, and cationic surfactants, from the viewpoint of improving the stability of non-polymer catechins; One or more active agents are more preferred, cationic proteins are even more preferred, and one or more selected from protamine and lactoferrin is 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 making the non-polymer catechins and the cationic substance coexist, the non-polymer catechins and the cationic substance may be mixed, and a solvent may be used. The solvent can be appropriately selected and used as long as it can disperse or dissolve the non-polymer catechins and the cationic substance and does not react with these components. Examples include water, physiological saline, buffers, organic solvents, and organic solvent aqueous solutions, and can be appropriately selected depending on the application. Examples of water include ion exchange water, distilled water, and natural water. Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, glycine buffer, glycylglycine buffer, Tris buffer, aspartic acid, and aspartate. , epsilon-aminocaproic acid. As the organic solvent, in addition to alcohols such as ethanol, hydrocarbons, ethers, etc. can be used. Note that the organic solvent concentration in the organic solvent aqueous solution can be selected as appropriate.
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。 Note that the coexistence of non-polymer catechins and cationic substances only needs to be such that both ultimately exist in the same system, and the timing and mixing order of coexistence of non-polymer catechins and cationic substances may be affected. is not particularly limited. Further, the temperature at which they are allowed to coexist is usually room temperature (20° C.±15° C.), but they 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。 From the viewpoint of improving the stability of non-polymer catechins, the amount of cationic substance used is determined as the mass ratio [(B)/(A)] of (B) cationic substance to (A) non-polymer catechins. It is preferably 0.0008 or more, more preferably 0.001 or more, even more preferably 0.099 or more, and preferably 10 or less, more preferably 0.6 or less, and even more preferably 0.5 or less. The range of the mass ratio [(B)/(A)] is preferably 0.0008 to 10, more preferably 0.001 to 0.6, and even more preferably 0.099 to 0.5. It 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 as an active ingredient a cationic substance having a binding constant for non-polymer catechins of 1.0×10 4 M −1 or more. Note that the specific embodiments of the non-polymer catechins and the cationic substance and the amount of the cationic substance used are as explained 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。
〔formulation〕
Non-polymer catechins have, for example, anticancer effect, anticancer metastasis effect, antitumor effect, antibacterial effect, antiviral effect, blood pressure regulation effect, blood cholesterol regulation effect, antiobesity effect, antioxidant effect, and deodorizing effect. It has been reported that it has various chemical and physiological active effects, such as anti-aging effects, anti-dementia effects (prevention of amyloid β accumulation and production suppression), anti-influenza effects, and anti-periodontal disease effects. 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）
Anticancer 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）
Anticancer metastasis effect (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 effects (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 action (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 effect (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) Mikio Nakayama et al., Effects of tea catechins and specific antibodies on influenza viruses. Journal of Infectious Diseases. 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 regulating 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) Yukihiko Hara et al., Regarding the ability of tea components to inhibit angiotensin I-converting enzyme. Nohka Journal. 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 effect (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., Blood cholesterol-lowering effect of (-)epigallocatechin gallate, a component of tea leaf catechin. Eishoku Journal. 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 Chemical. 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）
Deodorizing 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 effect (amyloid β accumulation prevention/production suppression)
(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 attenuates the neuronal NADPH-d/nNOS expression in the nodose ganglion of acute hypoxic rats. Brain Res. 2004, 999: 73-80 (non-patent literature 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 preventive effect (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）
Preventive effects of periodontal disease (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 fully express such chemical and physiologically active effects of the non-polymer catechins themselves, it is necessary that an effective amount of the non-polymer catechins be contained in the formulation. In the present invention, the stability of non-polymer catechins is improved by applying the stabilization method of the present invention to non-polymer catechins or adding the stabilizer of the present invention to non-polymer catechins. The various chemical and physiological active effects of catechins themselves can be fully expressed. For example, non-polymer catechins to which the stabilization method of the present invention is applied or non-polymer catechins containing the stabilizer of the present invention can be used as a formulation 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]
Anticancer agents, anticancer metastasis agents, antitumor agents, antibacterial agents, antiviral agents, blood pressure regulators, blood cholesterol regulators, antiobesity agents, antioxidants, deodorants, anti-aging agents, dementia prevention agents. agent, influenza preventive agent, periodontal disease preventive agent
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, "prevention" refers to 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. In addition, when used as a pharmacological preparation such as an anticancer drug, the use may be in humans or non-human animals, or in specimens derived therefrom, and may be therapeutic or non-therapeutic. may be used. Note that "non-therapeutic" is a concept that does not include medical treatment, that is, a method that does not involve surgery, treatment, or diagnosis of humans; This concept does not include methods 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 non-polymer catechins in the formulation can be appropriately selected depending on the type of formulation so that an effective amount is included. Note that the content of non-polymer catechins can be measured by an analytical method that is suitable for the situation of the measurement sample among the commonly known measurement methods; for example, it can be analyzed by liquid chromatography. be. Specifically, the method described in Examples below may be mentioned. In addition, during measurement, appropriate processing is performed as necessary, such as freeze-drying the sample to match the detection range of the device, or removing impurities from the sample to match the separation capability of the device. It may be applied.
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 formulation of the present invention may contain various additives used in the manufacture of common formulations. Additives can be selected as appropriate depending on the type of formulation, but examples include excipients, lubricants, disintegrants, binders, colorants, sweeteners, corrigents, adsorbents, preservatives, stabilizers, and humectants. agent, antistatic agent, pH adjuster, surfactant, starch, solvent, suspending agent.
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 preparation of the present invention can be appropriately selected depending on its type, and examples include liquid, jelly, gummy, syrup, dry syrup, tablet, powder, pill, troche, granule, and fine granule. , chewable formulations, orally disintegrating agents, and 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 formulation of the present invention is not particularly limited, and any appropriate method may be adopted depending on the type of formulation. For example, it can be produced by mixing non-polymer catechins, a cationic substance, and other components if necessary. As a mixing method, it is possible to employ an appropriate method such as stirring or shaking, and a mixing device may also be used. The mixing method of the mixing device may be a container rotating type or a container fixed type. As the container rotation type, for example, a horizontal cylindrical type, a V type, a double cone type, a cubic type, etc. can be adopted. Further, as the container fixed type, for example, a ribbon type, screw type, conical screw type, paddle type, fluidized bed type, Phillips blender, etc. can be adopted. When producing granules, it is possible to employ, for example, spray granulation, fluidized bed granulation, compression granulation, rolling granulation, stirring granulation, extrusion granulation, powder coating granulation, When tabletting, either wet tableting or dry tableting may be used. In order to obtain a concentrated liquid, known methods such as the normal pressure concentration method, in which the solvent is evaporated at normal pressure, the vacuum concentration method, in which the solvent is evaporated under reduced pressure, and the membrane concentration method, in which the solvent is removed by membrane separation, can be used. 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. Analysis of non-polymer catechins The sample solution was filtered with a filter (0.45 μm), and using a high performance liquid chromatograph (model SCL-10AVP, manufactured by Shimadzu Corporation), an octadecyl group-introduced packed column for liquid chromatography (L-column) was used. TM ODS 4.6 mmφ x 250 mm, 5 μm (manufactured by the Japan Chemical Evaluation and Research Institute) was installed, and 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 Kogyo was used and quantified using a calibration curve method. The mobile phase A solution was a distilled aqueous solution containing 0.1 mol/L acetic acid, and the B solution was an acetonitrile solution containing 0.1 mol/L acetic acid, the sample injection volume was 10 μL, and the UV detector wavelength was 280 nm. . Note that the gradient conditions 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 conditions Time (minutes) Concentration of liquid A (% by volume) Concentration of liquid B (% by volume)
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%
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) Protamine Weigh approximately 0.1 to 0.15 g of a sample and quantify it by the Kjeldahl method, which is a nitrogen quantitative method. Then, the content is determined using the following formula. In addition, for the determination by the Kjeldahl method, reference can be made to the 8th edition of the Official Japanese Standards for Food Additives. Further, 1 ml of 0.05 mo/L sulfuric acid = 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] / [Amount of sample collected (g) x 1000 in terms of dry matter] 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 Lactoferrin content can be measured by a latex agglutination method. The latex agglutination method is a latex agglutination nephelometric method using anti-lactoferrin antibody-sensitized latex, and is a method for quantifying lactoferrin having antigen-antibody reaction activity. Lactoferrin in the sample exhibits an antigen-antibody reaction with anti-lactoferrin antibodies bound to latex particles, resulting in agglutination. The change in absorbance of this aggregation is measured at a constant wavelength, and this is converted to calculate the lactoferrin content using a commercially available kit and optical analyzer. As a commercially available kit, for example, lactoferrin measurement reagent (for humans and cattle) (manufactured by Infinita Co., Ltd.) can be used. As an optical analyzer, an automatic biochemical analyzer BIOLIS24i (Tokyo Boeki Medisys 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 exhibits an antigen-antibody reaction with anti-HIV-Tat antibodies, and the content of HIV-Tat is measured by ELISA using a commercially available kit. As a commercially available kit, an anti-TAT immunoglobulin measurement ELISA kit (manufactured by Cosmo Bio Inc.) 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
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 Cetyltrimethylammonium chloride in a 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: Shim pack FC ODS (75mm x 2.0mm id, particle size 3μm) (Shimadzu Corporation)
・Mobile phase: 5mM ammonium acetate aqueous solution, 5mM 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) Polydiallyldimethylammonium chloride Polydiallyldimethylammonium 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. Analysis of the binding constant of a cationic substance Using 10mM phosphate buffer (pH 6.0) as a solvent, a cationic substance aqueous solution or a dextrin (β-cyclodextrin, γ-cyclodextrin) aqueous solution was measured using an isothermal titration calorimeter (ITC). Epigallocatechin gallate (EGCg) was filled into a sample cell (capacity 1.4 mL) manufactured by MicroCal (model name: VP-ITC) at regular intervals from a syringe rotating at 310 rpm at 25°C. It was added dropwise and the resulting change in heat amount was repeatedly measured. The change in heat value when the EGCg aqueous solution was dropped into a 10 mM phosphoric acid buffer containing no cationic substance or dextrin aqueous solution was also measured in the same manner, and was used as data on the heat of dilution. After subtracting the heat of dilution data from the thermal titration data of the EGCg aqueous solution to the cationic polymer aqueous solution or dextrin aqueous solution, analysis was performed using an analysis software (Origin 7) using a one-site binding model.
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. Measurement of pH The temperature of the sample was adjusted to 20° C., and the pH was measured 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. Stability evaluation 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 rate of non-polymer catechins was determined using 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 x 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 mixed uniformly 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。 Table 1 shows that the stability of non-polymer catechins can be improved by allowing a specific cationic substance to coexist 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 preparing a formulation 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
(parts by mass)
Powdered green tea extract *3 0.38
Protamine 0.01
Ion exchange water 99.61
Total 100.00
*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
(parts by mass)
Non-polymer catechins *1 0.10
Lactoferrin *4 0.01
Ion exchange water 99.89
Total 100.00
*1:Teavigo (Taiyo Kagaku Co., Ltd.): 94% non-polymer catechins
*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
(parts by mass)
Non-polymer catechins *1 0.10
HIV-tat *5 0.01
Ion exchange water 99.89
Total 100.00
*1:Teavigo (Taiyo Kagaku Co., Ltd.): 94% non-polymer catechins
*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
(parts by mass)
Non-polymer catechins *1 0.10
pVEC *6 0.01
Ion exchange water 99.89
Total 100.00
*1:Teavigo (Taiyo Kagaku Co., Ltd.): 94% non-polymer catechins
*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
(parts by mass)
Non-polymer catechins *1 0.10
Cetyltrimethylammonium chloride *7 0.01
Ion exchange water 99.89
Total 100.00
*1:Teavigo (Taiyo Kagaku Co., Ltd.): 94% non-polymer catechins
*7: Cortamine 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
(parts by mass)
Non-polymer catechins *1 0.10
Polydiallyldimethylammonium chloride *8 0.01
Ion exchange water 99.89
Total 100.00
*1:Teavigo (Taiyo Kagaku Co., Ltd.): 94% non-polymer catechins
*8: Marquardt 100 (Kao Corporation)
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005533864A (en) | 2002-07-26 | 2005-11-10 | ディーエスエム アイピー アセッツ ビー．ブイ． | Composition comprising lactoferrin |
| JP2009509960A (en) | 2005-09-22 | 2009-03-12 | 三井農林株式会社 | Black tea polyphenol and its use |
| JP2009091322A (en) | 2007-10-11 | 2009-04-30 | Kao Corp | Antimicrobial agent composition |
| JP2015174842A (en) | 2014-03-14 | 2015-10-05 | ライオン株式会社 | body fat reducing agent |
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2019
- 2019-12-24 JP JP2019232316A patent/JP7413005B2/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005533864A (en) | 2002-07-26 | 2005-11-10 | ディーエスエム アイピー アセッツ ビー．ブイ． | Composition comprising lactoferrin |
| JP2009509960A (en) | 2005-09-22 | 2009-03-12 | 三井農林株式会社 | Black tea polyphenol and its use |
| JP2009091322A (en) | 2007-10-11 | 2009-04-30 | Kao Corp | Antimicrobial agent composition |
| JP2015174842A (en) | 2014-03-14 | 2015-10-05 | ライオン株式会社 | body fat reducing agent |
Non-Patent Citations (1)
| Title |
|---|
| Wei YANG et al.，"Native and Thermally Modified Protein-Polyphenol Coassemblies: Lactoferrin-Based Nanoparticles and Submicrometer Particles as Protective Vehicles for (-)-Epigallocatechin-3-gallate"，Journal of Agricultural and Food Chemistry，2014年，Vol.62，p.10816-10827 |
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