JP7776161B2 - Intestinal regulator, anti-allergic agent, immune enhancer, agent for improving the intestinal adhesion of lactic acid bacteria - Google Patents
Intestinal regulator, anti-allergic agent, immune enhancer, agent for improving the intestinal adhesion of lactic acid bacteriaInfo
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Description
本発明は、整腸剤、抗アレルギー剤、免疫増強剤及び乳酸菌の腸管接着性向上剤に関する。 The present invention relates to an intestinal regulator, an antiallergic agent, an immune enhancer, and an agent for improving the intestinal adhesion of lactic acid bacteria.
動物の腸管において乳酸菌の増殖を促進すると、病原菌の侵入や有害菌の増殖を抑制できること、このような整腸作用は、下痢や便秘の改善や予防につながることはよく知られている。乳酸菌が腸管へ定着して増殖する為には、腸管における乳酸菌の付着（接着）が非常に重要であると考えられている。 It is well known that promoting the growth of lactic acid bacteria in the intestinal tract of animals can suppress the invasion of pathogenic bacteria and the growth of harmful bacteria, and that this intestinal regulating effect can lead to the improvement and prevention of diarrhea and constipation. It is thought that the adhesion (adhesion) of lactic acid bacteria in the intestinal tract is extremely important for them to colonize and grow in the intestinal tract.
更に近年、乳酸菌は抗アレルギー作用とも関係することが報告されてきている。
人の免疫システムは複数種のＴ細胞が司令塔の役割を果たしている。Ｔ細胞としては、主としてＩｇＡ抗体産生を促し細胞性免疫を活性化させるＴｈ１細胞と、Ｉ型アレルギーを引き起こすＩｇＥ抗体産生を促進させて液性免疫を活性化させるＴｈ２細胞とが知られている。このＴｈ１細胞とＴｈ２細胞とはお互いに抑制しあい、Ｔｈ１細胞よりＴｈ２細胞が優位に働くとアレルギー症状がおこりやすい。
腸管には体内の免疫細胞の７割が集中して存在しているとされ、体の免疫システムの主要な役割を果たしている。この腸管免疫に乳酸菌が重要な働きをすることが解明されてきている。例えば乳酸菌の菌体成分は、腸管においてマクロファージや樹状細胞のサイトカイン分泌を促進し、これによりＴｈ１細胞の働きを活発化することや、ＩｇＡ抗体産生を促すことが知られている。これによりＴｈ２細胞の働きが抑制されてＩｇＥ抗体産生が抑制され、アレルギーが改善されると考えられている。乳酸菌（及びその菌体成分）の腸管への接着は、このような腸管免疫刺激作用やそれに伴う抗アレルギー作用を高めるためにも非常に重要と考えられている。
Furthermore, in recent years, it has been reported that lactic acid bacteria are also associated with anti-allergic effects.
The human immune system is dominated by several types of T cells. Two types of T cells are known: Th1 cells, which primarily stimulate IgA antibody production and activate cellular immunity, and Th2 cells, which stimulate IgE antibody production, which causes type I allergies, and activate humoral immunity. These Th1 and Th2 cells suppress each other, and when Th2 cells dominate over Th1 cells, allergic symptoms are more likely to occur.
It is said that 70% of the body's immune cells are concentrated in the intestinal tract, where they play a key role in the body's immune system. It has been elucidated that lactic acid bacteria play an important role in this intestinal immunity. For example, it is known that the bacterial components of lactic acid bacteria promote cytokine secretion from macrophages and dendritic cells in the intestinal tract, thereby activating Th1 cell activity and promoting IgA antibody production. This is thought to suppress Th2 cell activity and IgE antibody production, thereby improving allergies. The adhesion of lactic acid bacteria (and their bacterial components) to the intestinal tract is thought to be extremely important for enhancing this intestinal immune stimulating effect and the associated anti-allergic effect.
従って、乳酸菌の腸管接着性を向上させる経口剤を用い、乳酸菌の腸管接着を促すことができれば整腸並びに抗アレルギーの予防及び改善が期待できる。そのような経口剤には安全性が高いことや安価に入手できることが求められるが、その開発は進んでおらず、患者・消費者の多様なニーズに十分に答えられていない。 Therefore, if oral agents that improve the intestinal adhesiveness of lactic acid bacteria can be used to promote intestinal adhesion, it is expected that intestinal regulation and the prevention and improvement of allergies will be achieved. Such oral agents must be highly safe and inexpensive to obtain, but development has not progressed well, and the diverse needs of patients and consumers have not been adequately met.
一方、花の抽出物は、健康食品等に利用され、これまで種々の作用が検討されているが（例えば特許文献１）、新たな用途が求められている。 On the other hand, flower extracts are used in health foods and other products, and various effects have been investigated (e.g., Patent Document 1), but new uses are desired.
従って、本発明の課題は、新たな乳酸菌の腸管接着性向上剤、整腸剤、抗アレルギー剤及び免疫増強剤を提供することにある。 Therefore, the object of the present invention is to provide a new agent for improving the intestinal adhesion of lactic acid bacteria, an intestinal regulator, an antiallergic agent, and an immune enhancer.
本発明者らは、乳酸菌の腸管接着性を高めることができる物質について鋭意検討した。その結果、安価且つ安全に入手可能な素材として、特定の花の抽出物を用いることで乳酸菌の腸管接着性を高めることができることを見出した。 The inventors conducted extensive research into substances that can increase the intestinal adhesiveness of lactic acid bacteria. As a result, they discovered that the intestinal adhesiveness of lactic acid bacteria can be increased by using extracts from specific flowers, which are inexpensive and safe to obtain.
本発明は前記知見に基づくものであり、ミソハギ科（Lythraceae）、キク科（Asteraceae）、マメ科（Fabaceae）、バラ科（Rosaceae）又はアヤメ科（Iridaceae）の花の抽出物を含有する整腸剤を提供するものである。 The present invention is based on the above findings and provides an intestinal regulator containing an extract of flowers from the Lythraceae, Asteraceae, Fabaceae, Rosaceae, or Iridaceae families.
また本発明は、ミソハギ科（Lythraceae）、キク科（Asteraceae）、マメ科（Fabaceae）、バラ科（Rosaceae）又はアヤメ科（Iridaceae）の花の抽出物を含有する抗アレルギー剤、免疫増強剤及び乳酸菌の腸管接着性向上剤を提供するものである。 The present invention also provides an anti-allergic agent, an immune enhancer, and an agent for improving the intestinal adhesion of lactic acid bacteria, which contain an extract of flowers from the Lythraceae, Asteraceae, Fabaceae, Rosaceae, or Iridaceae families.
本発明によれば、安全に摂取でき、安価に入手でき、且つ乳酸菌の腸管接着性向上作用に優れた整腸剤、抗アレルギー剤、免疫増強剤及び乳酸菌の腸管接着性向上剤が提供される。 The present invention provides an intestinal regulator, antiallergic agent, immune enhancer, and agent for improving the intestinal adhesion of lactic acid bacteria that can be safely ingested and obtained at low cost, and that has excellent effects of improving the intestinal adhesion of lactic acid bacteria.
また、本発明によれば、特定の花エキスは乳酸菌の腸管接着性が高いことから、これを経口摂取することにより腸管における乳酸菌の作用を高めることができ、ダイエット、美容、健康増進に優れた効果が期待できる。 Furthermore, according to the present invention, specific flower extracts have a high intestinal adhesive property for lactic acid bacteria, so that oral intake of this extract can enhance the activity of lactic acid bacteria in the intestinal tract, and is expected to have excellent effects on dieting, beauty, and health promotion.
以下、本発明をその好ましい実施形態に基づき説明する。本発明の剤は、ミソハギ科（Lythraceae）、キク科（Asteraceae）、マメ科（Fabaceae）、バラ科（Rosaceae）又はアヤメ科（Iridaceae）の花（以下、特定の花ともいう）の抽出物を含有するものである。
以下の説明は特に断らない限り、本発明の整腸剤、抗アレルギー剤、免疫増強剤及び乳酸菌の腸管接着性向上剤のいずれにも当てはまる。
The present invention will be described below based on preferred embodiments thereof. The agent of the present invention contains an extract of a flower of the family Lythraceae, Asteraceae, Fabaceae, Rosaceae, or Iridaceae (hereinafter also referred to as a specific flower).
Unless otherwise specified, the following explanation applies to any of the intestinal regulator, antiallergic agent, immunopotentiator and agent for improving the intestinal adhesion of lactic acid bacteria of the present invention.
（花の抽出物）
本発明は、ミソハギ科（Lythraceae）、キク科（Asteraceae）、マメ科（Fabaceae）、バラ科（Rosaceae）又はアヤメ科（Iridaceae）の花を用いることにより乳酸菌の腸管接着性を効果的に高めることができる。
(flower extract)
The present invention can effectively increase the intestinal adhesiveness of lactic acid bacteria by using flowers from the Lythraceae, Asteraceae, Fabaceae, Rosaceae, or Iridaceae families.
ミソハギ科としては、ザクロ（柘榴、石榴）が好ましく挙げられる。ザクロは、ミソハギ科ザクロ属に属する落葉高木であり、学名をPunica granatumという。 A preferred example of the Lythraceae family is the pomegranate. Pomegranate is a deciduous tree belonging to the genus Punica in the Lythraceae family, and its scientific name is Punica granatum.
キク科としては、ベニバナ（紅花）及びキク（菊）が好ましく挙げられる。ベニバナは、キク科ベニバナ属の一年草又は越年草をいう。学名をCarthamus tinctorius という。
またキクは、キク科キク属（Chrysanthemum）の植物である。キクとしては、キク科キク属のキク（学名：Chrysanthemum morifolium Ramatulle）又はシマカンギク（学名：Chrysanthemum indicum Linne）が好ましく挙げられる。
Preferred examples of the Asteraceae family include safflower and chrysanthemum. Safflower is an annual or biennial plant of the genus Carthamus in the Asteraceae family. Its scientific name is Carthamus tinctorius.
Chrysanthemum is a plant of the genus Chrysanthemum in the family Asteraceae. Preferred examples of chrysanthemum include Chrysanthemum morifolium Ramatulle and Chrysanthemum indicum Linne.
マメ科としては、クズ（葛）が好ましく挙げられる。クズは、マメ科クズ属（Pueraria）の植物である。クズとしては、プエラリア・トムソニイ（学名：Pueraria thomsonii ）、プエラリア・ロバータ（学名：Pueraria lobata）、プエラリア・スンバーギアナ（学名：Pueraria thunbergiana）等を例示できる。 As a member of the Fabaceae family, kudzu (kudzu) is a preferred example. Kudzu is a plant of the genus Pueraria in the Fabaceae family. Examples of kudzu include Pueraria thomsonii (scientific name: Pueraria lobata), and Pueraria thunbergiana (scientific name: Pueraria thunbergiana).
バラ科としては、サクラ（桜、櫻）、モモ（桃）、バラ（薔薇）が好ましく挙げられる。
サクラは、バラ科サクラ属の植物のうち、ウメ、モモ、アンズなどを除いた総称であり、一般にはサクラ亜属 (Subgen. Cerasus) に属する植物を言う。
モモはバラ科モモ属に属し、学名はPrunus persica BatschまたはPrunus persica Batsch var. davidiana Maximowiczという。モモの品種としては、例えば、ハクトウ（白桃）、オウトウ（黄桃）、ネクタリンなどが挙げられる。
バラは、バラ科バラ属（Rosa）の植物を言う。
Preferred examples of the Rosaceae family include cherry blossoms, peach trees, and roses.
Sakura is a general term for plants in the genus Prunus of the Rosaceae family, excluding plums, peaches, apricots, etc., and generally refers to plants belonging to the subgenus Cerasus.
Peaches belong to the genus Prunus in the family Rosaceae, and their scientific name is Prunus persica Batsch or Prunus persica Batsch var. davidiana Maximowicz. Examples of peach varieties include white peaches, yellow peaches, and nectarines.
Roses are plants of the genus Rosa in the family Rosaceae.
アヤメ科としては、サフラン（学名：Crocus sativus）が好ましく挙げられる。サフランは、地中海沿岸を原産とするアヤメ科の多年草である。 A preferred example of the Iridaceae family is saffron (scientific name: Crocus sativus). Saffron is a perennial plant of the Iridaceae family native to the Mediterranean coast.
花は、蕾から全開した花までのいずれの段階で採集した花であってもよい。また、開花後の花は、花の全体であってもよく、花弁、萼、雄しべ、雌しべ、柱頭、花床（未成熟期のもの）のいずれか１以上であってもよい。例えばサフランとしてはめしべを用いることが好ましく、クズは蕾を用いることが好ましい。 Flowers may be collected at any stage, from buds to fully opened flowers. Furthermore, flowers after opening may be the entire flower, or one or more of the petals, calyx, stamens, pistil, stigma, and receptacle (at the immature stage). For example, it is preferable to use the pistil for saffron, and it is preferable to use the bud for kudzu.
これらの花の抽出物を得るための抽出処理としては、水や有機溶媒等の抽出溶媒を用いた処理が挙げられる。抽出溶媒としては極性溶媒が挙げられる。極性溶媒としては、例えば、水、メタノール、エタノール、イソプロパノール、アセトン、１，３－ブチレングリコール、エチレングリコール、プロピレングリコール、グリセリン、酢酸、酢酸エチル、エーテル、ヘキサン等が挙げられる。これらのうち、水、メタノール、エタノール、含水エタノールが好ましい。尚、これらは１種のみ用いても良いし、２種以上併用しても良い。また抽出溶媒を用いずに生の花を搾汁することも抽出処理に含まれる。 Extraction processes for obtaining these flower extracts include processes using extraction solvents such as water and organic solvents. Examples of extraction solvents include polar solvents. Examples of polar solvents include water, methanol, ethanol, isopropanol, acetone, 1,3-butylene glycol, ethylene glycol, propylene glycol, glycerin, acetic acid, ethyl acetate, ether, and hexane. Of these, water, methanol, ethanol, and aqueous ethanol are preferred. These may be used alone or in combination. Extraction processes also include squeezing fresh flowers without using an extraction solvent.
抽出は生の花に対して行っても良いし、乾燥、加熱、切断や粉砕等を施した花に行っても良い。また抽出時に抽出溶媒は加温してもしなくてもよいが、加温する場合の溶媒温度は特に限定されるものではなく、花の抽出物を得るために一般に用いられる温度、例えば４０℃以上沸点以下が挙げられる。例えば、水であれば熱水であってもなくてもよい。熱水とは温度が７０℃以上の水のことを指す。 Extraction may be performed on fresh flowers, or on flowers that have been dried, heated, cut, or crushed. The extraction solvent may or may not be heated during extraction, but if heated, the solvent temperature is not particularly limited and may be any temperature commonly used to obtain flower extracts, such as 40°C or higher and up to the boiling point. For example, water may or may not be hot. Hot water refers to water with a temperature of 70°C or higher.
得られた抽出液に希釈、濃縮、乾燥、精製等の処理を施し、最終加工品である抽出物を得る。精製方法としては、例えば、活性炭処理、樹脂吸着処理、シリカゲル処理、イオン交換樹脂、液－液向流分配、膜分離等の方法が挙げられる。本発明の花の抽出物は、発酵過程（例えば抽出前原料の発酵過程又は抽出液の発酵過程）を経て得られたものであってもよく、これらの発酵過程を経ずに得られたものであってもよい。 The resulting extract is then subjected to dilution, concentration, drying, purification, and other processes to obtain the final processed product, the extract. Purification methods include, for example, activated carbon treatment, resin adsorption treatment, silica gel treatment, ion exchange resin, liquid-liquid countercurrent distribution, and membrane separation. The flower extract of the present invention may be obtained through a fermentation process (for example, a fermentation process of raw materials before extraction or a fermentation process of an extract), or it may be obtained without undergoing these fermentation processes.
本発明の剤において、特定の花の抽出物は液状、ペースト状、ジェル状、固体状のいずれであってもよく、固体状であることが品質の安定性等の点から好ましい。固体状としては、粉末状、粒状、顆粒状、細粒状、錠状、棒状、板状、ブロック状、固形状等が挙げられる。 In the agent of the present invention, the extract of the specific flower may be in any form, such as liquid, paste, gel, or solid, with solid form being preferred from the standpoint of quality stability, etc. Examples of solid forms include powder, granules, granules, fine granules, tablets, rods, plates, blocks, and solid forms.
本発明の剤は、乳酸菌の腸管接着作用が特に高い点から、特定の花の抽出物としてザクロ、ベニバナ、クズ、サクラ、サフラン、モモ及びバラから選ばれる少なくとも１種を含むことがとりわけ好ましい。 It is particularly preferable that the agent of the present invention contains at least one specific flower extract selected from pomegranate, safflower, kudzu, cherry blossom, saffron, peach, and rose, as this has a particularly high intestinal adhesion activity of lactic acid bacteria.
本発明の剤における特定の花の抽出物は、本発明の剤中、乾燥質量で０．０００１質量％以上であることが好ましく、０．０００５質量％以上５０質量％以下であることがより好ましく、０．００１質量％以上３０質量％以下であることが特に好ましい。 The extract of the specific flower in the agent of the present invention preferably accounts for 0.0001% by mass or more, more preferably 0.0005% by mass or more and 50% by mass or less, and particularly preferably 0.001% by mass or more and 30% by mass or less, on a dry mass basis.
本発明の剤は、植物由来成分として、実質的に特定の花の抽出物のみからなるものであってもよく、その他の植物由来成分を有していてもよい。例えば、本発明の剤における特定の花の抽出物以外の植物由来成分は、例えば本発明の剤中、８０質量％以下であることが好ましく、５０質量％以下であることがより好ましい。 The agent of the present invention may consist essentially of only the extract of a specific flower as a plant-derived component, or may contain other plant-derived components. For example, the plant-derived components other than the extract of a specific flower in the agent of the present invention preferably account for 80% by mass or less, and more preferably 50% by mass or less, of the agent of the present invention.
本発明の剤は、乳酸菌を非含有であってもよいが、乳酸菌を含有していることが、乳酸菌の腸管接着効果をより高める点から好ましい。乳酸菌は生菌である場合は腸内環境改善の点から好ましいが、死菌であってもよい。これは生菌のみならず死菌の菌体成分も腸管免疫を刺激するものとされていることや、死菌の菌体成分が生菌乳酸菌と餌となることなどに基づく。なお死菌である乳酸菌は腸管において有害物質を吸着することも知られている。本発明で使用される乳酸菌としては、代謝産物として乳酸を産生するものであれば特に限定されず、ヒトなどの動物において従来経口摂取されているものが挙げられ、例えば、Bifidobacterium属、Lactbacillus属、Enterococcus属、Leuconostoc属、Pediococcus属、Staphylococcus属、Tetragenococcus属、Bacillus属のものが挙げられる。
Bifidobacterium属としては、Bifidobacterium bifidum、Bifidobacterium breve、Bifidobacterium infantis、Bifidobacterium lactis、Bifidobacterium longum、Bifidobacterium adolescentis、Bifidobacterium mongolienseが挙げられる。
Lactbacillus属としては、Lactbacillus brevis、Lactbacillus gasseri、Lactobacillus acidophilus、Lactobacillus buchneri、Lactobacillus bulgaricus、Lactobacillus delburvecki、Lactobacillus casei、Lactobacillus crispatus、Lactobacillus curvatus、Lactobacillus halivaticus、Lactobacillus pentosus、Lactobacillus plantarum、Lactobacilus paracasei、Lactobacillus rhamnosus、Lactobacillus salivarius、Lactobacillus sporogenes、Lactobacillus sakei、Lactobacillus fructivorans、Lactobacillus hilgardii、Lactobacillus reuteri、Lactobacillus fermentumが挙げられる。
Enterococcusとしては、Enterococcus faecalis(Streptococcus faecalis と称されることもある)、Enterococcus faesium（Streptococcus faesiumと称されることもある)、Streptococcus thermophilus、Lactococcus lactis(Streptococcus lactisと称されることもある) が挙げられる。
Leuconostoc属としては、Leuconostoc mesenteroides、Leuconostoc oenos が挙げられる。
Pediococcus属としては、Pediococcus acidilactici、Pediococcus pentosaceusが挙げられる。
Staphylococcus属としては、Staphylococcus carnosus、Staphylococcus xylosusが挙げられる。
Tetragenococcus属としては、Tetragenococcus halophilusが挙げられる。Bacillus属としては、Bacillus coagulans、及びBacillus mesentericusなどが挙げられる。
とりわけ、Bacillus coagulans、Enterococcus faecalis、Bifidobacterium bifidum、Enterococcus faesium、Lactobacillus acidophilusが好ましい。これらは、１種を単独で使用してもよいし、２種以上を併用してもよい。
The agent of the present invention may not contain lactic acid bacteria, but it is preferable that it contains lactic acid bacteria in order to further enhance the intestinal adhesion effect of lactic acid bacteria. Live lactic acid bacteria are preferable in terms of improving the intestinal environment, but killed lactic acid bacteria may also be used. This is based on the fact that not only live bacteria but also the bacterial components of killed bacteria are thought to stimulate intestinal immunity, and that the bacterial components of killed bacteria serve as food for live lactic acid bacteria. Killed lactic acid bacteria are also known to adsorb harmful substances in the intestinal tract. The lactic acid bacteria used in the present invention are not particularly limited as long as they produce lactic acid as a metabolic product, and include those that have traditionally been orally ingested by animals such as humans, such as those belonging to the genera Bifidobacterium, Lactobacillus, Enterococcus, Leuconostoc, Pediococcus, Staphylococcus, Tetragenococcus, and Bacillus.
Examples of the genus Bifidobacterium include Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium adolescentis, and Bifidobacterium mongoliense.
Lactobacillus genus includes Lactobacillus brevis, Lactobacillus gasseri, Lactobacillus acidophilus, Lactobacillus buchneri, Lactobacillus bulgaricus, Lactobacillus delburvecki, Lactobacillus casei, Lactobacillus crispatus, Lactobacillus curvatus, Lactobacillus halivaticus, Lactobacillus Examples include Lactobacillus pentosus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus rhamnosus, Lactobacillus salivarius, Lactobacillus sporogenes, Lactobacillus sakei, Lactobacillus fructivorans, Lactobacillus hilgardii, Lactobacillus reuteri, and Lactobacillus fermentum.
Enterococcus includes Enterococcus faecalis (sometimes called Streptococcus faecalis), Enterococcus faesium (sometimes called Streptococcus faesium), Streptococcus thermophilus, and Lactococcus lactis (sometimes called Streptococcus lactis).
The genus Leuconostoc includes Leuconostoc mesenteroides and Leuconostoc oenos.
The genus Pediococcus includes Pediococcus acidilactici and Pediococcus pentosaceus.
Examples of the genus Staphylococcus include Staphylococcus carnosus and Staphylococcus xylosus.
The genus Tetragenococcus includes Tetragenococcus halophilus, and the genus Bacillus includes Bacillus coagulans and Bacillus mesentericus.
Among these, Bacillus coagulans, Enterococcus faecalis, Bifidobacterium bifidum, Enterococcus faesium, and Lactobacillus acidophilus are particularly preferred. These may be used alone or in combination of two or more.
本発明の剤が乳酸菌を含有する場合、乳酸菌の含有量は特に限定されないが、例えば菌体数として、本発明の剤中、1×103個以上、好ましくは1×105個以上1×1020個以下、更に好ましくは1×107個以上1×1015個以下とすることが、製剤の容易性及び乳酸菌の腸管付着効果を高める点から好ましい。 When the agent of the present invention contains lactic acid bacteria, the amount of lactic acid bacteria contained is not particularly limited. However, for example, it is preferable that the number of bacterial cells in the agent of the present invention be 1 x 103 or more, preferably 1 x 105 to 1 x 1020, and more preferably 1 x 107 to 1 x 1015, in terms of ease of formulation and enhancing the intestinal adhesion effect of the lactic acid bacteria.
本発明の剤は乳酸菌を含有する場合、乳酸菌と特定の花の抽出物とが同一剤に含まれていてもよく別々の剤に含まれていてもよい。別々の剤に含まれている場合は、本発明の剤は２剤以上の多剤型となる。同一剤に含まれている場合、本発明の剤は、１剤型であっても多剤型であってもよいが１剤型であることが摂取の簡便性等の点で好ましい。本発明の
剤の剤形は、１剤型及び多剤型のいずれに関わらず、固体状、液状、ペースト状、ゲル状
などが挙げられる。例えば、固体状としては、粉末状、粒状、顆粒状、錠状、棒状、板状、ブロック状、固形状、ハードカプセルやソフトカプセルのようなカプセル状、カプレット状、タブレット状、チュアブル状、スティック状等の各形態が挙げられる。液状としては例えば流動状、シロップ状等が挙げられる。これらは薬学的に許容される基材や担体を添加して、公知の製剤方法によって、各種の剤形に製剤可能である。
When the agent of the present invention contains lactic acid bacteria, the lactic acid bacteria and the specific flower extract may be contained in the same agent or in separate agents. When contained in separate agents, the agent of the present invention will be a multi-dose formulation consisting of two or more agents. When contained in the same agent, the agent of the present invention may be a single-dose or multi-dose formulation, although a single-dose formulation is preferred for ease of ingestion, etc. The dosage form of the agent of the present invention, regardless of whether it is a single-dose or multi-dose formulation, may be solid, liquid, paste, gel, etc. For example, solid forms include powder, granules, tablets, rods, plates, blocks, solids, capsules such as hard capsules and soft capsules, caplets, tablets, chewable tablets, sticks, etc. Liquid forms include, for example, fluids and syrups. These can be formulated into various dosage forms by adding pharmaceutically acceptable bases or carriers using known formulation methods.
例えば、乳酸菌を含有する本発明の剤の好ましい剤型としては、乳酸菌と前記特定の花の抽出物とを含み、粉末状、細粒状、顆粒状、錠状、ソフトカプセルやハードカプセル等のカプセル状、液状のいずれかである１剤型の形態や、前記特定の花の抽出物を含み、粉末状、細粒状、顆粒状、錠状、ソフトカプセルやハードカプセル等のカプセル状、液状である第１剤と、乳酸菌を含み、粉末状、細粒状、顆粒状、錠状、ソフトカプセルやハードカプセル等のカプセル状、液状のいずれかである第２剤とを有する２剤型の形態などが挙げられる。なお、本発明においては前記特定の花の抽出物を含む第１剤を単独で使用することにより、腸内に存在する乳酸菌やビフィズス菌の腸管接着性を向上させることもできる。本発明の剤が２剤に分かれている場合、上述した本発明の剤における特定の花の抽出物の好ましい割合は、２剤の合計量に対する割合とすることができる。 For example, preferred dosage forms of the agent of the present invention containing lactic acid bacteria include a single-dosage form containing lactic acid bacteria and the specific flower extract and in any of the following forms: powder, fine granules, granules, tablets, capsules such as soft capsules or hard capsules, or liquid; and a two-dosage form having a first agent containing the specific flower extract and in any of the following forms: powder, fine granules, granules, tablets, capsules such as soft capsules or hard capsules, or liquid; and a second agent containing lactic acid bacteria and in any of the following forms: powder, fine granules, granules, tablets, capsules such as soft capsules or hard capsules, or liquid. Note that in the present invention, the intestinal adhesiveness of lactic acid bacteria and bifidobacteria present in the intestine can also be improved by using the first agent containing the specific flower extract alone. When the agent of the present invention is divided into two agents, the preferred ratio of the specific flower extract in the agent of the present invention described above can be the ratio to the total amount of the two agents.
本発明の剤の経口摂取方法は限定されず、そのまま摂取するのであってもよく、また剤を水やお湯、牛乳、ヨーグルトなどに分散又は溶解させたものを摂取するのであってもよい。また本発明の剤が多剤型である場合は、複数剤を同時に摂取してもよく、別のタイミングで摂取してもよい。別のタイミングで摂取する場合は、例えば乳酸菌含有剤を花の抽出物含有剤より先に摂取してもよく、逆に花の抽出物含有剤を乳酸菌含有剤よりも先に摂取してもよいが、両者の摂取の時間差としては２４時間以内が好ましく、１８時間以内がより好ましく、１５時間以内が特に好ましい。また２剤の摂取方法は、同じであっても異なっていてもよく、異なる場合は例えば、乳酸菌含有剤はそのまま摂取し、花の抽出物含有剤は水やお湯、牛乳、ヨーグルトなどに分散して摂取する、という例があげられ、これは逆であってもよい。 The oral intake method for the agent of the present invention is not limited; it may be taken as is, or it may be taken after being dispersed or dissolved in water, hot water, milk, yogurt, etc. Furthermore, when the agent of the present invention is a multi-dose type, the multiple agents may be taken simultaneously or at different times. When taken at different times, for example, the lactic acid bacteria-containing agent may be taken before the flower extract-containing agent, or conversely, the flower extract-containing agent may be taken before the lactic acid bacteria-containing agent. The time difference between the intake of the two agents is preferably within 24 hours, more preferably within 18 hours, and particularly preferably within 15 hours. Furthermore, the intake methods for the two agents may be the same or different. When they are different, for example, the lactic acid bacteria-containing agent may be taken as is and the flower extract-containing agent may be taken after being dispersed in water, hot water, milk, yogurt, etc., or vice versa.
本発明の剤は前記特定の花の抽出物及び乳酸菌以外に、通常使用される他の成分を、本発明の効果を損なわない範囲で含有してもよい。このような成分としては、種々の賦形剤、結合剤、光沢剤、滑沢剤、安定剤、希釈剤、増量剤、増粘剤、乳化剤、酸化防止剤、ｐＨ調整剤、着色料、香料、添加剤などを挙げることができる。その他の成分の含有量は、本発明の剤の形態等に応じて適宜選択することができる。また本発明の剤が多剤型である場合、いずれの剤にいずれの他の成分を含有するかについても、その剤の形態に応じて適宜選択される。 In addition to the specific flower extract and lactic acid bacteria, the agent of the present invention may contain other commonly used ingredients to the extent that the effects of the present invention are not impaired. Such ingredients include various excipients, binders, glossing agents, lubricants, stabilizers, diluents, bulking agents, thickeners, emulsifiers, antioxidants, pH adjusters, colorants, fragrances, additives, etc. The content of other ingredients can be selected appropriately depending on the form of the agent of the present invention. Furthermore, when the agent of the present invention is in a multi-dosage form, which other ingredients are contained in which agent can be selected appropriately depending on the form of the agent.
本発明の剤の１日の経口投与量は前記特定の花の抽出物の乾燥質量として０．１ｍｇ以上であることが好ましい。本発明の剤は、連続的に、例えば毎日でも投与でき、長期的、例えば１ヶ月以上の間投与を継続して差し支えない。 The daily oral dose of the agent of the present invention is preferably 0.1 mg or more in terms of the dry mass of the extract of the specific flower. The agent of the present invention can be administered continuously, for example, daily, and can also be administered continuously over the long term, for example, for one month or more.
本発明の剤が乳酸菌を含有する場合もしない場合も、前記特定の花の抽出物の経口投与量を前提として、乳酸菌の１日の経口投与量は1×103個以上、特に1×105個以上1×1020
個以下であることが好ましい。
Whether the agent of the present invention contains lactic acid bacteria or not, the daily oral dose of lactic acid bacteria is 1×10 or more, particularly 1×10 or more and 1×10 or less, based on the oral dose of the extract of the specific flower.
It is preferable that the number is less than 1.
本発明の剤は、後述する実施例の記載から明らかな通り、前記特定の花の抽出物の作用により乳酸菌の腸管接着性を高めることができる。ここでいう腸管接着性とは、好ましくは腸管上皮（腸管上皮細胞）への接着性をいう。腸管接着性としては、個々の乳酸菌の接着性であってもよく、また集合体としての乳酸菌の接着性（集合体中の腸管接着（付着）した菌の割合）であってもよい。
このため、本発明の剤はこれを経口摂取することで、腸管における乳酸菌の作用を高めることができ、例えば整腸剤として用いることができる。整腸作用としては、有益腸内細菌（乳酸菌を含む）の増殖を促進する作用や有害腸内細菌の増殖を抑制する作用を挙げることができる。例えば、特許文献１に記載された、モモの花による瀉下作用及びこれを用いた抗便秘作用は、本発明でいう整腸作用に含まれない。また例えば、PPAR活性化によりもたらされる抗炎症作用は本発明でいう整腸作用に含まれない。
As will be apparent from the examples described below, the agent of the present invention can enhance the intestinal adhesiveness of lactic acid bacteria through the action of the extract of the specific flower. Here, intestinal adhesiveness preferably refers to adhesiveness to the intestinal epithelium (intestinal epithelial cells). Intestinal adhesiveness may refer to the adhesiveness of individual lactic acid bacteria, or the adhesiveness of lactic acid bacteria as a group (the proportion of bacteria in the group that adhere (attach) to the intestinal tract).
Therefore, oral administration of the agent of the present invention can enhance the activity of lactic acid bacteria in the intestinal tract, and can be used, for example, as an intestinal regulator. Examples of intestinal regulator effects include promoting the growth of beneficial intestinal bacteria (including lactic acid bacteria) and inhibiting the growth of harmful intestinal bacteria. For example, the laxative effect of peach flowers and the anti-constipation effect using them, as described in Patent Document 1, are not included in the intestinal regulator effects of the present invention. Furthermore, for example, the anti-inflammatory effect brought about by PPAR activation is not included in the intestinal regulator effects of the present invention.
本発明の剤は乳酸菌の腸管接着性を高めることができるため、腸管免疫等の免疫増強剤として用いることができるほか、アトピー性皮膚炎、アレルギー性鼻炎、花粉症、湿疹、蕁麻疹等の発疹、下痢や嘔吐等のアレルギー症状の予防や改善を図ることができる。前記の免疫増強剤の作用は、腸管においてＴｈ１細胞の働きを活発化したり、ＩｇＡ抗体産生を促すことを含む。 The agent of the present invention can increase the intestinal adhesiveness of lactic acid bacteria, and therefore can be used as an immune enhancer for intestinal immunity, etc., and can also prevent or improve allergic symptoms such as atopic dermatitis, allergic rhinitis, hay fever, eczema, rashes such as hives, diarrhea, and vomiting. The effects of the immune enhancer include activating the activity of Th1 cells in the intestinal tract and promoting IgA antibody production.
本発明の剤は、ヒトに対して好適に適用されるものであるが、それぞれの作用効果が奏される限り、ヒト以外の動物（例えば、マウス、ラット、ハムスター、イヌ、ネコ、ウシ、ブタ、サル等）に対して適用することもできる。 The agent of the present invention is preferably applied to humans, but can also be applied to animals other than humans (e.g., mice, rats, hamsters, dogs, cats, cows, pigs, monkeys, etc.) as long as the respective functional effects are achieved.
本発明の剤により腸管接着（付着）性を高める対象となる乳酸菌としては、本発明の剤に含有されていてもよい乳酸菌として前記で上げたものと同様のものを挙げることができる。本発明は更に、本発明の剤を含有する食品又は医薬品、医薬部外品などを提供する。
本発明は乳酸菌とともに本発明の剤を摂取して腸管における乳酸菌接着を促す方法（但し医療行為を除く）を提供する。
Lactic acid bacteria whose intestinal adhesion (adhesion) is enhanced by the agent of the present invention include the same lactic acid bacteria as those listed above as lactic acid bacteria that may be contained in the agent of the present invention. The present invention also provides foods, pharmaceuticals, quasi-drugs, etc. that contain the agent of the present invention.
The present invention provides a method (excluding medical procedures) for promoting adhesion of lactic acid bacteria in the intestinal tract by ingesting the agent of the present invention together with lactic acid bacteria.
以下、実施例を挙げて本発明を更に詳細に説明する。しかし本発明の範囲はかかる実施例に限定されない。以下、特に断らない場合「％」は質量％、「部」は質量部を表す。 The present invention will be explained in more detail below using examples. However, the scope of the present invention is not limited to these examples. Unless otherwise specified, "%" means "mass %" and "parts" means "parts by mass."
〔実施例１～１０、比較例１〕
（被験物質）
特定の花の抽出物として、以下の粉末を用いた。
・ベニバナ：ベニバナの花を水で抽出して得られた、市販の抽出物の粉末
・クズ：クズの花を熱水で抽出して得られた、市販の抽出物粉末
・バラ：バラの花びらを熱水で抽出して得られた、市販の抽出物粉末
・ザクロ：ザクロの花を含水エタノールで抽出して得られた、市販の抽出物粉末
・サクラ：サクラの花を含水エタノールで抽出して得られた、市販の抽出物粉末
・キク：キクの花を水で抽出して得られた、市販の抽出物粉末
・サフラン：サフランのめしべを含水エタノールで抽出して得られた、市販の抽出物の粉末
・モモ：白桃の花を熱水で抽出して得られた、市販の抽出物粉末
[Examples 1 to 10, Comparative Example 1]
(Test substance)
The following powders were used as extracts of specific flowers:
・Safflower: A commercially available extract powder obtained by extracting safflower flowers with water. ・Pueraria: A commercially available extract powder obtained by extracting pueraria flowers with hot water. ・Rose: A commercially available extract powder obtained by extracting rose petals with hot water. ・Pomegranate: A commercially available extract powder obtained by extracting pomegranate flowers with aqueous ethanol. ・Cherry: A commercially available extract powder obtained by extracting cherry blossoms with aqueous ethanol. ・Chrysanthemum: A commercially available extract powder obtained by extracting chrysanthemum flowers with water. ・Saffron: A commercially available extract powder obtained by extracting saffron pistils with aqueous ethanol. ・Peach: A commercially available extract powder obtained by extracting white peach flowers with hot water.
（接着能試験）
（１）ヒト結腸癌由来細胞Caco-2の培養および播種
（１－１）Passage 20の腸管上皮細胞株Caco-2細胞を用いた。
（１－２）トリプシン処理により浮遊させたCaco-2細胞を、75cm2フラスコから96 well plateに4.0×104/wellの細胞密度で播種した。
（１－３）培養培地を用い、37℃、5体積%CO2インキュベーター内で4日間培養した。この通常培地は、DMEMを10% FBS (Fatal Bovin Serum)、1%ペニシリン－ストレプトマイシン、1% NEAA（Non-Essential Amino Acids、SIGMA社）になるように調製した。この培養によりwell内でcaco-2の単層膜（腸管モデル）を作成した。
（１－４）（５）の試験の数時間前に試験培地に置換した。試験培地は、DMEMを2% FBS、1% NEAAになるように調製した。
(Adhesion ability test)
(1) Culture and seeding of human colon cancer-derived Caco-2 cells (1-1) Passage 20 intestinal epithelial cell line Caco-2 cells were used.
(1-2) Caco-2 cells were suspended by trypsinization and seeded from a 75 cm2 flask onto a 96-well plate at a cell density of 4.0 x 104/well.
(1-3) The cells were cultured for 4 days in a 37°C, 5% CO2 incubator using culture medium. This standard medium was prepared by adjusting DMEM to 10% FBS (Fatal Bovine Serum), 1% penicillin-streptomycin, and 1% NEAA (Non-Essential Amino Acids, SIGMA). This culture created a Caco-2 monolayer (intestinal model) in the well.
The medium was replaced with a test medium prepared by adding 2% FBS and 1% NEAA to DMEM a few hours before the tests in (1-4) and (5).
（２）Bacillus coagulansのグリセロールストック及び前培養
（２－１）粉体状の乳酸菌Bacillus coagulansをMRS液体培地にて72時間、37℃で培養した。
（２－２）培養液を採取し、グリセロールが30%になるように培養液を混ぜ、試験を行うまで-80℃で保存した（グリセロールストック）。
（２－３）B.coagulansのグリセロールストックを室温に戻し、37℃で温めたMRS液体培地へ播種し、同温で24時間培養後に下記（３）の蛍光標識及び（４）の検量線用サンプルの作製に用いた。
(2) Glycerol stock and preculture of Bacillus coagulans (2-1) Powdered lactic acid bacteria Bacillus coagulans was cultured in MRS liquid medium for 72 hours at 37°C.
(2-2) The culture medium was collected, mixed with glycerol to make the glycerol concentration 30%, and stored at −80°C until testing (glycerol stock).
(2-3) The glycerol stock of B. coagulans was returned to room temperature and inoculated into MRS liquid medium warmed to 37°C. After culturing at the same temperature for 24 hours, it was used for the preparation of fluorescent labels (see below in (3)) and samples for the calibration curve (see (4)).
（３）B. coagulansの蛍光標識
（３－１）B. coagulans菌を（２）で前培養した後の菌液100μL採取し、900mLのリン酸緩衝生理食塩液（PBS）へ懸濁、1000g×3分間遠心分離した。得られたペレットを1000μL PBSへ懸濁し、15μL carboxyfluorescein diacetate（CFDA、同仁化学研究所社製）を加え、30分間遮光、室温でインキュベートした。
（３－２）1000g×3分間遠心分離し、ペレットを1mL PBSで懸濁し、再度1000gx3分間遠心分離した。この操作を2回行った。
（３－３）ペレットを試験培地で懸濁し、得られた懸濁物を下記（５）の試験に用いた。
(3) Fluorescent Labeling of B. coagulans (3-1) After pre-cultivating B. coagulans in (2), 100 μL of the bacterial solution was collected and suspended in 900 mL of phosphate-buffered saline (PBS). The suspension was centrifuged at 1000 g for 3 minutes. The resulting pellet was suspended in 1000 μL of PBS, and 15 μL of carboxyfluorescein diacetate (CFDA, Dojindo Laboratories) was added. The suspension was incubated at room temperature for 30 minutes in the dark.
(3-2) After centrifugation at 1000 g for 3 minutes, the pellet was suspended in 1 mL of PBS and centrifuged again at 1000 g for 3 minutes. This procedure was repeated twice.
(3-3) The pellet was suspended in a test medium, and the resulting suspension was used in the test described below in (5).
（４）検量線用サンプルの作製
（４－１）上記（３－１）で蛍光標識した乳酸菌の一部をホルマリン固定した。
（４－２）同じ前培養したサンプルをBCP培地にて37℃、3日間培養し、BCP培地上のコロニー数を測定した（plate count）。
（４－３）plate countから細菌数を計算し、（４－１）でホルマリン固定したサンプルを既知数サンプルとして検量線用サンプルとした。
(4) Preparation of samples for calibration curve (4-1) A portion of the lactic acid bacteria fluorescently labeled in (3-1) above was fixed in formalin.
(4-2) The same pre-cultured samples were cultured in BCP medium at 37°C for 3 days, and the number of colonies on the BCP medium was counted (plate count).
(4-3) The number of bacteria was calculated from the plate count, and the samples fixed with formalin in (4-1) were used as samples with known numbers for the calibration curve.
（５）定着能比較試験
（５－１）下記表１の被験物質である 花抽出物粉末10mg量り取り、50mLファルコンチューブに入れ、1mg/mLになるように試験培地を加えた。ボルテックス後、各被験物質の最終濃度が下記表１の濃度となるように試験培地で希釈した。
（５－２）（５－１）において被験物質含有又は非含有の試験培地へ菌数を1x108/mLに調整した菌懸濁液を加え、B. coagulans濃度1x106/mLとした。（１－４）の細胞に１well当たり100μLとなる量で添加し（B. coagulans最終濃度1x105/well）、2時間37℃で培養した。なお比較例１では、被験物質非含有の試験培地を同量添加した。
（５－３） 培養終了後、各wellに150μL ホルマリン液を加え、4℃で30分以上固定した。
（５－４） PBSでwellを２回洗浄し、varioskanにて蛍光強度（励起光495nm、蛍光515nm）を測定した。
（５－５） （４－３）の検量線用サンプルをvarioskanにて蛍光強度を測定することで検量線を作成した。得られた検量線に基づき、（５－４）で測定した蛍光強度からCaco-2単層膜へ接着したB. coagulansの菌数を計算した。
（５－６）
得られた菌数の比較例１に対する相対値（％）を図１及び図２に示す。
(5) Comparative test of fixation ability (5-1) 10 mg of the flower extract powder, which is the test substance in Table 1 below, was weighed out and placed in a 50 mL Falcon tube, and test medium was added to make the concentration 1 mg/mL. After vortexing, each test substance was diluted with test medium to the final concentration in Table 1 below.
(5-2) A bacterial suspension prepared in (5-1) above, adjusted to a bacterial count of 1 x 10/mL, was added to the test medium containing or not containing the test substance, resulting in a B. coagulans concentration of 1 x 10/mL. This was added to the cells in (1-4) at a volume of 100 μL per well (final B. coagulans concentration of 1 x 10/well), and the cells were cultured for 2 hours at 37°C. In Comparative Example 1, the same volume of test medium not containing the test substance was added.
(5-3) After the incubation, 150 μL of formalin solution was added to each well, and the cells were fixed at 4° C. for 30 minutes or more.
(5-4) The wells were washed twice with PBS, and the fluorescence intensity (excitation light 495 nm, fluorescence 515 nm) was measured using a varioskan.
(5-5) A calibration curve was created by measuring the fluorescence intensity of the calibration sample (4-3) using a Varioskan. Based on the obtained calibration curve, the number of B. coagulans bacteria adhered to the Caco-2 monolayer was calculated from the fluorescence intensity measured in (5-4).
(5-6)
The relative values (%) of the obtained bacterial counts to those of Comparative Example 1 are shown in FIGS.
図１及び図２の結果から、特定の花の抽出物は、乳酸菌の腸管接着率を高めることが判る。また、本発明の剤は、乳酸菌の腸管接着性が高いことから、これを経口摂取することにより腸管における乳酸菌の作用を高めることができ、整腸作用や抗アレルギー作用、免疫増強作用、ダイエット、美容、健康増進に優れた効果が期待できる。 The results in Figures 1 and 2 show that extracts from specific flowers increase the intestinal adhesion rate of lactic acid bacteria. Furthermore, because the agent of the present invention has high intestinal adhesion properties, oral intake of this agent can enhance the activity of lactic acid bacteria in the intestinal tract, and is expected to have excellent effects on intestinal regulation, anti-allergic effects, immune enhancement, dieting, beauty, and health promotion.
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