JP7371851B2 - Composition containing oleanane-type triterpene that prevents or improves physical fatigue and feeling of fatigue - Google Patents
Composition containing oleanane-type triterpene that prevents or improves physical fatigue and feeling of fatigue Download PDFInfo
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- JP7371851B2 JP7371851B2 JP2019129760A JP2019129760A JP7371851B2 JP 7371851 B2 JP7371851 B2 JP 7371851B2 JP 2019129760 A JP2019129760 A JP 2019129760A JP 2019129760 A JP2019129760 A JP 2019129760A JP 7371851 B2 JP7371851 B2 JP 7371851B2
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- Prior art keywords
- fatigue
- acid
- oleanane
- triterpenes
- exercise
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- 235000013305 food Nutrition 0.000 claims description 17
- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 claims description 16
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Images
Description
本発明は、例えばオレアナン型トリテルペンを含有する抗疲労用組成物に関する。 The present invention relates to an anti-fatigue composition containing, for example, an oleanane-type triterpene.
疲労は、痛みや発熱とともに、生体の3大アラームとされる程、肉体的あるいは精神的な原因によって生じる過負荷の状態を表現する重要な生体警告シグナルである。しかしながら、これまでに疲労が生じる機序や疲労の自覚的感覚(疲労感)に至る機序は完全には解明されていない(非特許文献1;p188「3.疲労のバイオマーカー」を参照)。
Along with pain and fever, fatigue is an important biological warning signal that expresses a state of overload caused by physical or mental causes, so much so that it is considered one of the three major biological alarms. However, the mechanisms that cause fatigue and the mechanisms that lead to the subjective sensation of fatigue (feeling of fatigue) have not been completely elucidated so far (Non-Patent
健常者における疲労は、厚生省疲労調査 研究班の木谷らが「過度の肉体的・精神的活動により生じた独特の病的不快感と休養を求める欲求を伴う精神・身体機能の減弱状態」と定義している(非特許文献2;p200「はじめに」を参照)。従って「抗疲労」効果とは、精神又は身体に何らかの過負荷を与えた際に生じる不快感(疲労感)を緩和させたり、パフォーマンスの低下を抑制させたりする効果といえる。
Fatigue in healthy people is defined by Kitani et al. of the research team of the Ministry of Health and Welfare's Fatigue Survey as ``a state of weakened mental and physical function accompanied by unique pathological discomfort and a desire for rest caused by excessive physical and mental activity.'' (Non-Patent
日本疲労学会の制定する抗疲労臨床評価ガイドラインによると、疲労とは心身への過負荷により生じた活動能力や能率の低下のことを指し、疲労感は疲労が存在することを自覚する感覚とされる。さらに、ヒトを対象とした臨床試験において抗疲労効果を評価する方法として、自覚的疲労度や血中の酸化ストレスマーカー等の測定を挙げている(非特許文献3;p4「4.1 日常生活により問題となる疲労の定義」、p10「別表」を参照)。これら複数の評価項目を比較した試験を実施し、統計的に有意な差が認められた場合、疲労回復の効果を有していると判定される。特に自覚的疲労度を測定する方法であるVAS(Visual Analogue Scale)は、特定保健用食品の抗疲労臨床評価における疲労感の評価方法として有用とされており、信頼性の高い方法といえる(非特許文献4)。
According to the anti-fatigue clinical evaluation guidelines established by the Japan Fatigue Society, fatigue refers to a decline in activity ability and efficiency caused by overload on the mind and body, and fatigue is the feeling of being aware of the presence of fatigue. Ru. Furthermore, as a method for evaluating anti-fatigue effects in human clinical trials, the authors cite measurement of subjective fatigue level and blood oxidative stress markers (Non-patent
平成14年度に厚生労働省が実施した労働者健康状況調査によると、「普段の仕事で疲れる」とする労働者は72%にのぼることが確認された(非特許文献5;「1.身体の疲れ及び精神的ストレス等の状況 (1)普段の仕事での身体の疲れ」を参照)。現在では社会構造の複雑化やスピード化、高齢化に伴いますます疲労や疲労感が広く社会に蔓延していると予想され、過労防止や経済活性化のためにも、その対処策が求められている。
According to a worker health status survey conducted by the Ministry of Health, Labor and Welfare in fiscal 2002, it was confirmed that 72% of workers said they felt tired from their daily work (Non-Patent
疲労を回復するための手法として、経験的に、休養、睡眠、入浴、栄養、軽い運動、アロマテラピー等が利用されている。特に運動による肉体的な疲労の予防には、運動前に十分な糖質やアミノ酸を摂取し、エネルギーを蓄積させておく方法が広く行われている。さらに近年、抗疲労物質、抗疲労サプリメントとして、簡便に摂取することができる食品成分が様々提案されている。例えばセサミン、イミダゾールジペプチド、スフィンゴミエリン、カテキン類、レスベラトロール(特許文献1~4及び非特許文献6)等を摂取することが疲労の予防、及び回復に有効であると提案されている。
As methods for recovering from fatigue, rest, sleep, bathing, nutrition, light exercise, aromatherapy, etc. have been used empirically. In particular, a widely used method for preventing physical fatigue caused by exercise is to ingest sufficient carbohydrates and amino acids before exercise to accumulate energy. Furthermore, in recent years, various food components that can be easily ingested have been proposed as anti-fatigue substances and anti-fatigue supplements. For example, it has been proposed that ingesting sesamin, imidazole dipeptide, sphingomyelin, catechins, resveratrol (
一方、マスリン酸を始めとするオレアナン型トリテルペン類について、運動による骨格筋機能増強作用を促進させる作用(特許文献5)、大腸癌抑制作用(非特許文献7)、皮膚の美白(特許文献6)、破骨細胞の分化抑制及び骨吸収活性効果(特許文献7)、肥満予防効果(特許文献8)、難消化性デキストリン、コロソリン酸、マスリン酸及びトルメンチック酸を有効成分として含有する組成物について血糖値上昇抑制(特許文献9)、オレアノール酸について抗う蝕(特許文献10)、抗ガン作用(特許文献11)等が報告されている。しかしながら、これらいずれの文献にも、オレアナン型トリテルペン類の抗疲労作用、疲労感軽減作用については何ら示唆も開示もされていなかった。 On the other hand, oleanane-type triterpenes such as maslinic acid have the effect of promoting the effect of enhancing skeletal muscle function due to exercise (Patent Document 5), the effect of suppressing colorectal cancer (Non-Patent Document 7), and the skin whitening effect (Patent Document 6) , osteoclast differentiation inhibition and bone resorption activity effect (Patent Document 7), obesity prevention effect (Patent Document 8), blood sugar It has been reported that oleanolic acid suppresses the increase in oleanolic acid (Patent Document 9), has anti-caries effects (Patent Document 10), and has anticancer effects (Patent Document 11). However, none of these documents suggests or discloses any anti-fatigue effect or fatigue-reducing effect of oleanane-type triterpenes.
本発明は、上述の実情に鑑み、運動等の身体活動によって引き起こされる肉体的な疲労及び疲労感を予防及び改善するための組成物を提供することを目的とする。 In view of the above-mentioned circumstances, the present invention aims to provide a composition for preventing and improving physical fatigue and fatigue caused by physical activities such as exercise.
上記課題を解決するため鋭意研究を行った結果、オレアナン型トリテルペン類を含有する組成物を摂取することにより、簡便に疲労や疲労感を軽減できることを見出し、本発明を完成するに至った。 As a result of intensive research to solve the above problems, it was discovered that fatigue and fatigue can be easily alleviated by ingesting a composition containing oleanane-type triterpenes, and the present invention was completed.
すなわち、本発明は、以下を包含する。
(1)オレアナン型トリテルペン若しくはその塩又はそれらのプロドラッグを有効成分として含有する、抗疲労用組成物。
(2)オレアナン型トリテルペンが、マスリン酸、オレアノール酸及びそれらの混合物から成る群より選択される、(1)記載の抗疲労用組成物。
(3)主要トリテルペンとしてマスリン酸とオレアノール酸とを含有するオリーブ果実抽出物を有効成分として含有する、抗疲労用組成物。
(4)肉体的疲労及び/又は疲労感を予防及び/又は改善するための、(1)~(3)のいずれか1記載の抗疲労用組成物。
(5)(1)~(4)のいずれか1記載の組成物を含有する、抗疲労用飲食品。
(6)(1)~(4)のいずれか1記載の組成物を含有する、抗疲労用医薬品。
That is, the present invention includes the following.
(1) An anti-fatigue composition containing an oleanane-type triterpene, a salt thereof, or a prodrug thereof as an active ingredient.
(2) The anti-fatigue composition according to (1), wherein the oleanane-type triterpene is selected from the group consisting of maslinic acid, oleanolic acid, and mixtures thereof.
(3) An anti-fatigue composition containing as an active ingredient an olive fruit extract containing maslinic acid and oleanolic acid as major triterpenes.
(4) The anti-fatigue composition according to any one of (1) to (3), for preventing and/or improving physical fatigue and/or feeling of fatigue.
(5) An anti-fatigue food or drink containing the composition according to any one of (1) to (4).
(6) An anti-fatigue pharmaceutical containing the composition according to any one of (1) to (4).
本発明によれば、水球等の激しい運動や筋力トレーニングによって生じる疲労及び疲労感を予防及び改善することができる。 According to the present invention, fatigue and fatigue caused by intense exercise such as water polo or muscle training can be prevented and improved.
以下、本発明を詳細に説明する。 The present invention will be explained in detail below.
本発明に係る抗疲労用組成物(以下、「本発明に係る組成物」という)は、オレアナン型トリテルペン若しくはその塩又はそれらのプロドラッグを有効成分として含有するものである。本発明に係る組成物によれば、肉体的疲労及び/又は疲労感を予防及び/又は改善することができる。従って、本発明に係る組成物は、肉体的疲労及び/又は疲労感の予防剤、治療剤又は改善剤として使用することもできる。 The anti-fatigue composition according to the present invention (hereinafter referred to as "composition according to the present invention") contains an oleanane-type triterpene, a salt thereof, or a prodrug thereof as an active ingredient. According to the composition according to the present invention, physical fatigue and/or fatigue feeling can be prevented and/or improved. Therefore, the composition according to the present invention can also be used as a preventive, therapeutic, or improving agent for physical fatigue and/or fatigue.
本発明において、トリテルペンは炭素数30を基本骨格とする化合物であり、その代表例として五環性トリテルペンが挙げられる。ここで、五環性トリテルペンとは、トリテルペン類の1種であり、イソプレン単位6個から成る五環性の化合物で、炭素数は30個を基本とするが、生合成過程で転位、酸化、脱離あるいはアルキル化され炭素数が前後するものも含まれる。 In the present invention, a triterpene is a compound having a basic skeleton of 30 carbon atoms, and a typical example thereof is a pentacyclic triterpene. Here, pentacyclic triterpene is a type of triterpene, and is a pentacyclic compound consisting of 6 isoprene units, with a basic number of carbon atoms of 30, but during the biosynthesis process, it undergoes rearrangement, oxidation, It also includes those with different carbon numbers due to elimination or alkylation.
これらは、天然の植物から得ることも、人工的に得ることもできる。また、市販品も好適に利用することができる。五環性トリテルペンは、一般に、その骨格により分類されている。例えば、オレアナン型トリテルペン、ウルサン型トリテルペン、ルパン型トリテルペン、ホパン型トリテルペン、セラタン型トリテルペン、フリーデラン型トリテルペン、タラキセラン型トリテルペン、タラキサスタン型トリテルペン、マルチフロラン型トリテルペン、ジャーマニカン型トリテルペン等が挙げられる。 These can be obtained from natural plants or artificially. Moreover, commercially available products can also be suitably used. Pentacyclic triterpenes are generally classified according to their skeleton. Examples include oleanane-type triterpenes, ursane-type triterpenes, lupine-type triterpenes, hopane-type triterpenes, seratane-type triterpenes, Friederan-type triterpenes, taraxerane-type triterpenes, taraxastan-type triterpenes, multiflorane-type triterpenes, Germanican-type triterpenes, and the like.
本発明に係る組成物は、五環性トリテルペン類のうち、オレアナン型トリテルペンを有効成分として含有する。オレアナン型トリテルペンとしては、例えばマスリン酸、オレアノール酸、マスリン酸とオレアノール酸との混合物等が挙げられる。 The composition according to the present invention contains an oleanane triterpene as an active ingredient among pentacyclic triterpenes. Examples of oleanane-type triterpenes include maslinic acid, oleanolic acid, and a mixture of maslinic acid and oleanolic acid.
マスリン酸は、オリーブ果実及び葉、ナツメ、アーモンド、バナバ葉、セージ、リンゴ、クランベリー、カリン等に含まれる。オレアノール酸は、オリーブ果実及び葉、ブドウ、ビート、ナツメ、アーモンド、バナバ葉、セージ、サンザシ、ラズベリー、カリン、ローズマリー葉、グァバ、シソ葉、ブルーベリー、プルーン、ビワ、ザクロ、レモンバーム、バジル、ローズヒップ、カキ、センブリ等に含まれる。 Maslinic acid is found in olive fruits and leaves, jujubes, almonds, banaba leaves, sage, apples, cranberries, quince, etc. Oleanolic acid is found in olive fruits and leaves, grapes, beets, jujubes, almonds, banaba leaves, sage, hawthorn, raspberries, quince, rosemary leaves, guava, perilla leaves, blueberries, prunes, loquats, pomegranates, lemon balm, basil, rose. Contained in hips, oysters, and Japanese cabbage.
これらオレアナン型トリテルペンは、上述の植物から公知の方法で抽出、精製して得ることができる他、化学合成によって得ることもできる。オレアナン型トリテルペンは、単独の成分又は2以上の種類の成分の混合物(組合せ)であっても良い。 These oleanane-type triterpenes can be obtained by extraction and purification from the above-mentioned plants by known methods, or can also be obtained by chemical synthesis. The oleanane-type triterpene may be a single component or a mixture (combination) of two or more types of components.
オレアナン型トリテルペンは、上述の植物の抽出物の形態で用いても良い。特に古くからの食経験があり、オレアナン型トリテルペンが豊富に含まれており、搾油後の二次利用が可能なことから、オリーブ果実抽出物の形態を用いることが好ましい。当該オリーブ果実抽出物は、主要トリテルペンとしてマスリン酸とオレアノール酸とを含有する。 Oleanane-type triterpenes may be used in the form of extracts of the above-mentioned plants. In particular, it is preferable to use the form of olive fruit extract because it has been eaten for a long time, contains abundant oleanane-type triterpenes, and can be used for secondary use after oil extraction. The olive fruit extract contains maslinic acid and oleanolic acid as major triterpenes.
オレアナン型トリテルペンの製造方法としては、例えば乾燥、半乾燥又は未乾燥のオリーブ果実、搾油工程で生産されるオリーブオイル搾油粕を出発原料とし、マスリン酸等のトリテルペンが抽出可能な低級アルコール(エタノール、メタノール、n-プロパノール、イソプロパノール、n-ブタノール等)、又はその含水アルコールでトリテルペンを抽出する方法が挙げられる。必要であれば、ケン化処理、中和を行い、吸着剤としてオクタデシルシリカ(ODS)、シリカゲル、合成吸着剤等を使用して、分画、精製してマスリン酸及び/又はオレアノール酸を主成分として含むトリテルペンの混合物を得ても良い。このようなオリーブ果実から抽出されるトリテルペンには、概ねマスリン酸とオレアノール酸とが4:1の割合で含まれているが、オリーブ果実の生育状況や生育地域、あるいは搾油条件等により、当該比が1:1~7:1になる場合もある。 As a method for producing oleanane-type triterpenes, for example, dried, semi-dried or undried olive fruits and olive oil lees produced in the oil extraction process are used as starting materials, and lower alcohols (ethanol, ethanol, etc.) from which triterpenes such as maslinic acid can be extracted are used. Examples include a method of extracting triterpenes with methanol, n-propanol, isopropanol, n-butanol, etc.) or a hydrous alcohol thereof. If necessary, perform saponification treatment and neutralization, and use octadecyl silica (ODS), silica gel, synthetic adsorbent, etc. as an adsorbent to fractionate and purify to obtain maslinic acid and/or oleanolic acid as the main components. A mixture of triterpenes containing as Triterpenes extracted from such olive fruits generally contain maslinic acid and oleanolic acid in a ratio of 4:1, but this ratio may vary depending on the growing conditions of the olive fruit, the growing region, or the oil extraction conditions. may be 1:1 to 7:1.
他の植物を出発原料とする場合には、原料として使用する植物に適した方法でオレアナン型トリテルペンを得ることができる。また、得られるオレアナン型トリテルペンの成分の種類及びその構成比は原料として使用する植物に依存する。 When using other plants as the starting material, oleanane-type triterpenes can be obtained by a method suitable for the plant used as the starting material. Moreover, the types of components and their composition ratios of the obtained oleanane-type triterpene depend on the plant used as a raw material.
オレアナン型トリテルペンの塩としては、薬学的に許容される塩が好ましく、例えば、塩酸、硫酸、リン酸、臭化水素酸、ヨウ化水素酸、硝酸、ピロ硫酸、メタリン酸等の無機酸、又はクエン酸、安息香酸、酢酸、プロピオン酸、フマル酸、マレイン酸、酒石酸、コハク酸、スルホン酸(例えば、メタンスルホン酸、p-トルエンスルホン酸、ナフタレンスルホン酸)、アミノ酸(例えば、グルタミン酸)等の有機酸との塩、ナトリウム塩、カリウム塩等のアルカリ金属塩、リジン塩、アルギニン塩が挙げられる。 The salt of the oleanane type triterpene is preferably a pharmaceutically acceptable salt, such as an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid, pyrosulfuric acid, metaphosphoric acid, etc. Citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, tartaric acid, succinic acid, sulfonic acid (e.g. methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid), amino acids (e.g. glutamic acid), etc. Examples include salts with organic acids, alkali metal salts such as sodium salts and potassium salts, lysine salts, and arginine salts.
オレアナン型トリテルペン若しくはその塩のプロドラッグとは、生物系に投与した場合に、自発的な化学反応の結果として、又は触媒する酵素若しくは代謝反応により、オレアナン型トリテルペン又はその塩を生ずる全ての化合物を示す。水酸基において使用されるプロドラッグを構成する基としては、例えば、C2-7-アシル基、C1-6-アルコキシ(C2-7アシル)基、C1-6-アルコキシカルボニル(C2-7-アシル)基、C1-6-アルコキシカルボニル基、C1-6-アルコキシ(C2-7-アルコキシカルボニル)基、(C2-7-アシルオキシ)メチル基、1-(C2-7-アシルオキシ)エチル基、(C2-7-アルコキシカルボニル)オキシメチル基、1-〔(C2-7-アルコキシカルボニル)オキシ〕エチル基等が挙げられ、C2-7-アシル基、C1-6-アルコキシカルボニル基が好ましい。カルボキシル基において使用されるプロドラッグを構成する基としては、例えば、C1-6-アルキル基、C1-6-アルコキシ-C1-6-アルキル基、(C2-7-アシルオキシ)メチル基、1-(C2-7-アシルオキシ)エチル基、(C2-7-アルコキシカルボニル)オキシメチル基、1-〔(C2-7-アルコキシカルボニル)オキシ〕エチル基等が挙げられ、C1-6-アルキル基、C1-6-アルコキシ-C1-6-アルキル基が好ましい。 Prodrugs of oleanane-type triterpenes or their salts are defined as all compounds that, when administered to biological systems, produce oleanane-type triterpenes or their salts as a result of spontaneous chemical reactions or by catalyzed enzymatic or metabolic reactions. show. Examples of groups constituting prodrugs used in the hydroxyl group include C 2-7 -acyl group, C 1-6 -alkoxy (C 2-7 acyl) group, and C 1-6 -alkoxycarbonyl (C 2- 7 -acyl) group, C 1-6 -alkoxycarbonyl group, C 1-6 -alkoxy(C 2-7 -alkoxycarbonyl) group, (C 2-7 -acyloxy)methyl group, 1-(C 2-7 -acyloxy)ethyl group, (C 2-7 -alkoxycarbonyl)oxymethyl group, 1-[(C 2-7 -alkoxycarbonyl)oxy]ethyl group, etc., and C 2-7 -acyl group, C 1 A -6 -alkoxycarbonyl group is preferred. Groups constituting prodrugs used in the carboxyl group include, for example, C 1-6 -alkyl group, C 1-6 -alkoxy-C 1-6 -alkyl group, (C 2-7 -acyloxy)methyl group. , 1-(C 2-7 -acyloxy)ethyl group, (C 2-7 -alkoxycarbonyl)oxymethyl group, 1-[(C 2-7 -alkoxycarbonyl)oxy]ethyl group, etc., and C 1 A -6 -alkyl group and a C1-6 -alkoxy- C1-6 -alkyl group are preferred.
本発明に係る組成物の摂取量(投与量)は、摂取(投与)する肉体的疲労及び/又は疲労感を有する被験者の年齢、性別、症状の程度、摂取(投与)形態によって異なるが、有効成分(オレアナン型トリテルペン若しくはその塩又はそれらのプロドラッグ)換算で、例えば成人では1日当たり好ましくは0.1mgマスリン酸当量/kg体重以上であり、より好ましくは1.0mgマスリン酸当量/kg体重以上である。また特に摂取量(投与量)の上限はないが、60mgマスリン酸当量/kg体重を超えると製品コストの観点から好ましくない。 The amount of intake (dose) of the composition according to the present invention varies depending on the age, gender, severity of symptoms, and mode of intake (administration) of the subject who is ingesting (administering) the subject who has physical fatigue and/or feeling of fatigue. In terms of component (oleanane-type triterpene or its salt or prodrug thereof), for example, for adults, it is preferably 0.1 mg maslinic acid equivalent/kg body weight or more, more preferably 1.0 mg maslinic acid equivalent/kg body weight or more per day. . Although there is no particular upper limit for the intake (dose), it is undesirable from the viewpoint of product cost if it exceeds 60 mg maslinic acid equivalent/kg body weight.
マスリン酸当量とは、マスリン酸とマスリン酸以外の化合物の混合物の量を混合物に含まれるマスリン酸の質量で表現したものである。具体的には、1.0mgマスリン酸当量のオリーブ果実由来トリテルペンとは、1mgのマスリン酸を含む、オレアノール酸や例えば図1のチャートに示されたマスリン酸以外の他のピークの化合物との混合物の量を意味する。 The maslinic acid equivalent is the amount of a mixture of maslinic acid and a compound other than maslinic acid expressed by the mass of maslinic acid contained in the mixture. Specifically, 1.0 mg maslinic acid equivalent of olive fruit-derived triterpene refers to a mixture containing 1 mg maslinic acid with oleanolic acid or other peak compounds other than maslinic acid shown in the chart of Figure 1. means quantity.
本発明に係る組成物を、例えば疲労又は疲労感を伴う運動を行う期間や日常生活にあわせて好ましくは1~2週間、さらに好ましくは1~20週間にわたり、1日量を1~3回に分けて摂取(投与)する。また、疲労又は疲労感を伴う運動を行う期間又は日常生活中は、そのような運動又は日常生活の頻度にかかわらず、すなわち運動を行う日や疲労又は疲労感を伴う日常生活の日であっても、運動を行わない日や疲労又は疲労感を伴う日常生活の日でない日であっても毎日摂取(投与)することが好ましい。摂取(投与)のタイミングとしては、運動を行う日や疲労又は疲労感を伴う日常生活の日である場合、その日に行う運動や日常生活の前後を問わない。 The composition according to the present invention is administered in 1 to 3 doses per day, preferably for 1 to 2 weeks, more preferably for 1 to 20 weeks, depending on the period of exercise accompanied by fatigue or a feeling of fatigue, or daily life. Ingest (administer) separately. In addition, during the period of exercise or daily life accompanied by fatigue or a feeling of fatigue, regardless of the frequency of such exercise or daily life, i.e., on the day of exercise or the day of daily life accompanied by fatigue or a feeling of fatigue, It is also preferable to take (administer) the drug every day, even on days when you do not exercise or when you do not feel fatigued or fatigued in your daily life. The timing of intake (administration) does not matter, as long as it is a day of exercise or a day of daily life accompanied by fatigue or a feeling of fatigue, before or after the exercise or daily life of the day.
本発明に係る組成物は、助剤と共に任意の形態に製剤化して、経口投与又は非経口投与が可能な医薬品とすることができる。例えば、経口用の剤形としては、錠剤、口腔内速崩壊錠、カプセル、顆粒、細粒等の固形投薬形態、シロップ及び懸濁液のような液体投薬形態とすることができる。非経口の剤形としては、注射剤、点眼剤、点鼻剤、貼付剤、坐剤、皮膚外用剤の形態とすることができる。なお、医薬品には医薬部外品も含まれる。 The composition according to the present invention can be formulated into any form together with auxiliary agents to form a pharmaceutical product that can be administered orally or parenterally. For example, oral dosage forms can be solid dosage forms such as tablets, rapidly disintegrating tablets, capsules, granules, granules, etc., and liquid dosage forms such as syrups and suspensions. Parenteral dosage forms include injections, eye drops, nasal drops, patches, suppositories, and skin preparations. Note that pharmaceuticals also include quasi-drugs.
固形投薬形態とする場合、一般製剤の製造に用いられる種々の添加剤を適当量含んでいてもよい。このような添加剤として、例えば賦形剤、結合剤、酸味料、発泡剤、人工甘味料、香料、滑沢剤、着色剤、安定化剤、pH調整剤、界面活性剤等が挙げられる。 When formulated into a solid dosage form, it may contain appropriate amounts of various additives used in the manufacture of general pharmaceutical preparations. Examples of such additives include excipients, binders, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, stabilizers, pH adjusters, surfactants, and the like.
液体投薬形態とする場合、本発明に係る組成物は必要に応じてpH調整剤、緩衝剤、溶解剤、懸濁剤等、等張化剤、安定化剤、防腐剤等の存在下、常法により製剤化することができる。 When formulated into a liquid dosage form, the composition according to the present invention may be prepared in the presence of pH adjusting agents, buffering agents, solubilizing agents, suspending agents, etc., isotonic agents, stabilizers, preservatives, etc. as necessary. It can be formulated according to the method.
皮膚外用剤の形態としては、特に限定されず、例えば、乳液、クリーム、化粧水、パック、分散液、洗浄料、メーキャップ化粧料、頭皮・毛髪用品等の化粧品や、軟膏剤、クリーム剤、外用液剤等の医薬品等とすることができる。上記成分以外に、通常化粧品や医薬品等の皮膚外用剤に用いられる成分、例えば、美白剤、保湿剤、各種皮膚栄養成分、紫外線吸収剤、酸化防止剤、油性成分、界面活性剤、増粘剤、アルコール類、色剤、水、防腐剤、香料等を必要に応じて適宜配合することができる。 The form of external skin preparations is not particularly limited, and includes, for example, cosmetics such as emulsions, creams, lotions, packs, dispersions, cleaning agents, makeup cosmetics, scalp and hair products, ointments, creams, and external preparations. It can be a medicine such as a liquid preparation. In addition to the above ingredients, there are other ingredients commonly used in external skin preparations such as cosmetics and pharmaceuticals, such as whitening agents, moisturizers, various skin nutrition ingredients, ultraviolet absorbers, antioxidants, oily ingredients, surfactants, and thickeners. , alcohols, coloring agents, water, preservatives, fragrances, etc. may be appropriately blended as required.
本発明に係る組成物は、機能性食品、健康食品、特定保健用食品、栄養機能食品等の保健機能食品、特別用途食品(例えば、病者用食品)、健康補助食品、サプリメント等として調製されてもよい。例えば、本発明に係る組成物は、「肉体的疲労及び/又は疲労感を予防及び/又は改善する」等を表示した機能性表示食品に利用できる。サプリメントとして、例えば、一般的なサプリメントの製造に用いられる種々の添加剤と共に錠剤、丸状、カプセル(ハードカプセル、ソフトカプセル、マイクロカプセルを含む)状、粉末状、顆粒状、細粒状、トローチ状、ゼリー状、液状(シロップ状、乳状、懸濁状を含む)等の形状とすることができる。 The composition according to the present invention can be prepared as a functional food, a health food, a food for specified health uses, a food with health claims such as a food with nutritional function, a food for special purposes (e.g., food for patients), a health supplement, a supplement, etc. It's okay. For example, the composition according to the present invention can be used in a food with functional claims such as "prevents and/or improves physical fatigue and/or feeling of fatigue." Supplements include, for example, tablets, rounds, capsules (including hard capsules, soft capsules, and microcapsules), powders, granules, fine granules, troches, and jelly along with various additives used in the manufacture of general supplements. It can be in the form of a liquid (including syrup, emulsion, suspension), etc.
本発明に係る組成物は、飲食品に配合することができる。配合可能な飲食品としては、特に限定はないが、例えば、飴、グミ、チューインガム等の菓子類;クッキー、クラッカー、ビスケット、チョコレート、プリン、ゼリー、スナック菓子、米菓、饅頭、羊羹等の菓子類;アイスクリーム、アイスキャンディー、シャーベット、ジェラート等の冷菓;ドーナツ、ケーキ、食パン、フランスパン、クロワッサン等のベーカリー食品;うどん、そば、中華めん、きしめん等の麺類;白飯、赤飯、ピラフ等の米飯類;カレー、シチュー、ドレッシング等のソース類;ハム、ソーセージ、かまぼこ、ちくわ、魚肉ソーセージ等の練り製品;天ぷら、コロッケ、ハンバーグ等の各種惣菜類;ジュース、お茶等の飲料等が挙げられる。 The composition according to the present invention can be incorporated into food and drink products. Foods and drinks that can be mixed are not particularly limited, but include confectionery such as candy, gummies, and chewing gum; confectionery such as cookies, crackers, biscuits, chocolate, pudding, jelly, snacks, rice crackers, manju, and yokan. Frozen desserts such as ice cream, popsicles, sherbet, and gelato; Bakery foods such as donuts, cakes, white bread, French bread, and croissants; Noodles such as udon, soba, Chinese noodles, and kishimen; Rice products such as white rice, sekihan, and pilaf; Examples include sauces such as curry, stew, and dressing; paste products such as ham, sausage, kamaboko, chikuwa, and fish sausage; various side dishes such as tempura, croquettes, and hamburgers; and beverages such as juice and tea.
本発明に係る組成物の効果は、例えば自覚的疲労度の測定方法であるVAS(例えば、解析項目として「全身疲労感」;非特許文献4)や血中酸化ストレスマーカー(例えば、TBARS(Thio barbituric acid reactive substances:2-チオバルビツール酸反応性物質);新規抗疲労成分:イミダゾールジペプチド, 日本補完代替医療学会誌, 第6巻, 第3号, 2009年10月:123-129及び大石 修司, 運動と酸化ストレス-活性酸素と抗酸化防御のバランスの重要性-, IRYO, Vol. 69, No. 7 (317-324) 2015)の測定により評価することができる。例えば、疲労又は疲労感を伴う運動を行う被験者、あるいは疲労又は疲労感を伴う日常生活を送る被験者に対して本発明に係る組成物を摂取させる(又は投与する)。本発明に係る組成物を摂取(又は投与)してない等の対照群と比較して、VAS又は血中酸化ストレスマーカーの測定値が有意に低い場合、本発明に係る組成物は抗疲労効果を有すると判断することができる。
The effects of the composition according to the present invention are, for example, measured by VAS, which is a method of measuring subjective fatigue (e.g., "feeling of whole body fatigue" as an analysis item; Non-Patent Document 4), and blood oxidative stress markers (e.g., TBARS (Thio barbituric acid reactive substances (2-thiobarbituric acid reactive substances); Novel anti-fatigue ingredient: imidazole dipeptide, Journal of the Japanese Society of Complementary and Alternative Medicine,
一方、上述の本発明に係る組成物の記載に準じて、本発明は、本発明に係る組成物を患者又は被験者(ヒト)に投与するか、又は摂取させることを含む、肉体的疲労及び/又は疲労感の予防、治療及び/又は改善方法にも関する。 On the other hand, according to the above description of the composition according to the present invention, the present invention provides a method for reducing physical fatigue and/or physical fatigue, including administering or ingesting the composition according to the present invention to a patient or subject (human). The present invention also relates to methods for preventing, treating, and/or improving fatigue.
以下、実施例を用いて本発明をより詳細に説明するが、本発明の技術的範囲はこれら実施例に限定されるものではない。 Hereinafter, the present invention will be explained in more detail using Examples, but the technical scope of the present invention is not limited to these Examples.
〔オリーブ果実由来トリテルペンが疲労及び疲労感に及ぼす影響の評価〕
1.製造例1[オリーブ果実由来トリテルペンの製造方法]
圧搾等の公知の搾油法によりオリーブオイルを除去したオリーブ果実搾油粕を得た。
[Evaluation of the effects of olive fruit-derived triterpenes on fatigue and fatigue]
1. Production example 1 [Production method of olive fruit-derived triterpene]
Olive fruit pressed oil cake was obtained from which olive oil was removed by a known oil pressing method such as squeezing.
このオリーブ果実搾油粕100gに90%含水エタノール(v/v)を250g加えて、70℃で攪拌しながら2時間加熱した後、固液分離により得られた液体部分をエバポレーター等で減圧留去して濃縮液を得た。 Add 250 g of 90% aqueous ethanol (v/v) to 100 g of this olive fruit oil residue, heat it at 70°C for 2 hours with stirring, and then distill off the liquid part obtained by solid-liquid separation under reduced pressure using an evaporator or the like. A concentrated solution was obtained.
この濃縮液を水に分散させ、合成吸着樹脂アンバーライトXAD4(オルガノ社製)を担体としたカラムクロマトグラフィーに供し、50%含水エタノールから100%エタノールに至る10%刻みのステップワイズ溶出によりトリテルペン高含有画分を得、減圧留去して液油体状のオリーブ果実由来オレアナン型トリテルペンを得た。 This concentrated solution was dispersed in water and subjected to column chromatography using synthetic adsorption resin Amberlite The containing fraction was obtained and distilled under reduced pressure to obtain an olive fruit-derived oleanane-type triterpene in the form of a liquid oil.
図1は、オリーブ果実由来オレアナン型トリテルペン含有液のHPLC分析チャートである。Aのピークはマスリン酸、Bのピークはオレアノール酸である。ピークの同定は、標準品とのリテンションタイムの比較及びLC/MS解析により行った。定量値は、標準品のピーク面積を基準に算出した。このトリテルペン含有液にはマスリン酸とオレアノール酸が10:4の割合で含まれていた。 FIG. 1 is an HPLC analysis chart of a liquid containing oleanane-type triterpenes derived from olive fruits. The A peak is maslinic acid, and the B peak is oleanolic acid. Peak identification was performed by comparison of retention times with standard products and LC/MS analysis. The quantitative value was calculated based on the peak area of the standard product. This triterpene-containing liquid contained maslinic acid and oleanolic acid in a ratio of 10:4.
マスリン酸含有量が10質量%になるようにデキストリンを添加して混合し、水に分散した後、スプレードライして粉末のオリーブ果実由来トリテルペン剤とした。 Dextrin was added and mixed so that the maslinic acid content was 10% by mass, dispersed in water, and then spray-dried to obtain a powdered olive fruit-derived triterpene agent.
2.製造例2[試験食の作製]
表1で示した配合で原料を混合し、スティックゼリーを調製した。スティックゼリー1本当たりの内容量は10gであり、マスリン酸及びオレアノール酸の含有量は各々30mg、12mgである。
2. Production example 2 [Preparation of test food]
Raw materials were mixed according to the formulation shown in Table 1 to prepare stick jelly. The content per stick jelly is 10 g, and the contents of maslinic acid and oleanolic acid are 30 mg and 12 mg, respectively.
3.試験例1[オリーブ果実由来トリテルペンが疲労及び疲労感に及ぼす影響の評価]
(1) 被験者選択
国立大学法人筑波大学水球部に所属する健康な男子大学生12名を被験者として選択した。
(2) 試験内容
オリーブ果実由来トリテルペンが運動、及び日常生活で発生する疲労及び疲労感に及ぼす影響を評価するに当たり、被験者に表2に示す水球練習及び筋力トレーニングを含む運動介入を月曜日~日曜日の1週間行った。その際、製造例2に示すオリーブ果実由来トリテルペン剤を含む試験食(実施例)、又は含まない試験食(比較例)を運動後に毎日2本摂取させた。
3. Test Example 1 [Evaluation of the influence of olive fruit-derived triterpenes on fatigue and fatigue feeling]
(1) Selection of subjects Twelve healthy male university students who belong to the water polo club of the University of Tsukuba were selected as subjects.
(2) Test details In order to evaluate the effects of olive fruit-derived triterpenes on exercise and the fatigue and fatigue that occur in daily life, subjects underwent an exercise intervention including water polo practice and strength training shown in Table 2 from Monday to Sunday. I went for a week. At that time, the test food containing the olive fruit-derived triterpene agent shown in Production Example 2 (Example) or the test food not containing it (Comparative Example) were ingested twice daily after exercise.
なお、試験デザインは二重盲検クロスオーバー試験とし、被験者を無作為にA、Bの2群に分け、第1クールの1週間はA群に実施例のスティックゼリー、B群に比較例のスティックゼリーを摂取させ、浄化期間として試験食を摂取しない1週間を設けた後、第2クールの1週間ではA群に比較例のスティックゼリー、B群に実施例のスティックゼリーを摂取させた。 The study design was a double-blind crossover study, and the subjects were randomly divided into two groups, A and B. For one week of the first course, group A received the stick jelly of the example, and group B received the comparative example. After ingesting the stick jelly and allowing one week during which they did not ingest the test food as a cleansing period, in the second course of one week, Group A was allowed to ingest the stick jelly of the comparative example, and Group B was allowed to ingest the stick jelly of the example.
第1クール、第2クールの結果を統合し、実施例、比較例それぞれ12名分の測定値を得て、平均を比較、解析した。 The results of the first and second courses were combined to obtain the measured values for 12 people in each example and comparative example, and the averages were compared and analyzed.
(3) 方法
(3-1) 自覚的疲労度の測定
運動により発生する肉体的な疲労や疲労感を評価する項目として、運動翌日起床時の自覚的疲労度をVASにて1週間継続して評価した。例えば、火曜日起床時のVASによる自覚的疲労度の評価は、月曜日の運動及び日常生活の結果現れた疲労感であるため、月曜日の数値として記載した(表3)。なお、VASは10cmの直線の左端を「全く疲労感がない」状態である0とし、右端を「これ以上ないくらい疲労感がある」状態である10として、現在の状態が直線上のどの位置にあるかを10cmの直線と垂直に交わる棒線で記入させ、測定値とした。測定値をもとに、曜日ごとでのT検定により統計解析を行った。
(3) Method
(3-1) Measurement of subjective fatigue level As an item to evaluate the physical fatigue and feeling of fatigue caused by exercise, the subjective fatigue level when waking up the day after exercise was evaluated continuously for one week using VAS. For example, the evaluation of subjective fatigue level by VAS when waking up on Tuesday is a feeling of fatigue that appeared as a result of Monday's exercise and daily life, so it was recorded as Monday's value (Table 3). In addition, the VAS indicates where the current state is on the straight line, with the left end of the 10cm straight line being 0, which means ``I don't feel tired at all,'' and the right end being 10, which is ``I feel extremely tired.'' The students were asked to mark the value of the 10 cm line with a bar that intersects perpendicularly with the 10 cm straight line, which was then used as the measured value. Based on the measured values, statistical analysis was performed using a T-test for each day of the week.
(3-2) 血中酸化ストレスマーカーの測定
酸化ストレスマーカーを測定することにより、疲労の程度を評価することが可能とされている(新規抗疲労成分:イミダゾールジペプチド, 日本補完代替医療学会誌, 第6巻, 第3号, 2009年10月:123-129;P124「4. 酸化ストレスマーカーによる疲労評価」を参照)。
(3-2) Measurement of blood oxidative stress markers It is possible to evaluate the degree of fatigue by measuring oxidative stress markers (New anti-fatigue ingredient: imidazole dipeptide, Journal of the Japanese Society of Complementary and Alternative Medicine,
試験期間中の各月曜日の午前中に採血を行い、試験食摂取前後の血中TBARS(Thio barbituric acid reactive substances:2-チオバルビツール酸反応性物質)濃度を、TBARS測定キット(OxiSelect TBARS Assay Kit、CELL BIOLABOS, Inc)にて測定した。TBARSは各群の介入前後の比較をT検定、群間比較を2WAY-ANOVAにて統計解析を行った。 Blood was collected on the morning of each Monday during the test period, and the blood TBARS (Thio barbituric acid reactive substances) concentration before and after ingestion of the test food was measured using a TBARS measurement kit (OxiSelect TBARS Assay Kit). , CELL BIOLABOS, Inc.). TBARS performed statistical analysis using T-test for comparisons before and after the intervention of each group, and 2-way ANOVA for comparisons between groups.
なお、TBARSは、酸化ストレスに応答して濃度が上昇する物質の総称で、脂質ヒドロペルオキシドや、マロンジアルデヒドなどに代表されるアルデヒドなどが含まれる。また、TBARSは、運動性酸化ストレスの指標として広く研究されてきた対象であり、急性運動後に骨格筋や心筋、肝臓、血漿でのそのレベルが上昇することが示されている(大石 修司, 運動と酸化ストレス-活性酸素と抗酸化防御のバランスの重要性-, IRYO, Vol. 69, No. 7 (317-324) 2015;p319「1.急性運動」を参照)。 TBARS is a general term for substances whose concentration increases in response to oxidative stress, and includes lipid hydroperoxides and aldehydes such as malondialdehyde. In addition, TBARS has been widely studied as an indicator of exercise-induced oxidative stress, and its levels have been shown to increase in skeletal muscle, cardiac muscle, liver, and plasma after acute exercise (Shuji Oishi, Exercise Research and oxidative stress - the importance of the balance between active oxygen and antioxidant defenses -, IRYO, Vol. 69, No. 7 (317-324) 2015; see p. 319 “1. Acute exercise”).
(4) 結果
VASによる自覚的疲労度の測定の結果、表3で示す通り、全日程を通して、比較例と比べて実施例の方が低値を示していた。統計解析の結果、特に6日間試験食の摂取を続けた土曜日では、有意にVASの値が低値を示していた(P値<0.05)。
(4) Results
As shown in Table 3, the results of measuring the subjective fatigue level by VAS showed that the Example showed a lower value than the Comparative Example throughout the entire day. As a result of statistical analysis, VAS values were significantly lower, especially on Saturdays when the test food intake was continued for 6 days (P value <0.05).
また、オリーブ果実由来トリテルペン摂取の効果の大きさ(効果量)を解析するため、Cohen's dを求めた。Cohen's dは、t検定のような2グループの平均値の差を比較するときに使用される計算値で、算出される数値は、標準偏差を単位として平均値がどれだけ離れているかを表している。例えば、d = 1なら、1 標準偏差(SD)分だけ離れていることを意味する。なお、Cohen's dの値が0.8以上で「効果量大」、0.5以上で「効果量中」、0.2以上で「効果量小」、0.2未満では「効果ほとんど無し」と判定される(水本ら, 効果量と検定力分析入門 : 統計的検定を正しく使うために;2010年度部会報告論集「より良い外国語教育のための方法」: 47-73, Issue Date:2011-06-06)。 In addition, Cohen's d was calculated to analyze the effect size (effect size) of ingesting triterpenes derived from olive fruits. Cohen's d is a calculated value used when comparing the difference between the means of two groups, such as in a t-test, and the calculated value represents how far apart the means are in terms of standard deviation. There is. For example, d = 1 means they are 1 standard deviation (SD) apart. Furthermore, a Cohen's d value of 0.8 or higher is considered a "large effect," a value of 0.5 or higher is a "medium effect," a value of 0.2 or higher is a "small effect," and a value of less than 0.2 is considered "almost no effect." (Mizumoto et al. , Introduction to effect size and power analysis: How to use statistical tests correctly; 2010 Subcommittee Report Collection "Methods for Better Foreign Language Education": 47-73, Issue Date: 2011-06-06).
Cohen's dを元に効果量を比較した結果、週の後半になるに従って、効果量が大きくなる傾向がみられた(表3)。 As a result of comparing the effect sizes based on Cohen's d, there was a tendency for the effect sizes to increase as the week progressed (Table 3).
さらに、血中TBARS濃度を測定した結果、表4に示す通り、比較例では介入前と比べて介入後で有意に血中TBARS濃度が上昇していたのに対し、実施例では介入前と比べて介入後で血中TBARS濃度が有意に低値を示していた(P値(前後比較)<0.05)。また、各例の変化量を群間で比較したところ、有意な差がみられた(P値(群間比較)<0.05)。 Furthermore, as a result of measuring blood TBARS concentration, as shown in Table 4, blood TBARS concentration increased significantly after the intervention compared to before intervention in the comparative example, whereas in the example example compared to before intervention. The blood TBARS concentration was significantly lower after the intervention (P value (before and after comparison) <0.05). Furthermore, when the amount of change in each case was compared between groups, a significant difference was found (P value (comparison between groups) <0.05).
VASによる自覚的疲労度の数値が比較例よりも実施例の方が低値を示したことから、オリーブ果実由来トリテルペンを摂取することで、運動で発生する肉体的な疲労感が改善されることが明らかとなった(表3)。また、効果量が週の後半になるにつれて大きくなることから、運動後のオリーブ果実由来トリテルペン摂取が、運動当日の疲労を改善するだけでなく、翌日の疲労の予防にもつながっている可能性が示唆された。つまりオリーブ果実由来トリテルペンには疲労予防効果も期待できる。 The subjective fatigue level measured by VAS was lower in the example than in the comparative example, indicating that ingestion of olive fruit-derived triterpenes improves the feeling of physical fatigue that occurs during exercise. It became clear (Table 3). Furthermore, as the effect size increases as the week progresses, it is possible that ingesting triterpenes derived from olive fruits after exercise not only improves fatigue on the day of exercise, but also prevents fatigue the next day. It was suggested. In other words, triterpenes derived from olive fruits can also be expected to have anti-fatigue effects.
結果を詳しく考察すると、日曜日(月曜日起床時測定)はオフであるため、VASの数値は最も数値が低くなった。また、月曜日は水球練習があるため、疲労度が日曜日よりも若干上がった。火曜日と木曜日は筋力トレーニングを実施しているため、火曜日、木曜日をピークに疲労感が上昇し、筋力トレーニングから時間が経つほど疲労感が回復してきているものと推測された。 Taking a closer look at the results, we found that the VAS values were the lowest on Sundays (measurements were taken when waking up on Monday) because the day was off. Also, since I had water polo practice on Monday, my fatigue level was slightly higher than on Sunday. Since strength training was performed on Tuesdays and Thursdays, it was assumed that the feeling of fatigue increased after peaking on Tuesdays and Thursdays, and that the feeling of fatigue improved as time passed from the strength training.
また、比較例に比べて実施例で血中TBARS濃度が低値を示していたことから(表4)、血中酸化ストレスレベルが軽減していることが示唆された。 Furthermore, blood TBARS concentrations were lower in Examples than in Comparative Examples (Table 4), suggesting that blood oxidative stress levels were reduced.
これらのことから、オリーブ果実由来トリテルペンを摂取することで、運動で発生する酸化ストレスを軽減し、肉体的な疲労が予防、改善されることが示唆された。 These results suggest that ingesting olive fruit-derived triterpenes reduces oxidative stress caused by exercise and prevents and improves physical fatigue.
Claims (4)
前記オレアナン型トリテルペンがマスリン酸及びオレアノール酸の混合物であり、
運動で発生する肉体的疲労及び/又は疲労感を予防及び/又は改善するための、前記抗疲労用組成物(ただし、3-ヒドロキシ-3-メチル酪酸を含む場合を除く)。 An anti-fatigue composition containing an oleanane-type triterpene or a salt thereof as an active ingredient,
the oleanane-type triterpene is a mixture of maslinic acid and oleanolic acid,
The anti-fatigue composition (excluding cases containing 3-hydroxy-3-methylbutyric acid ) for preventing and/or improving physical fatigue and/or fatigue caused by exercise.
運動で発生する肉体的疲労及び/又は疲労感を予防及び/又は改善するための、前記抗疲労用組成物(ただし、3-ヒドロキシ-3-メチル酪酸を含む場合を除く)。 An anti-fatigue composition containing as an active ingredient an olive fruit extract containing maslinic acid and oleanolic acid as major triterpenes,
The anti-fatigue composition (excluding cases containing 3-hydroxy-3-methylbutyric acid ) for preventing and/or improving physical fatigue and/or fatigue caused by exercise.
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JP2002097135A (en) | 2000-09-19 | 2002-04-02 | Pola Chem Ind Inc | Skin care preparation for ameliorating damage of circulatory organ caused by stress |
WO2003057224A1 (en) | 2001-12-28 | 2003-07-17 | The Nisshin Oillio, Ltd. | Apoptosis inductor |
JP2008017734A (en) | 2006-07-11 | 2008-01-31 | Memory Secret Inc | Orally administrative composition for nutritious supplement and nutritious ingestion food for improving mental function |
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